bioRxiv Subject Collection: Neuroscience's Journal

Evidence for a push-pull interaction between superior colliculi in monocular dynamic vision mode
Visual perception can operate in two distinct vision modes - static and dynamic - that have been associated with different neural activity regimes in the superior colliculus (SC). The static vision mode (low flashing frequencies) is associated with strong SC activation modulated by cortical gain and inhibitory intertectal effects, while the dynamic vision mode (high flashing frequencies) evokes the continuity illusion, with associated suppression of SC neural activity. However, the pathway-wide mechanisms underpinning the dynamic vision mode remain poorly understood, especially in terms of corticotectal and tectotectal feedback. Here, we harness rat functional MRI combined with brain lesions to investigate whole-pathway interactions in the dynamic vision mode. In the SC, we find contralateral suppression of activity opposing positive ipsilateral neural activation upon monocular visual stimulation in the dynamic vision mode. A cortical amplification effect was confirmed for both static and dynamic vision modes through cortical lesions, while further lesioning ipsilateral SC led to a boost in the contralateral negative signals, suggesting an active push-pull interaction between ipsilateral and contralateral SCs during the dynamic vision mode regime. This push-pull interaction is specific to the dynamic vision mode; in the static vision mode, both SCs show similar response polarities. These results highlight hitherto unreported frequency-dependent modulations in the tectotectal pathway and further challenge the contemporary notion that intertectal connections solely serve as reciprocal inhibitory mechanisms for avoiding visual blur during saccade occurrence.

Laminar RNNs: using biologically-inspired network topology on the cortical laminar level in memory tasks
Advancements in neuroscience and artificial intelligence have been fueling one another for decades. In this study, we integrate a neuroimaging model of laminar-level connectomics into a biologically-inspired deep learning model of recurrent neural networks (RNNs) for working memory tasks. The resulting model offers a way to incorporate a more comprehensive representation of brain topology into artificial intelligence without diminishing the performance of the network compared to previous models.

Prefrontal 5α-reductase 2 mediates male-specific acute stress response
Acute stress triggers rapid brain responses, including increased allopregnanolone (AP) synthesis via 5-reductase (5R). However, the involvement of this enzyme in stress response remains elusive. Here, we investigated the roles of the two major 5R isoenzymes in acute stress. Acute stress increased mRNA and protein levels of 5R2, but not 5R1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Targeted mPFC downregulation of 5R2, but not 5R1, markedly reduced the responsiveness of males, but not females, to both stressful and arousing stimuli. Similar sex differences were observed in 5R2 knockout rats. While 5R1 regulated AP synthesis under baseline conditions, 5R2 enabled this process in response to acute stress. Single-nucleus transcriptomic analyses revealed that 5R2 enabled stress-induced protein synthesis in pyramidal neurons and glia of the mPFC. These findings underscore the pivotal role of 5R2 in shaping sex-related differences in acute stress reactivity.

Sound perception in realistic surgery scenarios: Towards EEG-based auditory work strain measures for medical personnel.
Surgical personnel face various stressors in the workplace, including environmental sounds. Mobile electroencephalography (EEG) offers a promising approach for objectively measuring how individuals perceive sounds. In this study, we utilized mobile EEG to explore how a realistic soundscape is perceived during simulated laparoscopic surgery. To examine the varying demands placed on personnel in different situations, we manipulated the cognitive demand during the surgical task, using a memory task. To assess responses to the soundscape, we calculated event-related potentials for distinct sound events and temporal response functions for the ongoing soundscape. Although participants reported varying degrees of demand under different conditions, no significant effects were observed on surgical task performance or EEG parameters. However, changes in surgical task performance and EEG parameters over time were noted, while subjective results remained consistent over time. These findings highlight the importance of using multiple measures to fully understand the complex relationship between sound processing and cognitive demand. Furthermore, in the context of combined EEG and audio recordings in real-life scenarios, sparse representations of the soundscape have advantages over more detailed representations. Our results indicate that both types of representations are equally effective in eliciting neural responses. Overall, this study marks a significant step towards objectively investigating sound processing in applied settings.

Effect of interhemispheric zero-phase entrainment of the intrinsic mu-rhythm on behavioral and neural markers of predictive coding
Goal-directed behavior requires the integration of information from the outside world and internal (somatosensory) sources about our own actions. Expectations (or 'internal models') are generated from prior knowledge and constantly updated based on sensory feedback. This optimized information integration ('predictive coding') results in a global behavioral advantage of anticipated action in the presence of uncertainty. Our goal was to probe the effect of phase entrainment of the sensorimotor mu-rhythm on visuomotor integration. Participants received transcranial alternating current stimulation over bilateral motor cortices (M1) while performing a visually-guided force adjustment task during functional magnetic resonance imaging. Inter-hemispheric zero-phase entrainment resulted in effector-specific modulation of performance precision and effector-generic minimization of force signal complexity paralleled by BOLD activation changes in bilateral caudate and increased functional connectivity between the right M1 and contralateral putamen, inferior parietal, and medial temporal regions. While effector-specific changes in performance precision were associated with contralateral caudate and hippocampal activation decreases, only the global reduction in force signal complexity was associated with increased functional M1 connectivity with bilateral striatal regions. We propose that zero-phase synchronization represents a neural mode of optimized information integration related to internal model updating within the recursive perception-action continuum associated with predictive coding.

Fast-spiking interneuron detonation drives high-fidelity inhibition in the olfactory bulb
Inhibitory circuits in the mammalian olfactory bulb (OB) dynamically reformat olfactory information as it propagates from peripheral receptors to downstream cortex. To gain mechanistic insight into how specific OB interneuron types support this sensory processing, we examine unitary synaptic interactions between excitatory mitral and tufted cells (MTCs), the OB projection cells, and a conserved population of anaxonic external plexiform layer interneurons (EPL-INs) using pair and quartet whole-cell recordings in acute mouse brain slices. Physiological, morphological, neurochemical, and synaptic analyses divide EPL-INs into distinct subtypes and reveal that parvalbumin-expressing fast-spiking EPL-INs (FSIs) perisomatically innervate MTCs with release-competent dendrites and synaptically detonate to mediate fast, short-latency recurrent and lateral inhibition. Sparse MTC synchronization supralinearly increases this high-fidelity inhibition, while sensory afferent activation combined with single-cell silencing reveals that individual FSIs account for a substantial fraction of total network-driven MTC lateral inhibition. OB output is thus powerfully shaped by detonation-driven high-fidelity perisomatic inhibition.

Cortex Folding by Combined Progenitor Expansion and Adhesion-Controlled Neuronal Migration
Folding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we find that combining the Flrt1/3 double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 results in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 results in enhanced formation of gyri. Single cell transcriptomics and simulations suggest that changes in adhesive properties of cortical neurons, their proportions and densities in the cortical plate, combined with lateral dispersion during their radial migration are important folding parameters. These results identify key developmental mechanisms that cooperate to promote cortical gyrification.

Impacts of Perinatal Nicotine Exposure on nAChR Expression and Glutamatergic Synaptic Transmission in the Mouse Auditory Brainstem
Exposure to nicotine in utero, often due to maternal smoking, significantly elevates the risk of auditory processing deficits in offspring. This study investigated the effects of chronic nicotine exposure during a critical developmental period on the functional expression of nicotinic acetylcholine receptors (nAChRs), glutamatergic synaptic transmission, and auditory processing in the mouse auditory brainstem. We evaluated the functionality of nAChRs at a central synapse and explored the impact of perinatal nicotine exposure (PNE) on synaptic currents and auditory brainstem responses (ABR) in mice. Our findings revealed developmentally regulated changes in nAChR expression in the medial nucleus of the trapezoid body (MNTB) neurons and presynaptic Calyx of Held terminals. PNE was associated with enhanced acetylcholine-evoked postsynaptic currents and compromised glutamatergic neurotransmission, highlighting the critical role of nAChR activity in the early stages of auditory synaptic development. Additionally, PNE resulted in elevated ABR thresholds and diminished peak amplitudes, suggesting significant impairment in central auditory processing without cochlear dysfunction. This study provides novel insights into the synaptic disturbances that contribute to auditory deficits resulting from chronic prenatal nicotine exposure, underlining potential targets for therapeutic intervention.

Collagen I is a critical organizer of scarring and CNS regeneration failure
Although axotomized neurons retain the ability to initiate the formation of growth cones and attempt to regenerate after spinal cord injury, the scar area formed as a result of the lesion in most adult mammals contains a variety of reactive cells that elaborate multiple extracellular matrix and enzyme components that are not suitable for regrowth. Newly migrating axons in the vicinity of the scar utilize upregulated LAR family receptor protein tyrosine phosphatases, such as PTP{sigma}, to associate with extracellular chondroitin sulphate proteoglycans (CSPGs), which have been discovered to tightly entrap the regrowing axon tip and transform it into a dystrophic non-growing endball. The scar is comprised of two compartments, one in the lesion penumbra, the glial scar, composed of reactive microglia, astrocytes and OPCs; and the other in the lesion epicenter, the fibrotic scar, which is made up of fibroblasts, pericytes, endothelial cells and inflammatory cells. While the fibrotic scar is known to be strongly inhibitory, even more so than the glial scar, the molecular determinants that curtail axon elongation through the injury core are largely uncharacterized. Here, we show that one sole member of the entire family of collagens, collagen I, creates an especially potent inducer of endball formation and regeneration failure. The inhibitory signaling is mediated by mechanosensitive ion channels and RhoA activation. Staggered systemic administration of two blood-brain barrier permeable-FDA approved drugs, aspirin and pirfenidone, reduced fibroblast incursion into the complete lesion and dramatically decreased collagen I, as well as CSPG deposition which were accompanied by axonal growth and functional recovery. The anatomical substrate for robust axonal regeneration was provided by laminin producing GFAP+ and NG2+ bridging cells that spanned the wound. Our results reveal a collagen I-mechanotransduction axis that regulates axonal regrowth in spinal cord injury and raise a promising strategy for rapid clinical application.

Establishing neuroanatomical correspondences across mouse and marmoset brain structures
Interest in the common marmoset is growing due to evolutionarily proximity to humans compared to laboratory mice, necessitating a comparison of mouse and marmoset brain architectures, including connectivity and cell type distributions. Creating an actionable comparative platform is challenging since these brains have distinct spatial organizations and expert neuroanatomists disagree. We propose a general theoretical framework to relate named atlas compartments across taxa and use it to establish a detailed correspondence between marmoset and mice brains. Contrary to conventional wisdom that brain structures may be easier to relate at higher levels of the atlas hierarchy, we find that finer parcellations at the leaf levels offer greater reconcilability despite naming discrepancies. Utilizing existing atlases and associated literature, we created a list of leaf- level structures for both species and establish five types of correspondence between them. One-to-one relations were found between 43% of the structures in mouse and 47% in marmoset, whereas 25% of mouse and 10% of marmoset structures were not relatable. The remaining structures show a set of more complex mappings which we quantify. Implementing this correspondence with volumetric atlases of the two species, we make available a computational tool for querying and visualizing relationships between the corresponding brains. Our findings provide a foundation for computational comparative analyses of mesoscale connectivity and cell type distributions in the laboratory mouse and the common marmoset.

Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology
Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain mature neuron morphology. Loss of function in C. elegans DIP-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find that dip-2 mutants display specific genetic interactions with sax-2, the C. elegans ortholog of Drosophila Furry and mammalian FRY. Combined loss of DIP-2 and SAX-2 results in severe disruption of neuronal morphology maintenance accompanied by increased release of neuronal extracellular vesicles (EVs). By screening for suppressors of dip-2 sax-2 double mutant defects we identified gain-of-function (gf) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A. In dip-2 sax-2 double mutants carrying either pad-1(gf) or tat-5(gf) mutation, EV release is reduced and neuronal morphology across multiple neuron types is restored to largely normal. PAD-1(gf) acts cell autonomously in neurons. The domain containing pad-1(gf) is essential for PAD-1 function, and PAD-1(gf) protein displays increased association with the plasma membrane and inhibits EV release. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains morphology of neurons and other types of cells, shedding light on the mechanistic basis of neurological disorders involving human orthologs of these genes.

Eye movements reveal age differences in how arousal modulates saliency priority but not attention processing speed
The arousal-biased competition theory posits that inducing arousal increases attentional priority of salient stimuli while reducing priority of non-pertinent stimuli. However, unlike in young adults, older adults rarely exhibit shifts in priority under increased arousal, and prior studies have proposed different neural mechanisms to explain how arousal differentially modulates selective attention in older adults. Therefore, we investigated how the threat of unpredictable shock differentially modulates attentional control mechanisms in young and older adults by observing eye movements. Participants completed two oculomotor search tasks in which the salient distractor was typically captured by attention (singleton search) or proactively suppressed (feature search). We found that arousal did not modulate attentional priority for any stimulus among older adults nor affect the speed of attention processing in either age group. Furthermore, we observed that arousal modulated pupil sizes and found a correlation between evoked pupil responses and oculomotor function. Our findings suggest age differences in how the locus coeruleus-noradrenaline system interacts with neural networks of attention and oculomotor function.

A novel critic signal in identified midbrain dopaminergic neurons of mice training inoperant tasks
In the canonical interpretation of phasic activation of dopaminergic neurons during Pavlovian conditioning, initially cell firing is triggered by unexpected rewards. Upon learning, activation instead follows the reward-predictive conditioned stimulus. When expected rewards are withheld, firing is inhibited. Here, we recorded optogenetically identified dopaminergic neurons of ventral tegmental area (VTA) in mice training in successive operant sensory discrimination tasks. A delay was imposed between nose-poke choices and trial outcome signals (reward or punishment). While animals were still performing at sub-criterion levels in the task, firing increased after correct choices, but prior to trial outcome signals. Thus, the neurons predicted whether choices would be rewarded, despite the animals' poor behavioral performance. Surprisingly, these neurons also fired after reward delivery, as if the rewards had been unexpected, but the cells were inhibited after punishment signals, as if the reward had been expected after all. These inconsistencies suggest extension of theoretical formulations of dopaminergic neuronal activity: it would embody multiple roles in temporal difference learning and actor-critic models. Furthermore, during chance and sub-criterion performance levels during task training, the mice performed other task strategies (e.g., alternation and spatial persistence) which did not reliably elicit rewards, again while these neurons predicted the correct choice. The reward prediction activity of these neurons could serve as critic signal for the preceding choice. These finding are consistent with the notion that multiple Bayesian belief representations must be reconciled prior to reaching criterion performance levels.

Timed sulfonylurea modulation improves locomotor and sensory dysfunction following spinal cord injury
Traumatic injury to the spinal cord (SCI) results in immediate necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progress hemorrhagic necrosis (PHN) and excessive excitation are the primary sources of neural injury triggered by various insults, causing neuronal cytotoxicity and the gradual enlargement of lesions. Recent approaches have involved blocking TRPM4, a contributor to PHN, using the sulfonylurea (SUR) subunits regulator glibenclamide. However, since SUR subunits are expressed in both neurons and glial cells in the spinal cord and sensory neurons, forming functional KATP channels, the use of glibenclamide can exacerbate the development of SCI-induced chronic pain. In this study, we explored a treatment strategy involving the administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals post-SCI. Our goal is to determine whether this approach significantly enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult male and female rats. Immunostaining, electrophysiological recording in vitro, spectrophotometric assay, Western blot, and behavioral tests were performed to detect the outcomes. Results showed that the timed application of glibenclamide and diazoxide at various post-SCI time points significantly improved locomotor function and mitigated the development of SCI-induced chronic pain. These preclinical studies introduce a promising treatment strategy for addressing SCI-induced dysfunction.

Sex differences emerge after the menopause transition:Females show accelerated decline in episodic memory for spatial context at midlife
Background and Objectives: The ability to remember past events in rich contextual detail (episodic memory) declines with advancing age, with accelerated decline around midlife. Past research indicates there may be sex differences in cognitive aging trajectories and risk for age-related neurodegenerative diseases, i.e. Alzheimer's Disease. Yet, little is known about how biological sex affects episodic memory in the adult lifespan. We examined age differences in episodic memory for spatial context in males and females. Research Design and Methods: 192 adults aged 21 to 65 (M=44, SD=13, 134 females) completed a face-location task measuring spatial context memory (correct spatial context retrieval rates) and facial item memory (correct recognition rates), and the California Verbal Learning Test version II (CVLT-II) measuring verbal item memory (long free recall, cued recall, and recognition rates). Changepoint regression analysis was used to estimate the slope of memory across age and any significant shifts in the slope (indicating critical transition periods). Results: Regression analyses revealed that the best fitting model for females on spatial context memory accuracy was a one-changepoint model, with gradual decline of 2% (SE=1) fewer correct responses per year of age from age 21 until age 50 (95% CI 41, 58), shifting to more rapid decline of 4% (SE=1) fewer correct responses per year of age until age 65. The best fitting model for males on spatial context memory accuracy was linear, with no significant changes across ages. The best fitting models for both sexes were linear for facial item memory accuracy, spatial context memory and facial item memory reaction times, and verbal item memory accuracy. Discussion and Implication: Males and females show similar decline on spatial context memory from young adulthood until midlife, after which females show greater decline than males. Importantly, disaggregating by sex indicated that past midlife effects on episodic memory for context may be driven by a specific group of females (post-menopausal), as accelerated decline occurred at the same time as menopause in midlife females and did not occur in midlife males.

Sex differences in change-of-mind neuroeconomic decision-making is modulated by LINC00473 in medial prefrontal cortex
Changing ones mind is a complex cognitive phenomenon involving a continuous re-appraisal of the trade-off between past costs and future value. Recent work modeling this behavior across species has established associations between aspects of this choice process and their contributions to altered decision-making in psychopathology. Here, we investigated the actions in medial prefrontal cortex (mPFC) neurons of long intergenic non-coding RNA, LINC00473, known to induce stress resilience in a striking sex-dependent manner, but whose role in cognitive function is unknown. We characterized complex decision-making behavior in male and female mice longitudinally in our neuroeconomic foraging paradigm, Restaurant Row, following virus-mediated LINC00473 expression in mPFC neurons. On this task, mice foraged for their primary source of food among varying costs (delays) and subjective value (flavors) while on a limited time-budget during which decisions to accept and wait for rewards were separated into discrete stages of primary commitments and secondary re-evaluations. We discovered important differences in decision-making behavior between female and male mice. LINC00473 expression selectively influenced multiple features of re-evaluative choices, without affecting primary decisions, in female mice only. These behavioral effects included changing how mice (i) cached the value of the passage of time and (ii) weighed their history of economically disadvantageous choices. Both processes were uniquely linked to change-of-mind decisions and underlie the computational bases of distinct aspects of counterfactual thinking. These findings reveal a key bridge between a molecular driver of stress resilience and psychological mechanisms underlying sex-specific decision-making capabilities.

Flp-recombinase mouse line for genetic manipulation of ipRGCs
Light has myriad impacts on behavior, health, and physiology. These signals originate in the retina and are relayed to the brain by more than 40 types of retinal ganglion cells (RGCs). Despite a growing appreciation for the diversity of RGCs, how these diverse channels of light information are ultimately integrated by the ~50 retinorecipient brain targets to drive these light-evoked effects is a major open question. This gap in understanding primarily stems from a lack of genetic tools that specifically label, manipulate, or ablate specific RGC types. Here, we report the generation and characterization of a new mouse line (Opn4FlpO), in which FlpO is expressed from the Opn4 locus, to manipulate the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells. We find that the Opn4FlpO line, when crossed to multiple reporters, drives expression that is confined to ipRGCs and primarily labels the M1-M3 subtypes. Labeled cells in this mouse line show the expected intrinsic, melanopsin-based light response and morphological features consistent with the M1-M3 subtypes. In alignment with the morphological and physiological findings, we see strong innervation of non-image forming brain targets by ipRGC axons, and weaker innervation of image forming targets in Opn4FlpO mice labeled using AAV-based and FlpO-reporter lines. Consistent with the FlpO insertion disrupting the endogenous Opn4 transcript, we find that Opn4FlpO/FlpO mice show deficits in the pupillary light reflex, demonstrating their utility for behavioral research in future experiments. Overall, the Opn4FlpO mouse line drives Flp-recombinase expression that is confined to ipRGCs and most effectively drives recombination in M1-M3 ipRGCs. This mouse line will be of broad use to those interested in manipulating ipRGCs through a Flp-based recombinase for intersectional studies or in combination with other, non-Opn4 Cre driver lines.

Chronic ethanol exposure produces long-lasting, subregion-specific physiological adaptations in RMTg-projecting mPFC neurons
Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) which facilitate the maladaptive behaviors interfering with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is a GABAergic midbrain region involved in aversive signaling and is functionally altered by chronic ethanol exposure. Our recent work identified a dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE significantly increased intrinsic excitability as well as excitatory and inhibitory synaptic drive in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE also increased excitatory synaptic drive in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol.

Effect of muscarinic blockade on the speed of attention shifting and learning
The study aimed to investigate to what extent blockade of muscarinic receptors affects the speed of endogenous versus exogenous attentional shift times, and how it affects learning induced improvements of attention shift times. Subjects viewed an array of 10 moving clocks and reported the time a clock indicated when cued. Target clocks were indicated by peripheral or central cues, including conditions of pre-cuing. This allowed assessing shift times when attention was pre-allocated, when peripheral cues triggered exogenous attention shifts, and when central cues triggered endogenous attention shifts. In study 1, each subject participated in 2 sessions (scopolamine/placebo), whereby the order of drug intake was counterbalanced across subjects, and subjects were blinded to conditions. Scopolamine/placebo was administered before a psychophysical experiment was conducted. In study 2, the effect of muscarinic blockade on learning induced improvements of attention shift times was investigated. Here scopolamine/placebo was administered immediately after the first (of two) psychophysical sessions, whereby a given subject either received scopolamine or placebo pills. Confirming previous results, we show that pre-cuing resulted in the fastest shift times, followed by exogenous cuing, with endogenous attentional shifts being slowest. Scopolamine application increased attentional shift times across all 3 conditions compared to placebo, but in a dose dependent manner. Additionally, blockade of muscarinic receptors immediately after the first session reduced learning dependent improvement of attention shift times. These results demonstrate that muscarinic receptors play an important role in attention shifting, and they contribute to learning of attention shifting.

Cell-surface receptor-mediated regulation of synaptic organelle distribution controls dendritic spine maturation
The spine apparatus (SA), an endoplasmic reticulum-related organelle present in a subset of mature dendritic spines, plays a key role in postsynaptic development and has been implicated in various neurological disorders. However, the molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the GPCR-like receptor GPR158 and a largely uncharacterized phospholipase C (PLC), PLCXD2, that controls SA abundance. Sparse genetic manipulations in vivo demonstrate that in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers dendritic spine maturation. Finally, we show that extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction. Together, our findings reveal how a postsynaptic receptor signaling complex regulates the local lipid microenvironment to control SA abundance required for the proper maturation of dendritic spines.

Data-driven analysis identifies female-specific social modulation deficit after chronic social defeat stress
Background: Chronic social defeat stress is a widely used depression model in male mice. Several proposed adaptations extend this model to females with variable, often marginal effects. We examine the if widely used male-defined metrics of stress are suboptimal in females and reveal sex-specific adaptations. Methods: Using a data-driven method we comprehensively classified social interaction behavior in 761 male and female mice after chronic social witness/defeat stress, examining social modulation of behavioral frequencies and associations with conventional metrics (i.e., social interaction (SI) ratio). Results: Social stress induces distinct behavioral adaptation patterns in males and females. SI ratio leads to underpowered analyses in females with limited utility to differentiate susceptibility/resilience. Data-driven analyses reveal failure of social adaptation in stressed female mice that is captured in attenuated velocity change from no target to target tests ({Delta}Velocity) and validate this in three female social stress models. Combining SI ratio and {Delta}Velocity optimally differentiates susceptibility/ resilience in females and this metric reveals resilient-specific adaptation in a resilience-associated neural circuit in female mice. Conclusions: We demonstrate that psychological or physical social defeat stress induces similar deficits in females that is qualitatively distinct from male deficits and inadequately sampled by male-defined metrics. We identify modulation of locomotion as a robust and easily implementable metric for rigorous research in female mice. Overall, our findings highlight the need to critically evaluate sex differences in behavior and implement sex-based considerations in preclinical model design.

Functional resilience of the neural visual recognition system post-pediatric occipitotemporal resection
In the typically developing (TD) brain, neural representations for visual stimulus categories (e.g., faces, objects, and words) emerge in bilateral occipitotemporal cortex (OTC), albeit with weighted asymmetry; in parallel, recognition behavior continues to be refined. A fundamental question is whether two hemispheres are necessary or redundant for the emergence of neural representations and recognition behavior typically distributed across both hemispheres. The rare population of patients undergoing unilateral OTC resection in childhood offers a unique opportunity to evaluate whether neural computations for visual stimulus individuation suffice for recognition with only a single developing OTC. Here, using functional magnetic resonance imaging, we mapped category selectivity (CS) and neural representations for individual stimulus exemplars using repetition suppression (RS) in the non-resected hemisphere of pediatric OTC resection patients (n = 9) and control patients with resection outside of OTC (n = 12), as well as in both hemispheres of TD controls (n = 21). There were no univariate group differences in the magnitude of CS or RS or any multivariate differences (per representational similarity analysis) in neural activation to faces, objects, or words across groups. Notwithstanding their comparable neural profiles, accuracy of OTC resection patients on face and object recognition, but not word recognition, was statistically inferior to that of controls. The comparable neural signature of the OTC resection patients' preserved hemisphere and the other two groups highlights the resilience of the system following damage to the contralateral homologue. Critically, however, a single OTC does not suffice for normal behavior, and, thereby, implicates the necessity for two hemispheres.

Pharmacological HDAC3 inhibition alters memory updating in young and old mice
Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry. One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o. mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-m.o.) mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed. To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

Resiliency to Alzheimer's disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging
Despite the presence of significant Alzheimer's disease (AD) pathology, characterized by amyloid {beta} (A{beta}) plaques and phosphorylated tau (pTau) tangles, some cognitively normal elderly individuals do not inevitably develop dementia. These findings give rise to the notion of cognitive 'resilience', suggesting maintained cognitive function despite the presence of AD neuropathology, highlighting the influence of factors beyond classical pathology. Cortical astroglial inflammation, a ubiquitous feature of symptomatic AD, shows a strong correlation with cognitive impairment severity, potentially contributing to the diversity of clinical presentations. However, noninvasively imaging neuroinflammation, particularly astrogliosis, using MRI remains a significant challenge. Here we sought to address this challenge and to leverage multidimensional (MD) MRI, a powerful approach that combines relaxation with diffusion MR contrasts, to map cortical astrogliosis in the human brain by accessing sub-voxel information. Our goal was to test whether MD-MRI can map astroglial pathology in the cerebral cortex, and if so, whether it can distinguish cognitive resiliency from dementia in the presence of hallmark AD neuropathological changes. We adopted a multimodal approach by integrating histological and MRI analyses using human postmortem brain samples. Ex vivo cerebral cortical tissue specimens derived from three groups comprised of non-demented individuals with significant AD pathology postmortem, individuals with both AD pathology and dementia, and non-demented individuals with minimal AD pathology postmortem as controls, underwent MRI at 7 T. We acquired and processed MD-MRI, diffusion tensor, and quantitative T1 and T2 MRI data, followed by histopathological processing on slices from the same tissue. By carefully co-registering MRI and microscopy data, we performed quantitative multimodal analyses, leveraging targeted immunostaining to assess MD-MRI sensitivity and specificity towards A{beta}, pTau, and glial fibrillary acidic protein (GFAP), a marker for astrogliosis. Our findings reveal a distinct MD-MRI signature of cortical astrogliosis, enabling the creation of predictive maps for cognitive resilience amid AD neuropathological changes. Multiple linear regression linked histological values to MRI changes, revealing that the MD-MRI cortical astrogliosis biomarker was significantly associated with GFAP burden (standardized {beta}=0.658, pFDR<0.0001), but not with A{beta} (standardized {beta}=0.009, pFDR=0.913) or pTau (standardized {beta}=-0.196, pFDR=0.051). Conversely, none of the conventional MRI parameters showed significant associations with GFAP burden in the cortex. While the extent to which pathological glial activation contributes to neuronal damage and cognitive impairment in AD is uncertain, developing a noninvasive imaging method to see its affects holds promise from a mechanistic perspective and as a potential predictor of cognitive outcomes.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies
Spread and aggregation of misfolded -synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed ''strains'' for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain (e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro -- termed Strain A and Strain B -- and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (PD Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

Dynamic Accumbal Overrepresentation of Reward Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure
The increasing prevalence of cannabis use during pregnancy has raised significant medical concerns, primarily related to the presence of {Delta}9-tetrahydrocannabinol (THC), which readily crosses the placenta and impacts fetal brain development. Previous research has identified midbrain dopaminergic neuronal alterations related to maternal THC consumption. However, the enduring consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during voluntary reward pursuit have not been specifically determined. Here, we characterize PCE rats during food (palatable pellets) or opioid (remifentanyl)-maintained reward seeking. We find that the supra motivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that in utero THC exposure leads to increased cue-evoked dopamine release responses and an overrepresentation of cue-aligned, effort-driven striatal patterns of encoding. Recapitulating findings in humans, drug-related neurobiological adaptations of PCE were more pronounced in males, who also showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders to a pronounced neurodevelopmental susceptibility to addiction-like disorders later in life.

Quick, Don't Move!: Wh-Movement and Wh-In-Situ Structures in Rapid Parallel Reading - EEG studies in English, Urdu, and Mandarin Chinese
A fundamental question in the cognitive neuroscience of language is how grammatical representations are reflected in the organization and activity of the brain. This is challenging in part because superficial differences between languages, e.g., word order, exert different demands on the memory systems that process these structures. Here, we present an electroencephalography (EEG) study to investigate the brain's responses to wh-constructions in English, Urdu, and Mandarin Chinese. In addition to the different word orders, writing systems, and morphological typologies of the 3 languages, these languages diverge with regard to how wh-constructions are formed: English requires filler-gap dependencies for wh-objects, whereas Urdu and Mandarin Chinese do not. We use a rapid parallel reading task, in which short sentences are displayed in parallel for 200ms to mitigate the different demands placed on memory systems. We show that neural responses distinguish wh-object constructions from their controls in midline anterior (Urdu, Mandarin Chinese) and right posterior sensors (English, Mandarin Chinese), from 200-400ms (English, Mandarin Chinese) and 500-800ms (English, Urdu). Although there is no detectable uniform, language-invariant response to wh-constructions across languages, there are a number of shared features in the evoked response between any pair of languages, i.e., wh-in-situ constructions generate an evoked response in midline anterior sensors. Moreover, behavioral evidence shows a robust cross-language cost of processing wh-object constructions, regardless of their surface form. This demonstrates that readers of diverse languages can process some grammatical information in a short 200ms fixation, and that the RPVP methodology may enable new ways of linking cognitive neuroscience of language to comparative syntax, i.e., the systematic description of similarities and differences between grammatical structures.

Oseltamivir (Tamiflu), a Commonly Prescribed Antiviral Drug, Mitigates Hearing Loss in Mice
Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric patients. Here, we performed an unbiased screen of 1,300 FDA-approved drugs for protection against cisplatin-induced cell death in an inner ear cell line, and identified oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, as a top candidate. Oseltamivir phosphate was found to be otoprotective by oral delivery in multiple established cisplatin and noise exposure mouse models. The drug conferred permanent hearing protection of 15-25 dB SPL for both female and male mice. Oseltamivir treatment reduced in mice outer hair cells death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. A potential binding protein, ERK1/2, associated with inflammation, was shown to be activated with cisplatin treatment and reduced by oseltamivir cotreatment in cochlear explants. Importantly, the number of infiltrating immune cells to the cochleae in mice post noise exposure, were significantly reduced with oseltamivir treatment, suggesting an anti-inflammatory mechanism of action. Our results support oseltamivir, a widespread drug for influenza with low side effects, as a promising otoprotective therapeutic candidate in both cisplatin chemotherapy and traumatic noise exposure.

Unraveling the complexity of rat object vision requires a full convolutional network - and beyond
Despite their prominence as model systems to dissect visual cortical circuitry, it remains unclear whether rodents are capable of truly advanced processing of visual information. Here, we considered several psychophysical studies of rat object vision, and we used a deep convolutional neural network (CNN) to measure the computational complexity required to account for the patterns of rat performances reported in these studies, as well as for the animals' perceptual strategies. We found that at least half of the CNN depth was required to match the modulation of rat classification accuracy in tasks where objects underwent variations of size, position and orientation. However, the full network was needed to equal the tolerance of rat perception to more severe image manipulations, such as partial occlusion and reduction of objects to their outlines. Finally, rats displayed a perceptual strategy that was way more invariant than that of the CNN, as they more consistently relied on the same set of diagnostic features across object transformations. Overall, these results reveal an unexpected level of sophistication of rat object vision, while reinforcing the intuition that, despite their proficiency in solving challenging image classification tasks, CNNs learn solutions that only marginally match those of biological visual systems.

Impact Of Learned Helplessness On Cognitive Performance And Resting-State Connectivity: An fMRI Study
Learned helplessness (LH) is the phenomenon of resignation in the face of a problematic situation and is caused by the feeling of lacking control in a situation due to internal or external factors. This means that an individual does not seek to resolve the situation they are confronted with and consciously or unconsciously chooses to be passive. The Dorsal Raphe Nucleus (DRN) core could be at the root of the persistent action of the LH phenomenon and influences regions such as the striatum and amygdala. It is thought that the LH phenomenon could affect self-perception and it has been shown that the default mode network (DMN) is often associated with self-reflection during the resting state (RS) phase. It is therefore possible that LH influences both self-perception and the DMN. Based on previous studies, we investigated how LH affects participants. We used functional MRI (fMRI) to test this hypothesis. Participants were divided into two groups, subjected to solvable (control group), and solvable plus unsolvable (LH group) cognitive tasks. We also measured electrodermal signals, OCEAN (Openness, Conscientiousness, Extraversion, Agreeableness, Neuroticism) personality scores, variables related to the anagram resolution, and related these to LH. The study revealed significant differences in the RS contrast between the two groups, with the Posterior Cingulate Cortex (PCC) (an area of the DMN) being more connected to the DRN in the LH group than in the control group, and a portion of the Superior Temporal Gyrus being more connected to the PCC in the control group than in the LH group. These results suggest that LH may have a direct impact on the DMN and could lead to the start of long-term changes.

Reinforcement learning when your life depends on it: a neuro-economic theory of learning
Synaptic plasticity enables animals to adapt to their environment, but memory formation can consume a substantial amount of metabolic energy, potentially impairing survival. Hence, a neuro-economic dilemma arises whether learning is a profitable investment or not, and the brain must therefore judiciously regulate learning. Indeed, in experiments it was observed that during starvation, Drosophila suppress formation of energy-intensive aversive memories. Here we include energy considerations in a reinforcement learning framework. Simulated flies learned to avoid noxious stimuli through synaptic plasticity in either the energy expensive long-term memory (LTM) pathway, or the decaying anesthesia-resistant memory (ARM) pathway. The objective of the flies is to maximize their lifespan, which is calculated with a hazard function. We find that strategies that switch between the LTM and ARM pathways based on energy reserve and reward prediction error, prolong lifespan. Our study highlights the significance of energy-regulation of memory pathways and dopaminergic control for adaptive learning and survival. It might also benefit engineering applications of reinforcement learning under resources constraints.

Chronic fluoxetine treatment desensitizes serotoninergic inhibition of GABA inputs and the intrinsic excitability of dorsal raphe serotonin neurons
Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical to normal brain function such mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to exert clinical benefits. The cellular mechanism underlying this delay was not fully understood. Here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons; this GABAergic regulation was reduced by 5-HT, which was prevented by G-protein-activated inwardly rectifying potassium (Girk) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of Girk channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment of fluoxetine, a widely used SSRI type antidepressant, this 5-HT inhibition of GABAergic inputs was substantially downregulated. Furthermore, the chronic fluoxetine treatment substantially downregulated the 5-HT activation of the inhibitory Girk current in 5-HT neurons. Taken together, our results suggest that chronic fluoxetine administration, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic, behaviorally important GABA neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulate somatic 5-HT autoreceptor-activated Girk channel-mediated hyperpolarization and decrease in input resistance and intrinsic excitability, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity, potentially contributing to the antidepressant effect of SSRIs.

Experience-dependent, sexually dimorphic synaptic connectivity defined by sex-specific cadherin expression
We describe here the molecular mechanisms by which juvenile experience defines patterns of sexually dimorphic synaptic connectivity in the adult nervous system of the nematode C. elegans. We show that starvation of juvenile males disrupts serotonin dependent activation of the CREB transcription factor in a nociceptive sensory neuron, PHB. CREB acts through a cascade of transcription factors to control expression of an atypical cadherin protein, FMI-1/Flamingo. During postembryonic development, FMI-1/Flamingo has the capacity to promote and maintain synaptic connectivity of the PHB nociceptive sensory to a command interneuron, AVA, in both sexes, but the serotonin transcriptional regulatory cassette antagonizes FMI-1/Flamingo expression in males, thereby establishing sexually dimorphic connectivity between PHB and AVA. A critical regulatory node in this process is the CREB-target LIN-29, a Zn finger transcription factor which integrates four different layers of information: sexual specificity, past feeding status, time and cell-type specificity. Our findings provide the mechanistic details of how an early juvenile experience defines sexually dimorphic synaptic connectivity.

Two-brain microstates: A novel method for quantifying task-driven inter-brain asymmetry
Joint action and interpersonal coordination between individuals are integral parts of daily life, and various behavioral tasks have been designed to study their emergence and maintenance. One example is the mirror-game paradigm, which examines the dynamics of two people improvising motion together. However, the underlying neural mechanisms remain poorly understood, and inter-brain methods underdeveloped. Previously, we reported unique individual behavioral and neural signatures of performing actions when observed by others using a mirror-game paradigm. Here, we explored inter-brain synchronization during the mirror-game paradigm using a novel approach employing two-brain EEG microstates. Microstates are quasi-stable configurations of brain activity that have been reliably replicated across studies, and proposed to be basic buildings blocks for mental processing. Expanding the microstate methodology to dyads of interacting participants (two-brain microstates) enables us to investigate quasi-stable moments of inter-brain synchronous and asymmetric activity. Interestingly, we found that conventional microstates fitted to individuals were not related to the different task conditions; however, the dynamics of the two-brain microstates were changed for the observed actor-observer condition, compared to all other conditions where participants had more symmetric task demands (rest, individual, joint). These results suggest that two-brain microstates might serve as a method for identifying inter-brain states during asymmetric real-time social interaction.

Reorganisation of circadian activity and the pacemaker circuit under novel light regimes
Many environmental features are cyclic, with predictable daily and yearly changes which vary across latitudes. Organisms cope with such change using internal timekeepers or circadian clocks which have evolved remarkable flexibility. This flexibility is evident in the waveforms of behavioural and underlying molecular rhythms. In today's world, many ecosystems experience artificial light at night, leading to unusual photoperiodic conditions. Additionally, occupational demands expose many humans to unconventional light cycles. Yet, practical means of manipulating activity waveforms for beneficial purposes are lacking. This requires an understanding of principles and factors governing waveform plasticity of activity rhythms. Even though waveform plasticity remains underexplored, few recent studies have used novel light regimes, inspired by shift work schedules, with alternating bright light and dim light (LDimLDim) to manipulate the activity waveform of nocturnal rodents. We undertook this study to understand what aspects of light regimes contribute to waveform flexibility and how the underlying neuronal circuitry regulates the behaviour by subjecting Drosophila melanogaster to novel light regimes. Using a range of LDimLDim regimes, we found that dim scotopic illumination of specific durations induces activity bifurcation in fruit flies, similar to mammals. Thus, we suggest evolutionarily conserved effects of features of the light regime on waveform plasticity. Further, we demonstrate that the circadian photoreceptor CRYPTOCHROME is necessary for activity bifurcation. We also find evidence for circadian reorganisation of the pacemaker circuit wherein the evening neurons regulate the timing of both bouts of activity under novel light regimes. Thus, such light regimes can be explored further to understand the dynamics and coupling within the circadian circuit. The conserved effects of specific features of the light regime open up the possibility of designing other regimes to test their physiological impact and leverage them for waveform manipulation to minimise the ill effects of unusual light regimes.

Hierarchical model of human brain oscillations
Whole-brain computational modelling of emergent brain dynamics has become an increasingly important tool for understanding the systems-level mechanisms that govern large-scale brain activity in health and disease. Neuronal synchronization and brain criticality are key candidates of such mechanisms both for healthy cognitive functions and in constituting mechanistic biomarkers for several brain disorders. Despite significant advances, there is not an abundance of modeling approaches that yield both in-vivo-like critical synchronization dynamics and observables that directly match those obtainable with multi-modal neuroimaging. Here, we advance a framework for hierarchical Kuramoto models where the simplest two-layer model comprises a network of pairwise coupled nodes which each contain a large number of oscillators. Already at two levels of hierarchy, this enables explicit representation of local and inter-areal coupling and observations of emergent multi-scale synchronization dynamics. We show here that the model produces observables of meso- and macro-scale synchronization dynamics that are physiologically plausible when compared to, e.g., magneto- and electroencephalographic (M/EEG) data. We also present here a novel approach for fitting this model with individual experimental data that uses not only functional connectivity but also critical dynamics to converge model parameters that are personalized with individual M/EEG and structural-connectivity data. We posit that brain-dynamics matched personalized models yield a basis for 'digital twins' that may support both clinical applications and basic research on the systems-level mechanisms of cognitive functions. The model and model fitting approach advanced here support both new mechanistic understanding of experimental observations and derivation of predictions for future research.

Resting state brain network segregation is associated with walking speed and working memory in older adults
Older adults exhibit larger individual differences in walking ability and cognitive function than young adults. Characterizing intrinsic brain connectivity differences in older adults across a wide walking performance spectrum may provide insight into the mechanisms of functional decline in some older adults and resilience in others. Thus, the objectives of this study were to: (1) determine whether young adults and high- and low-functioning older adults show group differences in brain network segregation, and (2) determine whether network segregation is associated with working memory and walking function in these groups. The analysis included 21 young adults and 81 older adults. Older adults were further categorized according to their physical function using a standardized assessment; 54 older adults had low physical function while 27 were considered high functioning. Structural and functional resting state magnetic resonance images were collected using a Siemens Prisma 3T scanner. Working memory was assessed with the NIH Toolbox list sorting test. Walking speed was assessed with a 400 m-walk test at participants' self-selected speed. We found that network segregation in mobility-related networks (sensorimotor, vestibular, and visual networks) was higher in younger adults compared to older adults. There were no group differences in laterality effects on network segregation. We found multivariate associations between working memory and walking speed with network segregation scores. Higher right anterior cingulate cortex network segregation was associated with higher working memory function. Higher right sensorimotor, right vestibular, right anterior cingulate cortex, and lower left anterior cingulate cortex network segregation was associated with faster walking speed. These results are unique and significant because they demonstrate higher network segregation is largely related to higher physical function and not age alone.

Cadherin 4 assembles a family of color-selective retinal circuits that respond to light offset.
Retinal interneurons and projection neurons (retinal ganglion cells, RGCs) connect in specific combinations in a specialized neuropil called the inner plexiform layer (IPL). The IPL is divided into multiple sublaminae, with neurites of each neuronal type confined to one or a few layers. This laminar specificity is a major determinant of circuit specificity and circuit function. Using a combination of approaches we show that RGCs targeting IPL sublamina 1 and 3a express the adhesion molecule cadherin 4 (Cdh4). Using calcium imaging and iterative immunostaining, we classified Cdh4-RGCs into 9 types that each encode unique aspects of dark visual stimuli. Cdh4 loss selectively disrupted the layer-targeting of these RGCs, reduced their synaptic inputs from interneurons, and severely altered their visual responses. Overexpression of Cdh4 in other retinal neurons directed their neurites to s1-3a through homophilic interactions. Taken together, these results demonstrate that Cdh4 is a novel layer targeting system for nearly a third of all RGC.

Widespread neural reorganization related to expertise in reading visual Braille
Shape features are crucial for reading. Here we investigate the effect of expertise in reading visual Braille, a script developed for touch that does not share the typical explicit shape information of other alphabets. We compared visual Braille readers and a naive control group and found that individually localized visual word form area VWFA) was selectively activated for visual Braille when compared to scrambled Braille, but only in expert Braille readers. Multivariate analyses showed that linguistic properties can be decoded from Latin in both groups and from Braille in expert readers. Yet, cross-script generalization failed to reveal common representations across Latin and Braille scripts in experts, suggesting script-specific orthographic representations. Primary visual cortex, shape-selective areas (LO), and linguistic areas (l-PosTemp) showed similar multivariate profiles to VWFA, but with cross-script generalization in left Posterior Temporal area only. We conclude that the linguistic properties of a visual script, rather than low-level line-junctions properties, play a major role in how the visual system, and VWFA in particular, processes scripts.

The Brain Computes Dynamic Facial Movements for Emotion Categorization Using a Third Pathway
Recent theories suggest a new brain pathway dedicated to processing social movement is involved in understanding emotions from biological motion, beyond the well-known ventral and dorsal pathways. However, how this social pathway functions as a network that computes dynamic biological motion signals for perceptual behavior is unchartered. Here, we used a generative model of important facial movements that participants (N = 10) categorized as "happy," "surprise," "fear," "anger," "disgust," "sad" while we recorded their MEG brain responses. Using new representational interaction measures (between facial features, MEGt source, and behavioral responses), we reveal per participant a functional social pathway extending from occipital cortex to superior temporal gyrus. Its MEG sources selectively represent, communicate and compose facial movements to disambiguate emotion categorization behavior, while occipital cortex swiftly filters out task-irrelevant identity-defining face shape features. Our findings reveal how social pathway selectively computes complex dynamic social signals to categorize emotions in individual participants.

Exercising with virtual reality is potentially better for the working memory and positive mood than cycling alone
Although virtual reality (VR) exercise has attracted attention as a factor in exercise habituation due to its mood-enhancing effects, its impact on brain function remains unclear. This study, involving 23 healthy university students, used functional magnetic resonance imaging (fMRI) to explore how VR exercise affects working memory, a key executive function, and its underlying neural mechanisms. Our findings indicate that a 10-min VR exercise session improved mood (arousal and vitality level) and working memory task performance (3-back task) more effectively than exercise or rest alone. Furthermore, the results confirmed that increased vitality from exercise and VR exercise interventions was associated with improved 3-back task performance. However, specific brain regions contributing to this enhancement remain unidentified. These results highlight VR exercise as the optimal exercise program for enhancing working memory function by increasing vitality level. These insights underscore VR's potential as a novel exercise modality with benefits extending beyond exercise adherence to potentially preventing dementia and depression.

TRIM9 controls growth cone responses to netrin through DCC and UNC5C
The guidance cue netrin-1 promotes both growth cone attraction and growth cone repulsion. How netrin-1 elicits these diverse axonal responses, beyond engaging the attractive receptor DCC and repulsive receptors of the UNC5 family, remains elusive. Here we demonstrate that murine netrin-1 induces biphasic axonal responses in cortical neurons: attraction at lower concentrations and repulsion at higher concentrations using both a microfluidic-based netrin-1 gradient and bath application of netrin-1. TRIM9 is a brain-enriched E3 ubiquitin ligase previously shown to bind and cluster the attractive receptor DCC at the plasma membrane and regulate netrin-dependent attractive responses. However, whether TRIM9 also regulated repulsive responses to netrin-1 remained to be seen. In this study, we show that TRIM9 localizes and interacts with both the attractive netrin receptor DCC and the repulsive netrin receptor, UNC5C, and that deletion of murine Trim9 alters both attractive and repulsive responses to murine netrin-1. TRIM9 was required for netrin-1-dependent changes in surface levels of DCC and total levels of UNC5C in the growth cone during morphogenesis. We demonstrate that DCC at the membrane regulates growth cone area and show that TRIM9 negatively regulates FAK activity in the absence of netrin-1. We investigate membrane dynamics of the UNC5C receptor using pH-mScarlet fused to the extracellular domain of UNC5C. Minutes after netrin addition, levels of UNC5C at the plasma membrane drop in a TRIM9-independent fashion, however TRIM9 regulated the mobility of UNC5C in the plasma membrane in the absence of netrin-1. Together this work demonstrates that TRIM9 interacts with and regulates both DCC and UNC5C during attractive and repulsive axonal responses to netrin-1.

Daily Acute Intermittent Hypoxia Elicits Age & Sex-Dependent Changes in Molecules Regulating Phrenic Motor Plasticity
Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (LTF). Repetitive daily AIH (dAIH) exposure enhances phrenic LTF, demonstrating a form of metaplasticity. Two additional factors impacting phrenic LTF are age and sex. For example, moderate AIH-induced phrenic LTF decreases with age in males, but increases in middle-aged females. However, little is known concerning cellular mechanisms of dAIH effects or age-dependent sexual dimorphism in phrenic LTF. Moderate AIH elicits distinct signaling cascades within phrenic motor neurons initiated by 5HT2 receptors (Q pathway) versus adenosine 2A or 5HT7 receptors (S pathway), respectively. The Q and S pathways interact via mutual crosstalk inhibition, a powerful regulator of phrenic LTF. To test the hypothesis that dAIH, age and sex effects on phrenic LTF are associated with differential expression of molecules known to regulate the Q and S pathways, we assessed mRNA of key regulatory molecules in ventral cervical homogenates from spinal segments containing the phrenic motor nucleus from young (3 month) and middle-aged (12 month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules regulating the Q and/or S pathways, mRNA was correlated with serum estradiol. Rats (n=8/group) were exposed to sham (21% O2) or dAIH (15, 1 min episodes of 10.5% inspired O2 per day) for 14 days, and sacrificed 24 hours post-dAIH. mRNA for molecules known to regulate phrenic LTF were assessed via RT PCR, including: brain derived neurotrophic factor (Bdnf); serotonin 2A (Htr2a); 2B (Htr2b); and (Htr7) receptors; adenosine 2a (Adora2a) receptors; exchange protein activated by cAMP (Epac1); p38 MAP kinase [Mapk14 () & Mapk11 ({beta})]; PKA catalytic subunit (Prkaa1); PKA regulatory subunit (Prkar1a); fractalkine (Cx3cl1); phosphodiesterase type 4 (Pde4b); NAPDH-gp91 (Cybb) and p47 (ncf1); and the PKC{delta} isoform (Prkcd). Significantly higher Pde4b, Adora2a, and Prkcd mRNA were found in young and middle-aged females versus age-matched males; Epac1 was elevated, but only in young females (p<0.001). Ncf1 was increased in middle-aged versus young adult rats of both sexes (p<0.01). Ncf1, Cx3cl1, Adora2a and Prkcd mRNA were reduced by dAIH in middle-aged females (p<0.01), but not other groups. Serum estradiol levels positively correlated with Epac1 (r2=0.29, p=0.002), Mapk14 (r2=0.31, p=0.001), Mapk11 (r2=0.20, p=0.014), and Prkar1a (r2=0.20 p=0.013) mRNA. With higher serum estradiol levels, dAIH decreased Mapk14 mRNA (slope difference p=0.001). Thus, age, sex and dAIH preconditioning influence molecules known to regulate the Q and S pathways to phrenic motor facilitation. These novel findings advance our understanding of phrenic LTF, and inform translational research concerning the therapeutic potential of dAIH to treat breathing deficits in individuals of different ages or sex.

Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease
We have developed a new method for treating Alzheimer's disease (AD) by targeting the LRP1 receptor at the blood-brain barrier (BBB) using a nanoscopic multivalent scaffold decorated with LRP1 targeting peptides. Our experiments on AD model mice have demonstrated that this treatment significantly reduces amyloid-{beta} (A{beta}) deposits and improves cognitive function. This study introduces a new approach to drug design that combines multivalent targeting with controlling membrane trafficking using the same tools for nanocarrier design, creating a novel therapeutic intervention. In doing so, we emphasize the crucial role that the BBB plays in AD pathogenesis, highlighting the vital importance of LRP1-mediated A{beta} clearance.

Altered markers of brain metabolism and excitability are associated with executive functioning in young children exposed to alcohol in utero
Prenatal alcohol exposure (PAE) is the leading known cause of birth defects and cognitive disabilities, with impacts on brain development and executive functioning. Abnormalities in structural and functional brain features are well-documented in children with PAE, but the effects of PAE on brain metabolism in children have received less attention. Levels of brain metabolites can be measured non-invasively using magnetic resonance spectroscopy (MRS). Here, we present the first study of PAE-related brain metabolite differences in early childhood (ages 3-8 years) and their associations with cognitive performance, including executive functioning (EF) and pre-reading skills. We measured metabolites in two cohorts of children with PAE and unexposed children using MRS in the anterior cingulate cortex (ACC; cohort 1) and left temporo-parietal cortex (LTP; cohort 2). Total choline (tCho), a marker of membrane/myelin metabolism, was elevated in both regions in children with PAE compared to UC, and glutamate+glutamine (Glx), a marker of excitability, was elevated in the ACC. The PAE group exhibited more difficulties with EF, and higher tCho was associated with better EF in both PAE and unexposed groups. In addition, elevated Glx in the ACC was associated with poorer inhibitory control within the PAE group only. LTP metabolites were not significantly associated with pre-reading skills in PAE or unexposed groups. Together, these findings point to altered membrane metabolism and excitability in young children with PAE. These findings provide new insight to potential mechanisms by which PAE disrupts brain development and cognitive functioning in early childhood.

A common computational and neural anomaly across mouse models of autism
Computational psychiatry has suggested that humans within the autism spectrum disorder (ASD) inflexibly update their expectations (i.e., Bayesian priors). Here, we leveraged high-yield rodent psychophysics (n = 75 mice), extensive behavioral modeling (including principled and heuristics), and (near) brain-wide single cell extracellular recordings (over 53k units in 150 brain areas) to ask (1) whether mice with different genetic perturbations associated with ASD show this same computational anomaly, and if so, (2) what neurophysiological features are shared across genotypes in subserving this deficit. We demonstrate that mice harboring mutations in Fmr1, Cntnap2, and Shank3B show a blunted update of priors during decision-making. Neurally, the differentiating factor between animals flexibly and inflexibly updating their priors was a shift in the weighting of prior encoding from sensory to frontal cortices. Further, in mouse models of ASD frontal areas showed a preponderance of units coding for deviations from the animals long-run prior, and sensory responses did not differentiate between expected and unexpected observations. These findings demonstrate that distinct genetic instantiations of ASD may yield common neurophysiological and behavioral phenotypes.

Stochastic growth and selective stabilization generate stereotyped dendritic arbors
Stereotyped dendritic arbors are shaped by dynamic and stochastic growth during neuronal development. It remains unclear how guidance receptors and ligands coordinate branch dynamic growth, retraction, and stabilization to specify dendritic arbors. We previously showed that extracellular ligand SAX-7/LICAM dictates the shape of the PVD sensory neuron via binding to the dendritic guidance receptor DMA-1, a single transmembrane adhesion molecule. Here, we perform structure-function analyses of DMA-1 and unexpectedly find that robust, stochastic dendritic growth does not require ligand-binding. Instead, ligand-binding inhibits growth, prevents retraction, and specifies arbor shape. Furthermore, we demonstrate that dendritic growth requires a pool of ligand-free DMA-1, which is maintained by receptor endocytosis and reinsertion to the plasma membrane via recycling endosomes. Mutants defective of DMA-1 endocytosis show severely truncated dendritic arbors. We present a model in which ligand-free guidance receptor mediates intrinsic, stochastic dendritic growth, while extracellular ligands instruct dendrite shape by inhibiting growth.

Closed-loop modulation of remote hippocampal representations with neurofeedback
Humans can remember specific events without acting on them and can influence which memories are retrieved based on internal goals. However, current animal models of memory typically present sensory cues to trigger retrieval and assess retrieval based on action. As a result, it is difficult to determine whether measured patterns of neural activity relate to the cue(s), the retrieved memory, or the behavior. We therefore asked whether we could develop a paradigm to isolate retrieval-related neural activity in animals without retrieval cues or the requirement of a behavioral report. To do this, we focused on hippocampal "place cells." These cells primarily emit spiking patterns that represent the animal's current location (local representations), but they can also generate representations of previously visited locations distant from the animal's current location (remote representations). It is not known whether animals can deliberately engage specific remote representations, and if so, whether this engagement would occur during specific brain states. So, we used a closed-loop neurofeedback system to reward expression of remote representations that corresponded to uncued, experimenter-selected locations, and found that rats could increase the prevalence of these specific remote representations over time; thus, demonstrating memory retrieval modulated by internal goals in an animal model. These representations occurred predominately during periods of immobility but outside of hippocampal sharp-wave ripple (SWR) events. This paradigm enables future direct studies of memory retrieval mechanisms in the healthy brain and in models of neurological disorders.

Development of Retinotopic Feedback: Layer 6 Pyramids to Lateral Geniculate Principal Cells
The development of many feedforward pathways in the brain, from sensory inputs to neocortex, have been studied and modeled extensively, but the development of feedback connections, which tend to occur after the development of feedforward pathways, have received less attention. The abundance of feedback connections within neocortex and between neocortex and thalamus suggests that understanding feedback connections is crucial to understanding connectivity and signal processing in the brain. It is well known that many neural layers are arranged topologically with respect to sensory input, and many neural models impose a symmetry of connections between layers, commonly referred to as reciprocal connectivity. Here, we are concerned with how such reciprocal, feedback connections develop so that the topology of the sensory input is preserved. We focus on feedback connections from layer 6 of visual area V1 to primary neurons in the Lateral Geniculate Nucleus (LGN). The proposed model is based on the hypothesis that feedback connections from V1-L6 to LGN use voltage-activated T-channels to appropriately establish and modify synapses in spite of unavoidable temporal delays. We also hypothesize that developmental spindling relates to synaptogenesis and memory consolidation.

Viral mimicry and memory deficits upon microglial deletion of ATRX
The importance of chromatin-mediated processes in neurodevelopmental and intellectual disability disorders is well recognised. However, how chromatin dysregulation in glial cells impacts cognitive abilities is less well understood. Here, we demonstrate that targeted loss of the ATRX chromatin remodeler in microglia alters chromatin accessibility profiles, leading to the de-repression of endogenous retroelements, triggering viral mimicry. Functionally, we find that ATRX microglial deficiency alters the electrophysiological properties of hippocampal neurons and causes deficits in object recognition and spatial memory. Overall, these findings demonstrate that ATRX is required in microglia to preserve chromatin structure and maintain microglial homeostasis. Disruption of these functions elicit neuroinflammation and cognitive deficits and potentially contribute to the pathology of human neurological disorders caused by ATRX mutations.

Non-Invasive Brain Mapping Localizes Essential Language Function in Surgical Glioma Patients
The essential neuroanatomical structure of language processing remains unclear. Here we show in a cohort of 79 consecutive glioma patients undergoing surgery in the dominant hemisphere that postoperative language deficits result from subcortical damage to individualized ROIs within normative white matter tracts. We integrate these findings into a data-driven, non-invasive brain mapping approach capable of using cortical transcranial magnetic stimulation (TMS) mappings and diffusion imaging to localize language-essential regions and predict the long-term functional outcome of personalized surgical strategies with an accuracy of 94%. We use this technique to create a group-level probabilistic atlas of functional white matter in glioma patients, revealing evidence for a novel, disease-specific pattern of subcortical connectivity deep to the temporo-parietal-occipital (TPO) junction that anatomically correlates with regional vulnerability to aphasic damage. This study provides novel insight into the functional anatomy of language processing while defining a reproducible approach for non-invasively mapping essential language function.

Comparing MEG and EEG measurement set-ups for a brain--computer interface based on selective auditory attention
Objective. Auditory attention modulates auditory evoked responses to target vs. non-target sounds in electro- and magnetoencephalographic (EEG/MEG) recordings. Employing whole-scalp MEG recordings and offline classification algorithms has been shown to enable high accuracy in tracking the target of auditory attention. Here, we investigated the decrease in accuracy when moving from the whole scalp MEG to lower channel count EEG recordings and when training the classifier only from the initial part of the recording instead of extracting training samples throughout the recording. Approach. To this end, we recorded simultaneous MEG (306 channels) and EEG (64 channels) in 18 healthy volunteers while they were presented with concurrent streams of spoken 'Yes'/ 'No' words and instructed to attend to one of them. We then trained support vector machine classifiers for predicting the target of attention from unaveraged trials of MEG/EEG. Classifiers were trained either on 204 MEG gradiometers or on EEG with 64, 30, 9 or 3 channels and with samples extracted randomly across or only from the beginning of the recording. Main results. The highest classification accuracy, 73% on average across the subjects for 1.0-s trials, was obtained with MEG when the training samples were randomly extracted throughout the recording. With EEG, the accuracies were 69%, 69%, 67%, and 63% when using 64, 30, 9, and 3 channels, respectively. When training the classifiers with the same amount of data but extracted only from the beginning of the recording, the accuracy dropped by 12 %-units on average, causing the result from the 3-channel EEG to fall below the chance level. Combining five consecutive trials partially compensated for this drop such that it was 1--8 %-units. Significance. While moving from whole-scalp MEG to EEG reduces classification accuracy, a usable auditory-attention-based brain-computer interfaces can be implemented with a small set of optimally-placed EEG channels.

THE NEURONAL ARCHITECTURE OF AUTONOMIC DYSREFLEXIA
Autonomic dysreflexia is a life-threatening medical condition characterized by episodes of uncontrolled hypertension that occur in response to sensory stimuli after spinal cord injury (SCI). The fragmented understanding of the mechanisms underlying autonomic dysreflexia hampers the development of therapeutic strategies to manage this condition, leaving people with SCI at daily risk of heart attack and stroke. Here, we expose the complete de novo neuronal architecture that develops after SCI and causes autonomic dysreflexia. In parallel, we uncover a competing, yet overlapping neuronal architecture activated by epidural electrical stimulation of the spinal cord that safely regulates blood pressure after SCI. The discovery that these adversarial neuronal architectures converge onto a single neuronal subpopulation provided a blueprint for the design of a mechanism-based intervention that reversed autonomic dysreflexia in mice, rats, and humans with SCI. These results establish a path for the effective treatment of autonomic dysreflexia in people with SCI.

Benchmarking methods for mapping functional connectivity in the brain
The networked architecture of the brain promotes synchrony among neuronal populations and the emergence of coherent dynamics. These communication patterns can be comprehensively mapped using noninvasive functional imaging, resulting in functional connectivity (FC) networks. Despite its popularity, FC is a statistical construct and its operational definition is arbitrary. While most studies use zero-lag Pearson's correlations by default, there exist hundreds of pairwise interaction statistics in the broader scientific literature that can be used to estimate FC. How the organization of the FC matrix varies with the choice of pairwise statistic is a fundamental methodological question that affects all studies in this rapidly growing field. Here we comprehensively benchmark the topological and geometric organization, neurobiological associations, and cognitive-behavioral relevance of FC matrices computed using a large library of 239 pairwise interaction statistics. We comprehensively investigate how canonical features of FC networks vary with the choice of pairwise statistic, including (1) hub mapping, (2) weight-distance trade-offs, (3) structure-function coupling, (4) correspondence with other neurophysiological networks, (5) individual fingerprinting, and (6) brain-behavior prediction. We find substantial quantitative and qualitative variation across FC methods. Throughout, we observe that measures such as covariance (full correlation), precision (partial correlation) and distance display multiple desirable properties, including close correspondence with structural connectivity, the capacity to differentiate individuals and to predict individual differences in behavior. Using information flow decomposition, we find that differences among FC methods may arise from differential sensitivity to the underlying mechanisms of inter-regional communication, with some more sensitive to redundant and some to synergistic information flow. In summary, our report highlights the importance of tailoring a pairwise statistic to a specific neurophysiological mechanism and research question, providing a blueprint for future studies to optimize their choice of FC method.

Skin Collagen Actively Regulates the Aging of Cutaneous Sensory Neurons
Despite significant progress in understanding the molecular processes of aging-associated neurodegeneration, the upstream mechanisms driving neuronal aging remain elusive. Here, we investigate the potential regulatory roles of non-neural tissues in neuronal aging, using Caenorhabditis elegans PVD polymodal neuron as a model. We find that cutaneous PVD neurons develop progressive excessive dendritic branching during normal aging, functionally correlated with age-related deficits in proprioception. Our study reveals that age-related reduction in skin collagens, a common change across species, triggers the aging process of PVD. Specifically, loss-of-function mutations or adulthood-specific RNAi knockdown of skin collagen genes, dpy-5 or col-120, which are downregulated with age, induce an early onset of PVD excessive dendritic branching and proprioception deficits. Overexpressing dpy-5 or col-120 mitigates the development of excessive branching without affecting lifespan, suggesting a skin collagens' role in promoting healthspan rather than longevity. Notably, neither dpy-5 or col-120 is not involved in aging-associated dendritic beading, another degenerative phenotype in PVD associated with harsh touch response deficits. Moreover, dpy-5 mutation induces ectopic branching in ALM, but does not affect PLM, two other cutaneous sensory neurons. Finally, we identify rig-3, a neuronal Immunoglobulin Superfamily member not expressed in PVD or the skin, functioning in the same pathway as skin collagen genes to preserve PVD neuron integrity during aging. Our findings reveal the causative role of age-related reduction in skin collagens in neuronal aging, selectively impacting distinct neuron subtypes and structures. This study underscores the importance of exploring multi-tissue strategies to comprehensively address the complexities of neuronal aging.

Mapping the spatial proteomic signature of dorsal and ventral hippocampus in a mouse model of early Alzheimer's disease: changes in synaptic plasticity-related proteins associated with sexual dimorphism
Background: An initial neuropathological hallmark of Alzheimer's disease (AD) is the hippocampal dysfunction caused by amyloid-{beta} (A{beta}) peptides accumulation. Soluble oligomeric forms of A{beta} shift synaptic plasticity induction threshold leading to memory deficits in male and female mice in early amyloidosis models. Some protein changes underlying those deficits have been previously studied, but the spatial distribution within the hippocampus, as well as the potential sex differences, remain unknown. Since each hippocampal region (dorsal vs. ventral) has clearly distinct functionality and connectivity, we postulated that some protein changes may be unique to each and might also be sex dependent. Methods: An innovative spatial proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry, which allows protein detection with spatial resolution directly on tissue sections. Brains from sixteen adult male and female mice intracerebroventricularly injected with A{beta}1-42 oligomers or vehicle were sectioned. MALDI imaging was performed using a RapifleXTM MALDI TissuetyperTM TOF/TOF mass spectrometer followed by protein identification by traditional tandem mass spectrometry (MS/MS) directly on the tissue. To precisely delineate both dorsal and ventral hippocampus, a Nissl staining was performed on succeeding tissue sections. Results: Of the 234 detected peptides, significant differences in expression levels were found in 34 proteins, due to treatment, sex, or hippocampal location. Moreover, a significant protein-protein interaction (PPI) was observed, showing a relationship to long-term potentiation (LTP), the functional basis of memory. Accordingly, 14 proteins related to synaptic plasticity and/or AD were selected to further study. Results showed many of the altered protein to modulate glycogen synthase kinase-3{beta} (GSK-3{beta}), a protein widely involved in the regulation of synaptic plasticity induction threshold. In fact, hippocampal GSK-3{beta} was found overactivated suggesting a facilitated long-term depression (LTD) instead of LTP in AD models. Conclusions: This study offers for the first time the specific protein changes in dorsal/ventral hippocampus in both male and female mice, that modulate GSK-3 {beta} activity, providing new insight in the pathogenesis of early AD and valuable potential biomarkers for early diagnosis and therapeutic targets.

Adaptation of pain-related projection neurons in acute but not chronic pain
Pain hypersensitivity is associated with increased activity of peripheral and central neurons along the pain neuroaxis. On the other hand, in other neuronal systems, increased activity leads to adaptive reduction of neuronal excitability to maintain homeostasis. Projection neurons (PNs) of spinal and medullary dorsal horns summate the activity of primary nociceptive and local central interneurons and convey it to higher centers. We show that at the peak of acute inflammatory pain, PNs reduce their intrinsic excitability and, consequently, action potential firing. When pain resolves, the excitability of PNs returns to baseline. Using electrophysiological and computational approaches, we found that an increase in potassium A-current (IA) underlies the decrease in the excitability of PNs in acute pain conditions. We hypothesized that an IA-induced decrease in PNs firing may restrain the output from the dorsal horn to prevent sensitization and pain chronification. Indeed, no changes of IA in PNs were observed in chronic pain conditions, and PNs exhibit increased intrinsic excitability and firing. Our results reveal an adaptive mechanism in acute pain conditions for regulating the output from the dorsal horn network, which, if interrupted, could trigger pain chronification.

autoMEA: Machine learning-based burst detection for multi-electrode array datasets
Neuronal activity in the highly organized networks of the central nervous system is the vital basis for various functional processes, such as perception, motor control, and cognition. Understanding interneuronal connectivity and how activity is regulated in the neuronal circuits is crucial for interpreting how the brain works. Multi-electrode arrays (MEAs) are particularly useful for studying the dynamics of neuronal network activity and their development as they allow for real-time, high-throughput measurements of neural activity. At present, the key challenge in the utilization of MEA data is the sheer complexity of the measured datasets. Available software offers semi-automated analysis for a fixed set of parameters that allow for the definition of spikes and bursts. However, this analysis remains time-consuming, user-biased, and limited by pre-defined parameters. Here, we present autoMEA, software for machine learning-based automated burst detection in MEA datasets. We exemplify autoMEA efficacy on neuronal network activity of primary hippocampal neurons from wild-type mice monitored using 24-well multi-well MEA plates. To validate and benchmark the software, we showcase its application using wild-type neuronal networks and two different neuronal networks modeling neurodevelopmental disorders to assess network phenotype detection. Detection of network characteristics typically reported in literature, such as synchronicity and rhythmicity, could be accurately detected compared to manual analysis using the autoMEA software. Additionally, autoMEA could detect reverberations, a more complex burst dynamic present in hippocampal cultures. Furthermore, autoMEA burst detection was sufficiently sensitive to detect changes in the synchronicity and rhythmicity of networks modeling neurodevelopmental disorders as well as detecting changes in their burst dynamics. Thus, we show that autoMEA reliably analyses neural networks measured with the multi-well MEA setup with the precision and accuracy compared to that of a human expert.

Frontotemporal connectivity changes reflect figure-ground reversal in multivoiced music
The neural processes underlying the perception of prominently heard voices (figure) and less prominently heard voices (ground), particularly when this prominence is naturally reversed while listening to music, remain inadequately investigated. We investigated changes in frontotemporal connectivity in response to figure-ground reversal within multivoiced music using Mozart's variation KV 265, including the "Twinkle, Twinkle, Little Star (TTLS)" melody based on our previous study of frontotemporal connectivity (TTLS connectivity), influenced by the emergence of the TTLS melody in the upper voice at the beginning of each variation, and independent of lower voices. We examined the consistency of the TTLS connectivity pattern across repetitions of the same phrases within each variation. Notably, TTLS connectivity changed only for the final repetition between variations sharing the same TTLS melody. This result indicates a perceptual reversal, processing the TTLS melody initially perceived as figure into the ground. Our data effectively illustrate how the brain dissects voices within the multidimensional structures of continuously changing music, reconstructing them through a momentary switch in figure-ground processes. These findings provide valuable insights into the neural processes associated with the dynamic experience of listening to music, a ubiquitous aspect of human life.

Embryonically Active Piriform Cortex Neurons Promote Intracortical Recurrent Connectivity during Development
Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used Targeted Recombination in Active Populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing of these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.