bioRxiv Subject Collection: Neuroscience's Journal

Prelimbic corticopontine neurons gate extinction learning
The prelimbic cortex is essential for association of temporally separated events, and impedes extinction of learned association. The network mechanism underlying reversal learning, however, remains elusive. Here, we found that mitochondria-dependent post-tetanic potentiation at synapses onto prelimbic corticopontine neurons impedes extinction learning without affecting initial associative learning. Rats underwent trace fear conditioning followed by extinction sessions. Pharmacological inhibition of post-tetanic potentiation using tetaraphenylphosphnium (TPP), a mitochondrial Ca2+ release blocker, accelerated extinction of trace fear memory, leaving trace fear memory formation intact. Optogenetic inhibition of corticopontine, but not commissural, neurons phenocopied these effects. Electrophysiological recordings and Ca2+ imaging revealed that TPP treatment reduced the persistent activity of corticopontine neurons encoding tone presentation. Mechanistically, associative learning triggers the bursting activity of prelimbic pyramidal neurons that induces post-tetanic potentiation of corticopontine neurons, an effect blocked by TPP treatment. Thus, we identified a prelimbic cell type- and local circuit-specific mechanism that selectively gates extinction learning.

Locus coeruleus activation 'resets' hippocampal event representations and separates adjacent memories
Memories reflect the ebb and flow of experiences, capturing unique and meaningful events from our lives. Using a combination of functional magnetic resonance imaging (fMRI), neuromelanin imaging, and pupillometry, we show that arousal and locus coeruleus (LC) activation transform otherwise continuous experiences into distinct episodic memories. As sequences unfold, encountering a context shift, or event boundary, triggers arousal and LC processes that predict later memory separation. Boundaries furthermore promote temporal pattern separation within left hippocampal dentate gyrus, which correlates with heightened LC responses to those same transition points. We also find that a neurochemical index of prolonged LC activation correlates with diminished arousal responses at boundaries, suggesting a connection between elevated LC output and impaired event processing. These findings align with the idea that arousal processes initiate a neural and memory reset in response to significant changes, constructing the very episodes that define everyday memory.

Task-related activity in auditory cortex enhances sound representation
In auditory-guided tasks, sound presentations often occupy a small fraction of the total task time. We studied here neuronal dynamics that spanned trial duration. Many neurons had large, slow, firing rate modulations, which were not driven by sounds, were larger than the sound evoked responses, and were locked to specific time points during the task, similar to responses of hippocampal time-sensitive neurons. Concurrently, responses to sounds differed between active behavior and passive listening conditions: in the active sessions, the on-going activity just before sound presentations was higher and the responses to target stimuli were weaker but more informative about the task-relevant sounds. We show that the slow firing rate modulations caused the increased on-going activity. Using a model, we demonstrate that higher on-going activity led to more synaptic depression of the cortico-cortical synapses, reducing the tendency to produce population spikes and resulting in weaker but more informative responses.

Characterization of direct Purkinje cell outputs to the brainstem
Purkinje cells (PCs) primarily project to cerebellar nuclei but also directly innervate the brainstem. Some PC-brainstem projections have been described previously, but most have not been thoroughly characterized. Here we use a PC-specific cre line to anatomically and electrophysiologically characterize PC projections to the brainstem. PC synapses are surprisingly widespread, with the highest densities found in the vestibular and parabrachial nuclei. However, there are pronounced regional differences in synaptic densities within both the vestibular and parabrachial nuclei. Large optogenetically-evoked PC-IPSCs are preferentially observed in subregions with the highest densities of PC synapses, suggesting that PCs selectively influence these areas and the behaviors they regulate. Unexpectedly, the pontine central gray and nearby subnuclei also contained a low density of PC synapses, and large PC-IPSCs are observed in a small fraction of cells. We combined electrophysiological recordings with immunohistochemistry to assess the molecular identities of these PC targets. PC synapses onto mesencephalic trigeminal neurons were not observed even though these cells are in close proximity to PC boutons. PC synapses onto locus coeruleus neurons are exceedingly rare or absent, even though previous studies concluded that PCs are a major input to these neurons. The availability of a highly selective cre line for PCs allowed us to study functional synapses, while avoiding complications that can accompany the use of viral approaches. We conclude that PCs directly innervate numerous brainstem nuclei, but only inhibit a small fraction of cells in many nuclei. This suggests that PCs target cell types with specific behavioral roles in brainstem regions.

Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors
De novo mutations in transcriptional regulators are emerging as key risk factors contributing to the etiology of neurodevelopmental disorders. Human genetic studies have recently identified ZMIZ1 and its de novo mutations as causal of a neurodevelopmental syndrome strongly associated with intellectual disability, autism, ADHD, microcephaly, and other developmental anomalies. However, the role of ZMIZ in brain development or how ZMIZ1 mutations cause neurological phenotypes is unknown. Here, we generated a forebrain-specific Zmiz1 mutant mouse model that develops brain abnormalities, including cortical microcephaly, corpus callosum dysgenesis, and abnormal differentiation of upper-layer cortical neurons. Behaviorally, Zmiz1 mutant mice show alterations in motor activity, anxiety, communication, and social interactions with strong sex differences, resembling phenotypes associated with autism. Molecularly, Zmiz1 deficiency leads to transcriptomic changes disrupting neurogenesis, neuron differentiation programs, and synaptic signaling. We identified Zmiz1-mediated downstream regulation of key neurodevelopmental factors, including Lhx2, Auts2, and EfnB2. Importantly, reactivation of the EfnB2 pathway by exogenous EFNB2 recombinant protein rescues the dendritic outgrowth deficits in Zmiz1 mutant cortical neurons. Overall, our in vivo findings provide insight into Zmiz1 function in cortical development and reveal mechanistic underpinnings of ZMIZ1 syndrome, thereby providing valuable information relevant to future studies on this neurodevelopmental disorder.

Cell type and locus-specific epigenetic editing of memory expression
Epigenetic modifications parallel multiple memory processes, but evidence that the epigenetic makeup of a single site can guide learnt behaviors has so far been lacking. Here, we developed CRISPR-based epigenetic editing tools to address this question in a cell type-specific, locus-restricted and temporally controllable manner in the adult mouse brain. Focusing on learning-induced neuronal populations, we provide a proof-of-principle that site-specific epigenetic dynamics are causally implicated in memory expression.

An instantaneous voice synthesis neuroprosthesis
Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one's own voice. Here, we demonstrate a "brain-to-voice" neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.

LncRNA 3222401L13Rik Is Up-regulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3
Aging is linked to a decline in cognitive functions and significantly increases the risk of neurodegenerative diseases. While molecular changes in all central nervous system (CNS) cell types contribute to aging-related cognitive decline, the mechanisms driving disease development or offering protection remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular functions and gene expression, yet their roles in aging, particularly within glial cells, are not well characterized. In this study, we investigated lncRNA expression profiles in non-neuronal cells from aged mice. We identified 3222401L13Rik, a previously unstudied lncRNA enriched in glial cells, as being specifically upregulated in astrocytes during aging. Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes essential for neuronal support and synapse organization. This function was also conserved in human iPSC-derived astrocytes. Additionally, we found that 3222401L13Rik mediates its cellular effects through interaction with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and that overexpression of Npas3 effectively rescued the functional deficits observed in astrocytes lacking 3222401L13Rik. Our findings suggest that upregulation of 3222401L13Rik in aging astrocytes acts as a compensatory mechanism to enhance neuronal and synaptic support, potentially delaying the onset of molecular and structural changes in both astrocytes and neurons. Strategies to boost 3222401L13Rik expression earlier in life may help mitigate age-associated loss of neuronal plasticity.

Seeing the Future: Anticipatory Eye Gaze as a Marker of Memory
Human memory is typically studied by direct questioning, and the recollection of events is investigated through verbal reports. Thus, current research confounds memory per-se with its report. Critically, the ability to investigate memory retrieval in populations with deficient verbal ability is limited. Here, using the MEGA (Memory Episode Gaze Anticipation) paradigm, we show that monitoring anticipatory gaze using eye tracking can quantify memory retrieval without verbal report. Upon repeated viewing of movie clips, eye gaze patterns anticipating salient events can quantify their memory traces seconds before these events appear on the screen. A series of experiments with a total of 126 participants using either tailor-made animations or naturalistic movies consistently reveal that accumulated gaze proximity to the event can index memory. Machine learning-based classification can identify whether a given viewing is associated with memory for the event based on single-trial data of gaze features. Detailed comparison to verbal reports establishes that anticipatory gaze marks recollection of associative memory about the event, whereas pupil dilation captures familiarity. Finally, anticipatory gaze reveals beneficial effects of sleep on memory retrieval without verbal report, illustrating its broad applicability across cognitive research and clinical domains.

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation
The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of -synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits -synuclein clearance and facilitates -synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical -synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein -syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of -synuclein from intersititial to cerebrospinal fluid. Using a mouse model of -synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased -synuclein aggregates. Our results indicate -synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinson's disease.

Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice
Stroke is a leading cause of long-term disability, often characterized by compromised motor function. Gamma band is known to be related to Parvalbumin interneurons (PV-IN) synchronous discharge and it has been found to be affected after stroke in humans and animals. Both Gamma band and PV-IN also play a key role in motor function, thus representing a promising target for post-stroke neurorehabilitation. Non-Invasive neuromodulatory approaches are considered a safe intervention and can be used for this purpose. This study presents a novel, clinically relevant, non-invasive and well-tolerated sub-acute treatment combining robotic rehabilitation with advanced neuromodulation techniques, validated in a mouse model of ischemic injury. In the sub-acute phase after stroke, we scored profound deficits in motor-related Gamma band regulation on the perilesional cortex. Accordingly, both at the perilesional and at the whole-cortex levels, the damage results in impaired PV-IN activity, with reduced firing rate and increased functional connectivity levels. Therefore, we tested the therapeutic potential of coupling robotic rehabilitation with optogenetic PV-driven Gamma band stimulation in a subacute post-stroke phase during motor training to reinforce the efficacy of the treatment. Frequency-specific movement-related Gamma band stimulation, when combined with physical training, significantly improved forelimb motor function. More importantly, by pairing robotic rehabilitation with a clinical-like non-invasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements mediated by the effective restoring of movement-related Gamma band power and increased PV-IN connections in premotor cortex. Our research introduces a new understanding of the role of parvalbumin-interneurons in post-stroke impairment and recovery. These results highlight the synergistic potential of combining perilesional Gamma band stimulation with robotic rehabilitation as a promising and realistic therapeutic approach for stroke patients.

Boundary conditions for synaptic homeodynamics during the sleep-wake cycle
Understanding synaptic dynamics during the sleep-wake cycle is crucial yet controversial. While some studies report synaptic depression during non-rapid eye movement (NREM) sleep, others observe synaptic potentiation. To find boundary conditions between these contradictory observations, we focused on learning rules and firing patterns that contribute to the synaptic dynamics. Using computational models, we found that under Hebbian and spike-timing dependent plasticity (STDP), wake-like firing patterns decrease synaptic weights, while sleep-like patterns strengthen synaptic weights. Conversely, under Anti-Hebbian and Anti-STDP, synaptic depression during NREM sleep was observed, aligning with the conventional synaptic homeostasis hypothesis. Moreover, synaptic changes depended on firing rate differences between NREM sleep and wakefulness. We provide a unified framework that could explain synaptic homeodynamics under the sleep-wake cycle.

Bidirectional Optogenetic Modulations of Peripheral Sensory Nerve Activity: Induction vs. Suppression through Channelrhodopsin and Halorhodopsin
In this study, we investigated the potential of optogenetics for modulating activity of peripheral sensory nerves, particularly tactile and proprioceptive afferents, which are vital for movement control. Using adeno-associated virus serotype 9 vector, we selectively transduced channelrhodopsin (ChR2) and halorhodopsin (eNpHR3.0) into large-diameter sciatic nerve afferents of rats. Diverging from conventional dorsal root ganglion (DRG) approaches, we applied optical stimulation at the distal portion of the afferent nerve. The intensity of optical stimulation varied to modulate the extent of induction and suppression of afferent activity. Then, the effect of optical stimulation was determined by the activity recorded in the dorsal root of the same afferents. Our findings show successful induction and suppression of activity in large-diameter afferents via optical stimulation. By increasing the intensity of blue (for ChR2) and yellow (for eNpHR3.0) light stimulation, the activity of fast-conducting afferent fibers was preferentially evoked or inhibited in an intensity-dependent manner. These data indicate that the activity of large-diameter afferents can systematically be regulated by optogenetics. The present innovative methodology for manipulating specific sensory modalities at the nerve level offers a targeted and accessible alternative to DRG stimulation, expanding the therapeutic scope of optogenetics for treating sensory disorders.

Low-level features predict perceived similarity for naturalistic images
The mechanisms by which humans perceptually organise individual regions of a visual scene to generate a coherent scene representation remain largely unknown. Our perception of statistical regularities has been relatively well-studied in simple stimuli, and explicit computational mechanisms that use low-level image features (e.g., luminance, contrast energy) to explain these perceptions have been described. Here, we investigate to what extent observers can effectively use such low-level information present in isolated naturalistic scene regions to facilitate associations between said regions. Across two experiments, participants were shown an isolated standard patch, then required to select which of two subsequently presented patches came from the same scene as the standard (2AFC). In Experiment 1, participants were consistently above chance when performing such association judgements. Additionally, participants' responses were well-predicted by a generalised linear multilevel model (GLMM) employing predictors based on low-level feature similarity metrics (specifically, pixel-wise luminance and phase-invariant structure correlations). In Experiment 2, participants were presented with thresholded image regions, or regions reduced to only their edge content. Their performance was significantly poorer when they viewed unaltered image regions. Nonetheless, the model still correlated well with participants' judgments. Our findings suggest that image region associations can be reduced to low-level feature correlations, providing evidence for the contribution of such basic features to judgements made on complex visual stimuli.

Sex differences in nucleus accumbens core circuitry engaged by binge-like ethanol drinking
Growing parity in Alcohol Use Disorder (AUD) diagnoses in men and women necessitates consideration of sex as a biological variable. In humans and rodents, the nucleus accumbens core (NAcc) regulates alcohol binge drinking, a risk factor for developing AUD. We labeled NAcc inputs with a viral retrograde tracer and quantified whole-brain c-Fos to determine the regions and NAcc inputs differentially engaged in male and female mice during binge-like ethanol drinking. We found that binge-like ethanol drinking females had 129 brain areas with greater c-Fos than males. Moreover, ethanol engaged more NAcc inputs in binge-like ethanol drinking females (as compared with males), including GABAergic and glutamatergic inputs. Relative to water controls, ethanol increased network modularity and decreased connectivity in both sexes and did so more dramatically in males. These results demonstrate that early-stage binge-like ethanol drinking engages brain regions and NAcc-inputs and alters network dynamics in a sex-specific manner.

More similarity than difference: comparison of within- and between-sex variance in early adolescent brain structure
Adolescent neuroimaging studies of sex differences in the human brain predominantly examine mean differences between males and females. This focus on between-groups differences without probing relative distributions and similarities may contribute to both conflation and overestimation of sex differences and sexual dimorphism in the developing human brain. We aimed to characterize the variance in brain macro- and micro-structure in early adolescence as it pertains to sex at birth using a large sample of 9-11 year-olds from the Adolescent Brain Cognitive Development (ABCD) Study (N=7,723). Specifically, for global and regional estimates of gray and white matter volume, cortical thickness, and white matter microstructure (i.e., fractional anisotropy and mean diffusivity), we examined: within- and between-sex variance, overlap between male and female distributions, inhomogeneity of variance via the Fligner-Killeen test, and an analysis of similarities (ANOSIM). For completeness, we examined these sex differences using both uncorrected (raw) brain estimates and residualized brain estimates after using mixed-effects modeling to account for age, pubertal development, socioeconomic status, race, ethnicity, MRI scanner manufacturer, and total brain volume, where applicable. The overlap between male and female distributions was universally greater than the difference (overlap coefficient range: 0.585 - 0.985) and the ratio of within-sex and between-sex differences was similar (ANOSIM R range: -0.001 - 0.117). All cortical and subcortical volumes showed significant inhomogeneity of variance, whereas a minority of brain regions showed significant sex differences in variance for cortical thickness, white matter volume, fractional anisotropy, and mean diffusivity. Inhomogeneity of variance was reduced after accounting for other sources of variance. Overlap coefficients were larger and ANOSIM R values were smaller for residualized outcomes, indicating greater within- and smaller between-sex differences once accounting for other covariates. Reported sex differences in early adolescent human brain structure may be driven by disparities in variance, rather than binary, sex-based phenotypes. Contrary to the popular view of the brain as sexually dimorphic, we found more similarity than difference between sexes in all global and regional measurements of brain structure examined. This study builds upon previous findings illustrating the importance of considering variance when examining sex differences in brain structure.

Comparison of test-retest reproducibility of DESPOT and 3D-QALAS for water T1 and T2 mapping
Purpose: Relaxometry, specifically T1 and T2 mapping, has become an essential technique for assessing the properties of biological tissues related to various physiological and pathological conditions. Many techniques are being used to estimate T1 and T2 relaxation times, ranging from the traditional inversion or saturation recovery and spin echo sequences to more advanced methods. Choosing the appropriate method for a specific application is critical since the precision and accuracy of T1 and T2 measurements are influenced by a variety of factors including the pulse sequence and its parameters, the inherent properties of the tissue being examined, the MRI hardware, and the image reconstruction. The aim of this study is to evaluate and compare the test retest reproducibility of two advanced MRI relaxometry techniques (Driven Equilibrium Single Pulse Observation of T1 and T2, DESPOT, and 3D Quantification using an interleaved Look Locker acquisition Sequence with a T2 preparation pulse, QALAS), for T1 and T2 mapping in a healthy volunteer cohort. Methods: 10 healthy volunteers underwent brain MRI at 1.3 mm3 isotropic resolution, acquiring DESPOT and QALAS data (about 11.8 and about 5 minutes duration, including field maps, respectively), test retest with subject repositioning, on a 3.0 Tesla Philips Ingenia Elition scanner. To reconstruct the T1 and T2 maps, we used an equation based algorithm for DESPOT and a dictionary based algorithm that incorporates inversion efficiency and B1 field inhomogeneity for QALAS. The test retest reproducibility was assessed using the coefficient of variation (CoV), intraclass correlation coefficient (ICC) and Bland Altman plots. Results: Our results indicate that both the DESPOT and QALAS techniques demonstrate good levels of test retest reproducibility for T1 and T2 mapping across the brain. Higher whole brain voxel to voxel ICCs are observed in QALAS for T1 (0.84) and in DESPOT for T2 (0.897). The Bland Altman plots show smaller bias and variability of T1 estimates for QALAS (mean of negative 0.02 s, and upper and lower limits of negative 0.14 and 0.11 s, 95% CI) than for DESPOT (mean of negative 0.02 s, and limits of negative 0.31 and 0.27 s). QALAS also showed less variability (mean 1.08 ms, limits negative 1.88 to 4.04 ms) for T2 compared to DESPOT (mean of 2.56 ms, and limits negative 17.29 to 22.41 ms). The within subject CoVs for QALAS range from 0.6% (T2 in CSF) to 5.8% (T2 in GM), while for DESPOT they range from 2.1% (T2 in CSF) to 6.7% (T2 in GM). The between subject CoVs for QALAS range from 2.5% (T2 in GM) to 12% (T2 in CSF), and for DESPOT they range from 3.7% (T2 in WM) to 9.3% (T2 in CSF). Conclusion: Overall, QALAS demonstrated better reproducibility for T1 and T2 measurements than DESPOT, in addition to reduced acquisition time.

Personalized whole-brain activity patterns predict human corticospinal tract activation in real-time
BACKGROUND: Transcranial magnetic stimulation (TMS) interventions could feasibly treat stroke-related motor impairments, but their effects are highly variable. Brain state-dependent TMS approaches are a promising solution to this problem, but inter-individual variation in lesion location and oscillatory dynamics can make translating them to the poststroke brain challenging. Personalized brain state-dependent approaches specifically designed to address these challenges are therefore needed. METHODS: As a first step towards this goal, we tested a novel machine learning-based EEG-TMS system that identifies personalized brain activity patterns reflecting strong and weak corticospinal tract (CST) output (strong and weak CST states) in healthy adults in real-time. Participants completed a single-session study that included the acquisition of a TMS-EEG-EMG training dataset, personalized classifier training, and real-time EEG-informed single pulse TMS during classifier-predicted personalized CST states. RESULTS: MEP amplitudes elicited in real-time during personalized strong CST states were significantly larger than those elicited during personalized weak and random CST states. MEP amplitudes elicited in real-time during personalized strong CST states were also significantly less variable than those elicited during personalized weak CST states. Personalized CST states lasted for ~1-2 seconds at a time and ~1 second elapsed between consecutive similar states. Individual participants exhibited unique differences in spectro-spatial EEG patterns between personalized strong and weak CST states. CONCLUSION: Our results show for the first time that personalized whole-brain EEG activity patterns predict CST activation in real-time in healthy humans. These findings represent a pivotal step towards using personalized brain state-dependent TMS interventions to promote poststroke CST function.

Population Representation of the Confidence in a Decision in the Lateral Intraparietal Area of the Macaque
Confidence in a decision is the belief, prior to feedback, that one's choice is correct. In the brain, many decisions are implemented as a race between competing evidence-accumulation processes. We ask whether the neurons that represent evidence accumulation also carry information about whether the choice is correct (i.e., confidence). Monkeys performed a reaction time version of the random dot motion task. Neuropixels probes were used to record from neurons in the lateral intraparietal (LIP) area. LIP neurons with response fields that overlap the choice-target contralateral to the recording site (Tin neurons) represent the accumulation of evidence in favor of contralateral target selection. We demonstrate that shortly before a contralateral choice is reported, the population of Tin neurons contains information about the accuracy of the choice (i.e., whether the choice is correct or incorrect). This finding is unexpected because, on average, Tin neurons exhibit a level of activity before the report that is independent of reaction time and evidence strength--both strong predictors of accuracy. This apparent contradiction is resolved by examining the variability in neuronal responses across the population of Tin neurons. While on average, Tin neurons exhibit a stereotyped level of activity before a contralateral choice, many neurons depart from this average in a consistent manner. From these neurons, the accuracy of the choice can be predicted using a simple logistic decoder. The accuracy of the choice predicted from neural activity reproduces the hallmarks of confidence identified in human behavioral experiments. Therefore, neurons that represent evidence accumulation can also inform the monkey's confidence.

Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration
The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naive, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.

Glucose uptake in pigment glia suppresses tau-induced inflammation and photoreceptor degeneration in Drosophila
Brain inflammation contributes to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human tau in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by inclusion formation and swelling of lamina glial cells. We found that inclusions are formed by glial phagocytosis, and swelling of the laminal cortex correlates with the expression of antimicrobial peptides (AMPs). Co-expression of human glucose transporter 3 (GLUT3) with tau in the retina does not affect tau levels but suppresses these inflammatory responses and photoreceptor degeneration. We also found that expression of GLUT3, specifically in the pigment glia, is sufficient to suppress inflammatory phenotypes and mitigate photoreceptor degeneration in the tau-expressing retina. Our results suggest that glial glucose metabolism contributes to inflammatory responses and neurodegeneration in tauopathy.

The Fragile X Messenger Ribonucleoprotein 1 regulates the morphology and maturation of human and rat oligodendrocytes
The Fragile X Messenger Ribonucleoprotein (FMRP) is an RNA binding protein that regulates the translation of multiple mRNAs and is expressed by neurons and glia in the mammalian brain. Loss of FMRP leads to Fragile X Syndrome (FXS), a common inherited form of intellectual disability and autism. While most research has been focusing on the neuronal contribution to FXS pathophysiology, the role of glia, particularly oligodendrocytes, is largely unknown. FXS individuals are characterised by white matter changes which imply impairments in oligodendrocyte differentiation and myelination. We hypothesized that FMRP regulates oligodendrocyte maturation and myelination during postnatal development. Using a combination of human pluripotent stem cell - derived oligodendrocytes and an Fmr1 knockout rat model, we studied the role of FMRP on mammalian oligodendrocyte development. We found that the loss of FMRP leads to shared defects in oligodendrocyte morphology in both rat and human systems in vitro which persist in the presence of FMRP expressing axons in chimeric engraftment models. Our findings point to species-conserved, cell-autonomous defects during oligodendrocyte maturation in FXS.

Ultraplex microscopy: versatile highly-multiplexed molecular labeling and imaging across scale and resolution
The molecular organization of cells and tissue is challenging to study due to the inefficiency of multiplexed molecular labeling methods and the limited options for combining microscopy modalities in a single specimen, especially when high spatial resolution is needed. Here we describe ultraplex microscopy, which combines serial multiplexing, ultrathin sectioning, and reversible embedding to circumvent incompatibilities between labeling and imaging techniques, enhance resolution, and expand multiplexing capacity within and across modalities. Samples can be labeled with antibodies, RNA probes, and tissue stains for imaging by brightfield, epifluorescence, super-resolution, and electron microscopy without specialized reagents or materials. We demonstrate applications in brain tissue including molecular profiling of single cells and axonal boutons, high-resolution molecular colocalization, and correlative imaging of fluorescent proteins with confocal and ultraplex microscopy. The power and versatility of ultraplex microscopy will be valuable in addressing currently intractable experimental questions in many systems and contexts.

MiniXL: An open-source, large field-of-view epifluorescence miniature microscope for mice capable of single-cell resolution and multi-brain region imaging
Capturing the intricate dynamics of neural activity in freely behaving animals is essential for understanding the neural mechanisms underpinning specific behaviors. Miniaturized microscopy enables investigators to track population activity at cellular level, but the field of view (FOV) of these microscopes have been limited and does not allow multiple-brain region imaging. To fill this technological gap, we have developed the eXtra Large field-of-view Miniscope (MiniXL), a 3.5g lightweight miniaturized microscope with an FOV measuring 3.5 mm in diameter and an electrically adjustable working distance of 1.9 mm +/- 0.2 mm. We demonstrated the capability of MiniXL recording the activity of large neuronal population in both subcortical area (hippocampal dorsal CA1) and deep brain regions (medial prefrontal cortex, mPFC and nucleus accumbens, NAc). The large FOV allows simultaneous imaging of multiple brain regions such as bilateral mPFCs or mPFC and NAc during complex social behavior and tracking cells across multiple sessions. As with all microscopes in the UCLA Miniscope ecosystem, the MiniXL is fully open-source and will be shared with the neuroscience community to lower the barriers for adoption of this technology.

Target interception in virtual reality is better for natural versus unnatural trajectory shapes and orientations
Human performance in perceptual and visuomotor tasks is enhanced when stimulus motion follows the laws of gravitational physics, including acceleration consistent with Earth's gravity, g. Here we used a manual interception task in virtual reality to investigate the effects of trajectory shape and orientation on interception timing and accuracy. Participants punched to intercept a ball moving along one of four trajectories that varied in shape (parabola or tent) and orientation (upright or inverted). We also varied the location of visual fixation such that trajectories fell entirely within the lower or upper visual field. Reaction times were faster for more natural shapes and orientations, regardless of visual field. Overall accuracy was poorer and movement time was longer for the inverted tent condition than the other three conditions, perhaps because it was imperfectly reminiscent of a bouncing ball. A detailed analysis of spatial errors revealed that interception endpoints were more likely to fall along the path of the final trajectory in upright vs. inverted conditions, suggesting stronger expectations regarding the final trajectory direction for these conditions. Taken together, these results suggest that the naturalness of the shape and orientation of a trajectory contributes to performance in a virtual interception task.

Novel Mouse Model of Alternating Hemiplegia of Childhood Exhibits Prominent Motor and Seizure Phenotypes
Pathogenic variants in ATP1A3 encoding the neuronal Na/K-ATPase cause a spectrum of neurodevelopmental disorders including alternating hemiplegia of childhood (AHC). Three recurrent ATP1A3 variants are associated with approximately half of known AHC cases and mouse models of two of these variants (p.D801N, p.E815K) replicated key features of the human disorder, which include paroxysmal hemiplegia, dystonia and seizures. Epilepsy occurs in 40-50% of individuals affected with AHC, but detailed investigations of seizure phenotypes were limited in the previously reported mouse models. Using gene editing, we generated a novel AHC mouse expressing the third most recurrent ATP1A3 variant (p.G947R) to model neurological phenotypes of the disorder. Heterozygous Atp1a3-G947R mice on a pure C57BL/6J background were born at a significantly lower frequency than wildtype (WT) littermates, but in vitro fertilization or outcrossing to a different strain (C3HeB/FeJ) generated offspring at near-Mendelian genotype ratios, suggesting a defect in reproductive fitness rather than embryonic lethality. Heterozygous mutant mice were noticeably smaller and exhibited premature lethality, hyperactivity, anxiety-like behaviors, severe motor dysfunction including low grip strength, impaired coordination with abnormal gait and balance, and cooling-induced hemiplegia and dystonia. We also observed a prominent seizure phenotype with lower thresholds to chemically (flurothyl, kainic acid) and electrically induced seizures, post-handling seizures, sudden death following seizures, and abnormal EEG activity. Together, our findings support face validity of a novel AHC mouse model with quantifiable traits including co-morbid epilepsy that will be useful as an in vivo platform for investigating pathophysiology and testing new therapeutic strategies for this rare neurodevelopmental disorder.

Preparing to act follows Bayesian inference rules
Predictive brain theories suggest that human brain sets-up predictive models to anticipate incoming sensory evidence. Recent studies demonstrated these models to be integrated already in sensory areas, shaping even perceptual outcomes. Here, we hypothesized that this integration process informs the entire functional hierarchy, thus scaling all the way down to the motor system. Operationally, we propose that cue-oriented cortico-spinal excitability (CSE) modulation serves the pre-activation of motor representations aligned to prior-congruent decisions. To this end, 62 participants completed a probabilistic discrimination task while we delivered bilateral single-pulse TMS over the two primary motor cortices (M1s) and recorded motor-evoked potentials (MEPs) to assess motor excitability associated to prior-congruent vs. incongruent actions separately encoded by the two hands. Our findings revealed that prior expectations shaped CSE well before action execution, predominantly by inhibiting the M1 cortex coding for the prior-incongruent action. Importantly, this physiological modulation underpinned the prior-induced bias in participants choices, highlighting the link between motor preparatory modulation and actual decision-making. Furthermore, we observed significant interindividual variability in prior-driven CSE modulations, revealing two distinct predictive strategies: the believers style, who heavily rely on prior, and the empiricists one, who downplay its role, maintaining CSE level mostly unbiased. Crucially, autistic and schizotypal traits drove these differences in prior-driven motor strategy, with believers characterized by schizotypal traits, whereas empiricists displaying autistic-like features. These results demonstrate how predictive models are integrated into action representations and highlight the role of prior-driven CSE modulations as a potential marker able to intercept interindividual differences in predictive styles.

Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model
Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (A{beta}) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate A{beta} pathology in vivo is unclear. Methods: To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated A{beta} plaque load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to A{beta} pathology upon Asrij depletion. Results: Asrij depletion ameliorates cognitive impairments, A{beta} deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-{kappa}B activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. Conclusions: In summary, we show that Asrij depletion ameliorates A{beta} pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.

Perisaccadic perceptual mislocalization strength depends on the visual appearance of saccade targets
We normally perceive a stable visual environment despite repetitive eye movements. To achieve such stability, visual processing integrates information across saccades, and laboratory hallmarks of such integration are robustly observed by presenting brief perimovement visual probes. In one classic phenomenon, perceived probe locations are grossly erroneous. This phenomenon is believed to depend, at least in part, on corollary discharge associated with saccade-related neuronal movement commands. However, we recently found that superior colliculus motor bursts, a known source of corollary discharge, can be different for different image appearances of the saccade target. Therefore, here we investigated whether perisaccadic perceptual mislocalization also depends on saccade-target appearance. We asked human participants to generate saccades to either low (0.5 cycles/deg) or high (5 cycles/deg) spatial frequency gratings. We always placed a high contrast target spot at grating center, to ensure matched saccades across image types. We presented brief perisaccadic probes, which were high in contrast to avoid saccadic suppression, and the subjects pointed (via mouse cursor) at their perceived locations. We observed stronger perisaccadic mislocalization for low spatial frequency saccade targets, and for upper visual field probe locations. This was despite matched saccade metrics and kinematics across conditions, and it was also despite matched probe visibility for the different saccade target images (low versus high spatial frequency gratings). To the extent that perisaccadic perceptual mislocalization depends on corollary discharge, our results suggest that such discharge might relay more than just spatial saccade vectors to the visual system; saccade-target visual features can also be transmitted.

Stabilizing microtubules aids neurite structure and disrupts syncytia formation in human cytomegalovirus-infected human forebrain neurons
Human cytomegalovirus (HCMV) is a prolific human herpesvirus that infects most individuals by adulthood. While typically asymptomatic in adults, congenital infection can induce serious neurological symptoms including hearing loss, visual deficits, cognitive impairment, and microcephaly in 10-15% of cases. HCMV has been shown to infect most neural cells with our group recently demonstrating this capacity in stem cell-derived forebrain neurons. Infection of neurons induces deleterious effects on calcium dynamics and electrophysiological function paired with gross restructuring of neuronal morphology. Here, we utilize an iPSC-derived model of the human forebrain to demonstrate how HCMV infection induces syncytia, drives neurite retraction, and remodels microtubule networks to promote viral production and release. We establish that HCMV downregulates microtubule associated proteins at 14 days postinfection while simultaneously sparing other cytoskeletal elements, and this includes HCMV-driven alterations to microtubule stability. Further, we pharmacologically modulate microtubule dynamics using paclitaxel (stabilize) and colchicine (destabilize) to examine the effects on neurite structure, syncytial morphology, assembly compartment formation, and viral release. With paclitaxel, we found improvement of neurite outgrowth with a corresponding disruption to HCMV-induced syncytia formation and Golgi network disruptions but with limited impact on viral titers. Together, these data suggest that HCMV infection-induced disruption of microtubules in human cortical neurons can be partially mitigated with microtubule stabilization, suggesting a potential avenue for future neuroprotective therapeutic exploration.

Neural mechanisms of awareness of action
The origins of awareness of action (AoA), the ability to report an action just performed, remain elusive. Differing theories ascribe AoA to pre-action, efferent motor/volitional mechanisms versus post-action, afferent sensory/perceptual neural mechanisms. To study these two types of mechanisms and others, we developed a paradigm where very similar aware and unaware actions occur repeatedly. Aware actions demonstrated larger neurophysiological signals both preceding and following movement. The differences included well-known volitional and perceptual event related potentials (PMP, N140, P300), as well as frontal midline theta, event-related alpha/beta desynchronization, and post-move blink rates. On longer time scales, we identified a novel event related potential preceding unaware moves, and found behavioral and pupillometric evidence for decreased attention and arousal over minutes concurrent with AoA loss. Our findings suggest that both dynamic, individual action-associated volitional and perceptual neural activity, as well as long-term attention and arousal states play a role in maintaining AoA.

Acute systemic macrophage depletion in osteoarthritic mice alleviates pain-related behaviors and does not affect joint damage
Background: Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes. Methods: We depleted CSF1R+ macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8- or 16-weeks post destabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kg i.p., 1x/day for 5 days), or treating female MaFIA mice 12 weeks post partial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1-3 days before and after depletion, and, 3-4 days after the last injection we examined joint histopathology and performed flow cytometry of the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naive vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment. Results: Eight- and 16-weeks post DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weeks post PMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII+ M1-like macrophages were significantly decreased, while CD163+MHCII- M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naive mice, and downregulated in DMM after acute macrophage depletion. Conclusions: Acute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insight into immune cell regulation in the DRG during OA.

Sapphire-Based Optrode for Low Noise Neural Recording and Optogenetic Manipulation
Electrophysiological recordings of neurons in deep brain regions using optogenetic stimulation are essential to understanding and regulating the role of complex neural activity in biological behavior and cognitive function. Optogenetic techniques have significantly advanced neuroscience research by enabling the optical manipulation of neural activities. Because of the significance of the technique, constant advancements in implantable optrodes that integrate optical stimulation with low-noise, large-scale electrophysiological recording are in demand to improve the spatiotemporal resolution for various experimental designs and future clinical applications. However, robust and easy-to-use neural optrodes that integrate neural recording arrays with high-intensity light emitting diodes (LEDs) are still lacking. Here, we propose a neural optrode based on Gallium Nitride (GaN) on sapphire technology, which integrates a high-intensity blue LED with a 5x2 recording array monolithically for simultaneous neural recording and optogenetic manipulation. To reduce the noise interference between the recording electrodes and the LED, which is in close physical proximity, three metal grounding interlayers were incorporated within the optrode, and their ability to reduce LED-induced artifacts during neural recording was confirmed through both electromagnetic simulations and experimental demonstrations. The capability of the sapphire optrode to record action potentials has been demonstrated by recording the firing of mitral/tuft cells in the olfactory bulbs of mice in vivo. Additionally, the elevation of action potential firing due to optogenetic stimulation observed using the sapphire probe in medial superior olive (MSO) neurons of the gerbil auditory brainstem confirms the capability of this sapphire optrode to precisely access neural activities in deep brain regions under complex experimental designs.

Moderate prenatal alcohol exposure alters GABAergic transmission and the action of acute alcohol in the CeM of adolescent rats
Individuals with prenatal alcohol exposure (PAE) are at a higher risk for developing alcohol use disorder (AUD). Using a rat model of PAE on gestational day 12 (G12; 2nd trimesters in humans), a critical period for amygdala development, we have shown disruptions in medial central amygdala (CeM) function, an important brain region associated with the development of AUD. In addition to this, acute ethanol (EtOH) increases GABA transmission in the CeM of rodents in a sex-dependent manner, a mechanism that potentially contributes to alcohol misuse. How PAE alters the effects of acute alcohol within the CeM is unknown. Given these findings, we investigated how PAE may interact with acute alcohol to alter neuronal and synaptic mechanisms in the CeM of adolescent rats in order to understand PAE-induced alcohol-related behaviors. Under basal conditions, PAE males showed reduced rheobase, indicative of reduced excitability, and females showed a reduction in GABA transmission, indicated by lower spontaneous inhibitory postsynaptic currents (sIPSCs). We found that acute EtOH increased sIPSCs in control males at a moderate concentration (66 mM), while PAE males showed increased sIPSCs only at a high concentration (88 mM). Adolescent females, regardless of PAE status, were largely insensitive to the effects of EtOH at all tested concentrations. However, PAE females showed a significant increase in sIPSCs at the highest concentration (88 mM). Overall, these findings support the hypothesis that PAE leads to sex-specific changes in synaptic activity and neuronal function. Future research is needed to better understand the specific mechanisms by which acute EtOH affects neurotransmission in the adolescent brain of individuals with a history of PAE.

Metabolic connectivity has greater predictive utility for age and cognition than functional connectivity.
Recently developed high temporal resolution functional [18F]-fluorodeoxyglucose positron emission tomography (fPET) offers promise as a method for indexing the dynamic metabolic state of the brain in vivo by directly measuring a timeseries of metabolism at the post-synaptic neuron. This is distinct from functional magnetic resonance imaging (fMRI) that reflects a combination of metabolic, haemodynamic and vascular components of neuronal activity. The value of using fPET to understand healthy brain ageing and cognition over fMRI is currently unclear. Here we use simultaneous fPET/fMRI to compare metabolic and functional connectivity and test their predictive ability for ageing and cognition. Whole-brain fPET connectomes showed moderate topological similarities to fMRI connectomes in 40 younger (mean age 27.9 years; range 20-42) and 46 older (mean 75.8; 60-89) adults. There were more age-related within- and between-network connectivity and graph metric differences in fPET than fMRI. fPET was also associated with performance in more cognitive domains than fMRI. These results suggest that ageing is associated with a reconfiguration of metabolic connectivity that differs from haemodynamic alterations. We conclude that metabolic connectivity has greater predictive utility for age and cognition than functional connectivity and that measuring glucodynamic changes has promise as a biomarker for age-related cognitive decline.

Selective inhibition in CA3: A mechanism for stable pattern completion through heterosynaptic plasticity
Engrams compete for successful retrieval in the CA3 of the hippocampus, but the detailed mechanisms of their formation remain elusive. Recent research reveals that hippocampal inhibitory neurons respond selectively to stimuli and exhibit diverse plasticity, implying their significance in engram formation. Conventional attractor network models for CA3 commonly employ global inhibition where inhibitory neurons uniformly reduce the activation of excitatory neurons. However, these models may not fully capture the diverse competition conditions arising from sparse distributed coding and not accurately reflect the specific roles of inhibitory neurons in engram competition. We propose an engram formation mechanism in CA3, highlighting the critical role of the association between excitatory and inhibitory neurons through heterosynaptic plasticity. In the proposed model, an inhibitory neuron is associated with specific neural assemblies and it selectively inhibits the excitatory neurons for retrieval that belong to competing assemblies. With a simplified dentate gyrus (DG) in a feed-forward structure, this proposed mechanism results in sparsely distributed engrams in CA3. The sparse distributed coding implemented in the model allows us to investigate the effects of selective inhibition on pattern completion under various configurations, such as partially overlapping competing engrams. Our results show that selective inhibition leads to more stable and improved retrieval performance than global inhibition alone. We observed the neural activities of the hippocampal subregions in the model for pattern separation and pattern completion, aligning with experimental findings on their respective roles.

Measuring the effects of age on contrast suppression
The apparent contrast of a suprathreshold central stimulus can be reduced by a surrounding stimulus - a phenomenon known as surround suppression. When stimuli are presented at the fovea, this effect reportedly increases in strength with age. The underlying mechanism proposed for this age dependence, a change in the balance of inhibition and excitation in cortex, makes this phenomenon potentially interesting as a biomarker of neurological dysfunction. Here, we attempt to repeat these measurements, but we use stimuli designed to control for untuned overlay masking, a different form of suppression thought to be of pre-cortical origin. We measured contrast matching thresholds in twenty younger (< 30) and seventeen older (>60) observers. Across all observers, we find weak suppression that has little or no orientation tuning and, importantly, no dependence on age. Our findings contradict those from earlier studies and suggest that effects relating to age may be dependent on the temporal parameters of this stimulus, and could arise from effects on other pre-cortical mechanisms.

BundleAGE: Predicting White Matter Age using Along-Tract Microstructural Profiles from Diffusion MRI
Brain Age Gap Estimation (BrainAGE) is an estimate of the gap between a person's chronological age (CA) and a measure of their brain's 'biological age' (BA). This metric is often used as a marker of accelerated aging, albeit with some caveats. Age prediction models trained on brain structural and functional MRI have been employed to derive BrainAGE biomarkers, for predicting the risk of neurodegeneration. While voxel-based and along-tract microstructural maps from diffusion MRI have been used to study brain aging, no studies have evaluated along-tract microstructure for computing BrainAGE. In this study, we train machine learning models to predict a person's age using along-tract microstructural profiles from diffusion tensor imaging. We were able to demonstrate differential aging patterns across different white matter bundles and microstructural measures. The novel Bundle Age Gap Estimation (BundleAGE) biomarker shows potential in quantifying risk factors for neurodegenerative diseases and aging, while incorporating finer scale information throughout white matter bundles.

Circadian clock in the lateral habenula affects motor function in mice through the regulation of daily rhythms in the nigrostriatal pathway
Alterations to the dopaminergic system can have several consequences on behaviour such as the development of disorders like addiction, schizophrenia, and Parkinsons. The lateral habenula (LHb) is uniquely positioned to act on a large group of dopaminergic (DA) neurons, sending inhibitory signals both directly and indirectly to the ventral tegmental area (VTA) and the substantia nigra (SN). Additionally, the LHb houses a circadian clock that appears to function independently from the central circadian pacemaker. We investigated the role of the LHb as a pacemaker for the production and release of DA along the nigrostriatal pathway. Using male and female Bmal1 floxed mice, we injected AAV-2/9 Cre-eGFP virus into the LHb to selectively knockout Bmal1, a clock gene essential for clock functioning. We found a significant impact on motor functioning in both male and female knockout mice. Analysis of daily rhythms of expression of circadian clock genes and genes involved in DA synthesis, and liquid chromatography coupled mass spectrometry for striatal DA measurements revealed blunting of rhythms in the dorsal striatum (DS) and (SN) of knockout animals, that may contribute to the observed behavioural phenotype. As proper functioning of the striatum is likely maintained by a mutual interaction of the circadian clock and DAergic system, these findings support that disrupting the LHb clock can impact functioning of the nigrostriatal DA pathway.

FORCE trained spiking networks do not benefit from fasterlearning while parameter matched rate networks do
There are considerable difficulties in training spiking recurrent neural networks versus the standard recurrent neural networks (RNNs) that are more closely associated with neural firing rates. Here, we investigate where these difficulties arise by training networks of spiking neurons and their parameter matched instantaneous rate RNNs in supervised learning tasks. We FORCE trained leaky integrate-and-fire spiking and their parameter matched instantaneous rate-networks across different dynamical tasks with the FORCE hyperparameters also matched. We found that when the learning rate was slow, spiking and rate networks largely operated identically, with FORCE training discovering highly correlated solutions to the weight matrices, and similar hyperparameter areas of successful convergence. In fact, these weight matrix solutions were broadly interchangeable between networks, with learned spiking network weights able to lead to correct dynamical decoding in the rate network and vice-versa. However, when learning is too fast, the correlations between the learned solutions drop precipitously, and the solutions are no longer swappable between networks, with some supervisors having completely different optimal hyperparameter zones between rate and spiking networks. These networks also qualitatively behave in different ways across network sizes for different learning rates: faster learning leads to better performance in rate networks across network size, while leading to no tangible change across network size in spiking networks aside from network instability. Our results show that some of the difficulties that arise in training spiking neural networks are due to overly fast learning, which rate networks can tolerate, but matched spiking networks cannot.

Ultra-low-field brain MRI morphometry: test-retest reliability and correspondence to high-field MRI
Magnetic resonance imaging (MRI) enables non-invasive monitoring of healthy brain development and disease. Widely used higher field (>1.5 T) MRI systems are associated with high energy and infrastructure requirements, and high costs. Recent ultra-low-field (<0.1T) systems provide a more accessible and cost-effective alternative. However, it is not known whether anatomical ultra-low-field neuroimaging can be used to extract quantitative measures of brain morphometry, and to what extent such measures correspond to high-field MRI. Here we scanned 23 healthy adults aged 20-69 years on two identical 64 mT systems and a 3 T system, using T1w and T2w scans across a range of (64 mT) resolutions. We segmented brain images into 4 global tissue types and 98 local structures, and systematically evaluated between-scanner reliability of 64 mT morphometry and correspondence to 3 T measurements, using correlations of tissue volume and Dice spatial overlap of segmentations. We report high 64 mT reliability and correspondence to 3 T across 64 mT scan contrasts and resolutions, with highest performance shown by combining three T2w scans with low through-plane resolution into a single higher-resolution scan using multi-resolution registration. Larger structures show higher 64 mT reliability and correspondence to 3 T. Finally, we showcase the potential of ultra-low-field MRI for mapping neuroanatomical changes across the lifespan, and monitoring brain structures relevant to neurological disorders. Raw images and code are publicly available (upon publication), enabling systematic validation of pre-processing and analysis approaches for ultra-low-field neuroimaging.

An Infralimbic Cortex Neuronal Ensemble Encoded During Learning Attenuates Fear Generalization Expression
Generalization expands learned experiences to flexible guide behavior when conditions change. A basic physical unit of memory storage and expression in the brain are sparse, distributed groups of neurons known as ensembles (i.e., the engram). The infralimbic (IL) subregion of the ventral medial prefrontal cortex plays a key role in modulating conditioned defensive responses. How IL neuronal ensembles established during learning contribute to generalized responses is unknown. In this set of experiments, generalization was tested in male and female mice by presenting a novel, ambiguous, tone generalization stimulus following Pavlovian defensive (fear) conditioning. The first experiment was designed to test a role for IL in generalization using chemogenetic manipulations. Results show IL bidirectionally regulates defensive behavior. IL silencing promotes a switch in defensive state from vigilant scanning to generalized freezing, while IL stimulation reduced freezing in favor of scanning. Leveraging activity-dependent tagging technology (ArcCreERT2 x eYFP system), a neuronal ensemble, preferentially located in IL superficial layer 2/3, was associated with the generalization stimulus. Remarkably, in the identical discrete location, fewer reactivated neurons were associated with the generalization stimulus at the remote timepoint (30 days) following learning. When an IL neuronal ensemble established during learning was selectively chemogenetically silenced, generalization increased. Conversely, IL neuronal ensemble stimulation reduced generalization. Overall, these data identify a crucial role for IL in suppressing generalized responses. Further, we uncovered an IL neuronal ensemble, formed during learning, functions to later attenuate the expression of generalization in the presence of ambiguous threat stimuli.

Neuronal basis of audio-tactile speech perception
Since childhood, we experience speech as a combination of audio and visual signals, with visual cues particularly beneficial in difficult auditory conditions. This study investigates an alternative multisensory context of speech, and namely audio-tactile, which could prove beneficial for rehabilitation in the hearing impaired population. We show improved understanding of distorted speech in background noise, when combined with low-frequency speech-extracted vibrotactile stimulation delivered on fingertips. The quick effect might be related to the fact that both auditory and tactile signals contain the same type of information. Changes in functional connectivity due to audio-tactile speech training are primarily observed in the visual system, including early visual regions, lateral occipital cortex, middle temporal motion area, and the extrastriate body area. These effects, despite lack of visual input during the task, possibly reflect automatic involvement of areas supporting lip-reading and spatial aspects of language, such as gesture observation, in difficult acoustic conditions. For audio-tactile integration we show increased connectivity of a sensorimotor hub representing the entire body, with the parietal system of motor planning based on multisensory inputs, along with several visual areas. After training, the sensorimotor connectivity increases with high-order and language-related frontal and temporal regions. Overall, the results suggest that the new audio-tactile speech task activates regions that partially overlap with the established brain network for audio-visual speech processing. This further indicates that neuronal plasticity related to perceptual learning is first built upon an existing structural and functional blueprint for connectivity. Further effects reflect task-specific behaviour related to body and spatial perception, as well as tactile signal processing. Possibly, a longer training regime is required to strengthen direct pathways between the auditory and sensorimotor brain regions during audio-tactile speech processing.

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces
Background and Purpose: An association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and Methods: This analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3). Results: On average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a person's BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a person's average BMI was associated with a 0.021 mm3/cm3 increase in MV-PVS volume (p<0.001). Conclusion: This longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a person's mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

Prefrontal Excitation/ Inhibition Balance Supports Adolescent Enhancements in Circuit Signal to Noise Ratio
The development and refinement of neuronal circuitry allow for stabilized and efficient neural recruitment, supporting adult-like behavioral performance. During adolescence, the maturation of PFC is proposed to be a critical period (CP) for executive function, driven by a break in balance between glutamatergic excitation and GABAergic inhibition (E/I) neurotransmission. During CPs, cortical circuitry fine-tunes to improve information processing and reliable responses to stimuli, shifting from spontaneous to evoked activity, enhancing the SNR, and promoting neural synchronization. Harnessing 7T MR spectroscopy and EEG in a longitudinal cohort (N = 164, ages 10-32 years, 283 neuroimaging sessions), we outline associations between age-related changes in glutamate and GABA neurotransmitters and EEG measures of cortical SNR. We find developmental decreases in spontaneous activity and increases in cortical SNR during our auditory steady state task using 40 Hz stimuli. Decreases in spontaneous activity were associated with glutamate levels in DLPFC, while increases in cortical SNR were associated with more balanced Glu and GABA levels. These changes were associated with improvements in working memory performance. This study provides evidence of CP plasticity in the human PFC during adolescence, leading to stabilized circuitry that allows for the optimal recruitment and integration of multisensory input, resulting in improved executive function.

Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Anxiety disorders are accompanied by changes in brain plasticity, stress vulnerability and heightened risk of depression. Here, we found that serum LPA16:0 abundance increased with trait anxiety in both human and mice and was sufficient to reduce the proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor, LPA1, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreased hippocampal neurogenesis and stress resilience, whereas LPA1 antagonism or the reduction of platelets, the main source of circulating LPA16:0, increased adult neurogenesis and resilience to acute stress. Finally, the inhibition of adult neurogenesis abolished the beneficial effect of LPA1 antagonism on resilience against both acute and chronic stress. Together, these findings identify LPA16:0-LPA1 signaling as a regulation mechanism of adult neurogenesis and a potential therapeutic target for mood disorders.

Behavioral and Eye-Tracking Evidence for Disrupted Event Segmentation during Continuous Memory Encoding Due to Short Video Watching
The widespread use of short-video platforms (e.g., TikTok), with over one billion monthly active users worldwide in 2023, necessitates an examination of their effects on cognitive functions. We hypothesized that because of the frequent, user-driven shifts in content during short-video watching, it mainly impairs event segmentation, a critical cognitive process in continuous perception and memory formation. To investigate this, we integrated memory encoding-retrieval tasks, eye-tracking technology, self-report questionnaires, and advanced machine learning analyses of eye movements. Our experiments (Study1 N=113, Study2 N=60), which varied the types of videos (random vs. personalized) and memory stimuli (continuous movies vs. static images), demonstrated that watching randomly selected short videos, particularly when integrated into daily viewing patterns, detrimentally affects memory encoding, especially in the initial and middle phases of continuous memory encoding. However, this impairment was not evident in trial-based image encoding tasks, suggesting a selective disruption in continuous memory processes. Intersubject correlation (ISC) analysis of eye movements revealed decreased synchronization at event boundaries during movie watching after exposure to random short videos. Furthermore, Hidden Markov Model (HMM) analyses indicated that participants were more likely to experience fragmented event segmentation during continuous memory encoding following exposure to random short videos. These findings underscore the potentially harmful impact of short-video watching on event segmentation and memory formation, emphasizing the role of recommendation algorithms in modulating human cognition.

Characterization and analysis of neuronal signaling using microelectrode array combined with rapid and localized cooling device for cryo-neuromodulation
Cryoanesthesia-a purely physical anesthesia treatment that freezes tissue and attenuate nerve activity-can provide fast treatment through freezing and thawing of cryo-machine and is inexpensive compared to other anesthetics. However, cryoanesthesia has not been widely adopted because securing safe and effective conditions requires quantitative measurement and analysis of neuronal signaling during freezing and recovery, for which research tools are limited. A lack of rapid and localized cooling technologies for quantitative cellular level analysis, in particular, hinders research on not only the optimal cryo-modulation of neuronal activities but also its influence to neighboring cells via cellular networks. Here, we introduce a novel cryo-neuromodulation platform, a high-speed precision probe-type cooling device (~20 C/s at cooling) that provides localized cooling combined with a microelectrode array (MEA) system. We explored the temperature conditions for efficient silencing and recovery of neuronal activities without cell damage. We found that electrical activities of neurons were fully recovered within 1 minute of cooling duration with the maximum cooling speed, which was also confirmed with calcium imaging. The impact of silenced neurons on the neighboring neural network was explored using the localized cooling and we perceived that its influence can be transmitted if the neuronal network is well organized. Our new cryo-device provides rapid and reversible control of neural activities, which allows not just quantitative analysis of the network dynamics, but also new applications in clinical settings.

Benchmarking macaque gene expression for horizontal and vertical translation
The spatial patterning of gene expression shapes cortical organization and emergent function. Advances in spatial transcriptomics make it possible to comprehensively map cortical gene expression in both humans and model organisms. The macaque is a particularly valuable model organism, due to its evolutionary similarity with the human. The translational potential of macaque gene expression rests on the assumption that it is a good proxy for spatial patterns of corresponding proteins (vertical translation) and for spatial patterns of ortholog human genes (horizontal translation). Here we systematically benchmark the spatial distribution of gene expression in the macaque cortex against (a) cortical receptor density in the macaque and (b) cortical gene expression in the human. We find that there is moderate cortex-wide correspondence between gene expression and protein density in the macaque, which is improved by considering layer specific gene expression. We find greater correspondence between orthologous gene expression in the macaque and human. Inter-species correspondence of gene expression exhibits systematic regional heterogeneity, with greater correspondence in unimodal than transmodal cortex, mapping onto patterns of evolutionary cortical expansion. We extend these results to additional micro-architectural features using macaque immunohistochemistry and T1w:T2w ratio, and replicate them using macaque RNA-seq and human RNA-seq gene expression. Collectively, the present results showcase both the potential and limitations of macaque spatial transcriptomics as an engine of translational discovery within and across species.

A virtual clinical trial of psychedelics to treat patients with disorders of consciousness
Disorders of consciousness (DoC), including the unresponsive wakefulness syndrome (UWS) and the minimally conscious state (MCS), have limited treatment options. Recent research suggests that psychedelic drugs, known for their complexity-enhancing properties, could be promising treatments for DoC. This study uses whole-brain computational models to explore this potential. We created individualised models for DoC patients, optimised with empirical fMRI and diffusion-weighted imaging (DWI) data, and simulated the administration of LSD and psilocybin. We used an in-silico perturbation protocol to distinguish between different states of consciousness, including DoC, anaesthesia, and the psychedelic state, and assess the dynamical stability of the brains of DoC patients pre- and post-psychedelic simulation. Our findings indicate that LSD and psilocybin shift DoC patients' brains closer to criticality, with a greater effect in MCS patients. In UWS patients, the treatment response correlates with structural connectivity, while in MCS patients, it aligns with baseline functional connectivity. This virtual clinical trial lays a computational foundation for using psychedelics in DoC treatment and highlights the future role of computational modelling in drug discovery and personalised medicine.

Engagement in moderate-intensity physical activity supports overnight emotional memory retention in older adults
Importance: Preserving the ability to vividly recall emotionally rich experiences contributes to quality of life in older adulthood. While prior work suggests that moderate-intensity physical activity (MPA) may bolster memory, it is unclear whether this extends to emotionally salient memories consolidated during sleep. Objective: To investigate associations between engagement in physical activity (PA) and overnight emotional memory retention and examine whether theoretically replacing 30-minutes of lower-intensity activity with MPA is associated with better consolidation. Design, Setting, and Participants: A cross-sectional study of 40 community-dwelling older adults free of neurological and psychiatric disorders. Data were collected from May 2018 to July 2022 and analyzed from January to July 2024. Exposures: Participants completed an overnight polysomnography (PSG) with emotional memory tested before and after sleep and a self-report questionnaire assessing habitual PA. Main Outcome(s) and Measures(s): Emotional memory performance was assessed via recognition memory or mnemonic discrimination performance. Overnight memory retention was calculated by subtracting immediate test from delayed test performance for both recognition memory and mnemonic discrimination, with more negative scores indicating lower memory retention. Frequency and duration of MPA, light-intensity PA, non-exertive activity, and sedentary behavior were calculated from the Community Health Activities Model Program for Seniors (CHAMPS) Activities Questionnaire for Older Adults. Isotemporal substitution modelling evaluated whether statistically reallocating time spent in sedentary and lower-intensity activity to MPA was associated with better overnight memory retention. Results: Data from 40 participants were analyzed (mean age=72.3, 26 female). Better overnight emotional recognition memory retention was associated with the frequency ({beta}=0.663, SE=0.212, p=0.003) and duration ({beta}=0.214, SE=0.101, p=0.042) of MPA. No relationships were found with mnemonic discrimination or neutral recognition memory. Statistically modelling the replacement of 30 minutes of lower-intensity activity with MPA was associated with better overnight retention of emotional memories ({beta}=0.108, SE=0.048, p=0.030), but not neutral ({beta}=-0.029, SE=0.069, p=0.679). Conclusions and Relevance: MPA may enhance sleep-dependent consolidation of emotional memories in older adults. Modest increases in MPA may yield significant benefits for sleep-dependent emotional memory retention. These findings may guide interventions to preserve memory function and inform public health recommendations by demonstrating that substituting even short durations of low-intensity activity for MPA could produce significant cognitive gains relevant for maintaining quality of life in older adulthood.

ROLE OF WORKING MEMORY IN INTERLIMB GENERALIZATION OF NEWLY LEARNED SKILLS
Newly acquired skill memory can generalize/transfer to the untrained arm. Such interlimb generalization of a learned skill has been shown to be symmetric in nature and is thought to be mediated by cognitive processes that emerge during skill learning. However, it is unknown whether engaging in other cognitively demanding tasks following skill acquisition can influence skill generalization. Our research goal was to uncover how a secondary task, involving working memory, interacts with a newly formed skill memory and influences subsequent interlimb generalization. To test this idea, we conducted a set of three experiments by recruiting right-handed young healthy individuals (N=92) who learned a novel motor skill (long or short training on a skilled reaching task) followed by performing a working memory or control task with the right arm. Finally, all individuals were tested for immediate or delayed (after 24 hours) interlimb skill generalization to the untrained left arm. We found significant immediate as well as delayed generalization in individuals who received long training on the motor skill task, irrespective of whether they performed working memory or control task. On the other hand, performing the working memory but not control task following short skill training impaired generalization when the untrained arm was tested 24 hours later. These findings indicate that short training reflecting early stages of skill learning and the subsequent skill memory stabilization are dependent on working memory such that the underlying neural interactions mediating these processes can have implications for skill generalization.

ClearScope: a fully integrated light sheet theta microscope for sub-cellular resolution imaging without lateral size constraints
Three-dimensional (3D) ex vivo imaging of cleared intact brains of animal models and large human and non-human primate postmortem brain specimens is important for understanding the physiological neural network connectivity patterns and the pathological alterations underlying neuropsychiatric and neurological disorders. Light-sheet microscopy has emerged as a highly effective imaging modality for rapid high-resolution imaging of large cleared samples. However, the orthogonal arrangements of illumination and detection optics in light sheet microscopy limits the size of specimen that can be imaged. Recently developed light sheet theta microscopy (LSTM) technology addressed this by utilizing a unique arrangement of two illumination light paths oblique to the detection light path, while allowing perpendicular arrangement of the detection light path relative to the specimen surface. Here, we report development of a next-generation, fully integrated, and user-friendly LSTM system for rapid sub-cellular resolution imaging uniformly throughout a large specimen without constraining the lateral (XY) size. In addition, we provide a seamlessly integrated workflow for image acquisition, data storage, pre- and post-processing, enhancement, and quantitative analysis. We demonstrate the system performance by high-resolution 3D imaging of intact mouse brains and human brain samples, and complete data analysis including digital neuron tracing, vessel reconstruction and design-based stereological analysis in 3D. This technically enhanced and user-friendly LSTM implementation will enable rapid quantitative mapping of molecular and cellular features of interests in diverse types of very large samples.

Connectivity of the neuronal network for contextual fear memory is disrupted in a mouse model of third-trimester binge-like ethanol exposure
Background: In rodents, third-trimester equivalent alcohol exposure (TTAE) produces significant deficits in hippocampal-dependent memory processes such as contextual fear conditioning (CFC). The present study sought to characterize changes in both behavior and Fos+ neurons following CFC in ethanol (EtOH)-treated versus saline-treated mice using TRAP2:Ai14 mice that permanently label Fos+ neurons following a tamoxifen injection. We hypothesized that TTAE would produce long-lasting disruptions to the networks engaged following CFC with a particular emphasis on the limbic memory system. Methods: On postnatal day 7, mice received either two injections of saline or 2.5 g/kg EtOH spaced 2 hours apart. The mice were left undisturbed until they reached adulthood, at which point they underwent CFC. After context exposure on day 2, mice received a tamoxifen injection. Brain tissue was harvested. Slides were automatically imaged using a Zeiss AxioScanner. Manual counts on a priori regions of interest were conducted. Automated counts were performed on the whole brain using the QUINT 2D stitching pipeline. Last, novel network analyses were applied to identify future regions of interest. Results: TTAE reduced context recall on day 2 of CFC. Fos+ neural density increased in the CA1 and CA3. Fos+ counts were reduced in the anteroventral (AV) and anterodorsal thalamus. The limbic memory system showed significant hyperconnectivity in male TTAE mice and the AV shifted affinity towards hippocampal subregions. Last, novel regions such as a subparafascicular area and basomedial amygdalar nucleus were implicated as important mediators. Discussion: These results suggest that CFC is mediated by the limbic memory system and is disrupted following TTAE. Given the increase in CA1 and CA3 activity, a potential hypothesis is that TTAE causes disruptions to memory encoding following day 1 conditioning. Future studies will aim to determine whether this disruption specifically affects the encoding or retrieval of fear memories.

Network influence determines the impact of cortical ensembles on stimulus detection
Observation of neural firing patterns can constrain theories for the types of activity patterns that the brain uses to guide behavior. However, directly perturbing these patterns, ideally with great specificity, is required to causally test any particular theory. We combined two-photon imaging and cellular resolution optogenetic photo-stimulation to causally test how neural activity in the mouse visual cortex is read out to detect visual stimuli. Contrary to expectations, targeted activation of highly sensitive neural ensembles did not preferentially modify behavior compared to random ensembles, contradicting a longstanding hypothesis for how neural activity drives stimulus detection. Instead, the main predictor of a targeted neural ensemble's impact on perception was its effect on network activity. This argues that downstream regions summate visual cortex activity without preferentially weighting more informative neurons to make sensory detection decisions. Comparing mouse behavioral performance to decoding models of neural activity implies that mice employ this simple, albeit suboptimal strategy to solve the task. This work challenges conventional notions for how sensory representations mediate perception and demonstrates that specific neural perturbations are critical for determining which features of neural activity drive behavior.

Awe is characterized as an ambivalent experience in the human behavior and cortex: integrated virtual reality-electroencephalogram study
Understanding complex emotions, characterized by the co-occurrence of positive and negative feelings, is crucial for unlocking the full spectrum of human affective experiences. However, the behavior and neural representation of ambivalent feelings, particularly during awe, remain elusive. To address this gap, we combined awe-inducing virtual reality clips, electroencephalogram, and a deep learning-based dimensionality reduction technique (N = 43). Behaviorally, awe ratings were precisely predicted by the duration and intensity of ambivalent feelings, not by single valence metrics. In the electrophysiological analysis, we identified participant- and clip-specific latent neural spaces sharing valence representation structures across individuals and stimuli. In these spaces, ambivalent feelings during awe were distinctly represented, and the variability in their distinctiveness specifically predicted awe ratings. Additionally, frontal delta oscillations mainly engaged in differentiating valence representations. Our findings demonstrate that awe is fundamentally an ambivalent experience reflected in both behavior and distinct patterns of electrophysiological activity. This work provides a new framework for understanding complex emotions and their neural underpinnings, with potential implications for affective neuroscience and mental health research.

Attention and working memory investigated through the P300 component in children practicing Karate at different stages of biological maturation
Aim: To investigate attention and working memory, comparing children practice Karate and non-Karate practitioners at different stages of biological maturation through the amplitude and latency of the P300 component during the execution of a Go/No-Go paradigm. Material and Methods: The P300 was analyzed for Fz, Cz, and Pz electrodes in 80 participants separated in two groups: an Karate practitioners group comprising Karate practitioners and comprising non-Karate practitioners. Each group was further subdivided according to the biological maturation range defined by Peak Height Velocity. In addition, the participants performed a Go/No-Go paradigm to measure amplitude and latency. Results: The EEG analysis showed Ffr electrodes Pz and Cz, an interaction was found between group and Peak Height Velocity for the amplitude variable (respectively: F = 45.858; d = 0.38; p < 0.001 / F = 10.411; d = 0.17; p = 0.004). For the Fz electrode, a main effect was found between group and Peak Height Velocity (respectively: F = 40.330; d = 0.34; p = 0.010 / F = 36.730; d = 0.30; p = 0.012) for the variable amplitude and latency. main effect between group and Peak Height Velocity (respectively: F = 7.719; d = 0.14; p = 0.012 / F = 38.370; d = 0.31; p = 0.010). Conclusions: In general, it is possible to conclude that participants in the Karate practitioners group exhibited electrocortical measures corresponding to greater efficiency in decision-making and attention processes, motor planning, working memory, attention allocation, motor execution, and greater attentional engagement. It was also demonstrated that, despite the children being at very close chronological ages, their biological maturation differed.

Neural Mechanisms of Feedback Processing and Behavioral Adaptation during Neurofeedback Training
The acquisition of new skills can be facilitated by providing individuals with feedback that reflects their performance. This process creates a closed loop that utilizes feedback processing and behavioral adaptation following feedback to promote effective training. Functional magnetic resonance imaging (fMRI)-based neurofeedback is a specific instantiation of this principle, where the brain is trained directly by providing feedback of its self-regulation. Neurofeedback is unique in that it is the most direct form of brain training and it trains something we do not normally have conscious access to - our brain activity. To understand how learning with neurofeedback or other forms of feedback is accomplished, it is essential to understand how the feedback is evaluated and how behavior is adjusted following guidance from the feedback signal. In this pre-registered mega-analysis, we re-analyzed data from eight intermittent fMRI neurofeedback studies (N = 153 individuals) to investigate brain regions whose activity and connectivity are associated with feedback processing and behavioral adaptation to feedback during neurofeedback training. We converted and harmonized feedback scores across studies, and computed their linear associations with brain activity and connectivity in parametric general linear model analyses. We observed that, during feedback processing, feedback scores were positively associated with (1) activity in key regions of the reward system, as well as the dorsal attention network, default mode network, and cerebellum; and with (2) reward system-related connectivity in the salience network. During behavioral adaptation (i.e., regulation after feedback), no significant associations were observed between feedback scores and either activity or associative learning-related connectivity. Our results demonstrate that neurofeedback is processed in the reward system, thereby endorsing the theory that reinforcement learning shapes this form of brain training towards behavioral change. In addition, the association of large-scale networks with feedback suggests that higher-level processing, involving the continuous transition between the evaluation of external feedback and the subsequent internal evaluation of the adopted cognitive state, is also involved in this type of learning. Our findings highlight the pivotal role of performance-related feedback as a driving force during learning, a conclusion that can potentially be extended to other processes beyond neurofeedback training.