bioRxiv Subject Collection: Neuroscience's Journal

From Sight to Insight: A Multi-task Approach with the Visual Language Decoding Model
Visual neural decoding aims to unlock the mysteries of how the human brain interprets the visual world. While early studies made some progress in decoding visual activity for singular type of information, they failed to concurrently reveal the multi-level interweaving linguistic information in the brain. Here, we developed a novel Visual Language Decoding Model (VLDM) capable of decoding categories, semantic labels, and textual descriptions from visual perceptual activities simultaneously. We selected the large-scale NSD dataset to ensure the efficiency of the decoding model in joint training and evaluation across multiple tasks. For category decoding, we achieved the effective classification of 12 categories with an accuracy of nearly 70%, significantly surpassing the chance level. For label decoding, we attained the precise prediction of 80 specific semantic labels with a 16-fold improvement over the chance level. For text decoding, the scores of the decoded text surpassed the corresponding baseline levels by remarkable margins on six evaluation metrics. This study contributes significantly to extensive applications in multi-layered brain-computer interfaces, potentially leading to more natural and efficient human-computer interaction experiences.

Cross-species modeling and enhancement of cognitive control with striatal brain stimulation
Brain disorders, particularly mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. We show a path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result, showing that DBS-like stimulation of the mid-striatum improves cognitive control in rats. Using this model, we identify a mechanism, improvement in domain-general cognitive control, and rule out competing hypotheses such as impulsivity. The rat findings explain prior human results and have immediate implications for clinical practice and future trial design.

Identifying regulators of associative learning using a protein-labelling approach in C. elegans
The ability to learn and form memories is critical for animals to make choices that promote their survival. The biological processes underlying learning and memory are mediated by a variety of genes in the nervous system, acting at specific times during memory encoding, consolidation, and retrieval. Many studies have utilised candidate gene approaches or random mutagenesis screens in model animals to explore key molecular drivers for learning and memory. We propose a complementary approach to identify this network of learning regulators, using the proximity-labelling tool TurboID, which promiscuously biotinylates neighbouring proteins, to snapshot the proteomic profile of neurons during learning. To do this, we expressed the TurboID enzyme in the entire nervous system of C. elegans and exposed animals to biotin only during the training step of a gustatory associative learning paradigm. Our approach revealed hundreds of proteins specific to 'trained' worms, including components of molecular pathways previously implicated in learning and memory formation in multiple species. We validated several novel regulators of learning involved in neurotransmission, including cholinergic receptors (ACC-1, ACC-3, GAR-1, LGC-46) and the putative glutaminase GLNA-3. These previously uncharacterised learning regulators show a clear impact on appetitive gustatory memory, but do not appear to have a generalised role in learning. In summary, we have shown that our approach to use proximity labelling to profile the brain of a small animal during training is a feasible and effective method to advance our knowledge on the biology of learning.

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures
In Alzheimers disease, it is theorised that amyloid beta (A{beta}) and tau pathology contribute to synapse loss. However, there is limited information on how endogenous levels of tau and A{beta} protein relate to patient characteristics, or how manipulating physiological levels of A{beta} impacts synapses, in living adult, human brain. Here, we employed live human brain slice cultures as a translational tool to assess endogenous tau and A{beta} release, pathology, and response to experimental manipulation. We found that the levels of A{beta}1-40 and tau detected in the culture medium depend on donor age, and brain region, respectively. Pharmacologically raising physiological A{beta} concentration enhanced levels of synaptic transcripts. Treatment of slices with A{beta}-containing Alzheimers disease brain extract resulted in postsynaptic A{beta} uptake and loss of presynaptic puncta. These data indicate that physiological and pathological A{beta} can have opposing effects on synapses in living human brain tissue.

2-D Neural Geometry Underpins Hierarchical Organization of Sequence in Human Working Memory
Working memory (WM) is constructive in nature. Instead of passively retaining information, WM reorganizes complex sequences into hierarchically embedded chunks to overcome capacity limits and facilitate flexible behavior. To investigate the neural mechanisms underlying hierarchical reorganization in WM, we performed three electroencephalography (EEG) and magnetoencephalography (MEG) experiments, wherein humans retained in WM a temporal sequence of items, i.e., syllables, which are organized into chunks, i.e., multisyllabic words. We demonstrate that the 1-D sequence is represented by 2-D neural representational geometry in WM, with separate dimensions encoding item position within a chunk and chunk position in the sequence. Critically, this 2-D geometry correlates with WM behavior and is observed consistently in different experimental settings, even during tasks discouraging hierarchical reorganization in WM. Overall, these findings strongly support that complex sequences are reorganized into factorized multi-dimensional neural representational geometry in WM, which also speak to general structure-based organizational principles given WM's involvement in many cognitive functions.

Wider spread of excitatory neuron influence in association cortex than sensory cortex
The basic structure of local cortical circuits, including the composition of cell types, is highly conserved across the cortical processing hierarchy. However, computational roles and the spatial and temporal properties of population activity differ fundamentally in sensory-level and association-level areas. In primary sensory cortex, the timescale of population activity is shorter and pairwise correlations decay more rapidly over distance between neurons, supporting a population code that is suited to encoding rapidly fluctuating sensory stimuli. In association cortex, the timescale of population activity is longer, and pairwise correlations are stronger over wider distances, a code that is suited to holding information in memory and driving behavior. Here, we tested whether these differences in population codes could potentially be explained by intrinsic differences in local network structure. We targeted single excitatory neurons optogenetically, while monitoring the surrounding ongoing population activity in sensory (auditory cortex) and association (posterior parietal cortex) areas in mice. While the temporal impacts of these perturbations were similar across regions, the spatial spread of excitatory influence was wider in association cortex than in sensory cortex. Our findings suggest that differences in recurrent connectivity could contribute to the different properties of population codes in sensory and association cortex, and imply that circuit models of cortical function should be tailored to the properties specific to individual regions.

Chromatin regulator Kdm6b is required for the establishment and maintenance of neural stem cells in mouse hippocampus
Neural stem cells (NSCs) in the mouse hippocampal dentate gyrus (DG) - a structure important to learning and memory - generate new neurons postnatally and throughout adult life. However, the regulators that enable this lifelong neurogenesis remain incompletely understood. Here we show that the chromatin regulator KDM6B is required for both the establishment and maintenance of NSCs in the mouse DG. Conditional deletion of Kdm6b in embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs, and hippocampal-dependent behaviors are defective. Kdm6b-deletion causes precocious neuronal differentiation, and the NSC population fails to become established in the postnatal DG. Using single cell RNA sequencing (scRNA-seq), we observed that Kdm6b-deletion disrupts the transcriptomic signature of NSC maintenance. Furthermore, deleting Kdm6b in adult DG NSCs induces early neuronal differentiation, and the NSC population is not properly maintained. These data illustrate the critical role that Kdm6b plays in adult DG neurogenesis, which may help understand how mutations in this chromatin regulator result in cognitive disorders in human patients.

An interim exploratory biomarker analysis of a Phase 2 clinical trial to assess the impact of CT1812 in Alzheimers disease
CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimers disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Ab) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing Phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in patients with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics can detect more than 2,000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

Ndufs4 knockout induces transcriptomic signatures of Alzheimer's Diseases that are partially reversed by mitochondrial complex I inhibitor
Mitochondrial dysfunction is well documented in Alzheimer Disease (AD). However, whether it instigates the onset of AD remains unclear. We demonstrate that a reduction of complex I activity in wild type (WT) mice caused by a global knockout of Ndufs4, an accessory mitochondrial complex I subunit, was sufficient to induce transcriptomic changes in the brain reminiscent of those observed in AD patients and familial mouse models of AD. Reduced complex I activity affected expression of genes in the networks related to mitochondrial homeostasis, neuronal and synaptic function. Transcriptomic signatures in male and female Ndufs4 KO mice reflected a different severity of AD phenotype. Unexpectedly, these changes were partially rescued by a neuroprotective small molecule mild complex I inhibitor CP2. Consistent with studies in AD mice, CP2 treatment in Ndufs4 KO mice augmented the expression of genes associated with mitochondrial biogenesis and turnover, synaptic activity, autophagy, redox balance, and reduced expression of genes related to inflammation. Female Ndufs4 KO mice demonstrated a greater reversal of gene expression toward WT mice. These studies provide further support for mitochondria as a causative factor of AD pathophysiology and complex I as a putative therapeutic target.

The Topology of Representational Geometry
Representational similarity analysis (RSA) is a powerful tool for abstracting and then comparing neural representations across brains, regions, models and modalities. However, typical RSA analyses compares pairs of representational dissimilarities to judge similarity of two neural systems, and we argue that such methods can not capture the shape of representational spaces. By leveraging tools from computational topology, which can probe the shape of high-dimensional data, we augment RSA to be able to detect more subtle yet real differences and similarities of representational geometries. This new method could be used in conjunction with regular RSA in order to make new inferences about neural function.

Neuronal-class specific molecular cues drive differential myelination in the neocortex
In the neocortex, oligodendrocytes produce distinct amounts of myelin in each cortical layer and along the axons of individual neuron types. Here we present a comprehensive single-cell molecular map of mouse cortical oligodendrocytes across different cortical layers and stages of myelination, spanning the initiation of cortical myelination into adulthood. We apply this dataset to show that neuron-class specific signals drive oligodendrocyte maturation and differential myelination across cortical layers. We find that each layer contains a similar compendium of oligodendrocyte classes, indicating that oligodendrocyte heterogeneity cannot explain layer-specific myelination. To evaluate whether neuronal diversity drives differential myelination across cortical layers, we generated a predicted ligand-receptor interactome between projection neuron types and oligodendrocyte states, across cortical layers and time. In vivo functional testing identified Fgf18, Ncam1, and Rspo3 as novel, neuron-derived pro-myelinating signals. Our results highlight neuron-class-dependent control of myelin distribution in the neocortex.

An axonal brake on striatal dopamine output by cholinergic interneurons
Depolarisation of distal axons is necessary for neurons to translate somatic action potentials into neurotransmitter release. Studies have shown that striatal cholinergic interneurons (ChIs) can directly drive ectopic action potentials in dopamine (DA) axons and trigger DA release. However, here we show that this action occurs within a broader context of axonal signal integration whereby activation of ChIs and depolarisation of DA axons by nicotinic receptors (nAChRs) limits the subsequent depolarisation and release of DA in response to ensuing activity. We demonstrate that activation of ChIs and nAChRs in ex vivo mouse striatum, even when it does not trigger DA release that is detectable by fast-scan cyclic voltammetry, limits DA release for ~100 ms by depressing subsequent axonal depolarisation and calcium summation. This axonal brake on DA release is stronger in dorsal than ventral striatum, and is unrelated to DA depletion. In vivo, antagonism of nAChRs in dorsal striatum elevated extracellular DA levels and promoted conditioned place-preference, underscoring its physiological relevance. Our findings reveal that under physiological conditions in vivo, ChIs acting via nAChRs dynamically attenuate DA output driven by DA neuron activity, leading to a predominantly inverse relationship between ACh and DA signalling that varies continuously with ChI activity.

Circadian clocks in human cerebral organoids
Circadian rhythms result from cell-intrinsic timing mechanisms that impact health and disease1,2. To date, however, neural circadian research has largely focused on the hypothalamic circuitry of nocturnal rodents3. Whether circadian rhythms exist in human brain cells is unknown. Here we show bona fide circadian rhythms in human neurons, glia, cerebral organoids, and cerebral organoid slices (ALI-COs)4-8. Human neural circadian rhythms are synchronised by physiological timing cues such as glucocorticoids and daily temperature cycles, and these rhythms are temperature-compensated across the range of normal human brain temperatures9. Astrocyte rhythms are phase-advanced relative to other cultures and they modulate neuronal clock responses to temperature shift. Cerebral organoid rhythms are more robust at physiological brain temperatures; the relative amplitude of these rhythms increases over time in culture and their resetting capacity recapitulates key neurodevelopmental transitions in glucocorticoid signalling10-14. Remarkably, organoid post-transcriptional bioluminescent clock reporter rhythms are retained even when those of their putative transcriptional drivers are indiscernible15, and electrophysiology recordings confirm circadian rhythms in functional activity of monocultures, organoids, and ALI-COs. Around one third of the cerebral organoid proteome and phosphoproteome are circadian-rhythmic, with temporal consolidation of disease-relevant, neural processes. Finally, we show that human brain organoid rhythms can be modulated and disrupted by commonly used brain-permeant drugs and mistimed cortisol exposure, respectively. Our results demonstrate that human brain cells and tissues develop their own circadian oscillations and that canonical mechanisms of the circadian clockwork may be inadequate to explain these rhythmic phenomena. 2D and 3D human neural cultures represent complementary and tractable models for exploring the emergence, disruption, and mechanics of the circadian neural clockwork, with important implications for chronobiology, brain function, and brain health.

Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke.
Inflammation is a key contributor to stroke pathogenesis and drives exacerbated brain damage leading to poor outcomes in patients. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. IL-1 and IL-1{beta} are the two major IL-1 type 1 receptor (IL-1R1) agonists from the IL-1 family, and although the role of IL-1{beta} in stroke has been extensively studied, the distinct roles of both isoforms, and particularly that of IL-1, remains largely unknown. Here we show that IL-1 and IL-1{beta} have different spatio-temporal expression profiles in the brain after experimental stroke, with an early IL-1 microglial expression (4 h post-stroke) and delayed IL-1{beta} expression in infiltrated neutrophils and a small (10%) microglial subset (24-72 h post-stroke). Using cell-specific deletion of IL-1 through tamoxifen-inducible Cre-loxP-mediated recombination, we examined the specific contribution of microglial-derived IL-1 in mouse models of permanent and transient ischemic stroke. Selective microglial IL-1 deletion did not influence brain damage, cerebral blood flow, IL-1{beta} expression, neutrophil infiltration, microglial nor endothelial activation up to 24 h after ischemic stroke. However, microglial IL-1 knock out (KO) mice showed reduced peri-infarct vessel density and reactive astrogliosis at 14 days post-stroke, alongside a worse functional recovery compared to wild-type (WT) mice. RNA sequencing analysis and subsequent pathway analysis on ipsilateral/contralateral cortex 4 h after stroke revealed a downregulation of the neuronal CREB signaling pathway in microglial IL-1 KO compared to WT mice. Our study identifies for the first time a critical role for microglial IL-1 in the regulation of neuronal activity, neurorepair and functional recovery after stroke, highlighting the importance of selectively targeting specific IL-1 mechanisms in brain injury to develop more effective therapies.

Apnoea suppresses brain activity in infants
Apnoea - the cessation of breathing - is commonly observed in premature infants. These events can reduce cerebral oxygenation and are associated with poorer neurodevelopmental outcomes. However, relatively little is known about how apnoea and shorter pauses in breathing impact brain function in infants, which will provide greater mechanistic understanding of how apnoea affects brain development. We analysed simultaneous recordings of respiration, electroencephalography (EEG), heart rate, and peripheral oxygen saturation in 124 recordings from 118 infants (post-menstrual age: 38.6 +/- 2.7 weeks [mean +/- standard deviation]) during apnoeas (pauses in breathing greater than 15 seconds) and shorter pauses in breathing between 5 and 15 seconds. EEG amplitude significantly decreased during both apnoeas and shorter pauses in breathing compared with normal breathing periods. Change in EEG amplitude was significantly associated with change in heart rate during apnoea and breathing pauses and, during apnoeas only, with oxygen saturation change. No associations were found between EEG amplitude and pause duration or post-menstrual age. The decrease in EEG amplitude may be a result of the changing metabolism and/or homeostasis following changes in oxygen and carbon dioxide concentrations, which alters the release of neurotransmitters. As apnoeas often occur in premature infants, frequent disruption to brain activity may impact neural development and result in long-term neurodevelopmental consequences.

Multi-orientation U-Net for Super-Resolution of Ultra-Low-Field Paediatric MRI
Purpose: Owing to the high cost of modern MRI systems, their use in clinical care and neurodevelopmental research is limited to hospitals and universities in high income countries. Ultra-low-field systems with significantly lower scanning costs bear the potential for global adoption, however their reduced SNR compared to 1.5 or 3T systems limits their applicability for research and clinical use. Methods: In this paper, we describe a deep-learning based super-resolution approach to generate high-resolution isotropic T2-weighted scans from low-resolution inputs. We train a multi-orientation U-Net, which uses multiple low-resolution anisotropic images acquired in orthogonal orientations to construct a super-resolved output. Results: Our approach exhibits improved quality of outputs compared to current state-of-the-art methods for super-resolution of ultra-low-field scans in paediatric populations. The average correlation value between volume estimates from high-field scans and super-resolved outputs rises to 0.77 using our method, compared to 0.71 using earlier techniques. Conclusion: Our research serves as proof-of-principle of the viability of training deep-learning based super-resolution models for use in neurodevelopmental research and presents the first U-Net trained exclusively on paired ultra-low-field and high-field data from infants.

Polygenic risk for depression and resting state functional connectivity of subgenual anterior cingulate cortex in young adults
Genetic variants may confer risks for depression by modulating brain structure and function. Prior evidence has underscored a key role of the subgenual anterior cingulate cortex (sgACC) in depression. Here, we built on the literature and examined how the resting state functional connectivity (rsFC) of the sgACC was associated with polygenic risks for depression. We followed published routines and computed seed-based whole-brain sgACC rsFC and polygenic risk scores (PRS) of 717 young adults curated from the Human Connectome Project. We performed whole-brain regression against PRS and severity of depression symptoms in a single model for all subjects and for men and women alone, controlling for age, sex (for all), race, severity of alcohol use, and household income, and evaluated the results at a corrected threshold. We found lower sgACC rsFC with the default mode network and frontal regions in association with PRS and lower sgACC-cerebellar rsFC in association with depression severity. We also noted sex differences in the connectivity correlates of PRS and depression severity. In an additional set of analyses, we observed a significant correlation between PRS and somatic complaints score and altered sgACC-somatosensory cortical connectivity in link with the severity of somatic complaints. Our findings collectively highlighted the pivotal role of distinct sgACC-based networks in the genetic predisposition to depression and the clinical manifestation of depression. Distinguishing the risk from severity markers of depression may have implications in developing early and effective treatments for individuals at risk for depression.

Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson's disease.
Identification of shared dysregulated genes and molecular mechanisms responsible for dopaminergic (DA) neuronal death in familial and sporadic forms of Parkinsons disease (PD) can offer the potential for common therapies in both types of PD. The gene expression profiles of DA neurons with sporadic and familial PD backgrounds and healthy DA neurons were obtained from the Gene Expression Omnibus database. Overlapping differentially expressed genes and hub genes were identified. These genes were subjected to Gene Ontology and Reactome pathway enrichment analyses. The roles of a select few differentially expressed genes in C. elegans DA neuron health were assessed. 40 genes, including 12 hub genes, were found dysregulated in DA neurons with sporadic and familial PD. Altering the expression of some of these genes in wild-type Caenorhabditis elegans promoted DA neuron degeneration and function. The study unveils shared molecular mechanisms in DA neurons for familial and sporadic PD, potentially driving DA neuron degeneration. Understanding their roles may lead to targeted therapies, early detection, and intervention. In vivo experiments support our hypothesis, suggesting the implication of these genes in PD neurodegeneration and neuroprotection.

An extremely fast neural mechanism to detect emotional visual stimuli: A two-experiment study
Defining the brain mechanisms underlying initial emotional evaluation is a key but unexplored clue to understand affective processing. Event-related potentials (ERPs), especially suited for investigating this issue, were recorded in two experiments (n=36 and n=35). We presented emotionally negative (spiders) and neutral (wheels) silhouettes homogenized regarding their visual parameters. In Experiment 1, stimuli appeared at fixation or in the periphery (200 trials per condition and location), the former eliciting a N40 (39 milliseconds) and a P80 (or C1: 80 milliseconds) component, and the latter only a P80. In Experiment 2, stimuli were presented only at fixation (500 trials per condition). Again, a N40 (45 milliseconds) was observed, followed by a P100 (or P1: 105 milliseconds). Analyses revealed significantly greater N40-C1P1 peak-to-peak amplitudes for spiders in both experiments, and ANCOVAs showed that these effects were not explained by C1P1 alone, but that processes underlying N40 significantly contributed. Source analyses pointed to V1 as a N40 focus (more clearly in Experiment 2). Sources for C1P1 included V1 (P80) and V2/LOC (P80 and P100). These results and their timing point to low-order structures (such as visual thalamic nuclei or superior colliculi) or the visual cortex itself, as candidates for initial evaluation structures.

SCN gene expression plasticity in response to photoperiod
Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus and synchronizes, or entrains, physiology and behavior to the prevailing light cycle from retinal input. The process of entrainment induces considerable plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the phase, waveform, period, and resetting properties of the SCN and its driven rhythms. To elucidate novel molecular mechanisms of photoperiod plasticity, we performed RNAseq on whole SCN dissected from mice raised in Long (LD 16:8) and Short (LD 8:16) photoperiods. Using differential rhythms analysis, we showed that fewer rhythmic genes were detected in Long photoperiod and that there was an overall phase advance of gene expression rhythms of 4-6 hours. However, a few genes showed significant phase delays, including GTP binding protein overexpressed in skeletal muscle (Gem), an SCN light responsive gene and light response modulator. Using differential expression analysis, we found significant expression changes in the clock-associated gene timeless circadian clock 1 (Timeless) and abundant changes in expression levels of SCN neural signaling genes related to light responses, neuropeptides, GABA, ion channels, and serotonin. Particularly striking were differences across photoperiods in the expression of the SCN neuropeptide signaling genes, prokineticin receptor 2 (Prokr2) and cholecystokinin (Cck), as well as convergent regulation of the expression of three SCN light response genes, dual specificity phosphatase 4 (Dusp4) and RAS, dexamethasone-induced 1 (Rasd1), and Gem. Transcriptional modulation of Dusp4 and Rasd1, and phase regulation of Gem, are compelling candidate molecular mechanisms for photoperiod-induced plasticity in the SCN light response. Similarly, transcriptional modulation of Prokr2 and Cck may critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity.

Human spinal cord activation during filling and emptying of the bladder
Recording neural activity from the spinal cord is crucial for gaining insights into how it functions. However, the neural activity of the human spinal cord is notoriously difficult to measure. The bony and fascial enclosures combined with the relatively small anatomic size of the spinal cord make it an unfavorable target for traditional functional neuroimaging techniques. Functional ultrasound imaging (fUSI) is an emerging neuroimaging technology that represents a new platform for studying large-scale neural dynamics with high sensitivity, spatial coverage and spatiotemporal resolution. Although it was originally developed for studying brain function, fUSI was recently extended for imaging the spinal cord in animals and humans. While these studies are significant, their primary focus is on the neuroactivation of the spinal cord in response to external sensory stimulations. Here, we combined fUSI with urodynamically-controlled bladder filling and emptying to characterize the hemodynamic response of the human spinal cord during the micturition cycle. Our findings provide the first practical evidence of the existence of bladder pressure-responsive regions, whose hemodynamic signal is strongly correlated with the bladder pressure.

AIBP controls amyloid beta induced TLR4 inflammarafts and mitochondrial dysfunction in microglia
Microglia-driven neuroinflammation plays an important role in the development of Alzheimer's disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 and other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (A{beta}) induced TLR4 inflammarafts in microglia in vitro and in APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and dilated ER. A{beta} plaques and neuronal cell death were significantly increased, and survival decreased in Apoa1bp-/- APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.

The Representation of Decision Variables in Orbitofrontal Cortex is Longitudinally Stable
The computation and comparison of subjective values underlying economic choices rely on the orbitofrontal cortex (OFC). In this area, distinct groups of neurons encode the value of individual options, the binary choice outcome, and the chosen value. These variables capture both the input and the output of the choice process, suggesting that the cell groups found in OFC constitute the building blocks of a decision circuit. Here we show that this neural circuit is longitudinally stable. Using two-photon calcium imaging, we recorded from mice choosing between different juice flavors. Recordings of individual cells continued for up to 20 weeks. For each cell and each pair of sessions, we compared the activity profiles using cosine similarity, and we assessed whether the cell encoded the same variable in both sessions. These analyses revealed a high degree of stability and a modest representational drift. A quantitative estimate indicated this drift would not randomize the circuit within the animal's lifetime.

When most fMRI connectivity cannot be detected: insights from time course reliability
The level of correlation between two phenomena is limited by the accuracy at which these phenomena are measured. Despite numerous group reliability studies, the strength of the fMRI connectivity correlation that can be detected given underlying within subject time course reliability remains elusive. Moreover, it is unclear how within subject time course reliability limits the robust detection of connectivity on the group level. We estimated connectivity from 50 individuals engaged in a working memory task. The grand mean connectivity of the connectome equaled r =0.41 (95% CI 0.31-0.50) for the test run and r =0.40 (95% CI 0.29-0.49) for the retest run. However, mean connectivity was reduced to r=0.09 (95% C.I. 0.03-0.16) when test-retest reliability and residual auto-correlations of single time courses were considered, suggesting that less than a quarter of the observed connectivity is reliably detectable. Null hypothesis significance testing (NHST)-based analysis revealed that within subject time course reliability markedly affects the significance levels at which paths can be detected at the group level. This was in particular the case when samples were small or connectome coordinates were randomly selected. With a sample of 50 individuals, the connectome of a test session was completely reproduced in retest sessions at P < 2.54e-6. Despite perfect group reproducibility at conservative p-values, on average only 0.81 percent of the observed connectivity could be attributed to working memory-related time course fluctuations after corrections. Time course reliability can offer valuable insights on the detectable connectivity and should be assessed more frequently in fMRI investigations.

In vivo timelapse imaging and analysis of Golgi satellite organelle distribution and movement in the neural progenitor cells of the brain
The dividing stem cells of the developing brain are the radial glial neural progenitor cells (NPCs), multifunctional cells that proliferate to generate all of the cells of the brain, but also act as scaffolds for their migrating neuron progeny, guideposts for pathfinding growing axons and regulators of synaptic activity. These remarkable cells perform these very different activities while remaining in contact with the inner and outer surface of the ever-growing brain. NPCs synthesize proteins locally to support the compartmentalized protein expression required for the cells to perform their specialized functions, but it is not clear how the necessary processing that normally occurs in the Golgi apparatus is achieved at locations far from the cell body. Golgi satellites, motile organelles and members of the protein maturation machinery, control protein glycosylation and maturation in polarized cells like neurons. To investigate whether NPCs also rely on Golgi satellites, we expressed a fluorescent reporter to label Golgi satellites in the NPCs in the intact brains of Xenopus laevis tadpoles. Quantitative analysis of in vivo timelapse images revealed dynamic, motile Golgi satellites that distribute throughout the cell, suggesting that NPCs have local proteostasis to support their diverse functions.

Longitudinal study of neurochemical, volumetric and behavioral changes in Q140 & BACHD mouse models of Huntingtons disease
Brain metabolites, detectable by magnetic resonance spectroscopy (MRS), have been examined as potential biomarkers in Huntingtons Disease (HD). In this study, the RQ140 and BACHD transgenic mouse models of HD were used to investigate the relative sensitivity of the metabolite profiling and the brain volumetry to characterize mouse HD. Magnetic resonance imaging (MRI) and 1H MRS data were acquired at 9.4 T from the transgenic mice and wild-type littermates every 3 months until death. Brain shrinkage was detectable in striatum of both mouse models at 12 months compared to littermates. In Q140 mice, increases in PCr and Gln occurred in striatum prior to cortex. Myo-inositol was significantly elevated in both regions from an early age. Lac, Ala and PE decreased in Q140 striatum. Tau increased in Q140 cortex. Metabolite changes in the BACHD cortex and striatum were minimal with a striatal decrease in Lac being most prominent, consistent with a dearth of ubiquitin and 1C2 positive aggregates detected in those regions. Binary logistical regression models generated from the Q140 metabolite data were able to predict the presence of disease in the BACHD striatal and previously published R6/2 metabolite data. Thus, neurochemical changes precede volume shrinkage and become potential biomarkers for HD mouse models Introduction

Revisiting the high-dimensional geometry of population responses in visual cortex
Recent advances in large-scale recording technology have spurred exciting new inquiries into the high-dimensional geometry of the neural code. However, characterizing this geometry from noisy neural responses, particularly in datasets with more neurons than trials, poses major statistical challenges. We address this problem by developing new tools for the accurate estimation of high-dimensional signal geometry. We apply these tools to investigate the geometry of representations in mouse primary visual cortex. Previous work has argued that these representations exhibit a power law, in which the n'th principal component falls off as 1/n. Here we show that response geometry in V1 is better described by a broken power law, in which two different exponents govern the falloff of early and late modes of population activity. Our analysis reveals that later modes decay more rapidly than previously suggested, resulting in a substantially larger fraction of signal variance contained in the early modes of population activity. We examined the signal representations of the early population modes and found them to have higher fidelity than even the most reliable neurons. Intriguingly there are many population modes not captured by classic models of primary visual cortex indicating there is highly redundant yet poorly characterized tuning across neurons. Furthermore, inhibitory neurons tend to co-activate in response to stimuli that drive the early modes consistent with a role in sharpening population level tuning. Overall, our novel and broadly applicable approach overturns prior results and reveals striking structure in a population sensory representation.

Epigenetic repression of cFos supports sequential formation of distinct spatial memories
Expression of the immediate early gene cFos modifies the epigenetic landscape of activated neurons with downstream effects on synaptic plasticity. The production of cFos is inhibited by a long-lived isoform of another Fos family gene, {Delta}FosB. It has been speculated that this negative feedback mechanism may be critical for protecting episodic memories from being overwritten by new information. Here, we investigate the influence of {Delta}FosB inhibition on cFos expression and memory. Hippocampal neurons in slice culture produce more cFos on the first day of stimulation compared to identical stimulation on the following day. This downregulation affects all hippocampal subfields and requires histone deacetylation. Overexpression of {Delta}FosB in individual pyramidal neurons effectively suppresses cFos, indicating that accumulation of {Delta}FosB is the causal mechanism. Water maze training of mice over several days leads to accumulation of {Delta}FosB in granule cells of the dentate gyrus, but not in CA3 and CA1. Because the dentate gyrus is thought to support pattern separation and cognitive flexibility, we hypothesized that inhibiting the expression of {Delta}FosB would affect reversal learning, i.e., the ability to successively learn new platform locations in the water maze. The results indicate that pharmacological HDAC inhibition, which prevents cFos repression, impairs reversal learning, while learning and memory of the initial platform location remain unaffected. Our study supports the hypothesis that epigenetic mechanisms tightly regulate cFos expression in individual granule cells to orchestrate the formation of time-stamped memories.

Associations between regional blood-brain barrier disruption, aging, and Alzheimers disease biomarkers in cognitively normal older adults
Background: Blood-brain barrier disruption (BBBd) has been hypothesized as a feature of aging that may lead to the development of Alzheimers disease (AD). We sought to identify the brain regions most vulnerable to BBBd during aging and examine their regional relationship with neuroimaging biomarkers of AD. Methods: We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBd, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBd than YA. In OA, Ktrans values were compared based on sex, A{beta} positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. Results: OA showed greater BBBd than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or A{beta} positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global A{beta} pathology, but there was a trend for an A{beta} status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. Discussion: Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBd in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of A{beta}.

Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice
Alzheimer's disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/- mice were implanted with 17 beta estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquisition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/- mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid beta40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity
BACKGROUND: Parkinson's disease is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations due to the degenerative process or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops. OBJECTIVE: To investigate the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity and markers of synaptic plasticity. METHODS: Bilateral nigrostriatal degeneration was induced by viral-mediated overexpression of human mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the dorsomedial striatum (DMS) were performed and spike probability in response to OFC stimulation was measured before and after a high frequency stimulation (HFS). Post-mortem analysis included stereological assessment of nigral neurodegeneration, BDNF and TrkB levels. RESULTS: Nigrostriatal neurodegeneration led to altered firing patterns of OFC neurons that were restored by PPX. HFS of the OFC led to an increased spike probability in the DMS, while dopaminergic loss had an opposite effect. PPX led to a decreased spike probability following HFS in control rats and failed to counteract the effect of dopaminergic neurodegeneration. These alterations were associated with decreased levels of BDNF and TrkB. CONCLUSIONS: Both nigral dopaminergic loss and PPX concur to alter fronstostriatal transmission, precluding adequate information processing in associative basal ganglia loops as a gateway for the development of non-motor symptoms or non-motor side-effects of DRT.

Glutamate as a co-agonist for acid-sensing ion channels to aggravate ischemic brain damage
Glutamate is traditionally viewed as the first messenger to activate N-methyl-D-aspartate receptors (NMDARs) and downstream cell death pathways in stroke, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other NMDAR-independent mechanisms. Here we show that glutamate and its structural analogs, in-cluding NMDAR antagonist L-AP5 (or APV), robustly potentiated currents mediated by acid-sensing ion channels (ASICs) which are known for driving acidosis-induced neurotox-icity in stroke. Glutamate increased the proton affinity and open probability of ASICs, ag-gravating ischemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagen-esis and structure-based in silico molecular docking and simulations uncovered a novel glu-tamate binding cavity in the extracellular domain of ASIC1a. Computational drug screen-ing of NMDAR competitive antagonist analogs identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs, providing strong neuroprotection efficacy comparable to that in ASIC1a or other cation ion channel knockout mouse models. We conclude that glutamate serves as the first messenger for ASICs to exacerbate neurotoxicity, and that selective blockage of glutamate binding sites on ASICs without affecting NMDARs may be of strategic im-portance for developing effective stroke therapeutics devoid of the psychotic side effects of NMDAR antagonists.

Cingulate cortex shapes early postnatal development of social vocalizations
The social dynamics of vocal behavior has major implications for social development in humans. We asked whether early life damage to the anterior cingulate cortex (ACC), which is closely associated with socioemotional regulation more broadly, impacts the normal development of vocal expression. The common marmoset provides a unique opportunity to study the developmental trajectory of vocal behavior, and to track the consequences of early brain damage on aspects of social vocalizations. We created ACC lesions in neonatal marmosets and compared their pattern of vocalization to that of age-matched controls throughout the first 6 weeks of life. We found that while early life ACC lesions had little influence on the production of vocal calls, developmental changes to the quality of social contact calls and their associated syntactical and acoustic characteristics were compromised. These animals made fewer social contact calls, and when they did, they were short, loud and monotonic. We further determined that damage to ACC in infancy results in a permanent alteration in downstream brain areas known to be involved in social vocalizations, such as the amygdala and periaqueductal gray. Namely, in the adult, these structures exhibited diminished GABA-immunoreactivity relative to control animals, likely reflecting disruption of the normal inhibitory balance following ACC deafferentation. Together, these data indicate that the normal development of social vocal behavior depends on the ACC and its interaction with other areas in the vocal network during early life.