bioRxiv Subject Collection: Neuroscience's Journal

Ultrastructural Organization of the Honeybee Blood-Brain Barrier and Comparison with Age
The blood-brain barrier is a near ubiquitous feature of animal nervous systems, adapted to maintain brain homeostasis across species occupying unique and dynamic environments. Understanding the structural and functional diversity of animal blood-brain barriers can aid our understanding of how this structure contributes to important areas of neuroscience such as behavior, health, and disease. The honeybee worker is a well-established model for exploring these dimensions of brain function, however, the honeybee worker blood-brain barrier has yet to be described. Here, we present the first global anatomic analysis and description of the honeybee worker blood-brain barrier and compare key ultrastructural features between two age groups. We describe the cellular makeup of the honeybee worker blood-brain barrier, patterns of heterogeneity in barrier structure throughout the brain, and highlight important areas of further study.

Activation mapping in multi-center rat sensory-evoked functional MRI datasets using a unified pipeline.
Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variations in experimental protocols. Here, we aggregated and analyzed 22 sensory-evoked rat fMRI datasets from 12 imaging centers, totaling scans from 220 rats, to assess the consistency of results across diverse protocols. We applied a standardized preprocessing pipeline and evaluated the impact of different hemodynamic response function models on group and individual level activity patterns. Our analysis revealed inter-dataset variability attributed to differences in experimental design, anesthesia protocols, and imaging parameters. We identified robust activation clusters in all (22/22) datasets. The comparison between stock human models implemented in software and rat-specific models showed significant variations in the resulting statistical maps. Our findings emphasize the necessity for standardized protocols and collaborative efforts to improve the reproducibility and reliability of rodent fMRI studies. We provide open access to all datasets and analysis code to foster transparency and further research in the field.

Psilocybin prevents habituation to familiar stimuli and preserves sensitivity to sound following repeated stimulation in mouse primary auditory cortex.
Psilocybin, a psychoactive substance derived from fungi, has been utilized historically by diverse cultures for both medicinal and non-medicinal purposes, owing to its ability to elicit profound sensory and cognitive alterations and sustain long-term changes in mood and cognition. Promising results from recent clinical studies have generated a wave of interest in employing psilocybin to treat neuropsychiatric and neuro-degenerative conditions. How psychedelics cause acute perceptual effects, and how these relate to long-lasting alterations is still debated. Whereas it is thought that perceptual disturbances may be caused by disrupted flow of information between sensory and higher order areas, in vivo studies have focused mostly on the latter. In particular, there has been little study of how psilocybin affects sensory representations in primary auditory cortex (A1). We used two-photon microscopy and wide field calcium imaging to examine how psilocybin affects A1 neuron response properties in the mouse. Administration of 1 mg/kg psilocybin prevented habituation of sound-evoked responses to repeated stimuli, maintaining overall responsiveness, bandwidth, and sound-level response thresholds after repeated stimulation. This was in contrast to marked habituation of responses and narrowing of tuning in controls. We observed no effect on overall distribution of best frequencies at the cortical level, suggesting psilocybin in A1 disrupts normal sensory gating, rather than tonotopic organization. This supports models of psychedelic action in which perceptual disturbances are driven by disrupted hierarchical sensory gating. With further research, influences of psychedelics on sensory representations could be harnessed to target maladaptive sensory processing in conditions such as tinnitus.

Restoration of Fbxo7 expression in dopaminergic neurons restores tyrosine hydroxylase in a mouse model of Parkinson's disease
Mutations in FBXO7 are linked to an atypical parkinsonism. Conditional knock out (KO) of Fbxo7 in dopaminergic neurons in a mouse model caused a neurodegenerative phenotype, including a significant reduction in striatal TH staining at 6 weeks of age and a significant loss of dopaminergic neurons in the SNpc. To test whether re-expression of Fbxo7 could act as a treatment to prevent or restore TH expression in the striatum in this model, we used a rAAV vector to deliver murine Fbxo7 and a mRuby fluorescent marker to dopaminergic neurons. We found that Fbxo7 expression, both before and after the TH loss, restored its expression in the striatum and nucleus accumbens in the mouse. This study therefore highlights that Fbxo7 is important for the integrity and persistence of the dopaminergic nigrostriatal pathway in the mammalian brain, which could be of relevance to Parkinson's disease with therapeutic implications.

When Attention Hurts: The Effect Of rTMS On Neural Correlates Of Time Perception
The parietal lobe plays a crucial role in the attentional networks that help shape our perception, including our perception of time. Based on neuropsychological and neurophysiological evidence, a "when" pathway including the right parietal lobe has been proposed as the critical cortical site for the discrimination of objects across time. When an oddball stimulus is presented in a stream of identical standard stimuli, it is perceived as lasting longer, even when its actual duration is shorter. While attentional capture seems to play a major role in this subjective expansion of time the cortical mechanisms responsible for this effect remain unclear. We therefore set to investigate the direct role of parietal brain areas in time perception using combined repetitive transcranial magnetic stimulation (rTMS) and electroencephalogram (EEG). We measured the perceived duration of an oddball stimulus in each participant before and after inhibitory 1-Hz rTMS stimulation at one of three scalp locations: the right intraparietal sulcus (rIPS), the right inferior parietal lobe (rIPL), or the occipital cortex as a control. EEG was recorded throughout. Stimulation over the rIPL caused a more veridical experience of times subjective expansion towards the oddball, while rTMS over the rIPS and the occipital cortex had no effect. These data provide theoretically challenging notions to the concept of the cortexes role within time perception and the mechanisms involved.

LPS-induced delirium-like behavior and microglial activation in mice correlate with bispectral electroencephalography (BSEEG)
Delirium is a multifactorial medical condition characterized by impairment across various mental functions and is one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Research focused on delirium has proven to be challenging due to a lack of objective measures for diagnosing patients, and few laboratory models have been validated. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes. We applied BSEEG to validate a lipopolysaccharide (LPS)-induced mouse model of delirium. Moreover, we investigated the relationship between BSEEG score, delirium-like behaviors, and microglia activation in hippocampal dentate gyrus and cortex regions in young and aged mice. There was a significant correlation between BSEEG score and impairment of attention in young mice. Additionally, there was a significant correlation between BSEEG score and microglial activation in hippocampal dentate gyrus and cortex regions in young and aged mice. We have successfully validated the BSEEG method by showing its associations with a level of behavioral change and microglial activation in an LPS-induced mouse model of delirium. In addition, the BSEEG method was able to sensitively capture an LPS-induced delirium-like condition that behavioral tests could not capture because of a hypoactive state.

Inversed association of locus coeruleus MRI integrity with structural volume and its impact on individual's inattentiveness
The locus coeruleus (LC) is a nucleus within the brainstem associated with physiological arousal and altered structure and function in the context of neurodegenerative disorders. Pathologies related to difficulties with attention have previously been associated with abnormalities in neurotransmitter production and sensitivity, suggesting the possibility of abnormality in neurotransmitter producing neural regions. One such region is the LC, associated with norepinephrine production. To examine the possibility that LC alteration is associated with inattentive symptom reporting, a set of analyses have been performed with 141 individuals age-ranged from 8 to 54. We found that the structural integrity value of the LC, especially on the right hemisphere, showed a significant negative association with the level of individual's inattentiveness score. Furthermore, LC volume size was significantly positively associated with inattention, and this finding was also lateralized to the right LC. Interestingly, an inverse association was found between structural integrity and volume size. These findings support the relationship between LC and attention-related behavior through both neuromelanin-sensitive and structural imaging, with important implications for the association between regional structure and function.

Context-Dependent Interaction Between Goal-Directed and Habitual Control Under Time Pressure
Habits are an important aspect of human behaviour. Habits are reflexive, inflexible, and fast, in contrast to goal-directed behaviour which is reflective, flexible, and slow. Current theories assume that habits and goal-directed actions are controlled by two separate but interacting systems. However, it is not clear how these two systems interact when actions must be made under time pressure. Here we use a task which induces habitual behaviour in the form of action sequences, while concurrently requiring participants to perform goal-directed actions that are either congruent or incongruent with the habit. This task thus allows for concurrent measurement of both goal-directed and habitual behaviour, thereby permitting a nuanced analysis of the interaction between these two control modes. Using computational modelling, we find that models where the influence of the habit depends on the number of repetitions, explain participant behaviour better than models that assume the habit to be constant. We further show that roughly half of the participants modulate their use of the habit depending on the context, i.e. they selectively inhibit the habit's influence when it is incongruent to their explicit goals, but not when both are congruent and the influence of the habit is adaptive. Additional drift-diffusion modelling of choice and reaction time data shows that proactive control is mobilized in the congruent task context whereas reactive control is mobilized in the incongruent task context. The present study thus indicates that habitual control is context-dependent and can be adaptively deployed via proactive and reactive control, rather than being a fixed or isolated mechanism.

Non-invasive brain stimulation over the Frontopolar Cortex promotes willingness to exert cognitive effort in a foraging-like sequential choice task
Individuals avoid spending cognitive effort unless expected rewards offset the perceived costs. Recent work employing tasks that provide explicit information about demands and incentives, suggests causal involvement of the Frontopolar Cortex (FPC) in effort-based decision-making. Using transcranial direct current stimulation (tDCS), we examined whether the FPC's role in motivating effort generalizes to sequential choice problems in which task demand and reward rates vary indirectly and as a function of experience. In a double-blind, within-subject design, 46 participants received anodal (i.e., excitatory) or sham stimulation over the right FPC during an Effort Foraging Task, which required choosing between harvesting patches for successively decreasing resources or traveling to replenished patches by performing a cognitive task with environment-specific difficulty. As expected, participants exited patches later (i.e., displayed lower exit thresholds) when travelling required greater (versus less) effort, indicating increased travel costs in high-effort environments. Under anodal tDCS, the difference in exit thresholds between environments was significantly smaller relative to sham. Finally, individual differences analyses hint that participants with lower self-reported motivation to exert effort exhibited greater travel cost reductions following tDCS. Together, these findings support the theorized causal role of the FPC in motivating cognitively effortful behavior, expand its role to more ecologically valid serial decisions and highlight the potential for tDCS as a tool to increase motivation with potential clinical applications.

Cortex-wide spatiotemporal motifs of theta oscillations are coupled to freely moving behavior
Multisensory information is combined across the cortex and assimilated into the continuous production of ongoing behavior. In the hippocampus, theta oscillations (4-12 Hz) radiate as large-scale traveling waves, and serve as a scaffold for neuronal ensembles of multisensory information involved in memory and movement-related processing. An extension of such an encoding framework across the neocortex could similarly serve to bind disparate multisensory signals into ongoing, coherent, phase-coded processes. Whether the neocortex exhibits unique large-scale traveling waves distinct from that of the hippocampus however, remains unknown. Here, using cortex-wide electrocorticography in freely moving mice, we find that theta oscillations are organized into bilaterally-symmetric spatiotemporal "modes" that span virtually the entire neocortex. The dominant mode (Mode 1) is a divergent traveling wave that originates from retrosplenial cortex and whose amplitude correlates with mouse speed. Secondary modes are asynchronous spiral waves centered over primary somatosensory cortex (Modes 2 & 3), which become prominent during rapid drops in amplitude and synchrony (null spikes) and which underlie a phase reset of Mode 1. These structured cortex-wide traveling waves may provide a scaffold for large-scale phase-coding that allows the binding of multisensory information across all the regions of the cortex.

Endosomal hyper-acidification via proton-activated chloride channel deletion in neurons impairs AMPA receptor endocytosis and LTD
Endosomal homeostasis is critical for neuronal function, including the post-synaptic trafficking of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Dynamic AMPAR trafficking is a major component of synaptic plasticity, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD) and is thought to be required for learning and memory. Dramatic alteration of endosomal pH has been reported to negatively affect synaptic transmission and neural development, but the underlying mechanisms by which pH is involved in AMPAR trafficking are unclear. Here, we show that the proton-activated chloride (PAC) channel localizes to early and recycling endosomes along neuronal dendrites and prevents hyper-acidification of endosomes. To directly measure AMPAR endocytosis, we used a new method to assess LTD using HaloTag-GluA2 and found that the loss of PAC reduces AMPAR internalization during chemical LTD in primary neurons, while AMPAR trafficking in unstimulated cells or during chemical LTP is unaffected. Consistently, pyramidal neuron-specific PAC knockout mice had impaired hippocampal LTD, but not LTP, and performed poorly in the Morris water maze reversal test, exhibiting an inability to adapt to changing environments (also referred to as behavioral flexibility). We conclude that proper maintenance of pH by PAC is important during LTD to regulate AMPAR trafficking in a manner critical for animal physiology and behavior.

A Water Relaxation Atlas for Age and Region specific Metabolite Concentration Correction
Metabolite concentration estimates from Magnetic Resonance Spectroscopy (MRS) are typically quantified using water referencing, correcting for relaxation time differences between metabolites and water. One common approach is to correct the water reference signal for differential relaxation within three tissue compartments (gray matter, white matter, and cerebrospinal fluid) using fixed literature values. However, water relaxation times (T1 and T2) vary between brain locations, in pathology, and with age. MRS studies, even those measuring metabolite levels across the lifespan, often ignore these effects, because of a lack of reference data. The purpose of this study is to develop a water relaxometry atlas and to integrate location and age appropriate relaxation values into the MRS analysis workflow. 101 volunteers (51 men, 50 women; ~10 male and 10 female participants per decade (from the 20s to 60s), were recruited. T1 weighted MPRAGE images ((1 mm)3 isotropic resolution) were acquired. Whole brain water T1 and T2 measurements were made with DESPOT ((1.4 mm)3 isotropic resolution). T1 and T2 maps were registered to the JHU MNI-SS/EVE atlas using affine and LDDMM transformation. The atlas's 268 parcels were reduced to 130 by combining homologous parcels. Mean T1 and T2 values were calculated for each parcel in each subject. Linear models of T1 and T2 as functions of age were computed, using age minus 30 as the predictor. Reference atlases of age 30 intercept and age-slope for T1 and T2 were generated. The atlas-based workflow was integrated into Osprey, which coregisters MRS voxels to the atlas and calculates location and age appropriate water relaxation parameters for quantification. The water relaxation aging atlas revealed significant regional and tissue differences in water relaxation behavior across adulthood. Using location and subject appropriate reference values in the MRS analysis workflow removes a current methodological limitation and is expected to reduce quantification biases associated with water referenced tissue correction, especially for studies of aging.

The oneirogen hypothesis: modeling the hallucinatory effects of classical psychedelics in terms of replay-dependent plasticity mechanisms
Classical psychedelics induce complex visual hallucinations in humans, generating percepts that are coherent at a low level, but which have surreal, dream-like qualities at a high level. While there are many hypotheses as to how classical psychedelics could induce these effects, there are no concrete mechanistic models that capture the variety of observed effects in humans, while remaining consistent with the known pharmacological effects of classical psychedelics on neural circuits. In this work, we propose the "oneirogen hypothesis," which posits that the perceptual effects of classical psychedelics are a result of their pharmacological actions inducing neural activity states that truly are more similar to dream-like states. We simulate classical psychedelics' effects via manipulating neural network models trained on perceptual tasks with the Wake-Sleep algorithm. This established machine learning algorithm leverages two activity phases, a perceptual phase (wake) where sensory inputs are encoded, and a generative phase (dream) where the network internally generates activity consistent with stimulus-evoked responses. We simulate the action of psychedelics by partially shifting the model to the 'Sleep' state, which entails a greater influence of top-down connections, in-line with the impact of psychedelics on apical dendrites. The effects resulting from this manipulation capture a number of experimentally observed phenomena including the emergence of hallucinations, increases in stimulus-conditioned variability, and large increases in synaptic plasticity. We further provide a number of testable predictions which could be used to validate or invalidate our oneirogen hypothesis.

ACE1 Does Not Influence Cerebral Aβ Degradation or Amyloid Plaque Accumulation in 5XFAD Mice
Alzheimers disease (AD) is the most common form of dementia, and multiple lines of evidence support the relevance of amyloid beta deposition and amyloid plaque accumulation in the neurotoxicity and cognitive decline in AD. Rare mutations in angiotensin converting enzyme 1 (ACE1) have been highly associated with late onset AD patients; however, the mechanism for ACE1 mutation in AD pathogenesis is unknown. Given the relevance of ACE1 with AD and the strong association of abeta to AD pathogenesis, we investigated whether ACE1 degrades abeta; and affects amyloid burden in 5XFAD mice in vivo. To investigate this, we analyzed 6-month-old 5XFAD mice with ACE1 loss of function. ACE1 loss of function was mediated either by crossing 5XFAD mice to ACE1 conditional knockout mice or administering 5XFAD mice with the ACE1 inhibitor enalapril. Our analyses revealed that ACE1 loss of function through both genetic and pharmacological methods does not affect amyloid plaque load and neuroinflammation in the hippocampus and cortex of 5XFAD mice.

Active reconfiguration of neural task states
The ability to switch between different tasks is a critical component of adaptive cognitive functioning, but a mechanistic understanding of this capacity has remained elusive. Longstanding debates over whether task switching requires active preparation remain hotly contested, in large part due to the difficulty of inferring task preparation from behavior alone. We make progress on this debate by quantifying neural task representations through high-dimensional linear dynamical systems fit to human electroencephalographic recordings. We find that these dynamical systems are highly predictive of macroscopic neural activity, and reveal neural signatures of active preparation that are shared with task-optimized neural networks. These findings help inform a classic debate about how we control our cognition, and offer a promising new paradigm for neuroimaging analysis.

Evaluation of scalp-based targeting methods of DLPFC for TMS therapy: EEG cap F3, Beam F3, CPC F3, and adjusted Beam F3
Repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) offers a promising approach for treating depression. Scalp-based targeting methods, including EEG Cap, Beam F3, CPC F3, and adjusted Beam F3, have evolved to enhance clinical application. Our study aims to evaluate and compare the accuracy, reliability, speed, and training efficacy of these four methods. Three trained technicians conducted repeated DLPFC targeting measurements on 10 3D-printed head models. Accuracy was assessed by calculating targeting error and electric field strength at the subgenual anterior cingulate cortex anti-correlated peak. Reliability was evaluated through inter- and intra-rater variability, and training efficacy was examined by comparing targeting errors between trained technicians and novices. CPC F3, Beam F3, and adjusted Beam F3 demonstrated comparable accuracy in terms of electric field strength, but CPC F3 had the lowest targeting error (4.2 mm). CPC F3 also exhibited the highest reliability (inter-rater variability at 3.3 mm, intra-rater variability at 2.3 mm). The EEG cap was the fastest method (80 seconds), while CPC F3 was faster than Beam F3 but slower than the EEG Cap. No significant differences in targeting error between trained technicians and novices were noted with CPC F3 and adjusted Beam F3. The comparative analysis of these four scalp-based targeting methods provides insights that can enhance clinical decision-making and practical application. While accuracy among CPC F3, Beam F3, and adjusted Beam F3 was comparable, CPC F3 emerges as highly practical due to its significantly better reliability, training efficacy, moderate speed, and straightforward implementation.

Test-Retest Reliability and repeatability of Behavioral and Electrophysiological Markers in an Eriksen Flanker Task
Cognitive control processes, specifically interference control and error monitoring, are often impaired across neuropsychiatric disorders and have been proposed as transdiagnostic markers of psychopathology and important treatment targets. Accurately probing them, however, requires understanding the psychometric properties of the measures used to assess cognitive control, including their intra- and interindividual stability over time. Using an Eriksen Flanker Task, we tested behavioral and electrophysiological readouts of cognitive control in 36 healthy individuals (26 female, 10 male, M age+/-SD=33.18+/-14.49, range=19-68) and evaluated their test-retest reliability across 48 hours by calculating Pearson correlations and Intraclass Correlation Coefficients (ICCs) to assess group-level stability. Moreover, we assessed repeatability through Coefficients of Variation (CVs) and Bland-Altman statistics, to investigate the degree of change in participants' absolute scores. We found satisfactory-to-excellent test-retest reliability for most cognitive control measures, with condition-specific metrics generally being more reliable than difference scores. Regarding repeatability, we observed considerable intraindividual variability in absolute scores over time, which differed widely between participants. These results demonstrate that measurements of cognitive control may display substantial intraindividual variability across sessions despite demonstrating high test-retest reliability and vice versa. Our findings expand the current literature by providing novel information about the stability of behavioral and physiological markers of cognitive control over time. Moreover, they may have important implications for the application and evaluation of clinical interventions by highlighting the usefulness of considering repeatability measures in addition to the more commonly reported test-retest reliability metrics, when tracking changes over time in clinically relevant processes within single individuals.

Effects of systemic oxytocin and beta-3 receptor agonist (CL 316243) treatment on body weight and adiposity in male diet-induced obese rats
Previous studies have implicated hindbrain oxytocin (OT) receptors in the control of food intake and brown adipose tissue (BAT) thermogenesis. We recently demonstrated that hindbrain [fourth ventricle (4V)] administration of oxytocin (OT) could be used as an adjunct to drugs that directly target beta-3 adrenergic receptors ({beta}3-AR) to elicit weight loss in diet-induced obese (DIO) rodents. What remains unclear is whether systemic OT can be used as an adjunct with the {beta}3-AR agonist, CL 316243, to increase BAT thermogenesis and elicit weight loss in DIO rats. We hypothesized that systemic OT and {beta}3-AR agonist (CL 316243) treatment would produce an additive effect to reduce body weight and adiposity in DIO rats by decreasing food intake and stimulating BAT thermogenesis. To test this hypothesis, we determined the effects of systemic (subcutaneous) infusions of OT (50 nmol/day) or vehicle (VEH) when combined with daily systemic (intraperitoneal) injections of CL 316243 (0.5 mg/kg) or VEH on body weight, adiposity, food intake and brown adipose tissue temperature (TIBAT). OT and CL 316243 monotherapy decreased body weight by 8.0 {+/-} 0.9% (P<0.05) and 8.6{+/-}0.6% (P<0.05), respectively, but OT in combination with CL 316243 produced more substantial weight loss (14.9& [plusmn] 1.0%; P<0.05) compared to either treatment alone. These effects were associated with decreased adiposity, energy intake and elevated TIBAT during the treatment period. The findings from the current study suggest that the effects of systemic OT and CL 316243 to elicit weight loss are additive and appear to be driven primarily by OT-elicited changes in food intake and CL 316243-elicited increases in BAT thermogenesis.

Mapping the Microstructure of Human Cerebral Cortex In Vivo with Diffusion MRI
Despite advances in diffusion MRI, which have led to remarkable progress in mapping white matter of the living human brain, the understanding of cerebral cortical microstructure in vivo and its relationship to macrostructure, myeloarchitecture, cytoarchitecture, chemoarchitecture, metabolism, and function lag far behind. We present neuromaps of 21 microstructural metrics derived from diffusion tensor, diffusion kurtosis, mean apparent propagator, and neurite orientation dispersion and density imaging of the young adult cerebral cortex. We demonstrate how cortical microstructure follows cytoarchitectural and laminar differentiation, aligns with the macroscale sensory-fugal and sensorimotor-association axes, and contributes to functional brain networks, neural oscillatory dynamics, neurotransmitter receptor/transporter distributions, and cognition and behavior. We find cortical microstructural covariation across individuals to encode functional and structural connectivity as well as gene expression and neurotransmitter similarity. Finally, our exploratory analysis suggests cortical microstructure from diffusion MRI could prove useful in investigating a broad array of neuropsychiatric disorders.

State and trait serotonin variations interact to shape the intrinsic connectivity and gradient architecture of the brain: a combined TPH2 genetics and tryptophan depletion study
Background: Serotonin (5-HT) critically regulates cognitive and emotional functions, and both stable and transient variations in 5-HT signaling have been associated with emotional dysregulations. However, findings regarding the neurofunctional effects of transient 5-HT variations have been highly inconsistent. Therefore, we examined whether individual variations in a central 5-HT-regulating genetic polymorphism (tryptophan hydroxylase 2, TPH2) represent a vulnerability or resilience factor for the effects of acute tryptophan depletion (ATD) on functional brain architecture. Method: The current study utilized a pharmacogenetic within-subject randomized placebo-controlled resting-state fMRI design with n=53 healthy male participants in combination with spontaneous intrinsic neural activity, functional connectivity, and connectome gradient analyses to compare the neurofunctional effects of ATD-induced transient reduction in central 5-HT signaling between TPH2 genotypes (a priori genotyping for rs4570625, GG n = 25 vs. TT n = 23). Results: ATD induced significant increases in spontaneous neural activity in hippocampal CA1 irrespective of genotype and enhanced communication of this region with the bilateral amygdala and the vmPFC specifically in GG carriers. ATD sharpened the intrinsic connectome gradient architecture in several large-scale networks, including the salience, frontoparietal, and default mode network. Conclusions: Our results identify a potential genetic marker for an increased vulnerability to the neural effects of transient variations in 5-HT signaling on the functional architecture of an anxiety- and stress-related brain circuit. Connectome gradient results underscore the regulatory role of 5-HT on the intricate organization of large-scale networks involved in emotional reactivity and regulation.

Temporal Dynamics of Nucleus Accumbens Neurons in Male Mice During Reward Seeking
The nucleus accumbens (NAc) regulates reward-motivated behavior, but the temporal dynamics of NAc neurons that enable free-willed animals to obtain rewards remain elusive. Here, we recorded Ca2+ activity from individual NAc neurons when mice performed self-paced lever-presses for sucrose. NAc neurons exhibited three temporally-sequenced clusters, defined by times at which they exhibited increased Ca2+ activity: approximately 0, -2.5 or -5 sec relative to the lever-pressing. Dopamine D1 receptor (D1)-expressing neurons and D2-neurons formed the majority of the -5-sec versus -2.5-sec clusters, respectively, while both neuronal subtypes were represented in the 0-sec cluster. We found that pre-press activity patterns of D1- or D2-neurons could predict subsequent lever-presses. Inhibiting D1-neurons at -5 sec or D2-neurons at -2.5 sec, but not at other timepoints, reduced sucrose-motivated lever-pressing. We propose that the time-specific activity of D1- and D2-neurons mediate key temporal features of the NAc through which reward motivation initiates reward-seeking behavior.

Neurophysiological Dynamics of Metacontrol States: EEG Insights into Conflict Regulation
Understanding the neural mechanisms underlying metacontrol and conflict regulation is crucial for insights into cognitive flexibility and persistence. This study employed electroencephalography (EEG), EEG-beamforming and directed connectivity analyses to explore how varying metacontrol states influence conflict regulation at a neurophysiological level. Metacontrol states were manipulated by altering the frequency of congruent and incongruent trials across experimental blocks in a modified flanker task, and both behavioral and electrophysiological measures were analyzed. Behavioral data confirmed the experimental manipulation's efficacy, showing an increase in persistence bias and a reduction in flexibility bias during increased conflict regulation. Electrophysiologically, theta band activity paralleled the behavioral data, suggesting that theta oscillations reflect the mismatch between expected metacontrol bias and actual task demands. Alpha and beta band dynamics differed across experimental blocks, though these changes did not directly mirror behavioral effects. Post-response alpha and beta activity were more pronounced in persistence-biased states, indicating a neural reset mechanism preparing for future cognitive demands. By using a novel artificial neural networks method, directed connectivity analyses revealed enhanced inter-regional communication during persistence states, suggesting stronger top-down control and sensorimotor integration. Overall, theta band activity was closely tied to metacontrol processes, while alpha and beta bands played a role in resetting the neural system for upcoming tasks. These findings provide a deeper understanding of the neural substrates involved in metacontrol and conflict monitoring, emphasizing the distinct roles of different frequency bands in these cognitive processes.

Levodopa impairs lysosomal function in sensory neurons in vitro
Parkinson's disease (PD) is the second-most common neurodegenerative disease worldwide. Patients are diagnosed based upon movement disorders, including bradykinesia, tremor and stiffness of movement. However, non-motor signs, including constipation, rapid eye movement sleep behavior disorder, smell deficits and pain are well recognized. Peripheral neuropathy is also increasingly recognized, as the vast majority of patients show reduced intraepidermal nerve fibers, and sensory nerve conduction and sensory function is also impaired. Many case studies in the literature show that high-dose levodopa, the primary drug used in the treatment of PD, may exacerbate neuropathy, thought to involve levodopa's metabolism to homocysteine. Here, we treated primary cultures of dorsal root ganglia and a sensory neuronal cell line with levodopa to examine effects on cell morphology, mitochondrial content and physiology, and lysosomal function. High-dose levodopa reduced mitochondrial membrane potential. At concentrations observed in the patient, levodopa enhanced immunoreactivity to beta III tubulin. Critically, levodopa reduced lysosomal content and also reduced the proportion of lysosomes that were acidic while homocysteine tended to have the opposite effect. Levodopa is a critically important drug for the treatment of PD. However, our data suggests that at concentrations observed in the patient, it has deleterious effects on sensory neurons that are not related to homocysteine.

A rich conformational palette underlies human CaV2.1-channel availability
Depolarization-evoked opening of CaV2.1 (P/Q-type) Ca2+-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of CaV2.1 response to voltage is unclear. Using voltage-clamp fluorometry and kinetic modeling, we optically tracked and physically characterized the structural dynamics of the four CaV2.1 voltage-sensor domains (VSDs). VSD-I seems to directly drive opening and convert between two modes of function, associated with VDI. VSD-II is apparently voltage-insensitive. VSD-III and VSD-IV sense more negative voltages and undergo voltage-dependent conversion uncorrelated with VDI. Auxiliary {beta}-subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. CaV2.1 VSDs are differentially sensitive to voltage changes brief and long-lived. Specifically the voltage-dependent conformational changes of VSD-I are linked to synaptic release and plasticity.

A post-injury immune challenge with lipopolysaccharide following adult traumatic brain injury alters neuroinflammation and the gut microbiome acutely, but has little effect on chronic outcomes
Patients with a traumatic brain injury (TBI) are susceptible to hospital-acquired infections, presenting a significant challenge to an already-compromised immune system. The consequences and mechanisms by which this dual insult worsens outcomes are poorly understood. This study aimed to explore how a systemic immune stimulus (lipopolysaccharide, LPS) influences outcomes following experimental TBI in young adult mice. Male and female C57Bl/6J mice underwent controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS or saline-vehicle at 4 days post-TBI, before behavioral assessment and tissue collection at 6 h, 24 h, 7 days or 6 months. LPS induced acute sickness behaviors including weight loss, transient hypoactivity, and increased anxiety-like behavior. Early systemic immune activation by LPS was confirmed by increased spleen weight and serum cytokines. In brain tissue, gene expression analysis revealed a time course of inflammatory immune activation in TBI or LPS-treated mice (e.g., IL-1{beta}, IL-6, CCL2, TNF), which was exacerbated in TBI+LPS mice. This group also presented with fecal microbiome dysbiosis at 24 h post-LPS, with reduced bacterial diversity and changes in the relative abundance of key bacterial genera associated with sub-acute neurobehavioral and immune changes. Chronically, TBI induced hyperactivity and cognitive deficits, brain atrophy, and increased seizure susceptibility, similarly in vehicle and LPS-treated groups. Together, findings suggest that an immune challenge with LPS early after TBI, akin to a hospital-acquired infection, alters the acute neuroinflammatory response to injury, but has no lasting effects. Future studies could consider more clinically-relevant models of infection to build upon these findings.

A depth map of visual space in the primary visual cortex
Depth perception is essential for visually-guided behavior. Computer vision algorithms use depth maps to encode distances in three-dimensional scenes but it is unknown whether such depth maps are generated by animal visual systems. To answer this question, we focused on motion parallax, a depth cue relying on visual motion resulting from movement of the observer. As neurons in the mouse primary visual cortex (V1) are broadly modulated by locomotion, we hypothesized that they may integrate vision- and locomotion-related signals to estimate depth from motion parallax. Using recordings in a three-dimensional virtual reality environment, we found that conjunctive coding of visual and self-motion speeds gave rise to depth-selective neuronal responses. Depth-selective neurons could be characterized by three-dimensional receptive fields, responding to specific virtual depths and retinotopic locations. Neurons tuned to a broad range of virtual depths were found across all sampled retinotopic locations, showing that motion parallax generates a depth map of visual space in V1.

Spontaneous emergence and drifting of sequential neural activity in recurrent networks
Repeating sequences of neural activity exist across diverse brain regions of different animals and are thought to underlie diverse computations. However, their emergence and evolution in the presence of ongoing synaptic plasticity remain poorly understood. To gain mechanistic insights into this process, we modeled how biologically-inspired rules of activity-dependent synaptic plasticity in recurrent circuits interact to produce connectivity structures that support sequential neuronal activity. Even under unstructured inputs, our recurrent networks developed strong unidirectional connections, resulting in spontaneous repeating spiking sequences. During ongoing plasticity these sequences repeated despite turnover of individual synaptic connections, a process reminiscent of synaptic drift. The turnover process occurred over different timescales, with certain connectivity types and motif structures leading to sequences with different volatility. Structured inputs could reinforce or retrain the resulting connectivity structures underlying sequences, enabling stable but still flexible encoding of inputs. Our model unveils the interplay between synaptic plasticity and sequential activity in recurrent networks, providing insights into how brains implement reliable but flexible computations.

Mitochondria-centered metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism
Background: Inclusion body myositis (IBM) is a disease of aging characterized by progressive muscle loss. Despite its positioning at the intersection of aging, mitochondrial dysfunction and chronic inflammation, limited studies have evaluated the underlying metabolic disturbances in IBM. Objective: To investigate the mitochondria-centered metabolomic map of IBM in muscle tissue, highlighting sex-specific differences, and to determine the correlation of the changes in metabolites and gene expression with clinical parameters. Methods: 37 IBM patients and 22 controls without a myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included age at biopsy, disease duration, manual motor test (MMT) score, and modified Rankin scale (MRS). A complementary battery of metabolomics platforms was used including untargeted, targeted, and central carbon metabolism. Metabolite levels and RNA-metabolomics integrated modules were correlated with clinical parameters. Results: Muscle samples from IBM patients had elevated TCA cycle intermediates with concomitant increase in anaplerotic amino acids, suggesting increased anaplerosis into the cycle. There was a decrease in upper glycolysis intermediates and an increase in most of the pentose phosphate pathway (PPP) metabolites. The PPP is the main source of NAPDH, a main antioxidant, and ribose-5-P a precursor of nucleic acids. There were marked sex-specific differences in the acylcarnitine profile, with a decrease in short-chain acylcarnitines only in males. Lastly, there was an increase in nucleic acid bases and a decrease in nucleotides. Several metabolites from various pathways had significant correlations with various clinical parameters, with the most pronounced sex-specific differences observed in correlations with acylcarnitines. RNA-metabolomics integration identified 4 modules, with the strongest correlation observed between one module and sex. The MMT score, an indicator of disease severity, showed a strong correlation with 3 modules. There were major sex specific differences with males having relatively similar correlation to the grouped (both sexes) analysis, while females had no significant correlation with any of the modules. Conclusion: Taken together, our findings identified clinically significant alterations in central carbon metabolism in IBM, with major differences between males and females. Future studies are needed to detect the longitudinal changes in metabolites over the disease course.

Modular representations emerge in neural networks trained to perform context-dependent tasks
The brain has a well-known large scale organization at the level of brain regions, where different regions have been argued to primarily serve different behavioral functions. This regional specialization has been explained theoretically as arising from constraints on connectivity and the physical geometry of the cortical sheet. In contrast, the structure of neural representations within a specific brain region is not well understood. Experimental and theoretical work has argued both for and against the existence of specialization at the level of single neurons, where single neurons might be specialized to encode only particular subsets of variables among those represented by the whole brain region. Here, we use artificial neural networks to study the emergence of this local structure and work to reconcile experimental results that show local structure in some cases but not in others. We show that specialization at the level of single neurons -- that is, an explicitly modular representation -- emerges to support context-dependent behavior, but only when the network starts from a specific representational geometry. We also outline cases in which either unstructured or population-level specialization (i.e., an implicitly modular representation) is learned. We show that both explicitly and implicitly modular solutions are abstract and allow for rapid learning and generalization on novel tasks as well as zero-shot transfer to novel stimuli. We further show that modular geometries facilitate the rapid learning of novel contexts that are related to previously seen contexts, while less structured geometries facilitate the rapid learning of novel unrelated contexts. Together, our findings clarify multiple conflicting experimental results. Further, they make numerous predictions for future experimental work and highlight the important joint roles of task structure and initial representational geometry in shaping learned representations.

Irregular light schedules induce alterations on daily rhythms and gene expression in mice
Synchronization of internal biological rhythms with external light-dark cycles is crucial for proper function and survival of the organisms, however modern life often imposes irregular light exposure, disrupting these internal clocks. This study investigated the effects of short-term shifted light-dark cycles on mice rhythmicity, and whether these alterations trigger molecular or behavioral changes. We evaluated locomotor activity, different behavioral domains and gene expression in the hypothalamus and medial prefrontal cortex. Despite non prominent behavioral impairments, such as anxiety or cognitive deficits, we observed a notable simplification in the locomotor activity patterns of the mice subjected to disrupted light-dark cycles. Molecular alterations included dysregulations in oscillations of core clock genes (Cry2, Per2) and disruptions in expression of genes involved in neuroplasticity, motivation, and stress responses, including GluA1, Crhr2, and Vip in both studied brain areas. Our study reveals that even brief light cycle shifts can disrupt circadian regulation at the molecular level, despite minimal behavioral changes. This molecular-behavioral discrepancy may suggest a complex adaptive response to drastic short-term light perturbations. Understanding the complex interplay between external light cues and internal biological rhythms regulation is crucial for mitigating the negative consequences of irregular light exposure on physiological processes and overall well-being.

UBE3A reinstatement restores behavior and proteome in an Angelman Syndrome mouse model of Imprinting Defects
Angelman Syndrome (AS) is a severe neurodevelopmental disorder with only symptomatic treatment currently available. Besides mutations within the UBE3A gene, AS is caused by deletions, imprinting center defects (mICD) or uniparental disomy of chromosome 15 (UPD). Current mouse models are Ube3a-centric and do not address expression changes of other 15q11-q13 genes on AS pathophysiology. Here, we studied a mouse line that harbors a mutation affecting the AS-PWS imprinting center, hence modeling mICD/UPD AS subtypes. mICD mice showed significant reduction in UBE3A protein, bi-allelic expression of Ube3a-ATS and Mkrn3-Snord115 gene cluster, leading to robust AS behavioral deficits and proteome alterations similar to Ube3aKO mice. Genetic UBE3A overexpression in mICD mice, mimicking therapeutic strategies that effectively activate the biallelic silenced Ube3a gene, resulted in a complete rescue of all behavioral and proteome alterations. Subsequently, treatment with an antisense oligonucleotide (ASO) to directly activate the biallelic silenced Ube3a gene in mICD mice also resulted in efficient reinstatement of UBE3A, alongside a partial rescue of behavioral phenotypes. Taken together, these findings demonstrate that UBE3A loss is the primary factor underlying AS phenotypes in the mICD/UPD mouse model, and also corroborate that UBE3A reinstatement is an attractive therapeutic strategy for mICD/UPD AS individuals.

Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes
The Leucine-rich repeat kinase 2 (LRRK2) not only plays a vital role in familial forms of Parkinson's disease (PD) but is also considered as a risk factor for idiopathic PD. For these reasons, LRRK2 is considered a promising drug target for PD treatment. Its multi-domain architecture enables a fine-tuned regulation of its biological function by orchestrating intra- and inter-molecular interactions. At the same time, it offers multiple targetable epitopes for fine-tuned modulation of its deregulated kinase activity caused by pathogenic risk variants. Here, we present BioID proximity proteomes of LRRK2 revealing new interactors, which we further characterized by a novel evolutionary and structural bioinformatics pipeline. Co-evolutionary analysis of the protein-protein interaction (PPI) network identified a structural and functional module enriched in cytoskeletal components linked to the centrosome and microtubules. Likely co-evolved with LRRK2 within this cluster is CYLD, a K-63 selective ubiquitin deubiquitinase which we found to stabilize LRRK2. Furthermore, structural prediction of binary interactions via AlphaFold-multimer revealed distinct groups of interactors engaging with LRRK2 dependent on specific conformations and epitopes. We found two distinct groups engaging with LRRK2 either in an N-terminal closed ("locked") or open ("unlocked") conformation, both of which are associated with specific structurally defined interfaces and biological processes. Furthermore, we identified distinct changes in the LRRK2 proximity proteome induced by the type I kinase inhibitor MLi-2 or by co-expression of the LRRK2 upstream effector RAB29. Dependent on its state of activity and conformation, these functional state-specific protein interactions link LRRK2 to distinct cellular sub-compartments, including centriolar satellites as well as vesicular sub-compartments.

Hierarchy of prediction errors shapes the learning of context-dependent sensory representations
How sensory information is interpreted depends on context. Yet, how context shapes sensory processing in the brain remains elusive. To investigate this question, we combined computational modeling and in vivo functional imaging of cortical neurons in mice during reversal learning of a tactile sensory discrimination task. During learning, layer 2/3 somatosensory neurons enhanced their response to reward-predictive stimuli, explainable as gain amplification from apical dendrites. Reward-prediction errors were reduced and confidence in the outcome prediction increased. Upon rule reversal, the lateral orbitofrontal cortex, through disinhibitory VIP interneurons, encoded a context-prediction error, signaling a loss of confidence. The hierarchy of prediction errors in cortical areas is mirrored in top-down signals modulating apical activity in the primary sensory cortex. Our model explains how contextual changes are detected in the brain and how errors in different cortical regions interact to reshape and update the sensory representation.

Serotonergic neurons in the dorsal raphe regulate visual attention
Visual attention enhances the neural representation of salient stimuli within the visual cortex. It is generally thought that this enhancement is driven by glutamatergic feedback from frontal cortical areas. Here we report the unexpected observation that dorsal raphe (DR) derived serotonin (5HT) controls visual attention. We developed a behavioral model that captured the way mice allocated attention to cued and uncued visual locations and features. Simultaneous photometry showed reduced DR activity when mice deployed attention to the cued locations and features, whereas high DR activity was observed when mice were less attentive. Optogenetic excitation of DR-5HT neurons impaired attention to the cue and degraded behavioral performance, while optogenetic suppression improved attention and performance. A genetically encoded sensor of 5HT release showed reduced 5HT levels in visual cortex when mice attend and detect stimuli. These results demonstrate that DR-5HT neurons are members of the brain's attentional circuit and suggest that 5HT is a novel biological carrier of visual attention.

The utility of explainable A.I. for MRI analysis: Relating model predictions to neuroimaging features of the aging brain
Introduction: Deep learning models highly accurately predict brain-age from MRI but their explanatory capacity is limited. Explainable A.I. (XAI) methods can identify relevant voxels contributing to model estimates, yet, they do not reveal which biological features these voxels represent. In this study, we closed this gap by relating voxel-based contributions to brain-age estimates, extracted with XAI, to human-interpretable structural features of the aging brain. Methods: To this end, we associated participant-level XAI-based relevance maps extracted from two ensembles of 3D-convolutional neural networks (3D-CNN) that were trained on T1-weighted and fluid attenuated inversion recovery images of 2016 participants (age range 18-82 years), respectively, with regional cortical and subcortical gray matter volume and thickness, perivascular spaces (PVS) and water diffusion-based fractional anisotropy of main white matter tracts.Results: We found that all neuroimaging markers of brain aging, except for PVS, were highly correlated with the XAI-based relevance maps. Overall, the strongest correlation was found between ventricular volume and relevance (r = 0.69), and by feature, temporal-parietal cortical thickness and volume, cerebellar gray matter volume and frontal-occipital white matter tracts showed the strongest correlations with XAI-based relevance. Conclusion: Our ensembles of 3D-CNNs took into account a plethora of known aging processes in the brain to perform age prediction. Some age-associated features like PVS were not consistently considered by the models, and the cerebellum was more important than expected. Taken together, we highlight the ability of end-to-end deep learning models combined with XAI to reveal biologically relevant, multi-feature relationships in the brain.

Dynamic functional adaptations during touch observation in autism: Connectivity strength is linked to attitudes towards social touch and social responsiveness
Autistic adults often experience differences in social interactions involving physical contact. Brain imaging studies suggest that these differences may be related to atypical brain responses to social-affective cues, affecting both the experience of receiving touch and observing it in others. However, it remains unclear whether these atypical responses are limited to specific brain regions or represent broader alterations in brain connectivity. The current study investigated how the functional network architecture is modulated during touch observation associated with autism and explored the extent to which changes in this architecture are associated with individual differences in social touch preferences and social responsiveness. By integrating generalized psychophysiological interaction (gPPI) analysis with independent component analysis (ICA), the current study analyzed existing fMRI datasets, in which 21 autistic and 21 non-autistic male adults viewed videos of social and nonsocial touch while undergoing MRI scans. A gPPI analysis of pre-defined regions of interest revealed that autistic adults exhibited increased connectivity between sensory and social brain regions. The strength of some of these connections was positively associated with a higher preference for social touch and greater social responsiveness, suggesting neural compensatory mechanisms that may help autistic adults better understand the meaning of touch. At the level of large-scale brain networks extracted using ICA, atypical connectivity was predominantly observed between the sensorimotor network and other networks involved in social-emotional processing. Increased connectivity was observed in the sensorimotor network during nonsocial touch, suggesting that embodied simulation, the process by which individuals internally simulate touch experience of others in this context, may be more engaged when observing human-object interactions than during human-to-human touch in autism. This study reveals atypical context-dependent modulation of functional brain architecture associated with autism during touch observation, suggesting that challenges in recognizing and using affective touch in social interactions may be associated with altered brain connectivity. Neural compensatory mechanisms in autistic individuals who enjoy social touch and show higher social responsiveness may function as adaptive social responses. However, these compensations appear to be limited to specific brain regions, rather than occurring at the level of large-scale brain networks.

Integrated data from R405W desmin knock-in mice highlight alterations of mitochondrial function, protein quality control, and myofibrillar structure in the initial stages of myofibrillar myopathy
Background: Mutations in the desmin gene cause skeletal myopathies and cardiomyopathies. The objective of this study was to elucidate the molecular pathology induced by the expression of R405W mutant desmin in murine skeletal muscle tissue. Methods: A comprehensive characterization of the skeletal muscle pathology in hetero- and homozygous R405W desmin knock-in mice was performed, employing grip strength, blood acylcarnitine and amino acid, histological, ultrastructural, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing and proteomic analyses. Results: Both hetero- and homozygous R405W desmin knock-in mice showed classical myopathological features of a myofibrillar myopathy with desmin-positive protein aggregation, degenerative changes of the myofibrillar apparatus, increased autophagic build-up, and mitochondrial alterations. Muscle weakness and increased blood concentrations of acylcarnitines and amino acids were only present in homozygous animals. During its translation, mutant desmin does not induce terminal ribosomal stalling. Analyses of RNA sequencing and proteomic data from soleus muscle of 3-month-old mice depicted 59 up- and 2 down-regulated mRNAs and 101 up- and 18 down-regulated proteins that were shared between the heterozygous and homozygous genotypes in the respective omics datasets compared to the wild-type genotype. Combined analysis of the omics data demonstrated 187 significantly dysregulated candidates distributed across four groups of regulation. A down-regulation on the mRNA and protein levels was observed for a multitude of mitochondrial proteins including essential proton gradient-dependent carriers. Up-regulation on both omics levels was present for the transcription factor Mlf1, which is a binding partner of protein quality control related Dnajb6. Down-regulated on mRNA but up-regulated on the protein level was the sarcomeric lesion marker Xirp2 (xin actin-binding repeat-containing protein 2), whereas Ces2c (acylcarnitine hydrolase) was regulated in the opposite way. Conclusions: The present study demonstrates that the expression of mutant desmin results in a myofibrillar myopathy in hetero- and homozygous R405W desmin knock-in mice. Combined morphological, transcriptomic and proteomic analyses helped to decipher the complex pattern of early pathological changes induced by the expression of mutant desmin. Our findings highlight the importance of major mitochondrial alterations, including essential proton gradient-dependent carriers as well as Dnajb6-related protein quality control and Xin-related myofibrillar damage, in the molecular pathogenesis of desminopathies.

Topographic organization of bidirectional connections between the cingulate region (infralimbic area and anterior cingulate area, dorsal part) and the interbrain (diencephalon) of the adult male rat
The medial prefrontal cortex [cingulate region (Brodmann, 1909) (CNG)] in the rat is a connectionally and functionally diverse structure. It harbors cerebral nuclei that use long-range connections to promote adaptive changes to ongoing behaviors. The CNG is often described across functional and anatomical gradients, a dorsal-ventral gradient being the most prominent. Topographic organization is a general feature of the nervous system, and it is becoming clear that such spatial arrangements can reflect connectional, functional, and cellular differences. Portions of the CNG are known to form reciprocal connections with cortical areas and thalamus; however, these connectional features have not been described in detail or mapped to standardized rat brain atlases. Here, we used co-injected anterograde (Phaseolus vulgaris leucoagglutinin) and retrograde (cholera toxin B subunit) tracers throughout the CNG to identify zones of reciprocal connectivity in the diencephalon [or interbrain (Baer, 1837) (IB)]. Tracer distributions were observed using a Nissl-based atlas-mapping approach that facilitates description of topographic organization. This draft report describes CNG connections of the infralimbic area (Rose & Woolsey, 1948) (ILA) and the anterior cingulate area, dorsal part (Krettek & Price, 1977) (ACAd) throughout the IB. We found that corticothalamic connections are predominantly reciprocal, and that ILA and ACAd connections tended to be spatially segregated with minimal overlap. In the hypothalamus (Kuhlenbeck, 1927), we found dense and specific ILA-originating terminals in the following Brain Maps 4.0 atlas territories: dorsal region (Swanson, 2004) (LHAd) and suprafornical region (Swanson, 2004) (LHAs) of the lateral hypothalamic area (Nissl, 1913), parasubthalamic nucleus (Wang & Zhang, 1995) (PSTN), tuberal nucleus, terete part (Petrovich et al., 2001) (TUte), and an ill-defined dorsal cap of the medial mammillary nucleus (Gudden, 1881) (MM). We discuss these findings in the context of feeding behaviors.

Hard-wired visual filters for environment-agnostic object recognition
Conventional deep neural networks (DNNs) are highly susceptible to variations in input domains, unlike biological brains which effectively adapt to environmental changes. Here, we demonstrate that hard-wired Gabor filters, replicating the structure of receptive fields in the brains early visual pathway, facilitate environment-agnostic object recognition without overfitting. Our approach involved fixing the pre-designed Gabor filters in the early layers of DNNs, preventing any alterations during training. Despite the restricted learning flexibility of this model, our networks maintained robust performance even under significant domain shifts, in contrast to conventional DNNs that typically fail in similar conditions. We found that our model effectively clustered identical classes across diverse domains, while conventional DNNs tend to cluster images by domain in the latent space. We observed that the fixed Gabor filters enabled networks to encode global shape information rather than local texture features, thereby mitigating the risk of overfitting.

Investigation of the effect of physiological factors on resting-state and task-based functional connectivity
Understanding the brain's functional network through functional connectivity (FC) is crucial for gaining deeper insights into brain functional mechanism and identifying a potential biomarker for diagnosing neurological disorders. Despite the development of various FC measures, their reliability under different conditions remains under-explored. Moreover, physiological noise can obscure true neural activity, and accordingly, introduce errors into FC patterns. This issue necessitates further investigation. In this study, we evaluate and compare the performance of various methods using Local Field Potential and Blood-Oxygen-Level-Dependent signals across different conditions. We also examine the impact of physiological artifacts on BOLD-FC results. Our comprehensive assessment covers multiple modalities of brain signals, diverse task paradigms, and varying noise levels. Our findings reveal that while Granger Causality-based methods exhibit significant limitations, particularly with BOLD data, multivariate techniques (e.g. partial correlation) demonstrate greater robustness in distinguishing between different types of connections within the network. Notably, our results indicate that physiological artifacts substantially affect FC values, leading to erroneous connectivity estimates, especially with bivariate methods. This research offers a foundational analysis of the effects of physiological artifacts on FC results and provides valuable insights for future studies.

Amyloid Beta Pathology Accelerates Alterations in the Visual Pathway of the 5xFAD Mouse
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid beta plaques and neurofibrillary tangles that leads to decreased quality of life due to behavioral, motor, and cognitive impairments. Due to the widespread pathological nature of AD, many brain regions are affected by amyloid beta plaques including regions important for vision such as the lateral geniculate nucleus (LGN) of the thalamus which is critical for relaying signals from the retina to the primary visual cortex. Using a wide range of techniques including electrophysiological approaches, in vivo and ex vivo imaging methods, and immunohistochemistry in a mouse model with progressing amyloidosis (5xFAD), the goal of this study was to determine whether AD-like pathology disrupts neuronal and synaptic structure and function in the visual system. In vivo electroretinogram recordings revealed photoreceptor dysfunction in the 6- and 9-month-old 5xFAD mice, while optical coherence tomography indicated no changes in retinal thickness. In the dorsolateral geniculate nucleus (dLGN), the rodent homolog of the primate LGN, we identified decreased densities of retinal ganglion cell axon terminals and fewer thalamocortical (TC) neuron cell bodies. No detectable deficits in excitatory synaptic function or TC neuron dendritic structure were seen in the dLGN, and reflexive visual behavior was also found to be normal in the 5xFAD mice. These results indicate relatively modest amyloid-triggered dysfunction in these stages of the visual system suggesting that amyloid beta plaque formation may play only a small role in the visual system dysfunction seen in AD patients. These results may also point to potential compensatory mechanisms that preserve function of visual pathways in the 5xFAD visual system.

Complex motion trajectories are represented by a population code from the ensemble activity of multiple motion-sensitive descending interneurons in locusts
Adaptive locust flight relies on rapid detection and processing of objects moving in the visual field. One identified neural pathway, comprised of the lobula giant movement detector (LGMD) and the descending contralateral movement detector (DCMD), responds preferentially to approaching objects. The LGMD receives retinotopic inputs from ipsilateral ommatidia and generates spikes in a 1:1 ratio in the DCMD, which synapses contralaterally with multiple locomotion-related neurons. Other motion-sensitive neurons have also been identified in locusts but are not as well characterized. To better understand how locusts process visual information, we used multichannel neural recordings within a stimulus arena and presented various complex visual stimuli to investigate the neural encoding of complex object motion. We found multiple discriminated units that responded uniquely to visual motion and categorized the responses. More units responded to motion trajectories with a looming component, compared to translations across the visual field. Dynamic factor analysis (DFA) of discriminated units revealed common trends that reflect the activity of neural ensembles. The numbers and types of common trends varied among motion trajectories. These results increase the understanding of complex visual motion processing in this tractable system.