bioRxiv Subject Collection: Neuroscience's Journal

Pupil dilations prior to freely timed actions reflect the reported timing of conscious intention
Freely timed actions are typically preceded by a slow anticipatory buildup of cortical brain activity, which has been extensively studied. However, such free actions are also preceded by slow pupil dilations in both humans and other animals, which have barely been examined. We investigated the neurocognitive significance of antecedent pupil dilations (APDs) in a voluntary-action paradigm. Participants performed self-paced actions and reported the timing of movement, conscious intention, or other events using a clock. APDs began a second or more before movement, and control conditions suggest that they did not reflect processing related to reporting demands, motor execution, or general anticipation. Critically, APD timing covaried with the reported timing of intention awareness but did not covary with the reported timing of overt movement or an external stimulus. Furthermore, decoding algorithms could distinguish APDs with above-chance accuracy more than 500 milliseconds before button-press. Our results suggest that APDs reflect a shift in awareness prior to movement onset and potentially offer a non-invasive method of predicting spontaneous movements before they occur.

Heart-brain coupling and its relevance for individual trait characteristics
A bulk of recent neurophysiological research has focused on how bodily functions are intertwined with neural activity, but the dynamic heart-brain coupling and its relevance for individual trait characteristics remains largely unexamined. Thus, our aim was to investigate how ongoing oscillatory brain activity is modulated by the natural fluctuations in heart rate variability (HRV). We further explored whether heart-brain coupling is associated with individual trait characteristics. Magnetoencephalography (MEG) together with electrocardiography (ECG) were used to record neural activity and HRV during rest. Self-reported trait characteristics were examined using Behavioral Inhibition and Activation Systems Scale (BIS/BAS) and attunement to internal bodily sensations using Body Vigilance Scale (BVS). Statistically significant increases were observed for low HRV vs. high HRV state in alpha and beta power (p < 0.05) indicating that oscillatory brain activity is modulated by fluctuations in HRV. Moreover, we demonstrated that heart-brain coupling was associated with self-reported behavioral approach and avoidance tendencies. The results of the moderator analysis further indicated that the relationship between heart-brain coupling and trait characteristics is at least partly moderated by the attunement to internal bodily sensations. Our findings bring insights to the intricate interplay between cardiac and neural signaling and its relationship with individual trait characteristics.

Unveiling the crucial role of betaine: Modulation of GABA homeostasis via SLC6A1 transporter (GAT1)
Betaine is an endogenous osmolyte that exhibits therapeutic potential by mitigating various neurological disorders. However, the underlying cellular and molecular mechanisms responsible for its neuroprotective effects remain puzzling. In this study, we describe a possible mechanism behind the positive impact of betaine in preserving neurons from excitotoxicity. Using electrophysiology, mass spectroscopy, radiolabelled cellular assay, and molecular dynamics simulation we demonstrate that betaine at mM concentration acts as a slow substrate of GAT1 (slc6a1), the predominant GABA transporter in the central nervous system. Intriguingly, when betaine is present at low concentration (0.01-3 mM) with GABA (at concentration <K0.5), it blocks the GABA reuptake. This GAT1 modulation occurs through the temporal inhibition of the transporter, i.e., the prolonged occupancy by betaine impedes the rapid transition of the transporter to the inward conformation. The temporal inhibition results in a crucial regulatory mechanism contributing to the maintenance of GABA homeostasis, preserving neurons from excitotoxicity.

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provide Insight into Pathological Processes
Acute retinal ischemia and ischemia-reperfusion injury are primary causes of retinal neural cell death and vision loss in retinal artery occlusion (RAO). The absence of an accurate mouse model simulating the retinal ischemic process has hampered progress in developing neuroprotective agents for RAO. A unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) mouse model was developed by employing silicone wire embolization combined with carotid artery ligation. The survival of retinal ganglion cells and visual function were evaluated to determine ischemia duration. Immunofluorescence staining, optical coherence tomography, and hematoxylin and eosin staining were utilized to assess changes in major classes of neural cells and retinal structure degeneration at two reperfusion durations. Transcriptomics was employed to investigate alterations in the pathological process of UPOAO following ischemia and reperfusion, highlighting transcriptomic differences between UPOAO and other retinal ischemia-reperfusion models. The UPOAO model successfully replicated the acute interruption of retinal blood supply seen in RAO. 60-minute ischemia was confirmed to lead the major retinal neural cells loss and visual function impairment. Notable thinning of the inner layer of the retina, especially the ganglion cell layer, was evident post-UPOAO. Temporal transcriptome analysis revealed various pathophysiological processes related to immune cell migration, oxidative stress, and immune inflammation during non-reperfusion and reperfusion periods. The resident microglia within the retina and peripheral leukocytes which access to the retina were pronounced increased on reperfusion periods. Comparison of differentially expressed genes between the UPOAO and high intraocular pressure models identified specific enrichments in lipid and steroid metabolism-related genes in the UPOAO model. The UPOAO model emerges as a novel tool for the screening of pathogenic genes, promoting further therapeutic research in RAO.

Representational similarity modulates neural and behavioral signatures of novelty
Novelty signals in the brain modulate learning and drive exploratory behaviors in humans and animals. Inherently, whether a stimulus is novel or not depends on existing representations in the brain, yet it remains elusive how stimulus representations influence novelty computation. In particular, existing models of novelty computation fail to account for the effects of stimulus similarities that are abundant in naturalistic environments and tasks. Here, we present a unifying, biologically plausible model that captures how stimulus similarities modulate novelty signals in the brain and influence novelty-driven learning and exploration. By applying our model to two publicly available data sets, we quantify and explain (i) how generalization across similar visual stimuli affects novelty responses in the mouse visual cortex, and (ii) how generalization across nearby locations impacts mouse exploration in an unfamiliar environment. Our model unifies and explains distinct neural and behavioral signatures of novelty, and enables theory-driven experiment design to investigate the neural mechanisms of novelty computation.

The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics
Prion diseases, or Transmissible Spongiform Encephalopathies (TSE), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc) of the cellular prion protein (PrPC). During the pathogenesis, the PrPSc seeds disseminate in the central nervous system and convert PrPC leading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrPSc structures. In this work, we implemented the recent developments on PrPSc structural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie Algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain specific phenotypes, tissue tropisms and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.

Ventral pallidal GABAergic neurons drive consumption in male, but not female rats
Food intake is controlled by multiple converging signals: hormonal signals that provide information about energy homeostasis, but also hedonic and motivational aspects of food and food cues that can drive non-homeostatic or hedonic feeding. The ventral pallidum (VP) is a brain region implicated in the hedonic and motivational impact of food and foods cues, as well as consumption of rewards. Disinhibition of VP neurons has been shown to generate intense hyperphagia, or overconsumption. While VP gamma-Aminobutyric acidergic (GABA) neurons have been implicated in cue-elicited reward seeking and motivation, the role of these neurons in the hyperphagia resulting from VP activation remains unclear. Here, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate or inhibit VP GABA neurons in sated male and female rats during chow and sucrose consumption. We found that activation of VP GABA neurons increases consumption of chow and sucrose in male rats, but not female rats. We also found that, while inhibition of VP GABA neurons tended to decrease sucrose consumption, this effect was not statistically significant. Together, these findings suggest that activation of VP GABA neurons can stimulate consumption of routine or highly palatable rewards selectively in male rats.

Electrophysiological responses to appetitive and consummatory behavior in the rostral nucleus tractus solitarius in awake, unrestrained rats
As the intermediate nucleus in the brainstem receiving information from the tongue and transmitting information upstream, the rostral portion of the nucleus tractus solitarius (rNTS) is most often described as a taste relay. Although recent evidence implicates the NTS in a broad neural circuit involved in regulating ingestion, there is little information about how cells in this structure respond when an animal is eating solid food. Here, single cells in the rNTS were recorded in awake, unrestrained rats as they explored and ate solid foods (Eating paradigm) chosen to correspond to the basic taste qualities: milk chocolate for sweet, salted peanuts for salty, Granny Smith apples for sour and broccoli for bitter. A subset of cells was also recorded as the animal licked exemplars of the five basic taste qualities: sucrose, NaCl, citric acid, quinine and MSG (Lick paradigm). Results showed that most cells were excited by exploration of a food-filled well, sometimes responding prior to contact with the food. In contrast, cells that were excited by food well exploration became significantly less active while the animal was eating the food. Most cells were broadly tuned across foods, and those cells that were recorded in both the Lick and Eating paradigms showed little correspondence in their tuning across paradigms. The preponderance of robust responses to the appetitive versus the consummatory phase of ingestion suggests that multimodal convergence onto cells in the rNTS may be used in decision making about ingestion.

Bilateral field advantage of spatial attention in macaque lateral prefrontal cortex
Allocating visual attention to behaviorally relevant stimuli is easier when distractors are located in the opposite visual hemifield relative to when they are in the same hemifield. The neural mechanisms underlying this bilateral field advantage remains unclear. We documented this effect in two macaques performing a covert spatial attention task in two different conditions: when the target and distracter were positioned in different hemifields (across condition), and when they were positioned on the top and bottom quadrants within the same visual hemifield (within condition). The animals behavioral performance at detecting a change in the attended stimulus was higher in the across relative to the within condition. We recorded the responses of lateral prefrontal cortex (LPFC, area 8A) neurons in one animal. The proportion of LPFC neurons encoding the allocation of attention was larger in the across relative to the within condition. The latter was accompanied by an increase in the ability of single neurons to discriminate the allocation of attention in the across relative to the within condition. Finally, we used linear classifiers to decode the allocation of attention from the activity of neuronal ensembles and found a similar bilateral field advantage in decoding performance in the across relative to the within condition. Our finding provides a neural correlate of the bilateral field advantage reported in behavioral studies of attention and suggest that the effect may originate within the LPFC circuitry.

Thalamocortical interactions reflecting the intensity of flicker light-induced visual hallucinatory phenomena
The thalamus has a critical role in the orchestration of cortical activity. Aberrant thalamocortical connectivity occurs together with visual hallucinations in various pathologies and drug-induced states, highlighting the need to better understand how thalamocortical interactions may contribute to hallucinatory phenomena. However, concurring symptoms and physiological changes that occur during psychopathologies and pharmacological interventions make it difficult to distil the specific neural correlates of hallucinatory experiences. Flicker light stimulation (FLS) at 10 Hz reliably and selectively induces transient visual hallucinations in healthy participants. Arrhythmic flicker elicits fewer hallucinatory effects while delivering equal amounts of visual stimulation, together facilitating a well-controlled experimental setup to investigate the neural correlates of visual hallucinations driven by flicker rhythmicity. In this study, we implemented rhythmic and arrhythmic FLS during fMRI scanning to test the elicited changes in cortical activation and thalamocortical functional connectivity. We found that rhythmic FLS elicited stronger activation in higher-order visual cortices compared to arrhythmic control. Consistently, we found that rhythmic flicker selectively increased connectivity between ventroanterior thalamic nuclei and higher-order visual cortices compared to arrhythmic control, which was also found be positively associated with the subjective intensity of visual hallucinatory effects. As these thalamic and cortical areas do not receive primary visual inputs, it suggests that the thalamocortical connectivity changes relate to a higher-order function of the thalamus, such as in the coordination of cortical activity. In sum, we present novel evidence for the role of specific thalamocortical interactions with ventroanterior nuclei within visual hallucinatory experiences. Importantly, this can inform future clinical research into the mechanistic underpinnings of pathologic hallucinations.

Nature exposure induces hypoalgesia by acting on nociception-related neural processing
Nature exposure has numerous psychological benefits, and previous findings suggest that exposure to nature reduces self-reported acute pain. Given the multi-faceted and subjective quality of pain and methodological limitations of prior research, it is unclear whether the evidence indicates genuine hypoalgesia or results from domain-general effects and subjective reporting biases. This preregistered functional neuroimaging study aimed to identify how nature exposure modulates nociception-related and domain-general brain responses to acute pain. We compared the self-reported and neural responses of healthy neurotypical participants (N = 49) receiving painful electrical shocks while exposed to virtual nature or to closely matched urban and indoor control settings. Replicating existing behavioral evidence, pain was reported to be lower during exposure to the natural compared to the urban or indoor control settings. Crucially, machine-learning-based multi-voxel signatures of pain demonstrated that this subjective hypoalgesia was associated with reductions in nociception-related rather than domain-general cognitive-emotional neural pain processing. Preregistered region-of-interest analyses corroborated these results, highlighting reduced activation of areas connected to lower-level somatosensory aspects of pain processing (such as the thalamus, secondary somatosensory cortex, and posterior insula). These findings demonstrate that nature exposure results in genuine hypoalgesia and that neural changes in lower-level nociceptive pain processing predominantly underpin this effect. This advances our understanding of how nature may be used as a non-pharmacological pain treatment. That this hypoalgesia was achieved with brief and easy-to-administer virtual nature exposure has important practical implications and opens novel avenues for research on the precise mechanisms by which nature impacts our mind and brain.

Connectivity at fine scale: mapping structural connective fields by tractography of short association fibres in vivo
The extraordinary number of short association fibres (SAF) connecting neighbouring cortical areas is a prominent feature of the large gyrified human brain. The contribution of SAF to the human connectome is largely unknown because of methodological challenges in mapping them. We present a method to characterise cortico-cortical connectivity mediated by SAF in topologically organised cortical areas. We introduce the 'structural connective fields' (sCF) metric which specifically quantifies neuronal signal propagation and integration mediated by SAF. This new metric complements functional connective field metrics integrating across contributions from short- and long-range white matter and intracortical fibres. Applying the method in the human early visual processing stream, we show that SAF preserve cortical functional topology. Retinotopic maps of V2 and V3 could be predicted from retinotopy in V1 and SAF connectivity. The sCF sizes increased along the cortical hierarchy and were smaller than their functional counterparts, in line with the latter being additionally broadened by long-range and intracortical connections. In vivo sCF mapping provides insights into short-range cortico-cortical connectivity in humans comparable to tract tracing studies in animal research and is an essential step towards creating a complete human connectome.

The mechanisms and neural signature of average numerosity perception
The human brain is endowed with an intuitive sense of number allowing to perceive the approximate quantity of items in a scene, or 'numerosity'. This ability is not limited to items distributed in space, but also to events unfolding in time and to the average numerosity of dynamic scenes. How the brain computes and represents the average numerosity over time however remains mostly unclear. Here we investigate the mechanisms and electrophysiological (EEG) signature of average numerosity perception. To do so, we used dynamic stimuli composed of 3-12 arrays presented for 50 ms each, and asked participants to judge the average numerosity of the sequence. Our results first show that the weight of different arrays in the sequence in determining the judgement is subject to both primacy and recency effects, depending on the length of the sequence. Moreover, we show systematic perceptual adaptation effects across trials, with the bias on numerical estimates depending on both the average numerosity and length of the preceding stimulus. The EEG results show numerosity-sensitive brain responses starting very early after stimulus onset, and that activity around the offset of the sequence can predict both the accuracy and precision of judgments. Additionally, we show a neural signature of the adaptation effect at around 300 ms, whereby the amplitude of brain responses can predict the strength of the bias. Overall, our findings support the existence of a dedicated, low-level perceptual mechanism involved with the computation of average numerosity, and highlight the processing stages involved with such process.

Endogenous opioid system modulates proximal and distal threat signals in the human brain
BACKGROUND Fear promotes rapid detection of threats and appropriate fight-or-flight responses. The endogenous opioid system modulates responses to pain and psychological stressors. Opioid agonists also have also anxiolytic effects. Fear and anxiety constitute major psychological stressors for humans, yet the contribution of the opioid system to acute human fear remains poorly characterized. METHODS: We induced intense unconditioned fear in the subjects by gradually exposing them to a living constrictor snake (threat trials) versus an indoor plant (safety trials). Brain haemodynamic responses were recorded from 33 subjects during functional magnetic resonance imaging (fMRI). In addition, 15 subjects underwent brain positron emission tomography (PET) imaging using [11C]carfentanil, a high affinity agonist radioligand for -opioid receptors (MORs). PET studies under threat or safety exposure were performed on separate days. Pupillary arousal responses to snake and plant exposure were recorded in 36 subjects. Subjective fear ratings were measured throughout the experiments. RESULTS: Self-reports and pupillometric responses confirmed significant experience of fear and autonomic activation during the threat trials. fMRI data revealed that proximity with the snake robustly engaged brainstem defense circuits as well as thalamus, dorsal attention network, and motor and premotor cortices. These effects were diminished during repeated exposures. PET data revealed that [11C]carfentanil binding to MORs was significantly higher during the fear versus safety condition, and the acute haemodynamic responses to threat were dependent on baseline MOR binding in the cingulate gyrus and thalamus. Finally, baseline MOR tone predicted dampening of the haemodynamic threat responses during the experiment. CONCLUSIONS: Preparatory response during acute fear episodes involves a strong motor component in addition to the brainstem responses. These haemodynamic changes are coupled with a deactivation of the opioidergic circuit, highlighting the role of MORs in modulating the human fear response.

Dysregulation of Kappa Opioid Receptor Neuromodulation of Lateral Habenula Synaptic Function following a Repetitive Mild Traumatic Brain Injury
Mild traumatic brain injury (mTBI) increases the risk of cognitive deficits, affective disorders, anxiety and substance use disorder in affected individuals. Substantial evidence suggests a critical role for the lateral habenula (LHb) in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between persistent mTBI-induced LHb hyperactivity due to synaptic excitation/inhibition (E/I) imbalance and motivational deficits in self-care grooming behavior in young adult male mice using a repetitive closed head injury mTBI model. One of the major neuromodulatory systems that is responsive to traumatic brain and spinal cord injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function is unknown. To address this, we first used retrograde tracing to anatomically verify that the mouse LHb indeed receives Dyn/KOR expressing projections. We identified several major KOR-expressing and Dyn-expressing synaptic inputs projecting to the mouse LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4week post-injury using the repetitive closed head injury mTBI model. Similar to what we previously reported in the LHb of male mTBI mice, mTBI presynaptically diminished spontaneous synaptic activity onto LHb neurons, while shifting synaptic E/I toward excitation in female mouse LHb. Furthermore, KOR activation in either mouse male/female LHb generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant reduction in E/I ratios and decreased excitatory synaptic drive to LHb neurons of male and female sham mice. Interestingly following mTBI, while responses to KOR activation at LHb glutamatergic synapses were observed comparable to those of sham, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition. Thus, in contrast to sham LHb, we observed a reduction in GABA release probability in response to KOR stimulation in mTBI LHb, resulting in a chronic loss of KOR-mediated net synaptic inhibition within the LHb. Overall, our findings uncovered the previously unknown sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. Further, we demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global suppression of excitatory synaptic drive to the mouse LHb which could act as an inhibitory braking mechanism to prevent LHb hyperexcitability. The additional engagement of KOR-mediated modulatory action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons in male and female mTBI mice.

Magnitude processing and integration entail perceptual processes independent from the task
The magnitude dimensions of visual stimuli, such as their numerosity, duration, and size, are intrinsically linked, leading to mutual interactions across them. Namely, the perception of one magnitude is influenced by the others, so that a large stimulus is perceived to last longer in time compared to a smaller one, and vice versa. The nature of such interaction is however still debated. In the present study we address whether magnitude integration could arise from 'automatic' perceptual processes, independently from the task performed, or whether it arises from active decision making. In two separate experiments, participants watched a series of dot-array stimuli modulated in numerosity, duration, and item size. In one case (task condition), the task required them to judge the stimuli in each trial, with the specific dimension to judge indicated by a cue presented after each stimulus. In the other case (passive condition), instead, participants passively watched the stimuli. The behavioural results obtained in the task show robust magnitude integration effects across all three dimensions. Then, we identified a neural signature of magnitude integration by showing that relatively early event-related potentials can predict the effect measured behaviourally. Finally, we demonstrate an almost identical modulation of brain responses in passive viewing, occurring at the same processing stages linked to the behavioural effect. The results thus suggest that magnitude integration likely occurs via automatic perceptual processes that are engaged irrespective of the task-relevance of the stimuli, and independently from decision making.

Voluntary adolescent alcohol exposure does not increase adulthood consumption of alcohol in multiple mouse and rat models
Adolescence is a period of increased risk taking, including increased alcohol and drug use. Multiple clinical studies report a positive relationship between adolescent alcohol consumption and risk of developing an alcohol use disorder (AUD) in adulthood. However, few preclinical studies have attempted to tease apart the biological contributions of adolescent alcohol exposure, independent of other social, environmental, and stress factors, and studies that have been conducted show mixed results. Here we use several adolescent voluntary consumption of alcohol models, conducted across three institutes and with two rodent species, to investigate the ramifications of adolescent alcohol consumption on adulthood alcohol consumption in controlled, preclinical environments. We consistently demonstrate a lack of increase in adulthood alcohol consumption. This work highlights that risks seen in both human datasets and other murine drinking models may be due to unique social and environmental factors, some of which may be unique to humans.

High-plex Digital Spatial Profiling Identifies Subregion-Dependent Directed Proteome Changes Across Multiple Variants of Dementia
Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in patients under the age of 65. Even in a single anatomical region, there is variance within pathological protein deposition as a result of FTLD. This spectrum of pathology leads to difficulty in identification of the disease during its progression and consequential varied post mortem clinicopathological diagnoses. NanoString GeoMx Digital Spatial Profiling (DSP) is a novel method that leverages the ability to spatially multiplex protein biomarkers of interest. We utilized NanoString DSP to investigate the proteome geography at two levels of the cortex and the subcortical white matter in patients with various types of dementia (Alzheimer's disease, FTLD-c9ALS, FTLD-17, FTLD-TDP, FTLD-GRN; n=6 per syndrome) and neurologically healthy controls (NHC). Analysis of 75 different protein biomarkers of interest revealed both a disease and cortical subregion specific biomarker profile. Layers II-V of the cortex from diseased individuals displayed the greatest protein dysregulation as compared to NHC. Additionally, out of all disease groups within cortical layer 1, II-V and white matter, the FTLD-17 group had the most significant protein dysregulation as compared to NHC--specifically associated with immune cell pathways. Traditional biomarkers of dementia, such as various phosphorylated tau proteins and amyloid-{beta} 42 displayed dysregulation, however our data suggest spatial enrichment in distinct to cortical sublayers. In conclusion, we observed that depending on the variant of disease, specific protein deposits either span multiple levels of cortical geography or only a single layer. Thus, the specific localization of these deposits could potentially be used to elucidate region-specific pathologic biomarkers unique to individual variants of dementia.

Time-restricted feeding prevents memory impairments induced by obesogenic diet consumption in mice, in part through hippocampal thyroid hormone signaling.
The consumption of calorie-rich diet has adverse effects on short and long-term memory, especially when introduced early in life when the brain is still under maturation. Time-restricted feeding (TRF) without calorie restriction has proven to be an efficient strategy to reduce the deleterious effects of diet-induced obesity on metabolism. TRF was also found beneficial to restore long-term memory in Alzheimer rodent models. Here, we show that 4 weeks of TRF restores the rhythmicity of some metabolic parameters together with short and long-term memory in mice fed a high fat-high sucrose (HFS) diet since weaning. Hippocampal translatome analyses indicated that impaired memory of mice under HFS ad libitum diet is accompanied by changes in genes associated to thyroid hormone signaling and astrocytic genes involved in the regulation of glutamate neurotransmission. TRF restored the diurnal variation of expression of part of these genes and intra-hippocampal infusion of T3, the active form of thyroid hormone rescued the memory performances of ad libitum HFS diet-fed mice. Thus, TRF has positive actions on metabolism as well as memory to fight obesity and its comorbidity in mice. The analogous time-restricted eating in humans is an easy to implement lifestyle intervention that should now be tested in obese adolescent with memory alterations.

Excitatory and inhibitory synapses form a tight subcellular balance along dendrites that decorrelates over development
A balance between excitation and inhibition is crucial for neurotypical brain function. Indeed, disruptions in this relationship are frequently associated with the pathophysiology of neurodevelopmental disorders. Nevertheless, how this balance is established during the dynamic period of neurodevelopment remains unexplored. Using multiple techniques, including in utero electroporation, electron microscopy and electrophysiology, we reveal a tight correlation in the distribution of excitatory and inhibitory synapses along dendrites of developing CA1 hippocampal neurons. This balance was present within short dendritic stretches (<20 microns), and surprisingly, was most pronounced during early development, sharply declining with maturity. The tight matching between excitation and inhibition was unexpected, as inhibitory synapses lacked an active zone when formed and exhibited compromised evoked release. We propose that inhibitory synapses form as a stabilising scaffold, to counterbalance growing excitation levels. This relationship diminishes over time, suggesting a critical role for a subcellular balance in early neuronal function and circuit formation.

Hippocampal sharp wave ripples mediate generalization and subsequent fear attenuation via closed-loop brain stimulation in rats
The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD.

From electrophysiology to drink: Adolescent alcohol consumption predicted by differences in functional connectivity and neuroanatomy
Alcohol consumption during adolescence has been associated with neuroanatomical abnormalities and the appearance of future disorders. However, the latest advances in this field point to the existence of risk profiles which may lead to some individuals into an early consumption. To date, some studies have established predictive models of consumption based on sociodemographic, behavioural, and anatomical-functional variables using MRI. However, the neuroimaging variables employed are usually restricted to local and hemodynamic phenomena. Given the potential of connectome approaches, and the high temporal dynamics of electrophysiology, we decided to explore the relationship between future alcohol consumption and electrophysiological connectivity measured by MEG in a cohort of 83 individuals aged 14 to 16. We calculated predictive models throughout multiple linear regressions based on behavioural, anatomical, and functional connectivity variables. As a result, we found a positive correlation between alcohol consumption and the functional connectivity in frontal, parietal, and frontoparietal connections. Also, we identified negative relationships of alcohol consumption with neuroanatomical variables. Finally, the linear regression analysis determined the importance of anatomical and functional variables in the prediction of alcohol consumption but failed to find associations with impulsivity, sensation-seeking, and executive function scales. As conclusion, the predictive traits obtained in these models were closely associated with changes occurring during neurodevelopment, suggesting the existence of different paths in neurodevelopment that have the potential to influence adolescents' relationship with alcohol consumption.

Social anxiety links of amygdala switch cross puberty
Socioemotional functions have been linked to the amygdala with reliable molecular mechanisms in animal studies. However, the links between human socioemotional transitions during puberty and amygdala development remain largely unestablished. By precisely tracing the structure of the amygdala with longitudinal data spanning childhood and adolescence, our aim is to capture the dynamic relationship between social anxiety and the geometry of the amygdala. Around the onset of puberty (10-11.5 years), we detected shifting associations of amygdala volume with social anxiety. Higher social anxiety is associated with a larger amygdala in mid-childhood but a smaller amygdala in early adolescence. Further geometry analysis revealed distinct deformed regions in the amygdala that underpinned the shift. Our findings reconcile inconsistent results from previous studies and demonstrate the potential to respect the intrinsic dimension of development in resolving the amygdala-anxiety relationships in understanding the full picture of puberty-triggering.

Body size interacts with the structure of the central nervous system: A multi-center in vivo neuroimaging study
Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subject's sex and age. However, corrections for body size are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1+-6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44[≤]r[≤]0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21[≥]r[≥]-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20[≥]r[≥]-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39[≤]r[≤]0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22[≥]r[≥]-0.25). Linear mixture of sex and age explained 26+-10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33+-11% when body height was added into the mixture model. Age itself explained only 2+-2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure.

Comparison between EEG and MEG of static and dynamic resting-state networks
The characterisation of resting state networks (RSNs) using neuroimaging techniques has significantly contributed to our understanding of the organisation of brain activity. Prior work has demonstrated the electrophysiological basis of RSNs and their dynamic nature, revealing transient activations of brain networks with millisecond timescales. While previous research has confirmed the comparability of RSNs identified by electroencephalography (EEG) to those identified by magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), most studies have utilised static analysis techniques, ignoring the dynamic nature of brain activity. Often, these studies use high-density EEG systems, which limit their applicability in clinical settings. Addressing these gaps, our research studies RSNs using medium-density EEG systems (61 sensors), comparing both static and dynamic brain network features to those obtained from a high-density MEG system (306 sensors). We assess the qualitative and quantitative comparability of EEG-derived RSNs to those from MEG, including their ability to capture age-related effects, and explore the reproducibility of dynamic RSNs within and across the modalities. Our findings suggest that both MEG and EEG offer comparable static and dynamic network descriptions, albeit with MEG offering some increased sensitivity and reproducibility. Such RSNs and their comparability across the two modalities remained consistent even when the data were reconstructed without subject-specific structural MRI images.

Corticocortical and Corticomuscular Connectivity Dynamicsin Standing Posture: Electroencephalography Study
Cortical involvements, including those in the sensorimotor, frontal, and occipitoparietal regions, are important mechanisms of neural control in human standing. Previous research has shown that cortical activity and corticospinal excitability vary flexibly in response to postural demand. However, it is unclear how corticocortical and corticomuscular connectivity is dynamically modulated during standing balance and over time. This study investigated the dynamics of this connectivity using electroencephalography (EEG) and electromyography (EMG). The EEG and EMG were measured in different 4 positions: sitting (ST), normal quiet standing (QS), one-leg standing (ON), and standing on a piece of wood (WD). For corticomuscular connectivity, we concentrated on sway-varying connectivity in the timing of peak velocity of postural sway in the anteroposterior direction. For the corticocortical connectivity, the time-varying connectivity was quantified, particularly in the {theta}-band connectivity which is linked to error identification, using a sliding-window approach. The study found that corticomuscular connectivity from the brain to the lower-limb muscle was strengthened during the sway peak in the {gamma}- and {beta}-frequency bands, while the connectivity strength from the muscle to the brain was decreased in the {theta}- and -band. For the timevarying connectivity, the {theta}-connectivity in all time-epoch was divided into 7 states including both posture-relevant and -irrelevant clusters. In one of the 7 states, the strong connectivity pairs were concentrated in the mid-central region and the proportion of epochs from the ON and WD conditions was significantly higher, indicating a functional role for posture balance. These findings shed light on electrodynamic connectivity which varies in response to postural demand. Those dynamics, particularly in the {theta}-band connectivity, can be used for ongoing monitoring and/or intervention for postural disability.

Sex specific effects of dorsomedial striatal cannabinoid receptor-1 signaling on Pavlovian outcome devaluation.
Cannabinoid-1 receptor (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual, sex, and experience-dependent differences in Pavlovian behaviors, we predicted a role for dorsomedial striatum CB1R signaling in driving sign-tracking and rigid responding in Pavlovian outcome devaluation. We trained male and female rats in Pavlovian Lever Autoshaping to determine sign-, or goal- or intermediate tracking groups. After extended Pavlovian training, we gave intra-DMS infusions of the CB1R inverse agonist, rimonabant, before satiety-induced outcome devaluation test sessions, in which we sated rats on training pellets (devalued) or home cage chow (valued) and examined responding to cues in brief nonreinforced Pavlovian Lever Autoshaping sessions. Overall, DMS CB1R signaling inhibition blocked Pavlovian outcome devaluation. After extended training, male rats were sensitive to devaluation while female rats were not. Inhibition of DMS CB1R signaling impaired Pavlovian outcome devaluation in male sign-tracking rats making their behavior more rigid but had no effects in female sign-tracking rats. Intra-DMS rimonabant infusions before reinforced sessions had no effects on Pavlovian sign- or goal-tracking in either sex. The sex-specific and CB1R-dependent effects were specific to outcome devaluation and were consistent between sign- and goal-tracking groups. Our results demonstrate that DMS endocannabinoid receptor signaling regulates behavioral flexibility in a sex-specific manner, suggesting differences in CB1R signaling in DMS between male and female rats.

Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks
We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may impair synaptic function in rat primary neuronal cultures. Out of the gene targets identified, we found that shRNA-mediated downregulation of Plcg2 in mouse dentate gyrus neurons consistently impaired dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and was associated with increased levels of Abeta; and TAU phosphorylation, potentially via the AKT/GSK3beta axis. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk and LoF carriers exhibit low mRNA/protein PLCG2 levels, consistent with nonsense-mediated mRNA decay mechanisms. Restoring PLCG2 levels in shPLCG2-hNCs fully reversed the disease-related phenotypes. Our findings indicate that the downregulation of PLCG2 increases the risk of AD by impairing synaptic function and increasing the levels of Abeta and TAU phosphorylation in neurons.

Divergent short-term plasticity creates parallel pathways for computation and behavior in an olfactory circuit
To enable diverse sensory processing and behavior, central circuits use divergent connectivity to create parallel pathways. However, linking subcellular mechanisms to the circuit-level segregation of computation has been challenging. Here, we investigate the generation of parallel processing within a divergent network in the Drosophila olfactory system, where single projection neurons target multiple types of lateral horn neuron (LHN). One LHN type generates sustained responses and adapts divisively to encode temporal odor contrast. The other generates transient responses and adapts subtractively to encode a form of positive temporal prediction error. These coding differences originate from subcellular differences in short-term plasticity in projection neuron axons. Prediction error arises from strongly facilitating synapses, which depend on the presynaptic priming factor Unc13B. The temporal contrast code arises from mildly depressing synapses that engage additional gain control implemented by the Na+/K+ ATPase in the postsynaptic neuron. Each LHN type makes corresponding dynamic contributions to behavioral odor attraction. Subcellular synaptic specialization is a compact and efficient way to generate diverse parallel information streams.

Early life growth and cellular heterogeneity in the short-lived African turquoise killifish telencephalon
The African turquoise killifish (Nothobranchius furzeri) is becoming a favorable model for neurobiological research. The combination of a short lifespan and a declining neuroregenerative capacity upon aging makes the killifish ideally suited for research on brain aging and regeneration. A remarkable cellular diversity makes up the young-adult killifish telencephalon, characterized by highly proliferative non-glial progenitors and four spatially distinct radial glia subtypes. In contrast to a relatively slow embryonic development, hatching is followed by a period of accelerated growth in the short-lived N. furzeri strain; GRZ. Accordingly, the brain of this teleost experiences a period of rapid expansion and maturation. In this study, we charted the growth progression of the killifish telencephalon during early post-embryonic development. We identified a dynamic cellular buildup of the neurogenic niches sustaining this explosive growth. Spatial data revealed specific differences between pallial and subpallial regions in terms of growth pace and cellular output. Spatial signatures comparable to zebrafish were identified for excitatory and inhibitory neuronal lineages, already present at hatching.

Reduction of Neuroinflammation and Seizures in a Mouse Model of CLN1 Batten Disease using the Small Molecule Enzyme Mimetic, N-Tert-Butyl Hydroxylamine.
Infantile neuronal ceroid lipofuscinosis (CLN1 Batten Disease) is a devastating pediatric lysosomal storage disease caused by pathogenic variants in the CLN1 gene, which encodes the depalmitoylation enzyme, palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients present with visual deterioration, psychomotor dysfunction, and recurrent seizures until neurodegeneration results in death, typically before fifteen years of age. Histopathological features of CLN1 include aggregation of lysosomal autofluorescent storage material (AFSM), as well as profound gliosis. The current management of CLN1 is relegated to palliative care. Here, we examine the therapeutic potential of a small molecule PPT1 mimetic, N-tert-butyl hydroxylamine (NtBuHA), in a Cln1-/- mouse model. Treatment with NtBuHA reduced AFSM accumulation both in vitro and in vivo. Importantly, NtBuHA treatment in Cln1-/- mice reduced neuroinflammation, mitigated epileptic episodes, and normalized motor function. Live cell imaging of Cln1-/- primary cortical neurons treated with NtBuHA partially rescued aberrant synaptic calcium dynamics, suggesting a potential mechanism contributing to the therapeutic effects of NtBuHA in vivo. Taken together, our findings provide supporting evidence for NtBuHA as a potential treatment for CLN1 Batten Disease.

Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy
Objective: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. Methods: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. Results: Using a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. Conclusion: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

Lateral Prefrontal Theta Oscillations Causally Drive a Computational Mechanism Underlying Conflict Expectation and Adaptation
Adapting our behavior to environmental demands relies on our capacity to perceive and manage potential conflicts within our surroundings. While evidence implicates the involvement of the lateral prefrontal cortex and theta oscillations in detecting conflict stimuli, their roles in conflict expectation remain elusive. Consequently, the exact computations and neural mechanisms underlying these cognitive processes still need to be determined. To address this gap, we employed an integrative approach involving cognitive computational modeling, fMRI, TMS, and EEG. Our results revealed a computational process underlying conflict expectation, which correlated with activity in the superior frontal gyrus (SFG). Furthermore, rhythmic TMS in the theta range applied over the SFG, but not over the inferior frontal junction, induced endogenous theta activity, enhancing computations associated with conflict expectation. These findings provide compelling evidence for the causal involvement of SFG theta activity in learning and allocating cognitive resources to address forthcoming conflict stimuli.

Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington's disease phenotypes in R6/2 mice
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSC) offer a scalable platform for NT delivery but has potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.

Accurate localization of cortical and subcortical sources of M/EEG signals by a convolutional neural network with a realistic head conductivity model: Validation with M/EEG simulation, evoked potentials, and invasive recordings
While electroencephalography (EEG) and magnetoencephalography (MEG) are well-established non-invasive methods in neuroscience and clinical medicine, they suffer from low spatial resolution. Particularly challenging is the accurate localization of subcortical sources of M/EEG, which remains a subject of debate. To address this issue, we propose a four-layered convolutional neural network (4LCNN) designed to precisely locate both cortical and subcortical source activity underlying M/EEG signals. The 4LCNN was trained using a vast dataset generated by forward M/EEG simulations based on a realistic head volume conductor model. The 4LCNN implicitly learns the characteristics of M/EEG and their sources from the training data without need for explicitly formulating and fine-tuning optimal priors, a common challenge in conventional M/EEG source imaging techniques. We evaluated the efficacy of the 4LCNN model on a validation dataset comprising forward M/EEG simulations and two types of real experimental data from humans: 1) somatosensory evoked potentials recorded by EEG, and 2) simultaneous recordings from invasive electrodes implanted in the brain and MEG signals. Our results demonstrate that the 4LCNN provides robust and superior estimation accuracy compared to conventional M/EEG source imaging methods, aligning well with established neuroscience knowledge. Notably, the accuracy of the subcortical regions was as accurate as that of the cortical regions. The 4LCNN method, as a data-driven approach, enables accurate source localization of M/EEG signals, including in subcortical regions, suggesting future contributions to various research endeavors such as contributions to the clinical diagnosis, understanding of the pathophysiology of various neuronal diseases and basic brain functions.

Nanoscale analysis of functionally diverse glutamatergic synapses in the neocortex reveals input and layer-specific organization
Discovery of synaptic nanostructures suggests a molecular logic for the flexibility of synaptic function. We still have little understanding of how functionally diverse synapses in the brain organize their nanoarchitecture due to challenges associated with super-resolution imaging in complex brain tissue. Here, we characterized single-domain camelid nanobodies for the 3D quantitative multiplex imaging of synaptic nano-organization in 6 m brain cryo sections using STED nanoscopy. We focused on thalamocortical (TC) and corticocortical (CC) synapses along the apical-basal axis of layer 5 pyramidal neurons as models of functionally diverse glutamatergic synapses in the brain. Spines receiving TC input were larger than CC spines in all layers examined. However, TC synapses on apical and basal dendrites conformed to different organizational principles. TC afferents on apical dendrites frequently contacted spines with multiple aligned PSD-95/Bassoon nanomodules, which are larger. TC spines on basal dendrites contained mostly one aligned PSD-95/Bassoon nanocluster. However, PSD-95 nanoclusters were larger and scaled with spine volume. The nano-organization of CC synapses did not change across cortical layers. These results highlight striking nanoscale diversity of functionally distinct glutamatergic synapses, relying on afferent input and sub-cellular localization of individual synaptic connections.

Reversal of Obesity by Enhancing Slow-wave Sleep via a Prokineticin Receptor Neural Circuit
Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealed Prokr2 in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2RLPO neurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2RLPO[->]PBN circuit or the postsynaptic PROKR2PBN neurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2PBN neurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.

Feeling Senseless Sensations: A Crossmodal study of mismatching tactile and virtual visual experience
To create highly immersive experiences in virtual reality (VR) it is important to not only include the visual sense but also to involve multimodal sensory input. To achieve optimal results, the temporal and spatial synchronization of these multimodal inputs is critical. It is therefore necessary to find methods to objectively evaluate the synchronization of VR experiences with a continuous tracking of the user. In this study a passive touch experience was incorporated in a visual-tactile VR setup using VR glasses and tactile sensations in mid-air. Inconsistencies of multimodal perception were intentionally integrated into a discrimination task. The participants' electroencephalogram (EEG) was recorded to obtain neural correlates of visual-tactile mismatch situations. The results showed significant differences in the event-related potentials (ERP) between match and mismatch situations. A biphasic ERP configuration consisting of a positivity at 120 ms and a later negativity at 370 ms was observed following a visual-tactile mismatch. This late negativity could be related to the N400 that is associated with semantic incongruency. These results provide a promising approach towards the objective evaluation of visual-tactile synchronization in virtual experiences.

Adolescent and adult mice use both incremental reinforcement learning and short term memory when learning concurrent stimulus-action associations
Computational modeling has revealed that human research participants use both rapid working memory (WM) and incremental reinforcement learning (RL) (RL+WM) to solve a simple instrumental learning task, relying on WM when the number of stimuli is small and supplementing with RL when the number of stimuli exceeds WM capacity. Inspired by this work, we examined which learning systems and strategies are used by adolescent and adult mice when they first acquire a conditional associative learning task. In a version of the human RL+WM task translated for rodents, mice were required to associate odor stimuli (from a set of 2 or 4 odors) with a left or right port to receive reward. Using logistic regression and computational models to analyze the first 200 trials per odor, we determined that mice used both incremental RL and stimulus-insensitive, one-back strategies to solve the task. While these one-back strategies may be a simple form of short-term or working memory, they did not approximate the boost to learning performance that has been observed in human participants using WM in a comparable task. Adolescent and adult mice also showed comparable performance, with no change in learning rate or softmax beta parameters with adolescent development and task experience. However, reliance on a one-back perseverative, win-stay strategy increased with development in males in both odor set sizes. Our findings advance a simple conditional associative learning task and new models to enable the isolation and quantification of reinforcement learning alongside other strategies mice use while learning to associate stimuli with rewards within a single behavioral session. These data and methods can inform and aid comparative study of reinforcement learning across species.

Human APOE allelic variants suppress the formation of diffuse and fibrillar Aβ deposits relative to mouse Apoe in transgenic mouse models of Alzheimer amyloidosis
Background: Apolipoprotein E (apoE) modulates the deposition of amyloid {beta} (A{beta}) aggregates in Alzheimers disease (AD) in an isoform-dependent manner. In transgenic mouse models of AD-amyloidosis, replacing mouse Apoe alleles with human APOE variants suppresses fibrillar A{beta} deposits. In the PD-APP transgenic mouse model, deletion of the Apoe gene led to selective reduction of fibrillar deposits with increased diffuse deposits. This finding suggested that apoE may have differential effects on different types of amyloid pathology. Methods: Here, we investigated the interaction between the type of A{beta} pathology in the brain and human apoE isoforms in different transgenic mouse models. Results: In the APPsi model that develops predominantly diffuse A{beta} plaques late in life, we determined that replacing mouse Apoe with human APOE3 or APOE4 genes potently suppressed diffuse amyloid formation, with apoE3 exhibiting a greater activity relative to apoE4. Relative to apoE4, apoE3 appeared to suppress A{beta} deposition in the cerebral vasculature. In a second cohort, we accelerated the deposition of diffuse A{beta} pathology by seeding, finding that seeded APPsi mice harboring APOE4 or APOE3 developed equal burdens of diffuse parenchymal A{beta}. Finally, in the recently developed SAA-APP model that has a mix of dense-core and fibrous A{beta} plaques, we found that replacing mouse apoE with human apoE suppressed deposition significantly, with the amyloid burden following the trend of Apoe>>APOE4> APOE3~APOE2. In the SAA-APP and seeded APPsi models, we found evidence of apoE protein associated with A{beta} plaques. Conclusions: Overall, these observations demonstrate a capacity for human apoE to suppress the deposition of both diffuse and fibrillar-cored deposits, relative to mouse apoE. Notably, in the seeded paradigm, the suppressive activity of human apoE3 and apoE4 appeared to be overwhelmed. Taken together, this study demonstrates that APOE genotype influences the deposition of both cored-fibrillar and diffuse amyloid.

Microstimulation reveals anesthetic state-dependent effective connectivity of neurons in cerebral cortex
Complex neuronal interactions underlie cortical information processing that can be compromised in altered states of consciousness. Here intracortical microstimulation was applied to investigate the state-dependent effective connectivity of neurons in rat visual cortex in vivo. Extracellular activity was recorded at 32 sites in layers 5/6 while stimulating with charge-balanced discrete pulses at each electrode in random order. The same stimulation pattern was applied at three levels of anesthesia with desflurane and in wakefulness. Spikes were sorted and classified by their waveform features as putative excitatory and inhibitory neurons. Microstimulation caused early (<10ms) increase followed by prolonged (11-100ms) decrease in spiking of all neurons throughout the electrode array. The early response of excitatory but not inhibitory neurons decayed rapidly with distance from the stimulation site over 1mm. Effective connectivity of neurons with significant stimulus response was dense in wakefulness and sparse under anesthesia. Network motifs were identified in graphs of effective connectivity constructed from monosynaptic cross-correlograms. The number of motifs, especially those of higher order, increased rapidly as the anesthesia was withdrawn indicating a substantial increase in network connectivity as the animals woke up. The results illuminate the impact of anesthesia on functional integrity of local circuits affecting the state of consciousness.

Generalization in motor learning: learning bimanual coordination with one hand
The ability to coordinate movements between the hands is crucial for many daily tasks. However, the precise mechanisms governing the storage and utilization of bimanual movement and the distinct contributions of each limb in this process are currently not fully understood. Two key questions persist: 1) How is the neural representation of bimanual coordination stored in the brain, and 2) How is the information governing bimanual coordination shared between hemispheres? In this investigation, we used a virtual partner (VP) to systematically address these issues by allowing the same coordination pattern (CP) to be acquired with unimanual and bimanual movements. More specifically, we used four experimental groups: unimanual (left, right) VP, bimanual, and control conditions. For each condition, retention and transfer tests were administered immediately and 6 hours after the initial practice. The control condition employed the same protocol as unimanual conditions without practice. As anticipated, performance after practice and during retention sessions indicated that all groups learned to perform the target CP. Furthermore, generalization from unimanual to bimanual occurred when the same type of visual feedback (VF) was provided. Interestingly, the absence of VF impaired motor generalization from unimanual to bimanual condition unless the participants initially practiced the task bimanually. Taken together, our results demonstrated that both limbs could access the memory representation of the CP. However, this globally shared representation appeared to be encoded in the visual-spatial domain. The conditions without VF underscored the importance of proprioception in forming a motor representation in intrinsic coordinates.

Dopaminergic inhibition of the inwardly rectifying potassium current in direct pathway medium spiny neurons in normal and parkinsonian striatum
Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that also profoundly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Here we show that in normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently strongly increasing D1-MSN spike firing that is behavior-promoting; this DA excitation of D1-MSNs is stronger when the DA depletion is more severe. The DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl2). In behaving parkinsonian mice, BaCl2 microinjection into the dorsal striatum stimulates movement but occludes the motor stimulation of D1R agonism. Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates D1R agonistic behavioral stimulation in normal and parkinsonian animals.

Exploring Neuroscience Researchers' Trust in Preprints through Citation Analysis
Preprints have emerged as efficient tools for fast and free dissemination of scientific findings. The present study explores the evolving landscape of preprints among the field of neuroscience and examines patterns and evolution of citations to preprints over time in this field. Leveraging bibliometric methods, we identified over 33,000 citations (1993-2022) to preprints within neuroscience publications indexed in Scopus. The findings elucidate a significant temporal increase in the number of documents citing preprints, reaching a peak of around 60 per 1,000 Scopus documents in 2021. Diverse document types, particularly reviews, exhibit a growing reliance on preprints as references. The most frequently cited preprint servers include bioRxiv, ArXiv, medRxiv, and PsyArXiv. Leading journals such as eLife and PLOS Computational Biology have cited preprints more than others. The United States takes the lead in citing preprints, followed by the United Kingdom and Germany. Using Scite.ai, motivations underlying preprint citations and the context in which they were cited were explored and the results are indicative of the mentioning nature of 93% of citations to preprints. Furthermore, the introduction and discussion sections have shown to include the highest number of citations to preprints. The findings highlight the dynamic transformation of preprints in neuroscience field.

Action potential propagation speed compensates for traveling distance in the human retina
Neural information processing requires accurately timed action potentials arriving from presynaptic neurons at the postsynaptic neuron. However, axons of ganglion cells in the human retina feature low axonal conduction speeds and vastly different lengths, which poses a challenge to the brain for constructing a temporally coherent image over the visual field. Combining results from microelectrode array recordings, human behavioral measurements, transmission electron microscopy, and mathematical modelling of the retinal nerve fiber layer, we demonstrate that axonal propagation speeds compensate for variations in axonal length across the human retina including the fovea. The human brain synchronizes the arrival times of action potentials at the optic disc by increasing the diameters of longer axons, which increases their propagation speeds.

The influence of sensory noise, confidence judgments, and accuracy on pupil responses and trial-by-trial reaction time adjustments in young and older people
Decision confidence and the engagement of pupil-linked arousal systems during perceptual decision-making modulate subsequent behavioural adjustments important for optimal performance. In this study, we investigated if the association between pupil responses, decision confidence and decision accuracy was altered in older adults and if these were related to trial-by-trial reaction time adjustments. We tested young and older adults, including men and women, with a dot motion discrimination task, while measuring task-related pupil responses. Auditory feedback was provided after each trial. Participants were instructed to report perceived motion direction and simultaneously their decision confidence. Confidence judgments of both age groups followed the typical signatures of decision confidence. However, older adults were overconfident in the presence of high sensory noise and negative feedback. Interactions between sensory noise, confidence judgments and accuracy revealed blunted pupil responses to performance lapses and negative feedback in older people. In young adults, low confidence in response to high internal noise evoked larger pupil responses than low confidence to high external noise and was associated with higher reaction time adjustments. These effects were reduced in older people. Low confidence responses and errors were associated with slower responses on the subsequent trial in an additive manner with the effect of errors being stronger in the older group. Pupil responses before feedback predicted subsequent reaction time in the older group. In conclusion, in older people, arousal systems showed reduced engagement following performance lapses and errors and impaired sensitivity to fluctuations in internal brain state that might be important for attentional regulation.

Distinct anatomical and functional corticospinal inputs innervate different spinal neuron types
The corticospinal tract exerts its influence on movement through spinal neurons, which can be divided into types that exhibit distinct functions. However, it remains unknown whether these functional distinctions are reflected in the corticospinal inputs that different types of spinal neurons receive. Using rabies monosynaptic tracing from individual neuron types in the cervical cord and 3D histological reconstruction in mice, we discovered that different types receive inputs distinctly distributed across cortex, and aligned with cell type function. This included a distinct, sparse distribution of direct inputs from cortex onto motor neurons. Coupling rabies tracing with activity measurement during motor behavior revealed different interneuron types receive different input activity patterns, primarily due to the topographical distribution of the corticospinal neurons contacting them. Our results establish that different spinal neuron types get distinct anatomical and functional inputs from the cortex, and reveal functionally relevant homology to primate corticospinal organization.

Coordination and persistence of aggressive visual communication in Siamese fighting fish
Animals coordinate their behavior with each other during both cooperative and agonistic social interactions. Such coordination often adopts the form of ''turn taking'', in which the interactive partners alternate the performance of a behavior. Apart from acoustic communication, how turn taking between animals is coordinated is not well understood. Furthermore, the neural substrates that regulate persistence in engaging in social interactions are poorly studied. Here, we use Siamese fighting fish (Betta splendens), to study visually-driven turn-taking aggressive behavior. Using encounters with conspecifics and with animations, we characterize the dynamic visual features of an opponent and the behavioral sequences that drive turn taking. Through a brain-wide screen of neuronal activity during coordinated and persistent aggressive behavior, followed by targeted brain lesions, we find that the caudal portion of the dorsomedial telencephalon, an amygdala-like region, promotes persistent participation in aggressive interactions, yet is not necessary for coordination. Our work highlights how dynamic visual cues shape the rhythm of social interactions at multiple timescales, and points to the pallial amygdala as a region controlling engagement in such interactions. These results suggest an evolutionarily conserved role of the vertebrate pallial amygdala in regulating the persistence of emotional states.

Preprocessing Choices for P3 Analyses with Mobile EEG: A Systematic Literature Review and Interactive Exploration
Preprocessing is necessary to extract meaningful results from electroencephalography (EEG) data. With many possible preprocessing choices, their impact on outcomes is fundamental. While previous studies have explored the effects of preprocessing on stationary EEG data, this research delves into mobile EEG, where complex processing is necessary to address motion artifacts. Specifically, we describe the preprocessing choices studies reported for analyzing the P3 event-related potential (ERP) during walking and standing. A systematic review of 258 studies (Scopus, Web of Science, PubMed) of the P3 during walking, identified 27 studies meeting the inclusion criteria (empirical study, EEG data of healthy humans, P3 during a gait and non-movement condition). Two independent coders extracted preprocessing choices reported in each study. Analysis of preprocessing choices revealed commonalities and differences, such as widespread use of offline filters but limited application of line noise correction (3 out of 27 studies). Notably, 63% of studies involved manual processing steps, and 52% omitted reporting critical parameters for at least one step. All studies employed unique preprocessing strategies. These findings align with stationary EEG preprocessing results, emphasizing the necessity for standardized reporting in mobile EEG research. We implemented an interactive visualization tool (Shiny app) to aid the exploration of the preprocessing landscape. The Shiny app allows users to structure the literature regarding different processing steps and processing combinations, thereby providing a meaningful overview. It is also possible to enter planned or preferred processing methods and compare own choices with the literature. The app thus helps to identify defensible preprocessing choices, specifically with a focus on P3 ERP analyses during standing and walking. It could be utilized to examine how these choices impact P3 results and understand the robustness of various processing options. We hope to increase awareness regarding the potential influence of preprocessing decisions and advocate for comprehensive reporting standards to foster reproducibility in mobile EEG research.

Brain rewiring during developmental transitions: A Comparative Analysis of Larva and Adult Drosophila melanogaster
The brain's ability to adapt through structural rewiring during developmental transitions is a fundamental aspect of neuroscience. Our study conducts a detailed comparison of Drosophila melanogaster's brain networks during larval and adult stages, revealing significant changes in neuronal wiring during developmental phases. The degree distribution of the larval brain deviates significantly from power-law behavior and fits well with the Weibull distribution. In contrast, the adult brain exhibits power-law behavior in its degree distribution, with the exponent for the out-degree distribution lying in the scale-free regime and the exponent for the in-degree distribution being close to this regime. This difference reflects a change in the robustness of brain development from larval to adult phases. The core of these networks also changes during development in terms of their cell composition and topological influence. The larval core comprises Mushroom Body neurons, while the adult core mainly has Antennal Lobe neurons. Moreover, all the core neurons in the larval brain are also part of the rich-club neurons, a group of neurons with high in/out degrees that are well connected, whereas the same is not true for the adult brain network. Additionally, the core of the larval brain displays a more heterogeneous connectivity profile in its second-order neighbors compared to adult brain neurons, indicating greater diversity in larval brain connectivity. Our work stands as a step forward in understanding the rewiring of brain networks across the life stages of Drosophila melanogaster.

Strategies for motion- and respiration-robust estimation of fMRI intrinsic neural timescales
Intrinsic neural timescale (INT) is a resting-state fMRI (rs-fMRI) measure that reflects the time window of neural integration within a brain region. Despite the potential relevance of INT to cognition, brain organization, and neuropsychiatric illness, the influences of physiological artifacts on INT have not been systematically considered. Two artifacts, head motion and respiration, pose serious issues in rs-fMRI studies. Here, we described their impact on INT estimation and tested the ability of two denoising strategies for mitigating these artifacts, high-motion frame censoring and global signal regression (GSR). We used a subset of the HCP Young Adult dataset with runs annotated for breathing patterns (Lynch et al., 2020) and at least one "clean" (reference) run that had minimal head motion and no respiration artifacts; other runs from the same participants (n = 46) were labeled as "non-clean." We found that non-clean runs exhibited brain-wide increases in INT compared to their respective clean runs and the magnitude of error in INT between non-clean and clean runs correlated with the amount of head motion. Importantly, effect sizes were comparable to INT effects reported in the clinical literature. GSR and high-motion frame censoring improved the similarity between INT maps from non-clean runs and their respective clean run. Using a pseudo-random frame-censoring approach, there was a relationship between the amount of censored frames and both the mean INT and mean error, suggesting that frame censoring itself biases INT estimation. A group-level correction procedure reduced this bias and improved similarity between non-clean runs and their respective clean run. Based on our findings, we offer recommendations for rs-fMRI INT studies, which include implementing GSR and high-motion frame censoring with Lomb-Scargle interpolation of censored data, and performing group-level correction of the bias introduced by frame censoring.

The Noisy Encoding of Disparity Model Predicts Perception of the McGurk Effect in Native Japanese Speakers
The McGurk effect is an illusion that demonstrates the influence of information from the face of the talker on the perception of auditory speech. The diversity of human languages has prompted many intercultural studies of the effect, including in native Japanese speakers. Studies of large samples of native English speakers have shown that the McGurk effect is characterized by high variability, both in the susceptibility of different individuals to the illusion and in the frequency with which different experimental stimuli induce the illusion. The noisy encoding of disparity (NED) model of the McGurk effect uses Bayesian principles to account for this variability by separately estimating the susceptibility and sensory noise for each individual and the strength of each stimulus. To test whether the NED model could account for McGurk perception in a non-Western culture, we applied it to data collected from 80 native Japanese-speaking participants. Fifteen different McGurk stimuli were presented, along with audiovisual congruent stimuli. The McGurk effect was highly variable across stimuli and participants, with the percentage of illusory fusion responses ranging from 3% to 78% across stimuli and from 0% to 91% across participants. Despite this variability, the NED model accurately predicted perception, predicting fusion rates for individual stimuli with 2.1% error and for individual participants with 2.4% error. Stimuli containing the unvoiced pa/ka pairing evoked more fusion responses than the voiced ba/ga pairing. Model estimates of sensory noise was correlated with participant age, with greater sensory noise in older participants. The NED model of the McGurk effect offers a principled way to account for individual and stimulus differences when examining the McGurk effect within and across cultures.

Representation of navigational affordances and ego-motion in the occipital place area
Humans effortlessly use vision to plan and guide navigation through the local environment, or "scene". A network of three cortical regions responds selectively to visual scene information, including the occipital (OPA), parahippocampal (PPA), and medial place areas (MPA) - but how this network supports visually-guided navigation is unclear. Recent evidence suggests that one region in particular, the OPA, supports visual representations for navigation, while PPA and MPA support other aspects of scene processing. However, most previous studies tested only static scene images, which lack the dynamic experience of navigating through scenes. We used dynamic movie stimuli to test whether OPA, PPA, and MPA represent two critical kinds of navigationally-relevant information: navigational affordances (e.g., can I walk to the left, right, or both?) and ego-motion (e.g., am I walking forward or backward? turning left or right?). We found that OPA is sensitive to both affordances and ego-motion, as well as the conflict between these cues - e.g., turning toward versus away from an open doorway. These effects were significantly weaker or absent in PPA and MPA. Responses in OPA were also dissociable from those in early visual cortex, consistent with the idea that OPA responses are not merely explained by lower-level visual features. OPA responses to affordances and ego-motion were stronger in the contralateral than ipsilateral visual field, suggesting that OPA encodes navigationally relevant information within an egocentric reference frame. Taken together, these results support the hypothesis that OPA contains visual representations that are useful for planning and guiding navigation through scenes.

A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology
Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal was to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters from Hippocampome.org. The software is released as open source to enable broad community reuse and encourage novel applications.

A survival-critical role for Drosophila giant interneurons during predation
Large axon-diameter descending neurons are metabolically costly but transmit information rapidly from sensory neurons in the brain to motor neurons in the nerve cord. They have thus endured as a common feature of escape circuits in many animal species where speed is paramount. Though often considered isolated command neurons triggering fast-reaction-time, all-or-none escape responses, giant neurons are just one of multiple parallel pathways enabling selection between behavioral alternatives. Such degeneracy among escape circuits makes it unclear if and how giant neurons benefit prey fitness. Here we competed Drosophila melanogaster flies with genetically-silenced Giant Fibers (GFs) against flies with functional GFs in an arena with wild-caught damselfly predators and find that GF silencing decreases prey survival. Kinematic analysis of damselfly attack trajectories shows that decreased prey survival fitness results from GF-silenced flies failing to escape during predator attack speeds and approach distances that would normally elicit successful escapes. When challenged with a virtual looming predator, fly GFs promote survival by enforcing selection of a short-duration takeoff sequence as opposed to reducing reaction time. Our findings support a role for the GFs in promoting prey survival by influencing action selection as a means to enhance escape performance during realistically complex predation scenarios.

The retina's neurovascular unit: Mueller glial sheaths and neuronal contacts
The neurovascular unit (NVU), comprising vascular, glial and neural elements, supports the energetic demands of neural computation, but this aspect of the retina's trilaminar vessel network is poorly understood. Only the innermost vessel layer - the superficial vascular plexus (SVP) - is ensheathed by astrocytes, like brain capillaries, whereas glial ensheathment in other layers derives from radial Mueller glia. Using serial electron microscopy reconstructions from mouse and primate retina, we find that Mueller processes cover capillaries in a tessellating pattern, mirroring the tiled astrocytic endfeet wrapping brain capillaries. However, gaps in the Mueller sheath, found mainly in the intermediate vascular plexus (IVP), permit different neuron types to contact pericytes and the endothelial cells directly. Pericyte somata are a favored target, often at spine-like structures with a reduced or absent vascular basement lamina. Focal application of adenosine triphosphate (ATP) to the vitreal surface evoked Ca2+ signals in Mueller sheaths in all three vascular layers. Pharmacological experiments confirmed that Mueller sheaths express purinergic receptors that, when activated, trigger intracellular Ca2+ signals that are amplified by IP3-controlled intracellular Ca2+ stores. When rod photoreceptors die in a mouse model of retinitis pigmentosa (rd10), Mueller sheaths dissociate from the deep vascular plexus (DVP) but are largely unchanged within the IVP or SVP. Thus, Mueller glia interact with retinal vessels in a laminar, compartmentalized manner: glial sheathes are virtually complete in the SVP but fenestrated in the IVP, permitting direct neural-to-vascular contacts. In the DVP, the glial sheath is only modestly fenestrated and is vulnerable to photoreceptor degeneration.

Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy
We previously reported altered neuronal Ca2+ dynamics in the motor cortex of 12-month-old JNPL3 tauopathy mice during quiet wakefulness or forced running, with a tau antibody treatment significantly restoring the neuronal Ca2+ activity profile and decreasing pathological tau in these mice 1. Whether neuronal functional deficits occur at an early stage of tauopathy and if tau antibody treatment is effective in younger tauopathy mice needed further investigation. In addition, neuronal network activity and neuronal firing patterns have not been well studied in behaving tauopathy models. In this study, we first performed in vivo two-photon Ca2+ imaging in JNPL3 mice in their early stage of tauopathy at 6 months of age, compared to 12 month old mice and age-matched wild-type controls to evaluate neuronal functional deficits. At the animal level, frequency of neuronal Ca2+ transients decreased only in 6 month old tauopathy mice compared to controls, and only when animals were running on a treadmill. The amplitude of neuronal transients decreased in tauopathy mice compared to controls under resting and running conditions in both age groups. Total neuronal activity decreased only in 6 month old tauopathy mice compared to controls under resting and running conditions. Within either tauopathy or wild-type group, only total activity decreased in older wild-type animals. The tauopathy mice at different ages did not differ in neuronal Ca2+ transient frequency, amplitude or total activity. In summary, neuronal function did significantly attenuate at an early age in tauopathy mice compared to controls but interestingly did not deteriorate between 6 and 12 months of age. A more detailed populational analysis of the pattern of Ca2+ activity at the neuronal level in the 6 month old cohort confirmed neuronal hypoactivity in layer 2/3 of primary motor cortex, compared to wild-type controls, when animals were either resting or running on a treadmill. Despite reduced activity, neuronal Ca2+ profiles exhibited enhanced synchrony and dysregulated responses to running stimulus. Further ex vivo electrophysiological recordings revealed reduction of spontaneous excitatory synaptic transmission onto and in pyramidal neurons and enhanced excitability of inhibitory neurons in motor cortex, which were likely responsible for altered neuronal network activity in this region. Lastly, tau antibody treatment reduced pathological tau and gliosis partially restored the neuronal Ca2+ activity deficits but failed to rescue altered network changes. Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies.

Layer-specific control of inhibition by NDNF interneurons
Neuronal processing of external sensory input is shaped by internally-generated top-down information. In the neocortex, top-down projections predominantly target layer 1, which contains NDNF-expressing interneurons, nestled between the dendrites of pyramidal cells (PCs). Here, we propose that NDNF interneurons shape cortical computations by presynap- tically inhibiting the outputs of somatostatin-expressing (SOM) interneurons via GABAergic volume transmission in layer 1. Whole-cell patch clamp recordings from genetically identified NDNF INs in layer 1 of the auditory cortex show that SOM-to-NDNF synapses are indeed modulated by ambient GABA. In a cortical microcircuit model, we then demonstrate that this mechanism can control inhibition in a layer-specific way and introduces a competition for dendritic inhibition between NDNF and SOM interneurons. This competition is mediated by a unique mutual inhibition motif between NDNF interneurons and the synaptic outputs of SOM interneurons, which can dynamically prioritise different inhibitory signals to the PC dendrite. NDNF interneurons can thereby control information flow in pyramidal cells by redistributing dendritic inhibition from fast to slow timescales and by gating different sources of dendritic inhibition, as exemplified in a predictive coding application. This work corroborates that NDNF interneurons are ideally suited to control information flow within cortical layer 1.

Fast feature- and category-related parafoveal previewing support natural visual exploration.
Studies on vision tend to prevent or control eye movements, while humans naturally saccade every ~250 ms. As the oculomotor system takes ~100 ms to initiate and execute a saccade, this leaves only ~150 ms to identify the fixated object and select the next saccade goal. This is very little time, suggesting that vision relies on parafoveal processing before and after the eye movement. However, evidence of high-level parafoveal access is sparse. The purpose of our study was to use magnetoencephalography (MEG) combined with eye-tracking and multivariate pattern analysis to identify the neuronal dynamics of parafoveal processing which support natural visual exploration. We demonstrated that future saccade goals in the parafovea could be decoded at the feature and category level peaking at ~90 ms and ~160 ms respectively. Simultaneously, decoding of fixated objects at the feature and category level peaked at ~70 ms and ~145 ms respectively. Also decoding feature and category specific neuronal information related to past parafoveal objects were sustained for ~230 ms after saccading away from them. The feature and category of objects in the parafovea could only be decoded if they were in the saccade goal. In sum, we provide insight on the neuronal mechanism of pre-saccadic attention by demonstrating that feature and category specific information of foveal and parafoveal objects can be extracted in succession within a ~150 ms time-interval and may serve to plan the next saccade. This information is maintained also after fixations and may support integration across the full visual scene. Our study provides novel insight on the temporal dynamics of foveal and parafoveal processing at the feature and semantic levels during natural visual exploration.

Analysis of changes in inter-cellular communications during Alzheimer's Disease pathogenesis reveals conserved changes in glutamatergic transmission in mice and humans
Analysis of system-wide cellular communication changes in Alzheimer's disease (AD) has recently been enabled by single nucleus RNA sequencing (snRNA-seq) and new computational methods. Here, we combined these to analyze data from postmortem human tissue from the entorhinal cortex of AD patients and compared our findings to those from multiomic data from the 5xFAD amyloidogenic mouse model at two different time points. Using the cellular communication inference tool CellChat we found that disease-related changes were largely related to neuronal excitability as well as synaptic communication, with specific signaling pathways including BMP, EGF, and EPHA, and relatively poor conservation of glial-related changes during disease. Further analysis using the neuron-specific NeuronChat revealed changes relating to metabotropic glutamate receptors as well as neuronal adhesion molecules including neurexins and neuroligins. Our results that cellular processes relating to excitotoxicity are the best conserved between 5xFAD mice and AD suggest that excitotoxicity is the main common feature between pathogenesis in 5xFAD mice and AD patients.

The ANTsX Ecosystem for Mapping the Mouse Brain
Precision mapping techniques coupled with high resolution image acquisition of the mouse brain permit the study of the spatial organization of gene expression and their mutual interaction for a comprehensive view of salient structural/functional relationships. Such research is facilitated by standardized anatomical coordinate systems, such as the well-known Allen Common Coordinate Framework (AllenCCFv3), and the ability to spatially map to such standardized spaces. The Advanced Normalization Tools Ecosystem is a comprehensive open-source software toolkit for generalized quantitative imaging with applicability to multiple organ systems, modalities, and animal species. Herein, we illustrate the utility of ANTsX for generating precision spatial mappings of the mouse brain and potential subsequent quantitation. We describe ANTsX-based workflows for mapping domain-specific image data to AllenCCFv3 accounting for common artefacts and other confounds. Novel contributions include ANTsX functionality for velocity flow-based mapping spanning the spatiotemporal domain of a longitudinal trajectory which we apply to the Developmental Common Coordinate Framework. Additionally, we present an automated structural morphological pipeline for determining volumetric and cortical thickness measurements analogous to the well-utilized ANTsX pipeline for human neuroanatomical structural morphology which illustrates a general open-source framework for tailored brain parcellations.

A brain-inspired algorithm improves cocktail party listening for individuals with hearing loss
Selective listening in competing-talker situations (restaurants, parties, etc.) is an extraordinarily difficult task for many people. For individuals with hearing loss, this difficulty can be so extreme that it seriously impedes communication and participation in daily life. Directional filtering is one of the only proven ways to improve speech understanding in competition, and most hearing devices now incorporate some kind of directional technology, although real-world benefits are modest, and many approaches fail in competing-talker situations. We recently developed a biologically inspired algorithm that is capable of very narrow spatial tuning and can isolate one talker from a mixture of talkers. The algorithm is based on a hierarchical network model of the auditory system, in which binaural sound inputs drive populations of neurons tuned to specific spatial locations and frequencies, and the spiking responses of neurons in the output layer are reconstructed into audible waveforms. Here we evaluated the algorithm in a group of adults with sensorineural hearing loss, using a challenging competing-talker task. The biologically inspired algorithm led to robust intelligibility gains under conditions in which a standard beamforming approach failed. The results provide compelling support for the potential benefits of biologically inspired algorithms for assisting individuals with hearing loss in cocktail party situations.

Double training reveals an interval-invariant subsecond temporal structure in the brain
Subsecond temporal perception is critical for understanding time-varying events. Many studies suggest that subsecond timing is an intrinsic property of neural dynamics, distributed across sensory modalities and brain areas. Furthermore, we hypothesize the existence of a more abstract and conceptual representation of subsecond time, which may guide the temporal processing of distributed mechanisms. However, one major challenge to this hypothesis is that learning in temporal interval discrimination (TID) consistently fails to transfer from trained intervals to untrained intervals. To address this issue, here we examined whether this interval specificity can be removed with double training, a procedure we originally created to eliminate various specificities in visual perceptual learning. Specifically, participants practiced the primary TID task, the learning of which per se was specific to the trained interval (e.g., 100 ms). In addition, they also received exposure to a new interval (e.g., 200 ms) through a secondary and functionally independent tone-frequency discrimination (FD) task. This double training successfully enabled complete transfer of TID learning to the new interval, indicating that training improved an interval-invariant component of temporal interval perception, which supports our general proposal of an abstract and conceptual representation of subsecond time in the brain. Keywords: Subsecond temporal perception, temporal interval discrimination, conceptual representation, perceptual learning, double training

Divergent gene expression in alcohol and opioid usedisorders results in consistent alterations in functional networks in the Dorsolateral Prefrontal Cortex
Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.

Alterations of PINK1-PRKN signaling in mice during normal aging
The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studied in vitro upon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagy in vivo is less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessment in vivo, setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.

Association of bidirectional network cores in the brain with conscious perception and cognition
The brain comprises a complex network of interacting regions. To understand the roles and mechanisms of this complex network, its structural features related to specific cognitive functions need to be elucidated. Among such relationships, recent developments in neuroscience highlight the link between network bidirectionality and conscious perception. Given the essential roles of both feedforward and feedback signals in conscious perception, it is surmised that subnetworks with bidirectional interactions are critical. However, the link between such subnetworks and conscious perception remains unclear due to the networks complexity. In this study, we propose a framework for extracting subnetworks with strong bidirectional interactions--termed the "cores" of a network--from brain activity. We applied this framework to resting-state and task-based fMRI data to identify regions forming strongly bidirectional cores. We then explored the association of these cores with conscious perception and cognitive functions. The central cores predominantly included cerebral cortical regions, which are crucial for conscious perception, rather than subcortical regions. Furthermore, the cores were composed of previously reported regions in which electrical stimulation altered conscious perception. These results suggest a link between the bidirectional cores and conscious perception. A meta-analysis and comparison of the core structure with a cortical functional connectivity gradient suggested that the central cores were related to lower-order sensorimotor functions. An ablation study emphasized the importance of incorporating bidirectionality, not merely interaction strength for these outcomes. The proposed framework provides novel insight into the roles of network cores with strong bidirectional interactions in conscious perception and lower-order sensorimotor functions.

Significance StatementTo understand the brains network, we must decipher its structural features linked to cognitive functions. Recent studies suggest the importance of subnetworks with bidirectional interactions for conscious perception, but their exact relationship remains unclear due to the brains complexity. Here we propose a framework for extracting subnetworks with strong bidirectional interactions, or network "cores." We applied it to fMRI data and explored the association of the extracted cores with conscious perception and cognitive functions. The central cores pre-dominantly included cerebral cortical regions rather than subcortical ones, and comprised previously reported regions wherein electrical stimulation altered conscious perception, suggesting the importance of strongly bidirectional cores for conscious perception. Additionally, further analysis including meta-analysis revealed the cores relation to lower-order sensorimotor functions.

A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants
Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the inherent complexity and heterogeneity of the disease and the "trial and error" approach in choosing the most effective antidepressant treatment for each patient, allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, to cross the blood-brain-barrier, and to be highly sensitive to changes in neuronal activity or activation of various neuronal receptors. Here we present evidence of a brain-enriched circRNA that is regulated by Serotonin 5-HT2A and Brain-Derived Neurotrophic Factor (BDNF) receptor activity and whose expression in the blood can predict response to SSRI treatment. We present data using circRNA-specific PCR in baseline whole blood samples from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) study, showing that before treatment this circRNA is differentially expressed between future responders and non-responders to sertraline. We further show that the expression of this circRNA is upregulated following sertraline treatment and that its trajectory of change post-treatment is associated with long-term remission. Furthermore, we show that the biomarker potential of this circRNA is specific to SSRIs, and not associated with prediction of response or remission after Placebo or Bupropion treatment. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting that the same circRNA is enriched in the brain and is regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.

Arachidonic acid incorporation into phosphatidylinositol by LPLAT11/MBOAT7 ensures radial glial cell integrity in developing neocortex
Arachidonic acid, a vital polyunsaturated fatty acid in brain development, is enriched in phosphatidylinositol (PI). The arachidonic acyl chain in PI is introduced by lysophospholipid acyltransferase 11 (LPLAT11)/membrane-bound O-acyltransferase 7 (MBOAT7), the loss of which causes cortical atrophy in humans and mice. Here, we show that LPLAT11 deficiency impaired indirect neurogenesis in the developing neocortex, resulting in fewer layer II-V neurons. LPLAT11-deficient radial glial cells had defects in differentiation into intermediate progenitor cells and increased apoptosis. Prior to these anomalies, LPLAT11 deficiency caused a fragmentation of the Golgi apparatus, accompanied by impaired apical trafficking of E-cadherin, and deregulated apical detachment. Moreover, impaired PI acyl chain remodeling led to a decreased amount of PI(4,5)P2, leading to Golgi apparatus fragmentation. Thus, these results clarify the underlying mechanism of cortical atrophy by LPLAT11 deficiency and highlight the critical role of arachidonic acid in PI in the integrity of radial glial cells.

Influence of aversive cue detection sensitivity on extinction in adult male rats
Threat detection prompts reactions classified either as fear (obvious, predictable, immediate threat) or anxiety (ambiguous, sustained, distant threat). Hypervigilance is a state of sensitivity to threatening stimuli and an attentional bias symptomatic of anxiety disorders. In rodents, threat detection can be measured by freezing behaviour and production of ultrasonic vocalisation (USV) alarm calls. The amygdala is classically associated with fear-like responses, whereas the bed nucleus of the stria terminalis (BNST) has been proposed to be preferentially recruited by anxiogenic stimuli. The conditioned responses triggered by aversive cues can be extinguished through repeated exposure of a subject to the threat stimulus but without any aversive reinforcement. The extent of extinction acquisition and consolidation are notedly variable across individuals. It has been reported that NMDA-type glutamate receptor co-agonists, like D-cycloserine, can enhance extinction consolidation. In the experiments herein, the salience of a threat cue was modified to compare the relative activation of the brain vigilance networks to an obvious cue, and to test whether sensitivity to the aversive cue at such a vigilance screen might predict subsequent ability to extinguish conditioned responses. We demonstrated activation of the BNST by a low salience aversive cue. Rats that had the propensity to make alarm ultrasonic vocalisation calls reacted more strongly to aversive cues and had deficits in conditioned freezing extinction. Finally, we demonstrated the potential to enhance extinction consolidation by targeting glycine transmission. Taken together these results demonstrate how threat detection and responses are sensitive to cue salience and can be manipulated by combined pharmacological and behavioural interventions.

Layer 6 corticocortical cells dominate the anatomical organization of intra and interhemispheric feedback
Cortico-cortical projection neurons couple functionally distinct areas within and between the cortical hemi-spheres via feedback and feedforward pathways that originate from different cortical laminae. Determining the logic of this long range circuitry is necessary for understanding how inter-areal cortical integration enables high level brain function involving multiple sensory, motor and cognitive processes. To address this we have performed a systematic anatomical analysis of the areal and laminar organization of the ipsilateral and contralateral cortical projection onto the primary visual (VISp), primary somatosensory barrel field (SSp-bfd) and primary motor (MOp) cortices. The resultant input maps reveal that although the ipsilateral hemisphere is the major source of cortical input, there is substantial bilateral symmetry regarding the relative contribution and areal identity of cortical input. Laminar analysis of these input areas show that intra and interhemispheric connectivity is mediated predominantly by excitatory Layer 6 corticocortical cells (L6 CCs). Based on cortical hierarchy analysis that compares the relative contribution of inputs from supra- (feedforward) and infra-granular (feedback) layers, we find that contra-hemispheric projections reflect a dominant feedback organization compared to their ipsi-cortical counterpart, independent of the target injection area. The magnitude of the interhemispheric difference in hierarchy was largest for sensory and motor areas compared to frontal, medial or lateral brain areas and can be explained by a proportional increase in input from L6 projection neurons. L6 CCs therefore not only dominate corticocortical communication but also reflect its inherent feedback organization.

Generators of the frequency-following response in the subthalamic nucleus: implications for non-invasive deep brain stimulation
While Deep Brain Stimulation (DBS) is effective treatment for several movement disorders, non-invasive stimulation modes have major clinical relevance. We report on a novel method holding potential for non-invasive subthalamic nucleus (STN) stimulation. We used an auditory frequency-following response task (FFR), a popular tool for studying the auditory brainstem as the neural response in the cortical and midbrain generator, as it precisely reflects the ongoing dynamics of a speech or non-speech sound. We recorded EEG and DBS electrodes from 5 patients, in 4 from the STN, and one from the anterior thalamus and a number of cortical and subcortical areas located in the hippocampus and frontal regions, during an FFR at a frequency higher than the upper limit of phase-locking in the cortex (333Hz). Our results revealed a neural response local to the STN, but not other structures. This finding is novel. Auditory perception in the basal ganglia is rather unexplored, and the STN generator of the FFR has likely gone unseen due to the limitations of our tools and research focus. The potential clinical implications are far-reaching. Future research should investigate whether auditory stimuli at common electrical stimulation frequencies and waveforms of electrical DBS stimulation can induce clinical improvement.

Developmental disruption of Mef2c in Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function
Background: MEF2C is strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy of Mef2c, or selectively lacking both copies of Mef2c in cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. Methods: Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. Results: Loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. Conclusions: MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.

ACTIVITY-DEPENDENT INTERNALIZATION OF GLUN2B-CONTAINING NMDARS IS REQUIRED FOR SYNAPTIC INCORPORATION OF GLUN2A AND SYNAPTIC PLASTICITY
NMDA-type glutamate receptors (NMDARs) are heterotetrameric complexes composed of two GluN1 and two GluN2 subunits. The precise composition of the GluN2 subunits determines the channel's biophysical properties and influences its interaction with postsynaptic scaffolding proteins and signaling molecules involved in synaptic physiology and plasticity. Consequently, the precise regulation of NMDAR subunit composition at synapses is crucial for proper synaptogenesis, neuronal circuit development, and synaptic plasticity, a cellular model of memory formation. In the forebrain during early development, NMDARs contain the GluN2B subunit, which is necessary for proper synaptogenesis and synaptic plasticity. In rodents, GluN2A subunit expression begins in the second postnatal week, replacing GluN2B-containing NMDARs at synapses in an activity- or sensory experience-dependent process. This switch in NMDAR subunit composition at synapses alters channel properties and reduces synaptic plasticity. The molecular mechanism regulating the switch remains unclear. We have investigated the role of activity-dependent internalization of GluN2B-containing receptors in shaping synaptic NMDAR subunit composition. Using a combination of molecular, pharmacological, and electrophysiological approaches in cultured organotypic hippocampal slices from rats of both sexes, we show that the process of incorporating GluN2A-containing NMDARs receptors requires activity-dependent internalization of GluN2B-containing NMDARs. Interestingly, blockade of GluN2A synaptic incorporation was associated with impaired potentiation of AMPA-mediated synaptic transmission, suggesting a potential coupling between the trafficking of AMPARs into synapses and that of GluN2A-containing NMDARs. These insights contribute to our understanding of the molecular mechanisms underlying synaptic trafficking of glutamate receptors and synaptic plasticity. They may also have implications for therapeutic strategies targeting NMDAR function in neurological disorders.

Neurocognitive Mechanism of Radiologists Perceptual Errors: Results of Preliminary Studies
BackgroundThe most prevalent type of radiologist error is failing to detect abnormalities on images, the so-called "perceptual error." This error type has been consistently measured and its prevalence remains essentially unchanged since it was first described in 1949.

PurposeThe purpose of this research is to identify a potential neurocognitive mechanism for perceptual error, in order to inform intervention strategies to reduce such errors in practice. These experiments evaluated the relationship between brain network activation states and radiologists perceptual errors on two distinct visual tasks utilizing functional MRI (fMRI) and functional Near Infrared Spectroscopy (fNIRs).

Materials and MethodsA prospective study was carried out with two fMRI experiments conducted on radiologist participants utilizing distinct types of visual tasks: the first requiring their continuous attention and the second task requiring visual search. For the first experiment, two modalities of functional brain imaging, functional MRI (fMRI) and functional Near-Infrared Spectrosocpic Imaging (fNIRs) were utilized. The second experiment was performed using fMRI alone, supplemented with eye-tracking. A third experiment using fNIRs alone was an observational study of subjects neurocognitive states during their usual practice.

ResultsA nearly fourfold increased risk of false-negative (FN) errors (misses) was demonstrated in the presence of a particular error-prone neurocognitive state (EPS) involving simultaneous co-activation of elements of the Default Mode Network (DMN) and Frontoparietal Network (FPN) of cerebral connectivity. We also found a high prevalence of the EPS in radiologists performing their normal interpretive tasks in their actual practice setting.

ConclusionOur results suggest that dynamic interactions between brain networks leading to a particular error-prone state (EPS) may underlie a substantial fraction of radiologists perceptual errors. We demonstrate that this EPS can be detected unobtrusively in the clinical setting. These results suggest potential intervention strategies for perceptual error, the largest class of radiologist errors in practice.

Key ResultsO_LIPeriodic episodes of a discrete neurocognitive state were observed in radiologists during specific visual tasks and in actual clinical settings.
C_LIO_LIThere was a nearly fourfold risk of perceptual error during this state. Most FN errors for the two visual tasks occurred during these brief episodes (p < 0.01).
C_LIO_LIThere was also a highly significant anti-correlation of the prevalence of the error-prone neurocognitive state (EPS) with subject age (p < 0.001).
C_LI

Summary StatementWe report experimental results corelating perceptual errors of radiologists to apparently random, episodic fluctuations in brain network activation. These produce an error-prone neurocognitive state outside of operator awareness or control that is associated with a nearly fourfold increase in the risk of perceptual error in our sample.

Analysis of Hippocampal Synaptic Function in a Rodent Model of Early Life Stress
Background: Early life stress (ELS) is an important risk factor in the aetiology of depression. Developmental glucocorticoid exposure impacts multiple brain regions with the hippocampus being particularly vulnerable. Hippocampal mediated behaviours are dependent upon the ability of neurones to undergo long-term potentiation (LTP), an N-methyl-D-aspartate receptor (NMDAR) mediated process. In this study we investigated the effect of ELS upon hippocampal NMDAR function. Methods: Hooded Long-Evans rat pups (n=82) were either undisturbed or maternally separated for 180 minutes per day (MS180) between post-natal day (PND) 1 and PND14. Model validation consisted of sucrose preference (n=18) and novelty supressed feeding (NSFT, n=34) tests alongside assessment of corticosterone (CORT) and paraventricular nucleus (PVN) cFos reactivity to stress and hippocampal neurogenesis (all n=18). AMPA/NMDA ratios (n=19), miniEPSC currents (n=19) and LTP (n=15) were assessed in whole-cell patch clamp experiments in CA1 pyramidal neurones. Results: MS180 animals showed increased feeding latency in the NSFT alongside increased overall CORT in the restraint stress experiment and increased PVN cFos expression in males but no changes in neurogenesis or sucrose preference. MS180 was associated with a lower AMPA/NMDA ratio with no change in miniEPSC amplitude or area. There was no difference in short- or long-term potentiation between MS180 and control animals nor were there any changes during the induction protocol. Conclusions: The MS180 model showed a behavioural phenotype consistent with previous work. MS180 animals showed increased NMDAR function with preliminary evidence suggesting that this was not concurrent with an increase in LTP.

A prefrontal cortex-lateral hypothalamus circuit controls stress-driven food intake
Stress can drive excessive intake of palatable high-caloric food. The medial prefrontal cortex (mPFC) is implicated in this, but through unknown downstream circuits and mechanisms. Here we show, in mice, that the projection from the mPFC to the lateral hypothalamus (LHA) is a critical substrate for stress-driven fat intake. We show that optogenetic stimulation of the mPFC-LHA increases fat intake under naive conditions. Using in vivo electrophysiology and ensemble tagging, we demonstrate that the mPFC-LHA network acutely responds to social stress. Combining patch clamp and optogenetics, we show that after social stress, plasticity occurs specifically at mPFC synapses onto LHA glutamatergic (but not GABAergic) neurons. Prior social stress primes the efficacy with which optogenetic stimulation of mPFC-LHA pathways drives fat intake, while chemogenetic inhibition of this network specifically blocks stress-driven increased fat intake. Our findings identify the mPFC as a top-down regulator of distinct LHA feeding networks, necessary for stress-eating behavior.