bioRxiv Subject Collection: Neuroscience's Journal

ALIGNING BRAINS INTO A SHARED SPACE IMPROVES THEIR ALIGNMENT TO LARGE LANGUAGE MODELS
Recent studies have shown that large language models (LLMs) can accurately predict neural activity measured using electrocorticography (ECoG) during natural language processing. To predict word-by-word neural activity, most prior work has estimated and evaluated encoding models within each electrode and subject-without evaluating how these models generalize across individual brains. In this paper, we analyze neural responses in 8 subjects while they listened to the same 30-minute podcast episode. We use a shared response model (SRM) to estimate a shared information space across subjects. We show that SRM significantly improves LLM-based encoding model performance. We also show that we can use this shared space to denoise the individual brain responses by projecting back into the individualized electrode space, and this process achieves a mean 38% improvement in encoding performance. The strongest improvement was observed for brain areas specialized for language comprehension, specifically in the superior temporal gyrus (STG) and inferior frontal gyrus (IFG). Critically, estimating a shared space allows us to construct encoding models that better generalize across individuals.

The GABAA receptor RDL modulates the auditory sensitivity of malaria mosquitoes.
Malaria mosquitoes mate in crowded, and noisy, swarms. A vital stage of their precopulatory behaviour involves detecting the faint flight tone of a mating partner amidst the noise from hundreds of other mosquitoes. This exquisite sensory performance is enabled by a complex auditory system with remarkable features. One such feature is their vast efferent control system, which provides the mosquito ear with the required plasticity to adapt to various external and internal changes. In this paper, we study the auditory role of GABA, one of the main efferent signalling molecules in the mosquito ear, and its interactions with octopamine, another neurotransmitter of the efferent network. We show that GABA is released in the malaria mosquito auditory nerve and that GABA receptors are expressed in the ear, including the GABAA receptor Resistance to Dieldrin (RDL), a target for the evolution of insecticide resistance. Using picrotoxin to antagonize RDL receptors, we discovered multiple auditory effects of GABA at the mechanical and electrical level. At the mechanical level, blocking RDL promotes the erection of antennal fibrillae and the cessation of flagellar self-sustained oscillations. These effects are not observed in knockouts of the octopamine receptor AgOctbeta2, suggesting that RDL auditory mechanical effects are mediated through octopamine release in the mosquito ear. Electrically, picrotoxin injection increases the spontaneous firing of auditory neurons and direct current (DC) responses of the nerve to mechanical stimulation both in wildtype and AgOctbeta2 mutants, indicating that RDL may also modulate auditory sensitivity via octopamine-independent pathways. In summary, our experiments uncover distinct auditory roles of GABA, as well as synergistic roles with octopamine. The data show a fundamental role of RDL in controlling the auditory function of malaria mosquitoes and implicate RDL signalling in mating of natural malaria mosquito populations.

TYK2 as a novel therapeutic target in Alzheimer Disease
Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS4. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death 4. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.

The Relationships of Resting-state Brain Entropy (BEN), Ovarian Hormones and Behavioral Inhibition and Activation Systems (BIS/BAS)
Entropy measures the irregularity or complexity of a system. Recent research on brain entropy (BEN) based on resting-state fMRI has provided complementary information to other metrics such as low-frequency fluctuations and cerebral blood flow. It has been established that neural plasticity, both pharmacological and nonpharmacological, as well as brain stimulation can influence BEN. However, it remains unknown whether BEN can reflect the effects of hormones. Furthermore, recent studies have indicated that ovarian hormones influence both the behavioral inhibition and activation systems. In our study, we utilized open-access available data from OpenNeuro to investigate the effects of ovarian hormones on BEN and their impact on BIS/BAS. Our results indicated a negative correlation between progesterone (PROG) and BEN in the frontal-parietal network and limbic system, while BEN showed a significant positive correlation with BAS-drive in the DLPFC. Additionally, a significant negative correlation was observed between PROG and BAS-drive. Further analysis revealed that DLPFC BEN mediates the negative correlation between PROG and BAS-drive. This suggests that PROG reduces BAS-drive by increasing the executive and inhibitory functions of DLPFC. We also analyzed the FC between DLPFC and the whole brain. DLPFC-IPL FC showed a significant positive correlation with BAS-drive, while DLPFC-LOFC FC exhibited a significant negative correlation with BAS-fun-seeking. Moreover, DLPFC-AG FC demonstrated a significant positive correlation with BAS-rewards. These results are consistent with the relationship between executive functions of the frontal-parietal network and impulsivity representation of BAS. Our study is the first to demonstrate that BEN can also reflect the impact of hormones on brain function. Additionally, we identified that the negative correlation between PROG and BAS-drive is mediated by left DLPFC BEN, providing new insights into our understanding of the effects of PROG on the brain and behavior.

Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia
Background: Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters cortical maturation of excitatory and inhibitory circuits that can be detected early with functional MRI. Methods. C57BL/6 mouse pups were exposed to an intermittent hypoxia (IH) regimen consisting of 12 to 20 daily hypoxic episodes of 5% oxygen exposure for 2 min at 37C from P3 to P7, followed by MRI at P12 and electrophysiological recordings in cortical slices and in vivo at several time points between P7 and P13. Behavioral tests were conducted at P41-P50 to assess animal activity and motor learning. Results. Adult mice after neonatal IH exhibited hyperactivity in open field test and impaired motor learning in complex wheel tasks. Patch clamp and evoked field potential electrophysiology revealed increased glutamatergic transmission accompanied by elevation of tonic inhibition. A decreased synaptic inhibitory drive was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo in the motor cortex with selective GABAA receptor inhibitor picrotoxin injection, as well as by the decreased interneuron density at P13. There was also an increased tonic depolarizing effect of picrotoxin after IH on principal cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase after picrotoxin injection in the IH group. Conclusions. Increased excitatory glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes, including impaired motor learning and hyperactivity. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH. The increased tonic inhibition, presumably due to tonic extrasynaptic GABA receptor drive, may be compensatory to the elevated excitatory glutamatergic transmission.

Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states
Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.

Data rescue in high-motion youth cohorts for robust and reproducible brain-behavior relationships
Recognition of the detrimental impact of participant motion on functional connectivity measures has led to the adoption of increasingly stringent quality control standards to minimize potential motion artifacts. These stringent standards can lead to the exclusion of many participants, creating a tension with a countervailing requirement for large sample sizes that can provide adequate statistical power, particularly for brain-behavior association studies. Here, we test and validate two techniques aimed at mitigating the impact of head motion on functional connectivity estimates, and show that these techniques enable the retention of a substantial proportion of participants who would otherwise be excluded based on motion criteria, such as a minimum mean framewise displacement (FD) threshold. Specifically, we first show that functional connectomes computed using time series data that have been ordered according to motion (i.e., framewise displacement - FD) and (1) subsetted to include the lowest-motion time points ("motion ordered") or (2) subsetted and resampled ("bagged") are reproducible, in that they enable the successful identification of an individual from a group using functional connectome fingerprinting. Second, we demonstrate that motion-ordered and bagged functional connectomes yield robust brain-behavior associations, which, when examined as a function of sample size, are comparable to those obtained using the standard full time series. Finally, we show that the utility of both approaches lies in maximizing participant inclusivity by allowing for the retention of high-motion participants that would otherwise be discarded. Given equivalent performance of the two approaches across these tests of reproducibility, validity, and utility, we conclude by recommending motion-ordering to enable data rescue, maximize inclusivity, and address the need for adequately powered samples in functional connectivity research, while maintaining stringent data quality standards. While our findings were reproducible across different head motion thresholds and edges in the functional connectome, we outline possibilities for further validation and assessment of generalization using other behavioral phenotypes and consortia datasets.

Play it by Ear: A perceptual algorithm for autonomous melodious piano playing with a bio-inspired robotic hand
Perception shapes the learning and performance of motor behavior in animals. In contrast to this inherent biological and psychological connection between perception and action, traditional artificial intelligence methods for robotics emphasize reward-driven extensive trial-and-error or error-driven control techniques. Our study goes back to the perceptual roots of biological learning and behavior, and demonstrates a novel end-to-end perceptual experience-driven approach for autonomous piano playing. Our 'Play it by Ear' perceptual learning algorithm, coupled to a bio-inspired 4-finger robotic hand, can replicate melodies on a keyboard after hearing them once, without explicit or prior knowledge of notes, the hand, or the keyboard. Our key innovation is an end-to-end pipeline that, after a brief period of 'motor babbling' by the hand, converts the sound of a melody into native musical percepts (note sequences and intensities) that it replays as sequences of key presses. In this way, any new melody consisting of notes experienced during babbling can be reproduced by the robotic musician hand on the basis of its percepts. This playback includes capturing the qualitative and quantitative musical dynamics and tempo with a nuance comparable with that of four human pianists performing the same melody. These compelling results emphasize the perceptual underpinnings of artistic performance as an alternative to traditional control-theoretical emphasis on state estimation and error correction. Our approach opens avenues for the development of simple machines that can still execute artistic and physical tasks that approach the nuance inherent in human behavior.

Role of microglia in stress-induced alcohol intake in female and male mice
Rates of alcohol use disorder (AUD) have escalated in recent years, with a particular increase among women. Women are more susceptible to stress-induced alcohol drinking, and preclinical data suggest that stress can increase alcohol intake in female rodents; however, a comprehensive understanding of sex-specific neurobiological substrates underlying this phenomenon is still emerging. Microglia, the resident macrophages of the brain, are essential for reshaping neuronal processes, and microglial activity contributes to overall neuronal plasticity. We investigated microglial dynamics and morphology in limbic brain structures of male and female mice following exposure to stress, alcohol or both challenges. In a modified paradigm of intermittent binge drinking (repeated drinking in the dark), we determined that female, but not male, mice increased their alcohol consumption after exposure to a physical stressor and re-exposure trials in the stress-paired context. Ethanol (EtOH) drinking and stress altered a number of microglial parameters, including overall number, in subregions of the amygdala and hippocampus, with effects that were somewhat more pronounced in female mice. We used the CSF1R antagonist PLX3397 to deplete microglia in female mice to determine whether microglia contribute to stress-induced escalation of EtOH intake. We observed that microglial depletion attenuated stress-induced alcohol intake with no effect in the unstressed group. These findings suggest that microglial activity can contribute to alcohol intake under stressful conditions, and highlight the importance of evaluating sex-specific mechanisms that could result in tailored interventions for AUD in women.

The disease-causing tau V337M mutation induces tau hypophosphorylation and perturbs axon morphology pathways
Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood due to our incomplete understanding of the normal functions of tau in development and aging and how these processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation. RNA-seq and phosphoproteomics revealed that both V337M tau and tau knockdown consistently perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. We conducted functional genomics screens to uncover regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau might perturb axon morphology pathways and tau hypophosphorylation via a "loss of function" mechanism, which could contribute to previously reported cognitive changes in preclinical MAPT gene carriers.

A chemically defined oviposition attractant and repellent of Black Soldier Flies (Hermetia illucens)
Black Soldier Flies (BSF), Hermetia illucens, are industrially important species. They can consume large amounts of spoilt organic material as larvae and bio-convert it to more useful biomass. Female BSF lay eggs in crevices adjacent to spoilt organic materials that serve as an oviposition attractant. These kairomones are central to maximising rearing efforts, yet the composition and origin of oviposition cues remain undefined, and no synthetic oviposition attractants are currently available. This work aimed to identify key components of naturally occurring oviposition attractants and to formulate an effective synthetic alternative for BSF. We have developed a novel oviposition assay and found larval food- and frass-based attractants to be the most effective at centralizing egg laying. We have identified the volatile compounds in the headspaces of putative attractants and established that the antennae of the female flies respond to some of these compounds. Behavioural validation using synthetic compounds allowed us to generate a mixture of 5 compounds (p-cresol, decanal, sulcatone, pentanoic acid, acetophenone) that cues oviposition as efficiently as currently used natural oviposition attractants. We also identified a synthetic mixture that deters oviposition in BSF. The synthetic attractant and repellent we generated are likely to simplify BSF rearing in research and industrial settings.

Hyperactive GluN2B impairs neuroplasticity and cognition in phenylketonuria
Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanism by which elevated Phe levels causes cognitive impairment remains unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. L-Phe exhibited dose-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in an activity-dependent downregulation of AMPARs during burst or sustained synaptic activity. Administration of L-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment of GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed impaired learning in the PahEnu2 PKU model. Collectively, these results suggest that the concentration of Phe in the cerebrospinal fluid of patients with PKU perturbs extrasynaptic NMDAR and synaptic plasticity, and that suppression of GluN2B may be a therapeutic strategy for improving cognitive function in patients with PKU.

Stimulus-specificity of surround-induced responses in primary visual cortex
Recent studies in mice challenge the traditional notion of the V1 receptive field (RF) showing increases in V1 firing rates for stimuli presented in the surround, in the absence of a visual input into the classical RF. While this effect has been interpreted as a prediction of the occluded content or a prediction error, an alternative explanation is that it reflects the representation of the uniform achromatic (gray) surface itself. To study this, we systematically investigated the dependence of V1 rate increases on the properties of distal surround stimuli. We recorded V1 and LGN neurons using Neuropixels in awake mice and demonstrated surround-induced responses in V1. That is, V1 firing rates increase by presenting a grating stimulus in the distal surround, while the RF is covered by a large gray patch up to 90{degrees} of diameter. LGN firing rates decreased for the same stimuli. V1 response latencies showed a systematic increase with the size of the gray patch. Surround-induced responses did not require spatial continuity or motion coherence of the surround stimulus and generalized to noisy textures and black/white luminance surfaces. Responses to black/white surfaces on a gray background had a similar magnitude and response latency as surround-induced responses with a black/white background. Based on these findings, we suggest that surround-induced responses primarily reflect the representation of the achromatic surface itself, which can contribute to image segmentation.

Structural diversity of Arc oligomers within the excitatory synapse
The Activity-Regulated Cytoskeleton-Associated protein (Arc) is pivotal in mediating synaptic plasticity responses in neuronal cells. In vitro studies suggest its ability to form high- and low-order oligomers, which are involved in neuronal trafficking. Despite its important functions, no direct observation of Arc oligomers in cells has been presented due to its highly regulated spatiotemporal expression, the small size of the structures, the lack of appropriate labelling strategies and the background associated to free diffusing cytosolic proteins. Here, we apply super resolution microscopy to observe Arc oligomeric states in cellular environment with focus on the excitatory synapse. In cells, we provide the first evidence of Arc high-order oligomers; we uncovered intermolecular interactions of Arc, its tendency to form liquid condensates and interaction with lipid bilayers. Arc high-order oligomers affect AMPA receptor surface levels. Together, our observations suggest a model by which Arc oligomerization mediates plasma membrane negative curvature favoring AMPA receptors endocytosis.

Excitatory-Inhibitory Homeostasis and Bifurcation Control in the Wilson-Cowan Model of Cortical Dynamics
Although the primary function of excitatory-inhibitory (E-I) homeostasis is the maintenance of mean firing rates, the conjugation of multiple homeostatic mechanisms is thought to be pivotal to ensuring edge-of-bifurcation dynamics in cortical circuits. However, computational studies on E-I homeostasis have focused solely on the plasticity of inhibition, neglecting the impact of different modes of E-I homeostasis on cortical dynamics. Therefore, we investigate how oscillations and edge-of-bifurcation dynamics are shaped by the diverse mechanisms of E-I homeostasis employed by cortical networks. Using the Wilson-Cowan model, we explore how distinct modes of E-I homeostasis maintain stable firing rates in models with varying levels of input and how it affects circuit dynamics. Our results confirm that E-I homeostasis can be leveraged to control edge-of-bifurcation dynamics and that some modes of homeostasis maintain mean firing rates under higher levels of input by modulating the distance to the bifurcation. Additionally, relying on multiple modes of homeostasis ensures stable activity while keeping oscillation frequencies within a physiological range. Our findings tie relevant features of cortical networks, such as E-I balance, the generation of gamma oscillations, and edge-of-bifurcation dynamics, under the framework of firing-rate homeostasis, providing a mechanistic explanation for the heterogeneity in the distance to the bifurcation found across cortical areas. In addition, we reveal the functional benefits of relying upon different homeostatic mechanisms, providing a robust method to regulate network dynamics with minimal perturbation to the generation of gamma rhythms and explaining the correlation between inhibition and gamma frequencies found in cortical networks.

Inhibitory circuits coordinate leg movements during Drosophila grooming
Limbs execute diverse actions coordinated by the nervous system through multiple motor programs. The basic architecture of motor neurons that activate muscles which articulate joints for antagonistic flexion and extension movements is conserved from flies to vertebrates. While excitatory premotor circuits are expected to establish sets of leg motor neurons that work together, our study uncovered an instructive role for inhibitory circuits. Using electron microscopy data for the Drosophila nerve cord, we categorized ~120 GABAergic inhibitory neurons from the 13A and 13B hemi-lineages into classes based on similarities in morphology and connectivity. By mapping their synaptic partners, we uncovered redundant pathways for inhibiting specific groups of motor neurons, disinhibiting antagonistic counterparts, or inducing alternation between flexion and extension. We tested the function of specific inhibitory neurons through optogenetic activation and silencing, using quantitative leg movement assays for coordination during grooming. Behavior experiments and modeling demonstrate that inhibition can induce rhythmic motion, highlighting the importance of inhibitory circuits in motor control.

Tool use fine-tunes arm and tool maps
There is evidence that the sensorimotor system builds fine-grained spatial maps of the limbs based on somatosensory signals. Can a hand-held tool be mapped in space with a comparable spatial resolution? Do spatial maps change following tool use? In order to address these questions, we used a spatial mapping task on healthy participants to measure the accuracy and precision of spatial estimates pertaining to several locations on their arm and on a hand-held tool. To study spatial accuracy, we first fitted linear regressions with real location as predictor and estimated location as dependent variables. Intercepts and slopes, representing constant offset and estimation error, were compared between arm and tool, and before to after tool use. We further investigated changes induced by tool use in terms of variable error associated with spatial estimates, representing their precision. We found that the spatial maps for the arm and tool were comparably accurate, suggesting that holding the tool provides enough information to the sensorimotor system to map it in space. Further, using the tool fine-tuned the user spatial maps, increasing the precision of the tool map to a greater extent than their arm map. Furthermore, this increased precision is focal to specific tool locations, i.e., the tool tip, which may work as a spatial anchor following tool use. Our results demonstrate that tool users possess dynamic maps of tool space that are comparable to body space.

Distinct roles of two thalamostriatal systems in learning processes of visual discrimination in common marmosets
The thalamostriatal projections arising from the intralaminar thalamic nuclei (ILN) constitute the principal source of input information to specified subregions of the striatum, a key structure of the cortico-basal ganglia circuitry. However, the roles of primate ILN in cortico-basal ganglia circuit functions remain unclear. Here, we performed immunotoxin-induced selective targeting of two representative structures of the ILN, the parafascicular nucleus (Pf) and centre median nucleus (CM) projecting to the caudate nucleus (Cd) and putamen (Pu), respectively, in common marmosets. Elimination of Pf-Cd neurons resulted in impaired reversal learning of a two-choice visual discrimination task, whereas removal of CM-Pu neurons disturbed the task acquisition. No marked impact of such manipulations was observed on either motor skill learning or spontaneous locomotor activity. Our findings reveal that the two thalamostriatal systems play distinct roles in the learning processes of external cue-dependent decision-making in nonhuman primates.

Uncoupling the CRMP2-CaV2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis model
Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics- invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate CaV2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.

Scalable electron tomography for connectomics
We demonstrate limited-tilt, serial section electron tomography (ET), which can non-destructively map brain circuits over large 3D volumes and reveal high-resolution, supramolecular details within subvolumes of interest. We show accelerated ET imaging of thick sections (>500 nm) with the capacity to resolve key features of neuronal circuits including chemical synapses, endocytic structures, and gap junctions. Furthermore, we systematically assessed how imaging parameters affect image quality and speed to enable connectomic-scale projects.

Refinement of efficient encodings of movement in the dorsolateral striatum throughout learning
The striatum is required for normal action selection, movement, and sensorimotor learning. Although action-specific striatal ensembles have been well documented, it is not well understood how these ensembles are formed and how their dynamics may evolve throughout motor learning. Here we used longitudinal 2-photon Ca2+ imaging of dorsal striatal neurons in head-fixed mice as they learned to self-generate locomotion. We observed a significant activation of both direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs, respectively) during early locomotion bouts and sessions that gradually decreased over time. For dSPNs, onset- and offset-ensembles were gradually refined from active motion-nonspecific cells. iSPN ensembles emerged from neurons initially active during opponent actions before becoming onset- or offset-specific. Our results show that as striatal ensembles are progressively refined, the number of active nonspecific striatal neurons decrease and the overall efficiency of the striatum information encoding for learned actions increases.

Sensory-Behavioral Deficits in Parkinson's Disease: Insights from a 6-OHDA Mouse Model
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the striatum, predominantly associated with motor symptoms. However, non-motor deficits, particularly sensory symptoms, often precede motor manifestations, offering a potential early diagnostic window. The impact of non-motor deficits on sensation behavior and the underlying mechanisms remains poorly understood. In this study, we examined changes in tactile sensation within a Parkinsonian state by employing a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) to deplete striatal dopamine (DA). Leveraging the conserved mouse whisker system as a model for tactile-sensory stimulation, we conducted psychophysical experiments to assess sensory-driven behavioral performance during a tactile detection task in both the healthy and Parkinson-like states. Our findings reveal that DA depletion induces pronounced alterations in tactile sensation behavior, extending beyond expected motor impairments. We observed diverse behavioral deficits, spanning detection performance, task engagement, and reward accumulation, among lesioned individuals. While subjects with extreme DA depletion consistently showed severe sensory behavioral deficits, others with substantial DA depletion displayed minimal changes in sensory behavior performance. Moreover, some exhibited moderate degradation of behavioral performance, likely stemming from sensory signaling loss rather than motor impairment. The implementation of a sensory detection task is a promising approach to quantify the extent of impairments associated with DA depletion in the animal model. This facilitates the exploration of early non-motor deficits in PD, emphasizing the importance of incorporating sensory assessments in understanding the diverse spectrum of PD symptoms.

In-Scanner Thoughts shape Resting-state Functional Connectivity: how participants rest matters.
Resting-state fMRI (rs-fMRI) scans--namely those lacking experimentally-controlled stimuli or cognitive demands--are often used to identify aberrant patterns of functional connectivity (FC) in clinical populations. To minimize interpretational uncertainty, researchers control for across-cohort disparities in age, gender, co-morbidities, and head motion. Yet, studies rarely, if ever, consider the possibility that systematic differences in inner experience (i.e., what subjects think and feel during the scan) may directly affect FC measures. Here we demonstrate that is the case using a rs-fMRI dataset comprising 471 scans annotated with experiential data. Wide-spread significant differences in FC are observed between scans that systematically differ in terms of reported in-scanner experience. Additionally, we show that FC can successfully predict specific aspects of in-scanner experience in a manner similar to how it predicts demographics, cognitive abilities, clinical outcomes and labels. Together, these results highlight the key role of in-scanner experience in shaping rs-fMRI estimates of FC.

Active enhancement of synapse driven depolarization of perisynaptic astrocytic processes
Electrophysiological properties underlie the fundamental mechanisms of the brain. Although astrocytes have typically been considered not electrically excitable, recent studies have shown depolarization of astrocytes induced by local extracellular potassium changes caused by neuronal activity. Interestingly, astrocytic depolarization is only induced within the periphery of the astrocyte, where astrocytes contact neurons. This depolarization affects the brain's information processing, as depolarization alters astrocyte functionality and neurotransmitter dynamics. However, specific mechanisms causing astrocytic depolarization have remained unknown due to the limitations of experimental techniques. Here, we construct a computational whole-cell astrocyte model containing experimentally verified astrocytic channels relevant to depolarization. Using our model, we suggest that previously reported potassium channels alone are insufficient for astrocyte depolarization and additional mechanisms are required. Our simulations show that NMDARs contribute to this depolarization by cooperating with Kir 4.1 to actively enhance extracellular potassium concentration and, thus, sustain depolarization.

Multiple distinct timescales of rapid sensory adaptation in the thalamocortical circuit
Numerous studies have shown that neuronal representations in sensory pathways are far from static but are instead strongly shaped by the complex properties of the sensory inputs they receive. Adaptation dynamically shapes the neural signaling that underlies our perception of the world, yet remains poorly understood. We investigated rapid adaptation across timescales from hundreds of milliseconds to seconds through simultaneous multi-electrode recordings from the ventro-posteromedial nucleus of the thalamus (VPm) and layer 4 of the primary somatosensory cortex (S1) in anesthetized mice in response to controlled, persistent whisker stimulation. Observations in VPm and S1 reveal a degree of adaptation that progresses through the pathway. Signatures of two distinct timescales of rapid adaptation in the firing rates of both thalamic and cortical neuronal populations were revealed, also reflected in the synchrony of the thalamic population and in the thalamocortical synaptic efficacy that was measured in putatively monosynaptically connected thalamocortical pairs. Controlled optogenetic activation of VPm further demonstrated that the longer timescale adaptation observed in S1 is likely inherited from slow decreases in thalamic firing rate and synchrony. Despite the degraded sensory responses, adaptation resulted in a shift in coding strategy that favors theoretical discrimination over detection across the observed timescales of adaptation. Overall, although multiple mechanisms contribute to rapid adaptation at distinct timescales, they support a unifying framework on the role of adaptation in sensory processing.

Replay of procedural experience is independent of the hippocampus
Sleep is critical for consolidating all forms of memory1-3, from episodic experience to the development of motor skills4-6. A core feature of the consolidation process is offline replay of neuronal firing patterns that occur during experience7,8. This replay is thought to originate in the hippocampus and trigger the reactivation of ensembles of cortical and subcortical neurons1,3,9-18. However, non-declarative memories do not require the hippocampus for learning or for sleep-dependent consolidation19-26 meaning what drives their consolidation is unknown. Here we show, using an unsupervised method, that replay occurs in the dorsal striatum of mice during offline consolidation of a non-declarative, procedural, memory and that this replay is generated independently of the hippocampus. Replay occurred at both real-world and time-compressed speeds and was also prioritised both at the level of the individual neurons and the type of neural sequence. Complete bilateral lesions of the hippocampus had no effect on any feature of this replay. Our results demonstrate that procedural replay during consolidation of a non-declarative memory is independent of the hippocampus. These results support the view that replay drives active consolidation of all types of memory during sleep but challenges the idea that the hippocampus is the source of this replay.

Vasopressin differentially modulates the excitability of rat olfactory bulb neuron subtypes
Vasopressin (VP) is essential for social memory already at the level of the olfactory bulb (OB), and OB VP cells are activated by social interaction. However, it remains unclear how VP modulates olfactory processing to enable enhanced discrimination of very similar odors, e.g., rat body odors. So far, it has been shown that VP reduces firing rates in mitral cells (MCs) during odor presentation in-vivo and decreases the amplitudes of olfactory nerve-evoked excitatory postsynaptic potentials (ON-evoked EPSPs) in external tufted cells in-vitro. We performed whole-cell patch-clamp recordings and population Ca2+ imaging on acute rat OB slices. We recorded ON-evoked EPSPs as well as spontaneous inhibitory postsynaptic currents (IPSCs) from two types of projection neurons, middle tufted cells (mTCs) and MCs. VP bath-application reduced the amplitudes of ON-evoked EPSPs and the frequencies of spontaneous IPSCs in mTCs but did not change those in MCs. Therefore, we analyzed ON evoked-EPSPs in inhibitory interneurons, i.e., periglomerular cells (PGCs) and granule cells (GCs), to search for the origin of increased inhibition in mTCs. However, VP did not increase the amplitudes of evoked EPSPs in either type of interneurons. We next performed two-photon population Ca2+ imaging in the glomerular layer and the superficial GC layer of responses to stronger ON stimulation than during patch-clamp experiments that should evoke action potentials in the measured cells. We observed that VP application increased ON-evoked Ca2+ influx in juxtaglomerular cell and GC somata and decreased it in the intraglomerular neuropil. Thus, our findings indicate inhibition by VP on projection neurons via strong ON input-mediated inhibitory interneuron activity.

Co-agonist glycine controls the occurrence of bursts by activating extrasynaptic NMDARs in nigral dopamine neurons
Dopamine control of movement initiation is correlated in time to the phasic activity of substantia nigra pars compacta neurons. The participation of NMDARs to the generation of bursts is essential but the mechanisms regulating their level of activation are unknown. Here, we reveal that triheteromeric NMDARs composed of GluN2B and GluN2D subunits are expressed both at synaptic and extrasynaptic sites but are activated by distinct co-agonists. D-serine is predominant for the activation of synaptic NMDARs whereas glycine is for extrasynaptic NMDARs. The pattern of bursts is insensitive to enzymatic depletion of either D-serine or glycine but the latter controls their occurrence. The co-agonist glycine through the activation of extrasynaptic NMDARs plays a central role in the generation of bursts responsible for the enhanced release of dopamine in postsynaptic areas initiating downstream motor-related behavior.

A New Halogenated Solvent For Ex Vivo Magnetic Resonance Imaging
Magnetic Resonance Imaging (MRI) is a prominent non-invasive imaging technique. Structural MRI, the most common MRI modality, interacts with the hydrogen nuclei in samples, also called protons. When using structural MRI to scan ex vivo tissues, the biological samples are often placed in proton-free liquids containing no hydrogen atoms to obtain clean images that do not require background removal. Several proton-free liquids have been used during the last two decades, but they are all per- and polyfluoroalkyl substances (PFAS), and PFAS have recently been recognized as a significant environmental concern. To find replacement solutions, new families of proton-free liquids without fluorine atoms will need to be investigated for stability and safety and to check potential effects on subsequent tissue staining. The present work is a preliminary step in that direction. We validate the MRI properties of a broadly used, affordable, non-PFAS, proton-free solvent that has, as far as we know, never been considered for ex vivo MRI scanning.