bioRxiv Subject Collection: Neuroscience's Journal

Investigation of the Fasciola Cinereum, Absent in BTBR mice, and Comparison with the Hippocampal Area CA2
The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including social learning, memory, and aggression, and is known to be a specific marker for the cornu ammonis area 2 (CA2) regions of the hippocampus. The fasciola cinereum (FC) is an anatomical region in which Avpr1b expressing neurons are prominent, but the functional roles of the FC have yet to be investigated. Surprisingly, the FC is absent in the inbred BTBR T+tf/J (BTBR) mouse strain used to study core behavioral deficits of autism. Here, we characterized and compared transcriptomic expression profiles using single nucleus RNA sequencing and identified 7 different subpopulations and heterogeneity within the dorsal CA2 (dCA2) and FC. Mef2c, involved in autism spectrum disorder, is more highly expressed in the FC. Using Hiplex in situ hybridization, we examined the neuroanatomical locations of these subpopulations in the proximal and distal regions of the hippocampus. Anterograde tracing of Avpr1b neurons specific for the FC showed projections to the IG, dCA2, lacunosum molecular layer of CA1, dorsal fornix, septofibrial nuclei, and intermediate lateral septum (iLS). In contrast to the dCA2, inhibition of Avpr1b neurons in the FC by the inhibitory DREADD system during behavioral testing did not impair social memory. We performed single nucleus RNA sequencing in the dCA2 region and compared between wildtype (WT) and BTBR mice. We found that transcriptomic profiles of dCA2 neurons between BTBR and WT mice are very similar as they did not form any unique clusters; yet, we found there were differentially expressed genes between the dCA2s of BTBR and WT mice. Overall, this is a comprehensive study of the comparison of Avpr1b neuronal subpopulations between the FC and dCA2. The fact that FC is absent in BTBR mice, a mouse model for autism spectrum disorder, suggests that the FC may play a role in understanding neuropsychiatric disease.

Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis
Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs' response to peripheral nerve injury.

Pharmacological stimulation of infralimbic cortex after fear conditioning facilitates subsequent fear extinction
The infralimbic (IL) division of the medial prefrontal cortex (mPFC) is a crucial site for extinc-tion of conditioned fear memories in rodents. Recent work suggests that neuronal plasticity in the IL that occurs during (or soon after) fear conditioning enables subsequent IL-dependent extinction learning. We therefore hypothesized that pharmacological activation of the IL after fear conditioning would promote the extinction of conditioned fear. To test this hypothesis, we characterized the effects of post-conditioning infusions of the GABAA receptor antagonist, pic-rotoxin, into the IL on extinction of auditory conditioned freezing in male and female rats. In four experiments, we found that picrotoxin injections performed immediately, 24 hours, or 13 days after fear conditioning reduced conditioned freezing to the auditory conditioned stimulus (CS) during both extinction training and extinction retrieval; this effect was observed up to two weeks after picrotoxin infusions. Interestingly, inhibiting protein synthesis inhibition in the IL immediately after fear conditioning prevented the inhibition of freezing by picrotoxin injected 24 hours later. Our data suggest that the IL encodes an inhibitory memory during the consoli-dation of fear conditioning that is necessary for future fear suppression.

Edinger-Westphal ghrelin receptor signalling regulates binge alcohol consumption in a sex specific manner
Background: Rates of risky drinking are continuing to rise, particularly in women, yet sex as a biological variable has been largely ignored. An emerging yet understudied potential component of this circuitry is the central projecting Edinger Westphal (EWcp), which is made up of two prominent, but distinct cell populations expressing either an array of neuropeptides (including cocaine and amphetamine regulated transcript; CART) or vGlut2 (glutamatergic). Methods: Here, we use a combination of approaches including genetic, molecular biology, behavioural testing, and electrophysiology to understand how the EWcp contributes to alcohol consumption in female versus male mice. Results: Chemogenetic inhibition of EWcp CART cells reduced binge drinking specifically in female, but not male mice. Further, inhibition of EWcp CART cells prevented ghrelin induced drinking, and viral mediated ghrelin receptor (Ghsr) knockdown in the EWcp reduced binge drinking in female, but not male mice. RNAscope revealed Ghsr expression across peptidergic (marked by CART) and glutamatergic populations in the EWcp, with neurons from female mice more sensitive to bath application of ghrelin than male mice. Targeted knockdown of Ghsr from distinct EWcp populations revealed GHSR signalling on peptidergic, but not glutamatergic cells mediate binge drinking in female mice. Finally, both a GHSR inverse agonist and antagonist delivered directly within the EWcp reduced binge drinking in female mice. Conclusions: These findings suggest the EWcp is a region mediating excessive alcohol bingeing through GHSR actions on peptidergic cells (CART expressing) in female mice and expand our understanding of the neural mechanism(s) underpinning how the ghrelin system mediates alcohol consumption.

Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections
Objective: Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 receptors (GLP-1R) in the dorsolateral septum (dLS; dLSGLP-1R) and their downstream projections on food intake and determine the relationship with feeding regulation. Methods: Using chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP-1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP-1R neurons to the lateral hypothalamic area (LHA) in regulating food intake. Results: Chemogenetic inhibition of dLSGLP-1R neurons increases food intake. LHA is a major downstream target of dLSGLP-1R neurons. The dLSGLP-1R[->]LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP-1R[->]LHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP-1R[->]LHA projection terminals in the LHA rapidly suppressed feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP-1R [->]LHA GABA release. Conclusions: Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.

Evidence for common spike-based temporal coding of overt and covert speech in pars triangularis of human Broca's area
Broca's area has long been described as a central region of cortical speech networks. Yet, its detailed role during speech production remains largely unknown and even sometimes debated. Recordings at the individual neuron level could help understand whether and how speech is encoded in this region but such data remain very scarce. Here we use direct intracortical recording in pars triangularis of human Broca's area to show that the encoding of speech in this region relies not only on spike rates but also on the precise timing of action potentials within individual spike trains. First, we found that the overall spike rate of the whole population remained unchanged between periods of rest, overt and covert speech, but that individual firing rates of a few neurons fluctuated across these conditions. These fluctuations resulted in different overall population dynamics across conditions. Next, we also observed that the temporal arrangement of spikes within individual spike trains was not purely random but also signed which sentence was produced. By matching ensemble spike trains based on inter-spike intervals, it was possible to decode which sentence had been pronounced well above chance and with a comparable accuracy than when using spike counts. Moreover, the temporal code characterizing the overt production of individual sentences was found to be largely conserved when the same sentences were covertly imagined and enabled to decode cover sentences with an accuracy 75% higher than when considering spike counts. Altogether, these results suggest the existence of 2 modes of speech encoding in Broca's area, one based on the modulation of individual firing rates and the other based on the precise temporal structure of individual spike trains, and that the latter type of encoding remains more largely conserved between overt and covert speech production.

The technical-reasoning network is recruited when people observe others make or teach how to make tools: An fMRI study
Cumulative technological culture is defined as the increase in efficiency and complexity of tools and techniques over generations. While the role of social cognitive skills in cultural transmission has been long acknowledged, recent accounts have emphasized that non-social cognitive skills such as technical reasoning, a form of causal reasoning aimed at understanding the physical world, are also at work during the social transmission of technical content. Here we contribute to this double process approach by reporting an fMRI study about the neurocognitive origins of social learning. Participants were shown videos depicting tool-making episodes in three social-learning conditions: Reverse engineering, Observation and Teaching. Our results showed that the technical-reasoning network, centred around the Area PF of the left inferior parietal cortex, was preferentially activated when watching tool-making episodes. Additionally, the teaching component was related to an activation of the right middle temporal gyrus. We propose that technical reasoning is at the heart of our technological culture and that the role of social cognition and teaching is to improve the learners technical reasoning by helping them concentrate on important parts of the technology. Thus, both technical reasoning and social-cognitive skills may play a key role in the cultural evolution of our technologies.

Parallel maturation of hippocampal memory and CA1 task representations
Hippocampal-dependent memory is known to emerge late in ontogeny and its full development is protracted. Yet, the changes in hippocampal neuronal function that underlie this delayed and gradual maturation remain relatively unexplored. To address this gap, we recorded ensembles of CA1 neurons while charting the development of hippocampal-dependent spatial working memory (WM) in rat pups (~2-4weeks of age). We found a sharp transition in WM development, with age of inflection varying considerably between individual animals. In parallel with the sudden emergence of WM, hippocampal spatial representations became abruptly task specific, remapping between encoding and retrieval phases of the task. Further, we show how the development of task phase remapping could partly be explained by changes in place field size during this developmental period as well as the onset of precise temporal coordination of CA1 excitatory input. Together, these results suggest that a hallmark of hippocampal memory development may be the emergence of contextually specific CA1 representations driven by the maturation of CA1 micro-circuits.

Operation regimes of spinal circuits controlling locomotion and role of supraspinal drives and sensory feedback
Locomotion in mammals is directly controlled by the spinal neuronal network, operating under the control of supraspinal signals and somatosensory feedback that interact with each other. However, the functional architecture of the spinal locomotor network, its operation regimes, and the role of supraspinal and sensory feedback in different locomotor behaviors, including at different speeds, remain unclear. We developed a computational model of spinal locomotor circuits receiving supraspinal drives and limb sensory feedback that could reproduce multiple experimental data obtained in intact and spinal-transected cats during tied-belt and split-belt treadmill locomotion. We provide evidence that the spinal locomotor network operates in different regimes depending on locomotor speed. In an intact system, at slow speeds (< 0.4 m/s), the spinal network operates in a non-oscillating state-machine regime and requires sensory feedback or external inputs for phase transitions. Removing sensory feedback related to limb extension prevents locomotor oscillations at slow speeds. With increasing speed and supraspinal drives, the spinal network switches to a flexor-driven oscillatory regime and then to a classical half-center regime. Following spinal transection, the spinal network can only operate in the state-machine regime. Our results suggest that the spinal network operates in different regimes for slow exploratory and fast escape locomotor behaviors, making use of different control mechanisms.

A Systematic Assessment of Robustness in CNS Safety Pharmacology
Irwin tests are key preclinical study elements for characterizing drug-induced neurological side effects. This multicenter study aimed to assess the robustness of Irwin tests across multinational sites during three stages of protocol harmonization. The projects were part of the EQIPD framework (Enhanced Quality in Preclinical Data, https://quality-preclinical-data.eu/), aiming to increase success rates in transition from preclinical testing to clinical application. Female and male NMRI mice were assigned to one of three groups (vehicle, 0.1 mg/kg MK-801, 0.3 mg/kg MK-801). Irwin scores were assessed at baseline and multiple times following injection of MK-801, a non-competitive NMDA antagonist, using local protocols (stage 1), a shared protocol with harmonized environmental design (stage 2), and fully harmonized Irwin scoring protocols (stage 3). The analysis based on the four functional domains (motor, autonomic, sedation, and excitation) revealed substantial data variability in stages 1 and 2. Although there was still marked overall heterogeneity between sites in stage 3 after complete harmonization of the Irwin scoring scheme, heterogeneity was only moderate within functional domains. When comparing treatment groups vs. vehicle, we found large effect sizes in the motor domain and subtle to moderate effects in the excitation-related and autonomic domain. The pronounced interlaboratory variability in Irwin datasets for the CNS-active compound MK-801 needs to be carefully considered by companies and experimenters when making decisions during drug development. While environmental and general study design had a minor impact, the study suggests that harmonization of parameters and their scoring can limit variability and increase robustness.

Parallel Multilink Group Joint ICA: Fusion of 3D Structural and 4D Functional Data Across Multiple Resting fMRI Networks
Multimodal neuroimaging research plays a pivotal role in understanding the complexities of the human brain and its disorders. Independent component analysis (ICA) has emerged as a widely used and powerful tool for disentangling mixed independent sources, particularly in the analysis of functional magnetic resonance imaging (fMRI) data. This paper extends the use of ICA as a unifying framework for multimodal fusion, introducing a novel approach termed parallel multilink group joint ICA (pmg-jICA). The method allows for the fusion of gray matter maps from structural MRI (sMRI) data to multiple fMRI intrinsic networks, addressing the limitations of previous models. The effectiveness of pmg-jICA is demonstrated through its application to an Alzheimer's dataset, yielding linked structure-function outputs for 53 brain networks. Our approach leverages the complementary information from various imaging modalities, providing a unique perspective on brain alterations in Alzheimer's disease. The pmg-jICA identifies several components with significant differences between HC and AD groups including thalamus, caudate, putamen with in the subcortical (SC) domain, insula, parahippocampal gyrus within the cognitive control (CC) domain, and the lingual gyrus within the visual (VS) domain, providing localized insights into the links between AD and specific brain regions. In addition, because we link across multiple brain networks, we can also compute functional network connectivity (FNC) from spatial maps and subject loadings, providing a detailed exploration of the relationships between different brain regions and allowing us to visualize spatial patterns and loading parameters in sMRI along with intrinsic networks and FNC from the fMRI data. In essence, developed approach combines concepts from joint ICA and group ICA to provide a rich set of output characterizing data-driven links between covarying gray matter networks, and a (potentially large number of) resting fMRI networks allowing further study in the context of structure/function links. We demonstrate the utility of the approach by highlighting key structure/function disruptions in Alzheimer's individuals.

The Pulfrich Effect in Virtual Reality
The Pulfrich effect, a visual phenomenon where a neural delay in one eye produces a depth misperception, has been directly studied on flat-panel displays but not in virtual reality (VR) environments. Through a series of three experiments, we investigated the relationship between luminance, contrast, dot spacing, and optical blur on the Pulfrich effect in VR and on the perception of motion. In the first two experiments, we found that low-reflectance stimuli produce a stronger Pulfrich effect than high-reflectance stimuli in VR, a result further accentuated by background luminance. Furthermore, the primary experiment showed that nullifying helix rotation motion is a powerful way to study the magnitude of the Pulfrich effect. With data from the first experiment, we developed a compelling VR illusion in which changing the color of a helix reverses the direction of perceived motion. Experiment 2 elaborated that low-reflectance stimuli only produce a stronger Pulfrich effect than high-reflectance stimuli when the stimulus is moving away from the delayed eye. Data from the first two experiments were successfully captured by power law function fits and linearized by plotting Pulfrich effect strength against logit-Michelson contrast. Our third experiment revealed that increasing blur and dot count in the helix stimulus increased the likelihood of perceiving up or down motion. All three experiments in tandem show that investigating well-known visual illusions such as the Pulfrich effect in virtual reality has the potential to reveal insights into visual perception as well as inform us about the effects of contrast and asymmetric lighting in spatial computing.

Alpha Traveling Waves during Working Memory: Disentangling Bottom-up Gating and Top-down Gain Control
While previous works established the inhibitory role of alpha oscillations during working memory maintenance, it remains an open question whether such an inhibitory control is a top-down process. Here, we attempted to disentangle this issue by considering the spatio-temporal component of waves in the alpha band, i.e., alpha traveling waves. We reanalyzed two pre-existing and open-access EEG datasets where participants performed lateralized delayed match-to-sample working memory tasks. In the first dataset, the distractor load was manipulated (2, 4, or 6), whereas in the second dataset, the memory span varied between 1, 3, and 6 items. In both datasets, we focused on the propagation of alpha waves on the anterior-posterior axis during the retention period. Our results reveal an increase in alpha-band forward waves as the distractor load increased, but also an increase in forward waves and a decrease in backward waves as the memory set size increased. Notably, our results also showed a lateralization effect: alpha forward waves exhibited a more pronounced increase in the hemisphere contralateral to the distractors, whereas the reduction in backward waves was stronger in the hemisphere contralateral to the targets. In short, the forward waves were regulated by distractors, whereas targets inversely modulated backward waves. Such a dissociation of goal-related and goal-irrelevant physiological signals suggests the co-existence of bottom-up and top-down inhibitory processes: alpha forward waves might convey a gating effect driven by distractor load, while backward waves may represent direct top-down gain control of downstream visual areas.

Surface-based probabilistic tractography uncovers segregated white matter pathways underlying spatial and non-spatial control
The frontal eye field (FEF) and the inferior frontal junction (IFJ) are regions that mediate orchestrating functions, with mounting neuroimaging evidence suggesting that they are specialized in the control of spatial versus non-spatial processing, respectively. We hypothesized that their unique patterns of structural connectivity (i.e., their connectivity fingerprints) underlie these specialized roles. To accurately infer the localization of FEF and IFJ in standard space, we carried out an activation likelihood estimation meta-analysis of fMRI paradigms targeting these regions. Using a surface-based probabilistic tractography approach, we tracked streamlines ipsilaterally from the inferred FEF and IFJ peaks to the dorsal and ventral visual streams on the native white matter surface parcellated using the atlas by Glasser et al. (2016). By contrasting FEF and IFJ connectivity likelihoods, we found predominant structural connectivity from FEF to regions of the dorsal visual stream (particularly in the left hemisphere) compared to the IFJ, and conversely, predominant structural connectivity from the IFJ to regions of the ventral visual stream compared to the FEF. Additionally, we analyzed the cortical terminations of the superior longitudinal fasciculus to the FEF and IFJ, implicating its first and third branches as segregated pathways mediating their communication to the posterior parietal cortex. The structural connectivity fingerprints of the FEF and IFJ support the view that the two visual stream architecture extend to the posterior lateral prefrontal cortex and provide converging anatomical evidence of their specialization in spatial versus non-spatial control.

The smoking cessation drug cytisine requires systemically circulating estrogen for sex-specific neuroprotection in female parkinsonian mice
The smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating estrogen mediates this effect, we employ two mouse models aimed at depleting systemically circulating estrogen: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating estrogen in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of estrogen depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson disease.

An inhibitory acetylcholine receptor gates context dependent mechanosensory processing in C. elegans
An animal's current behavior influences its response to sensory stimuli, but the molecular and circuit-level mechanisms of this context-dependent decision-making is not well understood. In the nematode C. elegans, inhibitory feedback from turning associated neurons alter downstream mechanosensory processing to gate the animal's response to stimuli depending on whether the animal is turning or moving forward. Until now, the specific neurons and receptors that mediate this inhibitory feedback were not known. We use genetic manipulations, single-cell rescue experiments and high-throughput closed-loop optogenetic perturbations during behavior to reveal the specific neuron and receptor responsible for receiving inhibition and altering sensorimotor processing. An inhibitory acetylcholine gated chloride channel comprised of lgc-47 and acc-1 expressed in neuron RIM receives inhibitory signals from turning neurons and performs the gating that disrupts the worm's mechanosensory evoked reversal response.

State-dependent Online Reactivations for Different Learning Strategies in Foraging
Reactivation of neural responses associated with navigation is thought to facilitate learning. We wondered whether reactivation is subject to contextual control, meaning that different types of learning promote different reactivation patterns. We trained macaques to forage in a first-person virtual maze and identified two distinct learning states prioritizing reward and information using unsupervised ethogramming based on low-level features. In orbitofrontal (OFC) and retrosplenial (RSC) cortices, representations of the goal, the path towards it, and recently traveled paths were strongly reactivated - online - during reward-prioritizing choices. During learning, reactivation of optimal paths increased in RSC after reward-prioritizing choices, and reactivation of uninformative paths decreased in RSC and OFC after information-prioritizing choices. Reactivation in OFC selectively covaried with ongoing RSC activity when prioritizing information; vice versa during prioritizing reward. These results highlight that cognitive states can drive learning and reactivation patterns can be tailored to the needs of the moment.

Link between respiratory pauses and vigilance states in freely moving mice
Respiratory patterns share bidirectional links with brain functions: they are modulated by sensory stimuli, attention and emotions, are affected in some cognitive disorders, but they also can influence perception, emotions and cognition. In particular, brain activity undergoes drastic changes when switching between vigilance states, such as transitions between wake and sleep - as do the overall respiratory rate. However, how the fine features of respiration, beyond its rate, accompany these transitions remains unclear. To address this question, we equipped freely-moving mice with both intra-nasal pressure sensors and hippocampus-targeted electrodes. The unprecedented accuracy of the respiratory signals in mice spontaneously alternating between wake, non-rapid-eye-movement (NREM) and REM sleep revealed that periods of respiratory pause with low or no airflow, are interspersed within phases of exhalation and inhalation. If pause durations impacted the respiratory rate in individual states, the effect of pauses differed across sleep and wake. This stemmed from strikingly different patterns across states: mainly pauses after inhalation during wake, mainly after exhalation in REM, and a mixture of both for NREM sleep. We verified that respiratory patterns are distinctive signatures for states by building an accurate machine-learning algorithm relying solely on respiration information for the prediction of vigilance states. Our experiments demonstrated that the information of missing pauses after inhalation and of breathing variability were instrumental to precise REM sleep prediction. Moreover, results highlighted that these vigilance state-respiration relationships can be generalized across animals. In agreement, kinetic indicators for exhalation and inhalation co-varied across states and were spared by animal-to-animal variations, while the duration of pauses after inhalation stood as an isolated, state-discriminant feature. Finally, dynamical analysis revealed that distinct breathing features adapt with different kinetics at the transition time points between different states, possibly accompanying distinct cortical changes. Our work therefore clarifies how different features of respiration, and in particular pauses in nasal airflow, are associated to the specific physiology of individual vigilance states and suggest new links with brain functions.

Mobile EEG for Neurourbanism Research - What Could Possibly Go Wrong?A Critical Review with Guidelines
Based on increasing incidents of mental ill-health associated with living in dense urban environments, the field of Neurourbanism developed rapidly, aiming at identifying and improving urban factors that impact the health of city dwellers. Neurourbanism and the closely related field of Neuro-Architecture have seen a surge in studies using mobile electroencephalography (EEG) to investigate the impact of the built and natural environment on human brain activity moving from the laboratory into the real world. This trend predominantly arises from the ready availability of affordable and portable consumer hardware, which not only guarantees operational simplicity but also frequently incorporates automated data analysis functions. This significantly streamlines the process of EEG data acquisition, analysis, and interpretation, seemingly challenging the necessity of specialized expertise in the method of EEG or neurosciences in general. As a consequence, numerous studies in the field of Neurourbanism have used such off-the-shelf systems in laboratory and real-world experimental protocols including active movement of participants through the environment. However, the recording and analysis of EEG data entails numerous requisites, the disregard of which may culminate in errors during data acquisition, processing, and subsequent interpretation, potentially compromising the scientific validity of the outcomes. The often relatively low number of electrodes offered by affordable and portable consumer EEG systems further restricts specific analyses approaches to the low-dimensional EEG data. Crucially, a large part of Neurourbanism studies used black-box analyses provided by such consumer systems or incorrectly applied complex data-driven analyses methods that are incompatible with the recorded low-dimensional data. The current manuscript delineates the prerequisites concerning EEG hardware and analytical methodologies applicable to stationary and mobile EEG protocols, whether conducted within a controlled laboratory environment or in real-world settings. It conducts a comprehensive review of EEG studies within the domain of Neurourbanism and Neuro-Architecture, assessing their adherence to these prerequisites. The findings reveal severe deficiencies in the utilization of hardware and data processing methods, thereby rendering these studies unsuitable for scientific scrutiny. Consequently, the present paper provides guidelines for the selection of EEG hardware and analytical strategies for researchers engaged in mobile EEG recordings, be it within a laboratory or real-world context, aimed at steering future investigations in the field of Neurourbanism and Neuro-Architecture.

A functional overlap between evidence accumulation, confidence, and changes of mind in the pre-supplementary motor area and insula
Evidence accumulation models have proven to be powerful tools to explain the temporal dynamics of decisions, as well as their metacognitive components such as confidence judgments and changes of mind. However, it is still unclear how and where in the brain evidence accumulation leads to these two metacognitive components. To better understand the functional overlap between evidence accumulation, confidence, and changes of mind, we recorded intracranial high-gamma activity in patients with focal epilepsy while they reported the motion direction of a random dot kinetogram with a computer mouse, and estimated their confidence level. We found an anatomical overlap between the neural correlates of evidence accumulation, confidence, and changes of mind in the pre-supplementary motor area, as well as in the orbitofrontal, inferior frontal, and insular cortices. Both mouse-tracking behaviour and electrophysiological results were reproduced with a post-decisional evidence accumulation model. After characterising the temporal dynamics of decision-making with mouse-tracking and intracranial electrophysiology, we conclude that confidence and changes of mind result from evidence accumulation instantiated before the decision in the pre-supplementary motor area, and after the decision in the insula.

Spectral graph model for fMRI: a biophysical, connectivity-based generative model for the analysis of frequency-resolved resting state fMRI
Resting state functional MRI (rs-fMRI) is a popular and widely used technique to explore the brain's functional organization and to examine if it is altered in neurological or mental disorders. The most common approach for its analysis targets the measurement of the synchronized fluctuations between brain regions, characterized as functional connectivity (FC), typically relying on pairwise correlations in activity across different brain regions. While hugely successful in exploring state- and disease-dependent network alterations, these statistical graph theory tools suffer from two key limitations. First, they discard useful information about the rich frequency content of the fMRI signal. The rich spectral information now achievable from advances in fast multiband acquisitions is consequently being under-utilized. Second, the analyzed FCs are phenomenological without a direct neurobiological underpinning in the underlying structures and processes in the brain. There does not currently exist a complete generative model framework for whole brain resting fMRI that is informed by its underlying biological basis in the structural connectome. Here, we propose that a different approach can solve both challenges at once: the use of an appropriately realistic yet parsimonious biophysical signal generation model followed by graph spectral (i.e. eigen) decomposition. We call this model a Spectral Graph Model (SGM) for fMRI, using which we can not only quantify the structure-function relationship in individual subjects, but also condense the variable and individual-specific repertoire of fMRI signal's spectral and spatial features into a small number of biophysically-interpretable parameters. We expect this model-based inference of rs-fMRI that seamlessly integrates with structure can be used to examine state and trait characteristics of structure-function relations in a variety of brain disorders.

Basal ganglia output - entopeduncular nucleus - coding of contextual kinematics and reward in the freely moving mouse
The entopeduncular nucleus (EPN) is often termed as one of the output nuclei of the basal ganglia owing to their highly convergent anatomy. The rodent EPN has been implicated in reward and value coding whereas the primate analogue internal Globus Pallidus has been found to be modulated by some movements and in some circumstances. In this study we sought to understand how the rodent EPN might be coding kinematic, reward, and value parameters, particularly during locomotion. Furthermore, we aimed to understand the level of movement representation: whole-body or specific body parts. To this end, mice were trained in a freely moving two-alternative forced choice task with two periods of displacement (Return and Go trajectories) and performed electrophysiological recordings together with video-based tracking. We found 1) robust reward, but not value, coding. 2) Spatio-temporal variables better explain EPN activity during movement compared to kinematic variables, while both types of variables were more robustly represented in reward-related movement. 3) Reward sensitive units encode kinematics similarly to reward insensitive ones. 4) Population dynamics that best account for differences between these two periods of movement can be explained by allocentric references like distance to reward port. 5) The representation of paw and licks is not mutually exclusive, discarding a somatotopic muscle-level representation of movement in the EPN. Our data suggest that EPN activity represents movements and reward in a complex way: highly multiplexed, influenced by the objective of the displacement, where trajectories that lead to reward better represent spatial and kinematic variables. Interestingly, there are intertwining representations of whole-body movement kinematics with single paw and licking variables. Further, reward and kinematic coding are not mutually exclusive, challenging the notion of distinct pathways for reward and movement processing.

Modeling responses of macaque and human retinal ganglion cells to natural images using a convolutional neural network
Linear-nonlinear (LN) cascade models provide a simple way to capture retinal ganglion cell (RGC) responses to artificial stimuli such as white noise, but their ability to model responses to natural images is limited. Recently, convolutional neural network (CNN) models have been shown to produce light response predictions that were substantially more accurate than those of a LN model. However, this modeling approach has not yet been applied to responses of macaque or human RGCs to natural images. Here, we train and test a CNN model on responses to natural images of the four numerically dominant RGC types in the macaque and human retina -- ON parasol, OFF parasol, ON midget and OFF midget cells. Compared with the LN model, the CNN model provided substantially more accurate response predictions. Linear reconstructions of the visual stimulus were more accurate for CNN compared to LN model-generated responses, relative to reconstructions obtained from the recorded data. These findings demonstrate the effectiveness of a CNN model in capturing light responses of major RGC types in the macaque and human retinas in natural conditions.

Multidimensional analysis of cortical interneuron synaptic features reveals underlying synaptic heterogeneity
Cortical interneurons are a diverse cell population, and it stands to reason that they deploy a diverse array of synapse types to fulfill their many roles in cortical function. However, little is known about interneuron synaptic diversity because we lack methods to extract features from synapse that might allow us to distinguish subgroups. Here, we develop an approach to aggregate image features from fluorescent confocal images of interneuron synapses and their post-synaptic targets, in order to characterize the heterogeneity of synapses at fine scale. We started by training a model that recognizes pre- and post-synaptic compartments and then determines the target of each interneuron synapse in the image. To accomplish this task, the model extracts hundreds of spatial and intensity features from each analyzed synapse, constructing a multidimensional data set, consisting of millions of synapses. We next used these image features to perform an unsupervised analysis on this dataset, and uncovered novel synaptic subgroups. These subgroups were spatially distributed in a highly structured manner that revealed the local underlying topology of the postsynaptic environment. Dendrite-targeting subgroups were clustered onto subdomains of the dendrite along the proximal to distal axis. Soma-targeting subgroups were enriched onto different postsynaptic cell types. Our analysis also discovered that the two main subclasses of interneurons, basket cells and somatostatin interneurons, utilize distinct strategies to enact inhibitory coverage. Thus, we present an image-based approach to study interneuron synapses that generates multidimensional data sets of synaptic features. This approach helped uncover novel interneuron biology, and begins to establish a conceptual framework for studying interneuron synaptic diversity.

Implantable Bioelectronics for Real-time in vivo Recordings of Enteric Neural Activity
The enteric nervous system represents a primary point of contact for a host of factors that influence bodily health and behavior. This division of the autonomic nervous system is unique in both its extensivity, with neurons distributed throughout the gastrointestinal tract from the esophagus to the rectum, and its capability for local information processing. Here, we show the construction and validation of a bioelectronic device to access neural information produced and processed in the gastrointestinal tract. We designed an implant and concurrent surgical procedure to place a neural recording device within the wall of the colon of rodents. We captured complex multi-frequency electrophysiological responses to neural stimulants and show that we can record activity in the context of mechanical activity mimicking gut motility. We also show the feasibility of utilizing this device for recording colonic activity in freely-moving animals. This work represents a step forward in devising functional bioelectronic devices for understanding the complex pathways of the gut-brain axis.

Switching between newly learned motor skills
Studies of cognitive flexibility suggest that switching between different tasks can entail a transient switch cost. Here, we asked whether analogous switch costs exist in the context of switching between different motor skills. We tested whether participants could switch between a newly learned skill associated with a novel visuomotor mapping, and an existing skill associated with an intuitive mapping. Participants showed increased errors in trials immediately following a switch between mappings. These errors were attributable to persisting with the pre-switch policy, rather than imperfect implementation or retrieval of the post-switch policy. A subset of our participants further learned a second new skill. Switching between these two novel skills was initially very challenging, but improved with further training. Our findings suggest that switching between newly learned motor skills can be challenging, and that errors in the context of switching between skills are primarily attributable to perseveration with the wrong control policy.

Enhancing tonic arousal improves voluntary but not involuntary attention in humans
Arousal and attention are pivotal brain functions for optimizing performance. Kahneman's attention model (1973) theorizes a key interplay between attention and arousal, yet this relationship remains poorly understood. We investigated this interaction in 16 healthy young adults performing an auditory attention task that simultaneously assessed phasic arousal, voluntary attention and involuntary attention. Tonic arousal was modulated by low or high arousing music, as measured using skin conductance, pupil size, and heart rate. Pupil dilation responses to distracting sounds highlight an intricate interplay between tonic and phasic arousal. Importantly, increasing tonic arousal does not influence involuntary attention, whereas it does improve voluntary attention, as shown by shorter and less variable reaction times and larger electroencephalographic brain responses to task-relevant targets. This study provides experimental evidence in humans that tonic arousal can influence the attentional balance by improving voluntary attention in a transient and sustained manner, rather than by impacting involuntary attention.

Arginine vasopressin activates serotonergic neurons in the dorsal raphe nucleus during neonatal development in vitro and in vivo
Birth stress is a strong risk factor for psychiatric disorders and associated with an exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. While it has been shown that AVP promotes firing of GABAergic interneurons leading to suppression of spontaneous perinatal hippocampal network events that suggest a protective function, its effect on developing subcortical networks is not known. Here we tested the effect of AVP on the neonatal dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. Using in vitro electrophysiological recording techniques, we show that AVP strongly excites neonatal 5-HT neurons via V1A receptors by increasing their excitatory synaptic inputs. Accordingly, AVP also promotes action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of 5-HT neurons. Our in vivo single unit recordings of identified neonatal 5-HT neurons under light urethane anaesthesia revealed two major firing patterns of neonatal 5-HT neurons, tonic regular firing and low frequency oscillations of regular spike trains. We confirmed that AVP also increases firing activity of putative 5-HT neurons in neonatal DRN in vivo. Finally, we show that neonatal DRN contains a sparse vasopressinergic innervation that is strongly sex dependent and originates exclusively from vasopressinergic cell groups in medial amygdala and bed nucleus of stria terminalis (BNST). Our results show, that in contrast to developing cortical networks where AVP promotes inhibition, AVP can also be strongly excitatory in immature subcortical networks such as the DRN 5-HT system. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own ongoing functional development as well as affect maturation of cortical target regions, which may increase the risk for psychiatric conditions later on.

Distinct and Asymmetric Neuronal Responses to Pitch- and Roll-Axis Vestibular Stimulation in larval zebrafish
The vestibular apparatus plays a pivotal role in maintaining postural equilibrium and processing movement signals, underscoring its importance in the study of certain neurological disorders. Here, we present a rotating light-sheet microscope, enabling brain-wide functional recordings during dynamic vestibular stimulation along both the roll and pitch axes in head-restrained zebrafish larvae. The system incorporates a double galvanometer mirror configuration, is amenable to 3D printing, and enhances scanning efficiency. Employing this apparatus, we have successfully conducted the first comprehensive mapping of zebrafish brain responses to dynamic pitch-tilt vestibular stimulation. Through Fourier and regression analyses, we report an asymmetry in neuronal recruitment during nose-up versus nose-down pitch tilts within critical regions including the cerebellum, oculomotor nucleus, caudal hindbrain, and vestibular nucleus, highlighting physiological adaptations to downward motion. We identified specific brain regions, notably the cerebellum and medial-rostral rhombencephalon, that exclusively respond to roll- but not pitch-tilt vestibular stimuli. Furthermore, we have identified a transgenic line that closely correlates with our functional mappings and demonstrates a significant response to vestibular stimulation. The elucidation of brain-wide neuronal circuits involved in vestibular processing establishes a foundational framework for subsequent detailed investigations into the molecular and genetic mechanisms underlying postural control and motion perception.

Role of Posterior Medial Thalamus in the Modulation of Striatal Circuitry and Choice Behavior
The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Altered patterning of neural activity in a tauopathy mouse model
Alzheimer's disease (AD) is a complex neurodegenerative condition that manifests at multiple levels and involves a spectrum of abnormalities ranging from the cellular to cognitive. Here, we investigate the impact of AD-related tau-pathology on hippocampal circuits in mice engaged in spatial navigation, and study changes of neuronal firing and dynamics of extracellular fields. While most studies are based on analyzing instantaneous or time-averaged characteristics of neuronal activity, we focus on intermediate timescales---spike trains and waveforms of oscillatory potentials, which we consider as single entities. We find that, in healthy mice, spike arrangements and wave patterns (series of crests or troughs) are coupled to the animal's location, speed, and acceleration. In contrast, in tau-mice, neural activity is structurally disarrayed: brainwave cadence is detached from locomotion, spatial selectivity is lost, the spike flow is scrambled. Importantly, these alterations start early and accumulate with age, which exposes progressive disinvolvement the hippocampus circuit in spatial navigation. These features highlight qualitatively different neurodynamics than the ones provided by conventional analyses, and are more salient, thus revealing a new level of the hippocampal circuit disruptions.

Feedback and Feedforward Regulation of Interneuronal Communication
We formulate a mechanistic model capturing the dynamics of neurotransmitter release in a chemical synapse. The proposed modeling framework captures key aspects such as the random arrival of action potentials (AP) in the presynaptic (input) neuron, probabilistic docking and release of neurotransmitter-filled vesicles, and clearance of the released neurotransmitter from the synaptic cleft. Feedback regulation is implemented by having the released neurotransmitter impact the vesicle docking rate that occurs biologically through autoreceptors on the presynaptic membrane. Our analytical results show that these feedbacks can amplify or buffer fluctuations in neurotransmitter levels depending on the relative interplay of neurotransmitter clearance rate with the AP arrival rate and the vesicle replenishment rate, with faster clearance rates leading to noise amplification. We next consider a postsynaptic (output) neuron that fires an AP based on integrating upstream neurotransmitter activity. Investigating the postsynaptic AP firing times, we identify scenarios that lead to band-pass filtering, i.e., the output neuron frequency is maximized at intermediate input neuron frequencies. We extend these results to consider feedforward regulation where in addition to a direct excitatory synapse, the input neuron also impacts the output indirectly via an inhibitory interneuron, and we identify parameter regimes where feedforward neuronal networks result in band-pass filtering.

Higher amplitudes of visual networks are associated with trait but not state- depression.
Despite depression being a leading cause of global disability, neuroimaging studies have struggled to identify replicable neural correlates of depression or explain limited variance. This challenge may, in part, stem from the intertwined state (current symptoms; variable) and trait (general propensity; stable) experiences of depression. Here, we sought to disentangle state from trait experiences of depression by leveraging a longitudinal cohort and stratifying individuals into four groups: those in remission (trait depression group), those with large longitudinal severity changes in depression symptomatology (state depression group), and their respective matched control groups (total analytic n=1,030). We hypothesized that spatial network organization would be linked to trait depression due to its temporal stability, whereas functional connectivity between networks would be more sensitive to state-dependent depression symptoms due to its capacity to fluctuate. We identified 15 large-scale probabilistic functional networks from resting-state fMRI data and performed group comparisons on the amplitude, connectivity, and spatial overlap between these networks, using matched control participants as reference. Our findings revealed higher amplitude in visual networks for the trait depression group at the time of remission, in contrast to controls. This observation may suggest altered visual processing in individuals predisposed to developing depression over time. No significant group differences were observed in any other network measures for the trait-control comparison, nor in any measures for the state-control comparison. These results underscore the overlooked contribution of visual networks to the psychopathology of depression and provide evidence for distinct neural correlates between state and trait experiences of depression.

Single cell approaches define forebrain neural stem cell niches and identify microglial ligands that enhance precursor-mediated remyelination
Here we used single cell RNA-sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We define the dorsal and lateral ventricular-subventricular zones (V-SVZ) as two distinct neighborhoods, and show that following white matter injury, dorsal NSCs are locally activated to make oligodendrocytes for remyelination. This activation is coincident with a robust increase in transcriptionally-distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, IGF1 and OSM, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.

Distinct roles of medial prefrontal cortex subregions in the consolidation and recall of remote spatial memories
It is a common believe that memories with time become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence demonstrating an impairing effect of prefrontal cortex (PFC) manipulations in the retrieval of remote memories paralleled by a lack of effect of hippocampal inhibition. What is more controversial is whether activity in the mPFC is required immediately after learning to initiate the consolidation process. Further question are possible functional differences among the subregions of the PFC in the formation and storage of remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the the anterior cingulate cortex (aCC) and the ventro-medial prefrontal cortex (vmPFC), that includes the infralimbic and the prelimbic cortices, before testing, and immediately after training, on the ability of CD1 mice to recall the location of the hidden platform in the Morris water maze. To this aim we injected in the vmPFC or in the aCC an AAV carrying the hM4Di receptor. Interestingly, pre-test administrations of clozapine-N-oxide (CNO) revealed that the aCC, but not the vmPFC, is necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO (3mg/kg) impaired memory recall at remote time points but not recent time points in both experimental groups. Overall, these findings revealed a functional dissociation between the two prefrontal areas, demonstrating that they are both involved in the early consolidation of remote spatial memories, but that only the aCC is engaged in their recall.

Palmitoylation regulates norepinephrine transporter trafficking and expression and is potentially involved in the pathogenesis of postural orthostatic tachycardia syndrome
Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. Previous research has outlined that NET activity and trafficking is modulated via reversible post-translational modifications like phosphorylation and ubiquitylation. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is another post-translational modification responsible for numerous biological mechanisms. In this study, we reveal that NET is dynamically palmitoylated and inhibition of this modification with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP), results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely with a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted WT hNET palmitoylation and elevated NET protein levels. The POTS associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable fragments. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of POTS.

Theta-Gamma Phase-Amplitude Coupling Supports Working Memory Performance in the Human Hippocampus
Phase-amplitude coupling (PAC) occurs in the human hippocampus during working memory and supports the contribution of the hippocampus in the maintenance of multiple items. Additionally, PAC has the potential to reveal the neural mechanisms underlying multi-item maintenance in the hippocampus by providing a putative architecture for multi-item representation. Theta and gamma range rhythms are prominent neuronal oscillations in the hippocampus. Studies on the role of theta frequency oscillation in local field potentials in human memory have shown mixed evidence for successful remembering. The role of gamma oscillatory activity in contributing to memory retrieval is not yet fully understood. They also interact with each other in the form of PAC during memory performance. This study aims to investigate the neurophysiological function of theta-gamma PAC in the human hippocampus during a multi-item working memory task and characterize its association with performance. Theta-gamma cross-coupling investigation in the electrocorticographic signals was performed from the hippocampus recording of ten epilepsy patients while they were engaged with the working memory task. The results show strong correlations between PAC levels and the subjects memory performance, but no correlation with theta and gamma power individually, specifically in the retrieval phase of a working memory task. These observations demonstrate the possible role of PAC in memory-related operations, suggesting a PAC-based neural mechanism for working memory in the hippocampus.

Primate V2 Receptive Fields Derived from Anatomically Identified Large-Scale V1 Inputs
In the primate visual system, visual object recognition involves a series of cortical areas arranged hierarchically along the ventral visual pathway. As information flows through this hierarchy, neurons become progressively tuned to more complex image features. The circuit mechanisms and computations underlying the increasing complexity of these receptive fields (RFs) remain unidentified. To understand how this complexity emerges in the secondary visual area (V2), we investigated the functional organization of inputs from the primary visual cortex (V1) to V2 by combining retrograde anatomical tracing of these inputs with functional imaging of feature maps in macaque monkey V1 and V2. We found that V1 neurons sending inputs to single V2 orientation columns have a broad range of preferred orientations, but are strongly biased towards the orientation represented at the injected V2 site. For each V2 site, we then constructed a feedforward model based on the linear combination of its anatomically- identified large-scale V1 inputs, and studied the response proprieties of the generated V2 RFs. We found that V2 RFs derived from the linear feedforward model were either elongated versions of V1 filters or had spatially complex structures. These modeled RFs predicted V2 neuron responses to oriented grating stimuli with high accuracy. Remarkably, this simple model also explained the greater selectivity to naturalistic textures of V2 cells compared to their V1 input cells. Our results demonstrate that simple linear combinations of feedforward inputs can account for the orientation selectivity and texture sensitivity of V2 RFs.

Compromised retinoic acid receptor beta (RARb) accelerates the onset of motor, cellular and molecular abnormalities in mouse model of Huntington's disease.
The mechanisms underlying detrimental effects of mutant huntingtin on striatal dysfunction in Huntington's disease (HD) are not well understood. Although retinoic acid receptor beta (RARb) emerged recently as one of the top regulators of transcriptionally downregulated genes in the striatum of HD patients and mouse models of HD its involvement in disease progression remains elusive. We report that genetically compromised RARb signaling accelerates onset of motor abnormalities in R6/1 mouse model of HD. Transcriptional profiling revealed that downregulation of RARb expression in Rarb+/-; R6/1 mice also accelerates transcriptional signature of disease progression by emergence of upregulated cluster of genes related to cell-cycle, stem cell maintenance and telencephalon development with concomitant downregulation of striatal cell-identity genes. The reactivation of proliferative activity demonstrated in the neurogenic niche and development-related transcriptional programs in the striatum prompt an attempt of lineage infidelity in HD striatum which may lead in consequence to disease-driving energy crisis as suggested by concomitant downregulation of transcripts essential for oxidative phosphorylation, a well-accepted correlate of HD physiopathology, and a metabolic change required for maintenance of proliferative activity and differentiation but not compatible with high energetic demand of differentiated and active neurons.

Heterogeneity in slow synaptic transmission diversifies Purkinje cell timing
The cerebellum plays an important role in diverse brain functions, ranging from motor learning to cognition. Recent studies have suggested that molecular and cellular heterogeneity within cerebellar lobules contributes to functional differences across the cerebellum. However, the specific relationship between molecular and cellular heterogeneity and diverse functional outputs of different regions of the cerebellum remains unclear. Here, we describe a previously unappreciated form of synaptic heterogeneity at parallel fiber synapses to Purkinje cells. In contrast to uniform fast synaptic transmission, we found that the properties of slow synaptic transmission varied by up to three-fold across different lobules of the mouse cerebellum, resulting in surprising heterogeneity. Depending on the location of a Purkinje cell, the time of peak of slow synaptic currents varied by hundreds of milliseconds. The duration and decay-time of these currents also spanned hundreds of milliseconds, based on lobule. We found that, as a consequence of the heterogeneous synaptic dynamics, the same brief stimulus was transformed into prolonged firing patterns over a range of timescales that depended on Purkinje cell location

Noise schemas aid hearing in noise
Human hearing is robust to noise, but the basis of this robustness is poorly understood. We explored whether internal models of environmental noise structure aid the perception of sounds in noise. One prediction of this hypothesis is that hearing should improve with exposure to a noise source, since noise properties can be better estimated with more samples. Consistent with this idea, we found that detection, recognition, and localization in real-world background noise improved with exposure to the background. A model that detected outliers from a distribution of background noise accounted for this pattern of performance. However, human performance was additionally enhanced for recurring backgrounds and was robust to interruptions in the background, suggesting listeners build up and maintain representations of noise properties over time. The results suggest noise robustness is supported by internal models--"noise schemas"--that capture the structure of noise and are used to estimate other concurrent sounds.

Nutrient Sensing Receptor GPRC6A Regulates mTORC1 Signaling and Tau Biology
Tauopathies, including Alzheimers disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies.

Significance StatementTauopathies, including Alzheimers disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.

Decomposed frontal corticostriatal ensemble activity changes across trials, revealing distinct features relevant to outcome-based decision making
The frontal cortex-striatum circuit plays a pivotal role in adaptive goal-directed behaviours. However, the mediation of decision-related signals through cross-regional transmission between the medial frontal cortex and the striatum by neuronal ensembles remains unclear. We analysed neuronal ensemble activity obtained through simultaneous multiunit recordings in the secondary motor cortex (M2) and dorsal striatum (DS) while the rats performed an outcome-based choice task. Tensor component analysis (TCA), an unsupervised dimensionality reduction approach at the single-trial level, was adopted for concatenated ensembles of M2 and DS neurons. We identified distinct three spatiotemporal neural dynamics (TCA components) at the single-trial level specific to task-relevant variables. Choice-position selective neural dynamics was correlated with the trial-to-trial fluctuation of behavioural variables. This analytical approach unveiled choice-pattern selective neural dynamics distinguishing whether the incoming choice was a repetition or switch from the previous choice. Other neural dynamics was selective to outcome. Choice-pattern selective within-trial activity increased before response choice, whereas outcome selective within-trial activity increased following response. These results suggest that the concatenated ensembles of M2 and DS process distinct features of decision-related signals at various points in time. The M2 and DS may collaboratively monitor action outcomes and determine the subsequent choice, whether to repeat or switch, for coordinated action selection.

Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells
Misfolded soluble trimeric species of superoxide dismutase 1 (SOD1) are associated with increased death in neuron-like cell models and greater disease severity in amyotrophic lateral sclerosis (ALS) patients compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may be a driver of disease pathology. Here, we uncovered the SOD1 trimer interactome - a map of potential tissue-selective protein binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers, comparing them to those of wild-type SOD1 dimers. We found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We also identified key pathways using transcriptomic data from motor neuron-like cells (NSC-34s) expressing SOD1 trimers. We discovered differential gene expression in cells that express SOD1 trimers with selective enrichment of genes responsible for protein localization to membranes and a global upregulation of cellular senescence pathways. We performed detailed computational and biochemical characterization of protein binding for septin-7, an SOD1 trimer binding partner. We found that septin-7 preferentially binds SOD1 trimers and co-localizes in neuron-like cells. We explore a double-edged sword theory regarding the toxicity of SOD1 trimers. These trimers are implicated in causing dysfunction not only in the central nervous system but also in muscle tissues. Our investigation highlights key protein factors and pathways within each system, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.

SummaryIn amyotrophic lateral sclerosis (ALS), misfolded soluble species of superoxide dismutase 1 (SOD1) are associated with disease severity and, specifically, trimeric forms of SOD1 are toxic in neuron-like cells compared to insoluble aggregates. The role of toxic SOD1 trimers in cells is unknown. Using molecular engineering and pull-down experiments, we found that SOD1 trimers have tissue-selective protein interactions that affect pathways such as dendritic spine morphogenesis and synaptic function in the nerves, energy, and amino acid metabolism in skeletal muscle. We investigated the SOD1 trimer transcriptome to reveal a global upregulation of genes associated with cellular senescence compared to SOD1 dimers. We further validated septin-7, a shared brain and spinal cord protein binding hit, using integrative computational and biochemical approaches, and confirmed that septin-7 binds SOD1 trimers and not native dimers. Taken together, we show evidence that SOD1 trimers play a central role in the convergence of ALS pathophysiology.

Graphical abstract

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