neuron

BKCa Channel Contributions to Cerebellar Regulated TSC-Associated Neuropsychiatric Disorders

Project Summary TSC is associated with neurodevelopmental disability including cognitive disability and autism spectrum disorders (ASD) that make up part of TSC associated neuropsychiatric disorders (TAND). The mechanisms for TAND remain poorly understood but studies have increasingly implicated cerebellar dysfunction in the pathogenesis of cognitive and behavioral deficits in both TSC and other neurodevelopmental disorders. A shared feature is cerebellar Purkinje cell (PC) dysfunction. Changes in intrinsic properties of PCs results in both motor and cognitive/ behavioral changes in disease models and in individuals afflicted by these disorders. Mechanistic underpinnings of these altered properties remain unknown, but a significant emerging body of data implicate ion channel dysfunction as the primary etiology of these deficits. The current proposal seeks to delineate the ion channel contribution to PC dysfunction and to TAND-relevant behaviors. In doing so, these studies will produce significant both short- and long-term impact. Short-term: These proposed studies will provide a mechanistic understanding of the contribution of ion channels to the neuronal dysfunction in the cerebellum that has been demonstrated to be causally linked to abnormal TAND-relevant behaviors. In addition, we will target specific ion channels both genetically and pharmacologically to evaluate the benefits of ion channel restoration on both electrophysiological abnormalities but also the TAND-relevant behaviors observed in the model. Long-term: These studies, thus, provide a framework for subsequent clinically-relevant therapeutic development for TAND. First, these studies will uncover the ability for TAND-relevant behaviors to be improved upon targeting ion channel alterations in TSC. These studies will also define molecular targets on which therapeutic development can be targeted, thereby potentially providing a molecular-informed pipeline for therapeutic development. In addition, these studies will utilize clinically-available, FDA-approved pharmacological agents to target ion channel function and investigate the potential therapeutic benefits for these agents for TAND-relevant behaviors. Thus, these studies will address a core gap in knowledge to achieve a better mechanistic understanding of TAND and to develop therapeutic opportunities to address TAND. These studies will not only reveal previously understudied and novel mechanistic underpinnings for these behaviors but will provide pre-clinical insights into the therapeutic utility of clinically-utilized agents for the treatment of TAND-related behaviors, thus potentially providing both immediate and long-term opportunities for the treatment of TAND. Moreover, although these studies focus on TSC, these mechanisms may prove generalizable beyond TSC and provide a shared basis and therapeutic opportunity for other neuropsychiatric/developmental conditions.

Cartilage targeting exosomes for OA gene therapy and pain treatment

Project Summary Gene therapy has the potential to facilitate targeted expression of therapeutic proteins to promote cartilage regeneration in osteoarthritis (OA). The dense, avascular, aggrecan-glycosaminoglycan rich negatively charged cartilage, however, hinders their transport to reach chondrocytes in effective doses. While viral vector mediated gene delivery has shown promise, concerns over immunogenicity and tumorigenic side-effects persist. To address this, we have developed surface-modified cartilage-targeting MSC exosomes as non-viral carriers for gene therapy. MSC derived exosomes have intrinsic therapeutic potential as they can induce cartilage repair and are non-immunogenic, making them desirable for gene delivery. We have engineered charge-reversed cationic exosomes by anchoring cartilage targeting optimally charged arginine-rich cationic peptide (CPC) motifs into the anionic exosome bilayer (Exo-CPC) by using buffer pH as a charge-reversal switch. Exo-CPC use charge interactions to penetrate through the full thickness of arthritic cartilage (close to tidemark) and deliver the packaged genetic material cargo to chondrocytes residing in the deep tissue layers while native anionic exosomes cannot. They can also bind within the synovial joint, making them effective for OA pain relief gene therapy. Here we will engineer charge-reversed Exo-CPC for delivery of IL-1RA (receptor antagonist of interleukin-1) mRNA and NaV1.8 (voltage gated sodium channel 1.8) inhibitor siRNA to stimulate both disease modifying response and long-term pain relief with a one-time intra-articular dose. IL-1RA mRNA targets are in the chondrocytes and synovium cells; Nav1.8 expressing nerves innervate into synovium and subchondral bone in OA – sites that Exo-CPC can readily target. Aim 1 will engineer cartilage targeting Exo-CPC for delivery of IL- 1RA mRNA and Nav1.8 inhibitor siRNA. Their ability to deliver IL-1RA mRNA to chondrocytes and IL-1RA protein translation efficiency will be evaluated in-vitro. Exo-CPC-Na v1.8’s ability to reduce NaV1.8 bioactivity of sensory nerves will also be evaluated. In Aim 2, their distribution intra-articular (proximity to NaV1.8-positive nerves), extra-articular, and DRG and spinal cord using partial meniscectomy NaV1.8-tdTomato reporter mice OA models will be evaluated. Additionally, their dose dependent reduction on MMP activity, neuronal excitability and pain- related behaviors, and any immunogenicity will be assessed. Aim 3 will use the determined functional doses to study the long-term disease modifying and pain-relief effects of mono and combination therapy with Exo-CPC- IL-1RA and Exo-CPC-Nav1.8 in rescuing injury induced tissue structural damage as well as in reducing pain (weight bearing asymmetry) for up to one month following IA administration in early vs. late stages (intervention at 2 vs 6 weeks) of MMT (medial meniscectomy) induced OA rats. The project paves way for utilizing the intrinsic therapeutic potential of MSC Exosomes as viral-free, non-immunogenic carriers for OA gene therapy by employing cartilage as a drug depot. Cationic exosomes can be used to deliver other OA gene targets, and can be widely used for targeting other negatively charged tissues like meniscus, ligaments, discs, fracture callus etc.

Neural circuits for disinhibition in the cerebellum

ABSTRACT Our long-term goal is to understand how the cerebellum adapts and improves movements in response to motor errors. A critical component of this process is signaling from olivary climbing fibers that, by providing strong excitatory drive onto Purkinje cells, induces long-term synaptic plasticity to instantiate corrective adjustments in motor behavior. However, this signaling process is tightly regulated by molecular layer interneurons (MLIs). By strongly inhibiting Purkinje cells, MLIs oppose climbing fiber-driven excitation and gate the induction of corrective plasticity. Thus, for error-driven climbing fiber-induced plasticity and learning to occur effectively, Purkinje cells must undergo disinhibition through the suppression of MLI-mediated input. Notably, MLI ensembles are composed of several subtypes and have a highly structured interconnectivity and are responsive to convergent climbing fiber inputs, suggesting that climbing fiber synchrony- whose functional significance is poorly understood- can selectively engage MLI networks to alter the state of Purkinje cell inhibition. This engagement may balance inhibition and excitation of Purkinje cells during motor errors, creating a circuit mechanism conducive for the acquisition of adaptive learning. The objective of this proposal is to determine how distinct MLI circuits are organized to modulate Purkinje cell excitability through disinhibition in a context-dependent manner, enabling plasticity and learning in response to motor errors. We will employ functional recordings, circuit-targeted activity manipulations, and behavioral analysis to reveal how error-driven instructive signaling emerges from these circuits. In the first aim, we will use in vivo high-density electrophysiology to map functional interactions among MLIs, climbing fibers, and Purkinje cells in the flocculus during the vestibulo-ocular reflex. We will test whether, during motor errors, climbing fibers synchronize their firing to selectively engage disinhibition of Purkinje cells through MLI subtypes in adapting versus non-adapting contexts. In the second aim, we will combine acute slice recordings and molecular anatomy to define direct versus spillover climbing fiber synapses onto MLI subtypes. We will identify synaptic markers and measure climbing-fiber-evoked currents in MLI subtypes, revealing how structural connectivity supports rapid, subtype-specific circuit engagement. In the third aim, we will determine how long-range inputs to the inferior olive, specifically inhibitory projections from the vestibular nuclei, dynamically tune climbing fiber synchrony in vivo and thereby learning through differential engagement of disinhibitory MLI networks. Using functional recording and optogenetic manipulation during the vestibulo- ocular reflex performance, we will establish causal links between climbing fiber synchrony, MLI network state, and adaptive behavior. By fully understanding the logic of instructive signaling, emergent from cerebellar circuit organization and behavioral engagement, we will advance our knowledge of cerebellum-dependent learning processes and provide broader insights into the neural mechanisms of learning and adaptation more generally.

Cytoskeletal connectors: Deciphering the fundamental mechanisms of cytoskeletal dynamics and transport

PROJECT SUMMARY The cytoskeleton is a dynamic network of filamentous structures, including microtubules and actin, that regulate essential cellular processes such as cell shape, growth, and signaling. Cytoskeleton also serves as tracks for molecular motors, which transport a variety of cellular cargoes, including organelles, macromolecules, and vesicles. These cargoes are linked to motors by specialized connector proteins. Disruptions in connector proteins are implicated in a range of neurodevelopmental and neurodegenerative diseases, as well as cancers. Despite their importance, these proteins continue to be understudied, primarily due to their perceived role as passive linkers and the technical challenges in working with them. However, recent discoveries suggest that connector proteins may play more active roles, in some cases even have enzymatic functions. This proposal aims to uncover mechanisms of connector protein functions through a detailed investigation of actin-microtubule and motor-cargo interactions. Actin and microtubules are linked by the spectraplakin family of large and evolutionarily conserved proteins, critical for neuronal development and differentiation. Recent discoveries of ATPase domains within these proteins suggest they may haves beyond simply linking cytoskeletal components. One goal of this proposal is to investigate the role of spectraplakin’s ATPase domains via structural, biochemical, and cell biology approaches. Another goal is to explore how dynamic changes in motor-cargo connectors facilitate the transport of diverse cargoes along microtubule tracks. The focus will be on the cytoplasmic dynein-1 (dynein) and the connectors (adaptors) that activate and link dynein to cargo. Dynein is a microtubule minus-end directed motor that plays essential roles in cell division, and transports hundreds of different cellular cargoes. While several motor-cargo connectors have been identified, the regulatory mechanisms enabling cargo transport are not fully understood. We are investigating whether connector proteins work together to activate dynein movement and/or facilitate cargo handoff between different dynein complexes. Using innovative approaches, including time- resolved cryo-EM, complex in-vitro reconstitutions, and live-cell imaging in induced neurons, we are uncovering critical mechanisms that govern cytoskeletal connector proteins, furthering our understanding of how the cytoskeleton regulates essential cellular processes.

COCHLEAR SIGNALING MEDIATED BY HENSEN’S CELLS

PROJECT SUMMARY/ABSTRACT The organ of Corti has two types of auditory sensory cells (inner and outer hair cells) surrounded by nearly a dozen different types of supporting cells organized in a very meticulous pattern. Hair cells mediate the mechano-electrical transduction process of the organ of Corti and thus most cochlear auditory research has focused on these sensory cells. In contrast, much less is known about the different types of cochlear supporting cells, even though they likely impact hair cell function. Hensen’s cells are located laterally to the outer hair cell rows and appear to be the only cell type in the cochlear epithelium that expresses TRPA1 channels. These channels are widely known for their role as sensors of tissue damage and inflammation in nociceptive neurons. Not surprisingly, we recently found that Hensen’s cells are main sensors of tissue damage in the cochlear epithelium via the activation of TRPA1 channels (Velez-Ortega et al., Nat Commn, 2023). Additionally, our preliminary data also supports the role of Hensen’s cells in signaling pathways important for the proper innervation of the organ of Corti (aim 1), for the transmission of cochlear damage signals to the brain (aim 2), and for the regulation of hearing sensitivity after acoustic trauma (aim 3). Thus, here we will explore the hypothesis that TRPA1- mediated signaling pathways in the Hensen’s cells are required for the proper innervation and auditory function of the organ of Corti. In Aim 1 we will perform a detailed comparison of the morphology and synapses of afferent cochlear neurons of wild-type and Trpa1-/- mice at several developmental stages (using immunolabeling, confocal microscopy, STED microscopy, and electron microscopy) to assess the role of TRPA1 activity on the postnatal refinement of the cochlear innervation. Aim 2 will evaluate whether the afferent type II spiral ganglion neurons (SGN) can be activated downstream of TRPA1 channel gating in Hensen’s cells by testing responses of neonate and adult type II SGN to TRPA1 agonists (via live-cell time-lapse calcium imaging and patch clamp recordings of type II SGN dendrites). Aim 3 will test the impact of TRPA1 signaling in Hensen’s cells to the operating point of the cochlear transducer (via the recording of cochlear microphonics) and to cochlear tuning (via the recording of ABR tuning curves). This study is significant because it will contribute to our understanding of the cellular (Hensen’s cells plus type II SGN) and molecular (TRPA1 channels) mechanisms of the elusive cochlear nociceptive pathway. In addition, given that the loss of TRPA1 channels does not affect hearing thresholds in mice, we believe that undiagnosed deficits in TRPA1-dependent responses in the human population could represent a hidden susceptibility for cochlear damage after noise exposure or other insults.

Dissecting the role for astrocytes in mediating adverse outcomes of maternal immune activation.

Prenatal infections cause maternal immune activation (MIA), a major risk factor for several neurodevelopmental disorders, including schizophrenia, autism spectrum disorders (ASD), and attention deficit hyperactivity disorder (ADHD). Consequently, elucidating the mechanisms by which MIA alters brain function is critical for understanding the pathophysiology of these disorders and developing effective treatments. While the effects of MIA on neurons and microglia have been extensively studied, the impact of MIA on astrocytes, key regulators of brain physiology and homeostasis, remain unknown that significantly impedes our understanding the mechanisms of MIA-induced neurobehavioral abnormalities. To address this major knowledge gap, we conducted pilot studies that suggest that MIA increases impulsivity-like behaviors and amphetamine-induced hyperactivity and enhances extracellular levels of glutamate (GLU) and dopamine (DA) in the dorsal striatum (DS). MIA also increased pro-inflammatory signatures of astrocytes, including up- regulation of the Nuclear Factor kappa B (NF-κB) pathway and increased GFAP immunoreactivity in DS astrocytes. Collectively, these novel findings support our overarching hypothesis that MIA increases astrocyte reactivity, leading to increased gliotransmission (e.g., GLU), which in turn enhances DS DA release and DA- dependent behaviors. To test this hypothesis, we will leverage the expertise of the research team in molecular, physiological and neurobehavioral approaches and conduct the following Specific Aims: In Aim 1, we will identify the MIA-induced cellular and physiological changes characteristic of astrocyte reactivity. In Aim 2, we will determine the circuit mechanisms by which MIA increases DA signaling. In Aim 3, we will identify the molecular mechanisms whereby reactive astrocytes contribute to MIA-induced cellular and behavioral abnormalities. These studies will enhance the current understanding of the effects of MIA on brain functions and generate new insight into potential treatment strategies for MIA-associated neurodevelopmental disorders.

Linking Single-Cell Transcriptomic, Morphological, and Temporal Signatures of Vulnerability in Neurodegeneration

Neurodegeneration involves complex cellular phenotypes and molecular changes that vary widely among the cells of the nervous system. Current methodologies permit either detailed molecular profiling (e.g., single-cell transcriptomics) or functional phenotyping (e.g., live imaging of neuronal activity), but not both in the same cells. Thus, it is difficult to directly link a neuron's functional state or fate with its gene expression profile. To address this limitation, we developed an innovative technology, VISTA-FISH (Video Imaging with Spatial- Temporal Analysis by FISH), that couples prospective live-cell imaging with high-resolution spatial transcriptomic profiling of the same cells. This approach enables in situ comparisons of gene expression in neurons that exhibit divergent behaviors or outcomes. Using VISTA-FISH, we will profile iPS-derived human neurons to link single-cell gene expression, morphology, and temporal phenotypes to study molecular pathways driving resilience as well as susceptibility. After exposing neurons carrying TDP43 and C9orf72 mutations to a stimulus inducing TDP43 aggregation, we will jointly record TDP43 localization and neuron activity using live-cell microscopy, then measure single-cell gene expression of the same cells (Aim 1). We will also combine live-cell measurements of TDP43 half-life with CRISPR screening and single-cell gene expression (Aim 2). These rich datasets will enable us to determine transcriptomic changes associated with differences in protein aggregation, protein synthesis, and protein degradation in individual cells, providing an unprecedented molecular perspective on factors responsible for vulnerability and resilience to neurodegeneration.

Impact of environmental toxicants on frontal cortical circuits

Abstract: Human mercury (Hg) exposure has been known for many decades to produce cognitive impairment and mood disorder symptoms. Hg is a global pollutant that poses widespread potential for neurotoxic exposure, earning it a position on the WHO’s list of the top 10 chemicals of major public health concern. However, little is known about the neural mechanisms that lead to neuropsychiatric symptoms from Hg exposure. The objective of this application is to identify specific mechanisms, within the neocortical circuits that control emotion and cognition, that are disrupted by the neurotoxicant, methylmercury (MeHg). The neocortex exhibits especially strong bioaccumulation of Hg, magnifying the risk to these circuits. Therefore, we hypothesize that chronic MeHg exposure leads to persistent circuit dysfunction in prefrontal and insular cortices (mPFC and aIC) – two brain regions critical in control of emotion and cognition. Our recent work showed that mPFC neurons in brain slices are negatively affected by acute MeHg exposure, resulting in hyperexcitability and altered synaptic transmission. Currently, it unknown how these acute effects on synaptic transmission translate to altered neuronal function in vivo. This proposal applies an integrative approach to determine the in vivo effects of MeHg on mPFC and aIC circuits, at the systems neurophysiology, synaptic and molecular levels. We will compare the effects of MeHg exposure on in vivo spiking activity patterns in brain regions of the mPFC-aIC circuit, using multiunit electrophysiological recordings in awake animals. Action potentials will be recorded simultaneously from multiple neurons, distributed across cortical layers, to evaluate effects on spike frequency, temporal patterning and correlation. Using acute brain slices derived from animals chronically treated with MeHg in vivo, electrophysiologically recorded synaptic estimates will be made to compare the effects of MeHg exposure on synaptic transmission and EI-balance within brain regions of the mPFC-aIC circuit. Based on previous evidence, we hypothesize that TDP-43 hyper-phosphorylation and aggregation link MeHg exposure to mPFC and aIC dysfunction. Therefore, immunohistochemistry will be used to measure TDP-43 hyper-phosphorylation and nuclear redistribution from animals treated in vivo +/- MeHg. In addition, tissue will be co-labeled with antibodies for nPAS4, a well-stablished molecular marker of activity, to determine whether TDP-43 hallmarks correlate with MeHg-induced hyper-excitability. The results of our study will substantively improve our mechanistic understanding of how Hg disrupts frontal cortical function and contribute to our understanding of the biological basis of emotional and cognitive sympoms. Identifying specific actions of MeHg at the functional microcircuitry level and cellular/molecular level will help significantly in finding novel targets for therapeutic interventions. If our hypothesis is correct, this will also raise the question of the extent to which chronic low-level environmental mercury exposure contributes to the etiology of fronto-cortical disorders with symptoms that overlap mercury exposure but do not have definitive genetic origins. This is particularly important because fronto-cortical disorders are predominantly sporadic in nature.

Molecular strategies for resolving differential regulation of dopamine subpopulations

Project Summary/Abstract Dopamine neurons in the ventral tegmental area (VTA) fire action potentials in complex patterns of tonic and phasic activity in response to environmental stimuli and during behavioral tasks. Transcriptomic, anatomical, and functional studies have established that VTA dopamine neurons can be divided into multiple subpopulations with variable gene expression, projection patterns, and response profiles. We recently completed a transcriptomic study that identified genetic markers for three distinct subpopulations of VTA dopamine neurons, and also found evidence for variability in ion channel gene expression between populations that correlated with differences in activity-dependent gene expression. However, much remains unknown regarding how specific genes encoding ion channels, receptors, transcription factors, or other signaling components contribute to the variability in baseline physiological properties observed across the VTA. Here we propose to combine slice electrophysiology recordings of VTA dopamine neurons with post-hoc single-cell sequencing analysis (i.e. patch-seq), which will allow us to directly correlate gene expression and physiological properties in order to identify candidate genes that may be key drivers of the variability between subpopulations. We also propose to validate and utilize a novel dual-recombinase CRISPR/Cas9 system for targeted gene mutagenesis in intersectional neuronal populations, which will provide a mechanism for testing gene function with unprecedented precision. We will use this approach to test the function of two candidate ion channel genes, the potassium channels Kcnh5 and Kcnh7, previously identified in our transcriptomic study as potential contributors to dopamine neuron action potential firing properties. We hypothesize that these genes are important for enabling rapid action potential firing in highly excitable dopamine neurons found in specific subpopulations. As a whole, with this proposal we aim to generate a valuable dataset linking gene expression in VTA dopamine neurons with physiology and subpopulation identification, as well as develop an intersectional gene mutagenesis strategy that can be used throughout the brain to precisely target neuronal subpopulations to test gene function. With this approach, we hope to facilitate future precision targeting of the dopamine system and dopamine-dependent behaviors.

Role of Two Medial Prefrontal Long-Range Recurrent Networks in Behavior Initiation and Inhibition

Abstract The medial prefrontal cortex (mPFC) is critical for executive function, yet how its dorsal (dmPFC) and ventral (vmPFC) motor-projecting (MP) neurons coordinate behavioral initiation, inhibition, and cognitive flexibility remains poorly understood. This R21 leverages four translational behavioral paradigms (head-fixed Persistent Licking/Shock-Escape; freely moving FED3-based Reversal Learning/Stop-Signal), high-density neural recordings, circuit manipulations, and Brian2 spiking neural network modeling to test our central hypothesis: dmPFC MP neurons drive action initiation and adaptive switching, while vmPFC MP neurons suppress impulsivity and perseveration. In Aim 1a, we quantify behavior using kinematic analyses (jerk, velocity, z-scored) aligned with human executive dysfunction metrics (Action Latency [AL], Reversal Accuracy [RA], Perseveration Errors [PE], Stop-Signal Reaction Time [SSRT]), combined with optogenetic (stGtACR2/ChR2) and chemogenetic (PSAM/varenicline) perturbations. Aim 1b employs optotagging and population analyses (PCA, SVM, Total Spiking Probability Edges) to decode dmPFC/vmPFC MP dynamics across tasks, resolving specialized versus mixed functional roles. Aim 1c integrates these datasets into Brian2 spiking network models to predict neural-behavioral correlations, validated through cross-validation. Exploratory analyses will link murine kinematic signatures to human stop-signal/reversal learning metrics. By elucidating strain-specific (C57BL/6 vs. CD1) circuit mechanisms and delivering translatable biomarkers (AL, RA, PE, SSRT, kinematics), this work addresses a critical gap in understanding neuropsychiatric disorders like ADHD (impulsivity) and schizophrenia (perseveration). The study’s innovative combination of recurrent neural network theory, FED3-based assays, and New Approach Methodology (NAM)-compliant computational modeling pioneers high-risk, high-reward tools for circuit dissection, fully aligning with NIH’s 2025 priorities.

Multi-modal Micro Electrode Fluidic Array (MEFA) Shells for Brain Organoids

Abstract Brain organoids (BOs) derived from human stem cells bridge the gap between monolayer cell culture studies and animal models, which have well-documented limitations. Monolayer cell culture models fail to accurately replicate the 3D interconnectivity in the brain; animal models, while helpful, are limited due to interspecies differences, with most research focusing on rather phenotypical rather than mechanistic aspects. Concurrent with the advancement of BO models is the urgent need to develop 3D micro instrumentation supporting these organoids to investigate brain development and disease in their accurate physiological environment. Conventional microelectrode arrays (MEAs) used for neuronal cell culture studies are planar, which limits recording access to a small fraction of cells on the bottom side of the organoid. Also, conventional microfluidics is inherently planar, and while recent advances in 3D MEAs and 3D microfluidics have enabled electrical and chemical interrogation in 3D, combining both features with tunability and precision to allow independent and simultaneous control is challenging. Recently, we reported new 3D micro instrumentation in the form of 3D shell MEAs and demonstrated its applicability for electrical recording from BOs. They feature lithographically patterned and chip-integrated electrodes and self-folding polymer shells that can be triggered to wrap around BOs to measure electrical activity from the entire organoid surface. The 3D MEA shell system is modeled on and resembles a miniaturized electroencephalography (EEG) cap; the process used to make them is size-scalable, chip-integrated, and mass- producible. In the research, we aim to develop and validate 3D Micro Electrode Fluidic Array (MEFA) shells with multi-modal electrical recording and biochemical control capabilities, offering high spatiotemporal resolution, tunability, and scalability. Since 3D spatiotemporal patterns of neurochemicals play a critical role in molecular and cellular events of neural development and disease, we propose to apply and validate the MEFA shells in two studies that mimic neurodevelopment and monitor the spatiotemporal effects in neurological disorders and their treatments in vitro. We anticipate that the proposed 3D MEFAs would revolutionize brain sciences by permitting real-time, in-situ studies of electrical and chemical stimulation and interrogation of BOs in a high- throughput manner. The proposed 3D scalable, reproducible, and tunable 3D micro instrumentation for BOs has broad relevance to understanding brain development in utero and the development of anatomically accurate drug and toxicity screening platforms for brain sciences and neurological disorders.

Addressing C-F bonds and amyloid-formation in biological systems

The ingestion, pulmonary inhalation, and dermal infiltration of C-F bond-containing compounds, most commonly found in the form of per- and polyfluoroalkyl organic acids, causes oxidative stress, inflammation, DNA damage, and developmental defects in infants and adults. These chemicals accumulate in the brain, disrupt neurological function and compromise cognitive and locomotory behavior. Yet, we lack a high-resolution road-map of the interactions between C-F bonds and biomolecular assemblies driving the trajectory towards neurodegenerative outcomes. This gap constitutes a significant barrier to advancing measures designed to mitigate C-F chemistry-associated neurotoxicity. Emerging experimental and computational data from our laboratory reveals that perfluorooctanoic acid, perfluorodecanoic acid and perfluorosulfonic acid corrupt biomolecular structures through C-F:side-chain interactions in tested soluble, globular proteins found in milk and tissues (matrices where C-F chemistries have been detected). Furthermore, they impaired the physiological function in these proteins through displacement of physiological ligands or by compromising the binding of co-factors. The neuroblastoma-derived SHSY-5Y cell line insulted with the said C-F moieties displayed altered gene expression corresponding to reactive oxygen species (ROS), protein ubiquitination, inflammation along with compromised cytoskeletal integrity. C-F bond ingestion ablated dopaminergic (DA) neurons in the nematode C. elegans and induced locomotory deficits in a manner mimicking paraquat. Based on these findings, we propose to gather data towards our hypothesis that C-F bond exposure perturbs biomolecular, cellular and organismal assemblies to onset neurodegeneration-linked trajectories. In Aim 1, we will determine whether organic fluoroacids alter mRNA levels in differentiated SHSY-5Y cells and in neuroprotective gut bacteria (Lactobacillus rhamnosus, Bifidobacterium lactis and Lactobacillus acidophilus). We will examine whether the neuroblastoma cell line exposed to C-F chemistry displays readouts designed to inform the onset of neurodegeneration-associated trajectories (including α-synuclein aggregation). In Aim 2, we will further address in a preclinical model whether C-F burden induces protein aggregation (α-synuclein, amyloid β, mHTT), interferes with dopaminergic neuronal assembles and induces locomotory deficits. Completion of the proposed work will complement ongoing experimental biophysical, structural (crystallographic, NMR) and computational (docking, molecular dynamics simulations) mapping of the interactions between these anthropogenic “forever” chemicals and amyloid-forming proteins potentially resulting in a soluble-to-toxic transformation. It will prepare the stage for vertebrate testing. The findings from this relatively understudied area likely exposes interventional targets for C-F chemistry associated neurotoxicity, spurs therapeutic efforts and can also guide the development of more biocompatible alternatives.

Chromatin-Based Mechanisms Linking Transcriptional Dysregulation to Genome Instability in Neurodevelopmental Disorders.

PROJECT SUMMARY/ABSTRACT Neurons depend on a finely tuned interplay between chromatin regulation and genome maintenance, yet they are acutely vulnerable to DNA damage generated during activity-dependent transcription of long, synaptic genes. Disruption of this balance is increasingly recognized as a driver of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD), intellectual disability, and epilepsy. High-confidence genetic studies converge on regulators of histone H3 lysine 4 (H3K4) methylation, such as the writers ASHIL and Klv1T2C and the eraser KDNISB, as recurrently mutated loci in NTIDs. The overarching goal of this study is to investigate how dysregulated H3K4 methylation compromises genome integrity in human neurons, thereby contributing to the pathogenesis of NDDs. The central, hypothesis is that coordinated II3K4 methylation safeguards neuronal genomes by maintaining an open chromatin architecture that permits the efficient detection and repair of transcription-coupled DNA lesions. The rationale/Or this study is to define the epigenetic control of DNA repair, which will illuminate a shared pathogenic hub across multiple ~I)D-linked genes. During the mentoredK99 phase, I will define how ASHIL, KMT2C, and KDM5B regulate chromatin structure and DNA repair at baseline and during transcriptional stress. Aim-1: I will use isogenic iPSC-derived cortical neurons with patient-relevant mutations or CRrSPRi knockdowns of these regulators, applying an integrated multi-omic pipeline: CUT&Tag and Micro-C to map H3K4 methylation and 3D chromatin topology. Aim-2: I will use Paired-Damage-seq, and CUT&RUN to chart oxidative lesions, repair synthesis, and recruitment of key repair factors; and RNA-seq to relate damage hotspots to altered gene expression. Aims l and 2 will be performed under the guidance of Dr. Lizarraga and Dr. Morrow, experts in the field of neurodevelopmental biology. My advisory team brings unique and complementary skills, enhancing my knowledge in 3D chromatin structure, transcription-coupled repair, gene editing, and multi-omics analysis. I will utilize these skills in the R00 phase (Aim 3), expanding the framework to include additional H3K4 regulators (e.g., LSD1, KMT2A) and broader neural lineages, thereby developing a comprehensive model. This study is innovative in its integration of single-cell D.NA damage mapping with chromatin topology and transcriptional profiling, enabling a direct and mechanistic connection between disrupted H3K4 methylation and genome instability. By uncovering how H3.K4 methylation prevents transcription-coupled genome instability in the developing brain, this research will address a critical gap in our understanding of NDD mechanisms. This award will enable me to launch an independent research program dedicated to determining mechanisms of chromatin-based processes that maintain genome stability in the developing human brain.

2-Deoxyglucose Therapy for Organophosphate Intoxication

Project Summary The main goal of this project is to determine the therapeutic potential of glycolysis inhibition as an adjunct to midazolam therapy in mitigating the long-term neurological effects from acute organophosphate pesticide and nerve agent (OPNA) exposure. Novel countermeasures are desperately needed for effective mitigation of morbidity and long-term effects of OPNAs. A variety of agents targeting glutamate, GABA and oxidative stress have been proposed, but glycolysis inhibitors have not been widely studied in OPNA intoxication. Dysregulated glucose metabolism plays a key role in seizures and neuronal injury following OPNA exposure. 2-Deoxyglucose (2-DG), a selective glycolysis inhibitor, has anticonvulsant and neuroprotection effects and hence can effectively mitigate acute and long-term OPNA neurotoxicity. In this project, we seek to identify the glycolysis inhibition as novel adjunct neuroprotection to midazolam therapy for OPNA exposure, with the goal of identifying 2-DG or related drugs as medical countermeasures. The glycolytic pathway represents a logical target for such intervention because glycolysis controls seizures and neuronal injury by regulating glucose utilization and activity in neurons and astrocytes in the brain. The proposed therapy is based on the hypothesis that acute OPNA neurotoxicity imparts sustained activation of the glycolysis pathway in the brain and therefore, 2- DG and selective glycolysis inhibitors prevents long-term neuronal damage neurological dysfunction. This hypothesis will be tested by using the FDA-approved (2-DG) or clinical-stage glycolytic inhibitors in two distinct OPNA models in rats: (Aim 1) To investigate the protective efficacy of 2-DG and novel glycolysis inhibitors against DFP-induced acute and long-term neuronal damage and neurological dysfunction. (Aim 2) Aim 2 (Year 2). To determine brain penetration, pilot toxicity and pharmacokinetic of 2-DG or other lead drug in naïve and DFP-exposed animals. Test drugs will be evaluated as per the NIH rigor criteria in a dose-related design in male and female rats and behavior/neuropathology will be checked for 3 months post-exposure. 2-DG and test drugs will be given starting 40-min after exposure to ONAs. Three primary outcome measures will be addressed for therapy effectiveness: (i) acute adjunct neuroprotection; (ii) chronic neuroprotectant efficacy; and (iii) prevention of neurological and behavioral deficits. The primary measures of neuroprotection include longitudinal MRI scanning, and extent of neurodegeneration, neuroinflammation, aberrant neurogenesis, and mossy fiber sprouting. Key neurological outcomes include memory deficits, depression, anxiety behavior, and neurological/motor deficits. The outcome of this project will provide “proof-of-efficacy” of a novel glycolytic therapy with FDA-approvable, repurposed drugs with promising potential to limit long-term effects of OPNAs in humans. Thus, the overall impact of the outcome is enormous for civilians, especially in developing a highly effective and safe post-exposure medical countermeasure for chemical nerve agents.

Continued HIV Production From Infected Macrophage In People On ART

PROJECT ABSTRACT After a few weeks of antiretroviral therapy (ART), HIV-1 RNA often decays to undetectable levels in blood. The initial decay is typically rapid due to the loss of short-lived, HIV-infected CD4+ T cells, but despite being adherent to ART, some people experience a subsequent period of slower decay and may require months to years to reach virologic suppression. The clinical significance of ‘slow decay’ of HIV-1 RNA after starting ART is currently unknown. Assessing the clinical significance of ‘slow decay virus’ requires identify the mechanisms generating it and exploring whether there is ongoing inflammation and neuronal damage in these people. There are three potential mechanisms that may generate ‘slow decay virus’ and they may have very different clinical implications. (1) Continued HIV-1 replication due to ineffective ART, poor ART adherence or drug- resistance. (2) Alternatively, ART could stop HIV-1 replication, but HIV-1 virions may continue to be produced by HIV-infected CD4+ T cells or (3) macrophage. Virus production without replication that emerges at the time of ART initiation is called primary nonsuppresible viremia (NSV) and is mechanistically distinct from secondary NSV observed in people who were previously suppressed. We recently examined four people who required approximately a year to become suppressed and found that ART stopped HIV-1 replication, but HIV-infected macrophage continued to produce substantial amounts of virus. These preliminary results are consistent with the long-held belief that after starting ART there is a period of rapid viral decay due to loss of HIV-infected CD4+ T cells, but some people have a subsequent period of slower decay due to continued virus production from long- lived, HIV-infected macrophage. The proposed work will expand on these observations and examine the mechanisms generating ‘slow decay virus’ in a much larger cohort of people on ART and explore the clinical implications of having ‘slow decay virus’ after starting ART (i.e. primary NSV). We will use existing, archived, longitudinal blood samples from 99 people in the MACS/WIHS Combined Cohort Study (MWCCS) who did not suppress HIV-1 RNA to undetectable levels by 6 months on ART (i.e. people with ‘slow decay virus’) and samples from 30 people who suppressed virus with typical, rapid kinetics. The proposed experiments will identify the mechanisms generating ‘slow decay virus’ during ART and the clinical implications of ‘slow decay virus’ (Aim 1). In our previous study, we also observed that ‘slow decay virus’ produced by macrophage often had nonsense/frameshift mutations in the HIV-1 vpr gene that may have promoted continued HIV-1 production from macrophage during ART. Specifically, we will explore whether ‘slow decay virus’ populations produced by macrophage have mutations in vpr or other genes that impact macrophage survival and/or HIV-1 production from infected macrophage (Aim 2). We will accomplish these aims using cutting-edge, but highly rigorous approaches. Accomplishing these aims will address clinical concerns about ‘slow decay virus’, the source of ‘slow decay virus’ as well as the role that Vpr plays in HIV-1 persistence and expression in macrophage during ART.

Pathogenic mechanisms of expanded ZFHX3 in SCA4 cerebellar organoids

Spinocerebellar ataxia type 4 (SCA4) is a disabling neurodegenerative disease characterized by progressive cerebellar ataxia, and the causative GGC-repeat expansion in ZFHX3 (ZHFX3-exp) was just discovered this year by our lab and others. Our research aims to understand how ZFHX3-exp causes SCA4 and to identify molecular therapeutic targets that can be quickly advanced into clinical trials. SCA4 is one of the four poly-glycine diseases that share the presence of neuronal intranuclear inclusion (NIIs) as a disease hallmark. In SCA4, NIIs are positive for ZFHX3, p62 and ubiquitin, indicating the loss of proteostasis as a mechanism of neurodegeneration. In addition, ZFHX3 RNA-gain-of-function may also contribute to neurodegeneration. Beyond this, knowledge of the disease mechanisms that underly SCA4 is extremely limited and there are currently no disease-modifying treatments for SCA4 or other polyG/NII diseases. There are no SCA4 mouse models and because of the high GC content in the repeat expansion complicates the production of SCA4 mouse models. We propose a novel approach to characterizing SCA4 Purkinje cell (PC) pathogenesis using human cerebellar organoids. Our approach allows for rapidly advancing the understanding of the pathogenesis and potential treatments of SCA4. Using cerebellar organoids will enable investigation on functional PCs, cerebellar neurodegeneration and the testing of potential therapeutic strategies. In aim 1, we will generate cerebellar organoids from five SCA4 patient-derived iPSC lines, and normal control iPSCs from individuals of the same family. These iPSC lines are already established in our laboratory. In aim 2, we will investigate PC viability, NII protein composition, proteostasis pathways, RNA gain-of-function and cell-type-specific dysregulated pathways by single nucleus RNA sequencing. In addition, we will study potential therapeutic targets by lentiviral knockdown and single nucleus RNA sequencing. SCA4 patient iPSCs express overabundant STAU1 and ATXN2. We will evaluate how lowering the abundance of these proteins modifies the PC molecular phenotype. Together, these experiments will establish a model to greatly enhance the understanding of human PC neurodegeneration, the pathological mechanisms of SCA4 and possible avenues of treatment.

A PROTAC Strategy to Combat Botulinum Neurotoxicity

PROJECT SUMMARY/ABSTRACT Botulinum neurotoxin (BoNT), the causative agent of botulism, is the most potent toxin known to humans. While BoNTs are widely recognized for their therapeutic and cosmetic applications, such as Botox™, their increasing use has raised concerns about iatrogenic botulism. Due to their extreme lethality, ease of production, and history of weaponization, the Centers for Disease Control and Prevention (CDC) classifies BoNTs as a Category A bioterrorism threat. Among the seven major serotypes (A-G), BoNT/A, BoNT/B, and BoNT/E account for over 95% of human botulism cases with A being the most prevalent. Despite the severity of botulism, no approved therapeutic exists to rescue intoxicated neurons. The current treatment, a heptavalent antitoxin, can only slow disease progression and requires early administration and prolonged hospitalization due to the inability of antibodies to penetrate infected cells. In the field of small- molecule inhibitors (SMIs), promising scaffolds targeting BoNT/A have been discovered, offering opportunities for further derivatization to incorporate bifunctional approaches. Developing a clinically viable therapeutic requires inhibiting the zinc (Zn2+) metalloprotease light chain (LC) as well as addressing toxin persistence. Through extensive inhibitor screening, we have identified two classes of small molecules that inhibit BoNT/A with submicromolar affinity and demonstrate efficacy in both cellular and animal models. However, the transient nature of these inhibitors necessitates the need of a sustained clearance approach. To achieve this, we propose integrating our previously identified BoNT/A LC SMIs with a targeted protein degradation (TPD) technology for toxin elimination. Based upon the background outlined, vide supra, our research strategy for the ablation of BoNT/A will be focused upon the following three specific objectives: 1) Structural Optimization – Utilize molecular docking, and structure-activity relationship (SAR) analysis to modify inhibitors for TPD ligand attachment. 2) Degrader Design – Development of ubiquitin-protease system (UPS)-based proteolysis-targeting chimeras (PROTACs) and autophagy-targeting chimeras to enhance degradation efficiency. 3) Cellular Evaluation – Assess enzyme inhibition, toxin clearance, degradation kinetics in cells.

Noninvasive Neuromodulation to Improve Hand Motor Function in Multiple Sclerosis

Project Summary/Abstract Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease that affects nearly one million Americans. Although more than 75% of persons with MS (PwMS) experience hand motor impairments that reduce independence and quality of life, current treatments primarily aim to slow disease progression through pharmacological approaches and rehabilitation and often do not improve motor function. Recent evidence shows that reduced corticospinal transmission is strongly associated with motor impairment severity in PwMS, highlighting the need for targeted strategies to strengthen residual corticospinal pathways. Therefore, this project aims to evaluate the therapeutic potential of paired corticospinal-motoneuronal stimulation (PCMS) in improving hand dexterity in PwMS. PCMS, a noninvasive mechanism-driven neuromodulation approach, enhances corticospinal transmission by producing long-term potentiation-like effects at the corticospinal-motoneuronal synapse by precisely pairing transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS). This project first aims to examine the effects of a single PCMS session on corticospinal transmission and hand motor function in PwMS. Using a randomized, crossover design, 25 PwMS will complete two sessions: (1) PCMS and (2) sham-PCMS. Each session will deliver 180 paired TMS-PNS stimuli over 30 minutes. The primary outcome is performance on the 9-Hole Peg Test (9HPT). Secondary outcomes include pinch grip force, maximal voluntary contraction (MVC), MEP amplitude and latency, F-wave parameters, and M- max amplitude. It is hypothesized that PCMS will enhance corticospinal transmission and improve hand motor performance compared to sham stimulation. Second, this project will examine the effects of PCMS combined with hand motor training in PwMS. Forty-eight PwMS will be randomized to receive either PCMS or sham-PCMS combined with motor training over 10 sessions in 3–4 weeks. Outcomes will be assessed at baseline, post- intervention, and one-month follow-up. It is hypothesized that PCMS participants receiving PCMS with motor training to show greater functional gains than those receiving sham-PCMS with motor training and the functional gains will be better maintained in the PCMS with motor training group at follow-up. This project is the first to apply PCMS in PwMS, leveraging a noninvasive neuromodulation strategy to specifically enhance corticospinal output for improving manual dexterity. Findings will establish proof-of-concept for this intervention in PwMS and guide future studies optimizing stimulation protocols and evaluating clinical efficacy on a larger scale. Ultimately, this work may lead to a new therapeutic approach to improve dexterity, independence, and quality of life for people living with MS.

Predictive Coding Light

Current machine learning systems consume vastly more energy than biological brains. Neuromorphic systems aim to overcome this difference by mimicking the brain’s information coding via discrete voltage spikes. However, it remains unclear how both artificial and natural networks of spiking neurons can learn energy-efficient information processing strategies. Here we propose Predictive Coding Light (PCL), a recurrent hierarchical spiking neural network for unsupervised representation learning. In contrast to previous predictive coding approaches, PCL does not transmit prediction errors to higher processing stages. Instead, it suppresses the most predictable spikes and transmits a compressed representation of the input. Using only biologically plausible spike-timing based learning rules, PCL reproduces a wealth of findings on information processing in visual cortex and permits strong performance in downstream classification tasks. Overall, PCL offers a new approach to predictive coding and its implementation in natural and artificial spiking neural networks

Consciousness at the edge of chaos

Over the last 20 years, neuroimaging and electrophysiology techniques have become central to understanding the mechanisms that accompany loss and recovery of consciousness. Much of this research is performed in the context of healthy individuals with neurotypical brain dynamics. Yet, a true understanding of how consciousness emerges from the joint action of neurons has to account for how severely pathological brains, often showing phenotypes typical of unconsciousness, can nonetheless generate a subjective viewpoint. In this presentation, I will start from the context of Disorders of Consciousness and will discuss recent work aimed at finding generalizable signatures of consciousness that are reliable across a spectrum of brain electrophysiological phenotypes focusing in particular on the notion of edge-of-chaos criticality.

Spike train structure of cortical transcriptomic populations in vivo

The cortex comprises many neuronal types, which can be distinguished by their transcriptomes: the sets of genes they express. Little is known about the in vivo activity of these cell types, particularly as regards the structure of their spike trains, which might provide clues to cortical circuit function. To address this question, we used Neuropixels electrodes to record layer 5 excitatory populations in mouse V1, then transcriptomically identified the recorded cell types. To do so, we performed a subsequent recording of the same cells using 2-photon (2p) calcium imaging, identifying neurons between the two recording modalities by fingerprinting their responses to a “zebra noise” stimulus and estimating the path of the electrode through the 2p stack with a probabilistic method. We then cut brain slices and performed in situ transcriptomics to localize ~300 genes using coppaFISH3d, a new open source method, and aligned the transcriptomic data to the 2p stack. Analysis of the data is ongoing, and suggests substantial differences in spike time coordination between ET and IT neurons, as well as between transcriptomic subtypes of both these excitatory types.

The tubulin code in neuron health and disease : focus on detyrosination

Astrocytes: From Metabolism to Cognition

Different brain cell types exhibit distinct metabolic signatures that link energy economy to cellular function. Astrocytes and neurons, for instance, diverge dramatically in their reliance on glycolysis versus oxidative phosphorylation, underscoring that metabolic fuel efficiency is not uniform across cell types. A key factor shaping this divergence is the structural organization of the mitochondrial respiratory chain into supercomplexes. Specifically, complexes I (CI) and III (CIII) form a CI–CIII supercomplex, but the degree of this assembly varies by cell type. In neurons, CI is predominantly integrated into supercomplexes, resulting in highly efficient mitochondrial respiration and minimal reactive oxygen species (ROS) generation. Conversely, in astrocytes, a larger fraction of CI remains unassembled, freely existing apart from CIII, leading to reduced respiratory efficiency and elevated mitochondrial ROS production. Despite this apparent inefficiency, astrocytes boast a highly adaptable metabolism capable of responding to diverse stressors. Their looser CI–CIII organization allows for flexible ROS signaling, which activates antioxidant programs via transcription factors like Nrf2. This modular architecture enables astrocytes not only to balance energy production but also to support neuronal health and influence complex organismal behaviors.

Cellular Crosstalk in Brain Development, Evolution and Disease

Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.

Low intensity rTMS: age dependent effects, and mechanisms underlying neural plasticity

Neuroplasticity is essential for the establishment and strengthening of neural circuits. Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical excitability and shows promise in the treatment of some neurological disorders. Low intensity magnetic stimulation (LI-rTMS), which does not directly elicit action potentials in the stimulated neurons, have also shown some therapeutic effects, and it is important to determine the biological mechanisms underlying the effects of these low intensity magnetic fields, such as would occur in the regions surrounding the central high-intensity focus of rTMS. Our team has used a focal low-intensity (10mT) magnetic stimulation approach to address some of these questions and to identify cellular mechanisms. I will present several studies from our laboratory, addressing (1) effects of LIrTMS on neuronal activity and excitability ; and (2) neuronal morphology and post-lesion repair. The ensemble of our results indicate that the effects of LI-rTMS depend upon the stimulation pattern, the age of the animal, and the presence of cellular magnetoreceptors.

How the presynapse forms and functions”

Nervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) that supply presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is largely unknown. I will discuss our recent advances in our understanding of how key components of the presynaptic machinery for neurotransmitter release are transported and assembled focussing on our studies in genome-engineered human induced pluripotent stem cell-derived neurons. Specifically, I will focus on the composition and cell biological identity of the axonal transport vesicles that shuttle key components of neurotransmission to nascent synapses and on machinery for axonal transport and its control by signaling lipids. Our studies identify a crucial mechanism mediating the delivery of SV and active zone proteins to developing synapses and reveal connections to neurological disorders. In the second part of my talk, I will discuss how exocytosis and endocytosis are coupled to maintain presynaptic membrane homeostasis. I will present unpublished data regarding the role of membrane tension in the coupling of exocytosis and endocytosis at synapses. We have identified an endocytic BAR domain protein that is capable of sensing alterations in membrane tension caused by the exocytotic fusion of SVs to initiate compensatory endocytosis to restore plasma membrane area. Interference with this mechanism results in defects in the coupling of presynaptic exocytosis and SV recycling at human synapses.

Cause & Consequences of neuronal Tau protein ‘activation’

Memory Decoding Journal Club: "Binary and analog variation of synapses between cortical pyramidal neurons

Binary and analog variation of synapses between cortical pyramidal neurons

“Brain theory, what is it or what should it be?”

n the neurosciences the need for some 'overarching' theory is sometimes expressed, but it is not always obvious what is meant by this. One can perhaps agree that in modern science observation and experimentation is normally complemented by 'theory', i.e. the development of theoretical concepts that help guiding and evaluating experiments and measurements. A deeper discussion of 'brain theory' will require the clarification of some further distictions, in particular: theory vs. model and brain research (and its theory) vs. neuroscience. Other questions are: Does a theory require mathematics? Or even differential equations? Today it is often taken for granted that the whole universe including everything in it, for example humans, animals, and plants, can be adequately treated by physics and therefore theoretical physics is the overarching theory. Even if this is the case, it has turned out that in some particular parts of physics (the historical example is thermodynamics) it may be useful to simplify the theory by introducing additional theoretical concepts that can in principle be 'reduced' to more complex descriptions on the 'microscopic' level of basic physical particals and forces. In this sense, brain theory may be regarded as part of theoretical neuroscience, which is inside biophysics and therefore inside physics, or theoretical physics. Still, in neuroscience and brain research, additional concepts are typically used to describe results and help guiding experimentation that are 'outside' physics, beginning with neurons and synapses, names of brain parts and areas, up to concepts like 'learning', 'motivation', 'attention'. Certainly, we do not yet have one theory that includes all these concepts. So 'brain theory' is still in a 'pre-newtonian' state. However, it may still be useful to understand in general the relations between a larger theory and its 'parts', or between microscopic and macroscopic theories, or between theories at different 'levels' of description. This is what I plan to do.

Neural circuits underlying sleep structure and functions

Sleep is an active state critical for processing emotional memories encoded during waking in both humans and animals. There is a remarkable overlap between the brain structures and circuits active during sleep, particularly rapid eye-movement (REM) sleep, and the those encoding emotions. Accordingly, disruptions in sleep quality or quantity, including REM sleep, are often associated with, and precede the onset of, nearly all affective psychiatric and mood disorders. In this context, a major biomedical challenge is to better understand the underlying mechanisms of the relationship between (REM) sleep and emotion encoding to improve treatments for mental health. This lecture will summarize our investigation of the cellular and circuit mechanisms underlying sleep architecture, sleep oscillations, and local brain dynamics across sleep-wake states using electrophysiological recordings combined with single-cell calcium imaging or optogenetics. The presentation will detail the discovery of a 'somato-dendritic decoupling'in prefrontal cortex pyramidal neurons underlying REM sleep-dependent stabilization of optimal emotional memory traces. This decoupling reflects a tonic inhibition at the somas of pyramidal cells, occurring simultaneously with a selective disinhibition of their dendritic arbors selectively during REM sleep. Recent findings on REM sleep-dependent subcortical inputs and neuromodulation of this decoupling will be discussed in the context of synaptic plasticity and the optimization of emotional responses in the maintenance of mental health.

Neurobiological constraints on learning: bug or feature?

Understanding how brains learn requires bridging evidence across scales—from behaviour and neural circuits to cells, synapses, and molecules. In our work, we use computational modelling and data analysis to explore how the physical properties of neurons and neural circuits constrain learning. These include limits imposed by brain wiring, energy availability, molecular noise, and the 3D structure of dendritic spines. In this talk I will describe one such project testing if wiring motifs from fly brain connectomes can improve performance of reservoir computers, a type of recurrent neural network. The hope is that these insights into brain learning will lead to improved learning algorithms for artificial systems.

Expanding mechanisms and therapeutic targets for neurodegenerative disease

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. By re-analyzing RNA-sequencing datasets from human FTD/ALS brains, we discovered dozens of novel cryptic splicing events in important neuronal genes. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies, but how those variants increase risk for disease is unknown. We discovered that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harboring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function. Recent analyses have revealed even further changes in TDP-43 target genes, including widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

The Direct Impact Of Amyloid-Beta Oligomers On Neuronal Activity And Neurotransmitter Releases On In Vivo Analysis

Neural Signal Propagation Atlas of C. elegans

In the age of connectomics, it is increasingly important to understand how the nodes and edges of a brain's anatomical network, or "connectome," gives rise to neural signaling and neural function. I will present the first comprehensive brain-wide cell-resolved causal measurements of how neurons signal to one another in response to stimulation in the nematode C. elegans. I will compare this signal propagation atlas to the worm's known connectome to address fundamental questions of structure and function in the brain.

The cellular phase of Alzheimer’s Disease and the path towards therapies

Single-neuron correlates of perception and memory in the human medial temporal lobe

The human medial temporal lobe contains neurons that respond selectively to the semantic contents of a presented stimulus. These "concept cells" may respond to very different pictures of a given person and even to their written or spoken name. Their response latency is far longer than necessary for object recognition, they follow subjective, conscious perception, and they are found in brain regions that are crucial for declarative memory formation. It has thus been hypothesized that they may represent the semantic "building blocks" of episodic memories. In this talk I will present data from single unit recordings in the hippocampus, entorhinal cortex, parahippocampal cortex, and amygdala during paradigms involving object recognition and conscious perception as well as encoding of episodic memories in order to characterize the role of concept cells in these cognitive functions.

Rejuvenating the Alzheimer’s brain: Challenges & Opportunities

Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

Join Us for the Memory Decoding Journal Club! A collaboration of the Carboncopies Foundation and BPF Aspirational Neuroscience. This time, we’re diving into a groundbreaking paper: "Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala

Fear learning induces synaptic potentiation between engram neurons in the rat lateral amygdala. This study by Marios Abatis et al. demonstrates how fear conditioning strengthens synaptic connections between engram cells in the lateral amygdala, revealed through optogenetic identification of neuronal ensembles and electrophysiological measurements. The work provides crucial insights into memory formation mechanisms at the synaptic level, with implications for understanding anxiety disorders and developing targeted interventions. Presented by Dr. Kenneth Hayworth, this journal club will explore the paper's methodology linking engram cell reactivation with synaptic plasticity measurements, and discuss implications for memory decoding research.

Retinal input integration in excitatory and inhibitory neurons in the mouse superior colliculus in vivo

Cholinergic Interneurons

Impact of High Fat Diet on Central Cardiac Circuits: When The Wanderer is Lost

Cardiac vagal motor drive originates in the brainstem's cardiac vagal motor neurons (CVNs). Despite well-established cardioinhibitory functions in health, our understanding of CVNs in disease is limited. There is a clear connection of cardiovascular regulation with metabolic and energy expenditure systems. Using high fat diet as a model, this talk will explore how metabolic dysfunction impacts the regulation of cardiac tissue through robust inhibition of CVNs. Specifically, it will present an often overlooked modality of inhibition, tonic gamma-aminobuytric acid (GABA) A-type neurotransmission using an array of techniques from single cell patch clamp electrophysiology to transgenic in vivo whole animal physiology. It also will highlight a unique interaction with the delta isoform of protein kinase C to facilitate GABA A-type receptor expression.

Pharmacological exploitation of neurotrophins and their receptors to develop novel therapeutic approaches against neurodegenerative diseases and brain trauma

Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.

Regulation of cortical circuit maturation and plasticity by oligodendrocytes and myelin

Spatio-temporal Regulation of Gene Expression in Neurons: Insights from Imaging mRNAs Live in Action

Vision for perception versus vision for action: dissociable contributions of visual sensory drives from primary visual cortex and superior colliculus neurons to orienting behaviors

The primary visual cortex (V1) directly projects to the superior colliculus (SC) and is believed to provide sensory drive for eye movements. Consistent with this, a majority of saccade-related SC neurons also exhibit short-latency, stimulus-driven visual responses, which are additionally feature-tuned. However, direct neurophysiological comparisons of the visual response properties of the two anatomically-connected brain areas are surprisingly lacking, especially with respect to active looking behaviors. I will describe a series of experiments characterizing visual response properties in primate V1 and SC neurons, exploring feature dimensions like visual field location, spatial frequency, orientation, contrast, and luminance polarity. The results suggest a substantial, qualitative reformatting of SC visual responses when compared to V1. For example, SC visual response latencies are actively delayed, independent of individual neuron tuning preferences, as a function of increasing spatial frequency, and this phenomenon is directly correlated with saccadic reaction times. Such “coarse-to-fine” rank ordering of SC visual response latencies as a function of spatial frequency is much weaker in V1, suggesting a dissociation of V1 responses from saccade timing. Consistent with this, when we next explored trial-by-trial correlations of individual neurons’ visual response strengths and visual response latencies with saccadic reaction times, we found that most SC neurons exhibited, on a trial-by-trial basis, stronger and earlier visual responses for faster saccadic reaction times. Moreover, these correlations were substantially higher for visual-motor neurons in the intermediate and deep layers than for more superficial visual-only neurons. No such correlations existed systematically in V1. Thus, visual responses in SC and V1 serve fundamentally different roles in active vision: V1 jumpstarts sensing and image analysis, but SC jumpstarts moving. I will finish by demonstrating, using V1 reversible inactivation, that, despite reformatting of signals from V1 to the brainstem, V1 is still a necessary gateway for visually-driven oculomotor responses to occur, even for the most reflexive of eye movement phenomena. This is a fundamental difference from rodent studies demonstrating clear V1-independent processing in afferent visual pathways bypassing the geniculostriate one, and it demonstrates the importance of multi-species comparisons in the study of oculomotor control.

Circuit Mechanisms of Remote Memory

Memories of emotionally-salient events are long-lasting, guiding behavior from minutes to years after learning. The prelimbic cortex (PL) is required for fear memory retrieval across time and is densely interconnected with many subcortical and cortical areas involved in recent and remote memory recall, including the temporal association area (TeA). While the behavioral expression of a memory may remain constant over time, the neural activity mediating memory-guided behavior is dynamic. In PL, different neurons underlie recent and remote memory retrieval and remote memory-encoding neurons have preferential functional connectivity with cortical association areas, including TeA. TeA plays a preferential role in remote compared to recent memory retrieval, yet how TeA circuits drive remote memory retrieval remains poorly understood. Here we used a combination of activity-dependent neuronal tagging, viral circuit mapping and miniscope imaging to investigate the role of the PL-TeA circuit in fear memory retrieval across time in mice. We show that PL memory ensembles recruit PL-TeA neurons across time, and that PL-TeA neurons have enhanced encoding of salient cues and behaviors at remote timepoints. This recruitment depends upon ongoing synaptic activity in the learning-activated PL ensemble. Our results reveal a novel circuit encoding remote memory and provide insight into the principles of memory circuit reorganization across time.

Dimensionality reduction beyond neural subspaces

Over the past decade, neural representations have been studied from the lens of low-dimensional subspaces defined by the co-activation of neurons. However, this view has overlooked other forms of covarying structure in neural activity, including i) condition-specific high-dimensional neural sequences, and ii) representations that change over time due to learning or drift. In this talk, I will present a new framework that extends the classic view towards additional types of covariability that are not constrained to a fixed, low-dimensional subspace. In addition, I will present sliceTCA, a new tensor decomposition that captures and demixes these different types of covariability to reveal task-relevant structure in neural activity. Finally, I will close with some thoughts regarding the circuit mechanisms that could generate mixed covariability. Together this work points to a need to consider new possibilities for how neural populations encode sensory, cognitive, and behavioral variables beyond neural subspaces.

Mouse Motor Cortex Circuits and Roles in Oromanual Behavior

I’m interested in structure-function relationships in neural circuits and behavior, with a focus on motor and somatosensory areas of the mouse’s cortex involved in controlling forelimb movements. In one line of investigation, we take a bottom-up, cellularly oriented approach and use optogenetics, electrophysiology, and related slice-based methods to dissect cell-type-specific circuits of corticospinal and other neurons in forelimb motor cortex. In another, we take a top-down ethologically oriented approach and analyze the kinematics and cortical correlates of “oromanual” dexterity as mice handle food. I'll discuss recent progress on both fronts.

Gene regulatory mechanisms of neocortex development and evolution

The neocortex is considered to be the seat of higher cognitive functions in humans. During its evolution, most notably in humans, the neocortex has undergone considerable expansion, which is reflected by an increase in the number of neurons. Neocortical neurons are generated during development by neural stem and progenitor cells. Epigenetic mechanisms play a pivotal role in orchestrating the behaviour of stem cells during development. We are interested in the mechanisms that regulate gene expression in neural stem cells, which have implications for our understanding of neocortex development and evolution, neural stem cell regulation and neurodevelopmental disorders.

Understanding the complex behaviors of the ‘simple’ cerebellar circuit

Every movement we make requires us to precisely coordinate muscle activity across our body in space and time. In this talk I will describe our efforts to understand how the brain generates flexible, coordinated movement. We have taken a behavior-centric approach to this problem, starting with the development of quantitative frameworks for mouse locomotion (LocoMouse; Machado et al., eLife 2015, 2020) and locomotor learning, in which mice adapt their locomotor symmetry in response to environmental perturbations (Darmohray et al., Neuron 2019). Combined with genetic circuit dissection, these studies reveal specific, cerebellum-dependent features of these complex, whole-body behaviors. This provides a key entry point for understanding how neural computations within the highly stereotyped cerebellar circuit support the precise coordination of muscle activity in space and time. Finally, I will present recent unpublished data that provide surprising insights into how cerebellar circuits flexibly coordinate whole-body movements in dynamic environments.

Clonal analysis at single cell level helps to understand neural crest development

Recent research on the neural crest has revealed the multipotency and plasticity of nerve-associated Schwann cell precursors, which can differentiate into diverse cell types, including parasympathetic neurons, neuroendocrine cells, and mesenchymal stem cells. These findings challenge the traditional view of peripheral nerves, highlighting their role as niches for migratory progenitor cells that contribute to tissue formation and regeneration.

Sensory tuning in neuronal movement commands

Use case determines the validity of neural systems comparisons

Deep learning provides new data-driven tools to relate neural activity to perception and cognition, aiding scientists in developing theories of neural computation that increasingly resemble biological systems both at the level of behavior and of neural activity. But what in a deep neural network should correspond to what in a biological system? This question is addressed implicitly in the use of comparison measures that relate specific neural or behavioral dimensions via a particular functional form. However, distinct comparison methodologies can give conflicting results in recovering even a known ground-truth model in an idealized setting, leaving open the question of what to conclude from the outcome of a systems comparison using any given methodology. Here, we develop a framework to make explicit and quantitative the effect of both hypothesis-driven aspects—such as details of the architecture of a deep neural network—as well as methodological choices in a systems comparison setting. We demonstrate via the learning dynamics of deep neural networks that, while the role of the comparison methodology is often de-emphasized relative to hypothesis-driven aspects, this choice can impact and even invert the conclusions to be drawn from a comparison between neural systems. We provide evidence that the right way to adjudicate a comparison depends on the use case—the scientific hypothesis under investigation—which could range from identifying single-neuron or circuit-level correspondences to capturing generalizability to new stimulus properties

The cell biology of Parkinson’s disease: a role for primary cilia and synaptic vesicle pleomorphism in dopaminergic neurons

Metabolic-functional coupling of parvalbmunin-positive GABAergic interneurons in the injured and epileptic brain

Parvalbumin-positive GABAergic interneurons (PV-INs) provide inhibitory control of excitatory neuron activity, coordinate circuit function, and regulate behavior and cognition. PV-INs are uniquely susceptible to loss and dysfunction in traumatic brain injury (TBI) and epilepsy but the cause of this susceptibility is unknown. One hypothesis is that PV-INs use specialized metabolic systems to support their high-frequency action potential firing and that metabolic stress disrupts these systems, leading to their dysfunction and loss. Metabolism-based therapies can restore PV-IN function after injury in preclinical TBI models. Based on these findings, we hypothesize that (1) PV-INs are highly metabolically specialized, (2) these specializations are lost after TBI, and (3) restoring PV-IN metabolic specializations can improve PV-IN function as well as TBI-related outcomes. Using novel single-cell approaches, we can now quantify cell-type-specific metabolism in complex tissues to determine whether PV-IN metabolic dysfunction contributes to the pathophysiology of TBI.

Neural mechanisms governing the learning and execution of avoidance behavior

The nervous system orchestrates adaptive behaviors by intricately coordinating responses to internal cues and environmental stimuli. This involves integrating sensory input, managing competing motivational states, and drawing on past experiences to anticipate future outcomes. While traditional models attribute this complexity to interactions between the mesocorticolimbic system and hypothalamic centers, the specific nodes of integration have remained elusive. Recent research, including our own, sheds light on the midline thalamus's overlooked role in this process. We propose that the midline thalamus integrates internal states with memory and emotional signals to guide adaptive behaviors. Our investigations into midline thalamic neuronal circuits have provided crucial insights into the neural mechanisms behind flexibility and adaptability. Understanding these processes is essential for deciphering human behavior and conditions marked by impaired motivation and emotional processing. Our research aims to contribute to this understanding, paving the way for targeted interventions and therapies to address such impairments.

Maturation and plasticity of cortical interneurons

Probing neural population dynamics with recurrent neural networks

Large-scale recordings of neural activity are providing new opportunities to study network-level dynamics with unprecedented detail. However, the sheer volume of data and its dynamical complexity are major barriers to uncovering and interpreting these dynamics. I will present latent factor analysis via dynamical systems, a sequential autoencoding approach that enables inference of dynamics from neuronal population spiking activity on single trials and millisecond timescales. I will also discuss recent adaptations of the method to uncover dynamics from neural activity recorded via 2P Calcium imaging. Finally, time permitting, I will mention recent efforts to improve the interpretability of deep-learning based dynamical systems models.

The role of mitopohagy in neuronal physiology

Navigating semantic spaces: recycling the brain GPS for higher-level cognition

Humans share with other animals a complex neuronal machinery that evolved to support navigation in the physical space and that supports wayfinding and path integration. In my talk I will present a series of recent neuroimaging studies in humans performed in my Lab aimed at investigating the idea that this same neural navigation system (the “brain GPS”) is also used to organize and navigate concepts and memories, and that abstract and spatial representations rely on a common neural fabric. I will argue that this might represent a novel example of “cortical recycling”, where the neuronal machinery that primarily evolved, in lower level animals, to represent relationships between spatial locations and navigate space, in humans are reused to encode relationships between concepts in an internal abstract representational space of meaning.

Modelling the fruit fly brain and body

Through recent advances in microscopy, we now have an unprecedented view of the brain and body of the fruit fly Drosophila melanogaster. We now know the connectivity at single neuron resolution across the whole brain. How do we translate these new measurements into a deeper understanding of how the brain processes sensory information and produces behavior? I will describe two computational efforts to model the brain and the body of the fruit fly. First, I will describe a new modeling method which makes highly accurate predictions of neural activity in the fly visual system as measured in the living brain, using only measurements of its connectivity from a dead brain [1], joint work with Jakob Macke. Second, I will describe a whole body physics simulation of the fruit fly which can accurately reproduce its locomotion behaviors, both flight and walking [2], joint work with Google DeepMind.

Combined electrophysiological and optical recording of multi-scale neural circuit dynamics

This webinar will showcase new approaches for electrophysiological recordings using our silicon neural probes and surface arrays combined with diverse optical methods such as wide-field or 2-photon imaging, fiber photometry, and optogenetic perturbations in awake, behaving mice. Multi-modal recording of single units and local field potentials across cortex, hippocampus and thalamus alongside calcium activity via GCaMP6F in cortical neurons in triple-transgenic animals or in hippocampal astrocytes via viral transduction are brought to bear to reveal hitherto inaccessible and under-appreciated aspects of coordinated dynamics in the brain.

Modeling human brain development and disease: the role of primary cilia

Neurodevelopmental disorders (NDDs) impose a global burden, affecting an increasing number of individuals. While some causative genes have been identified, understanding the human-specific mechanisms involved in these disorders remains limited. Traditional gene-driven approaches for modeling brain diseases have failed to capture the diverse and convergent mechanisms at play. Centrosomes and cilia act as intermediaries between environmental and intrinsic signals, regulating cellular behavior. Mutations or dosage variations disrupting their function have been linked to brain formation deficits, highlighting their importance, yet their precise contributions remain largely unknown. Hence, we aim to investigate whether the centrosome/cilia axis is crucial for brain development and serves as a hub for human-specific mechanisms disrupted in NDDs. Towards this direction, we first demonstrated species-specific and cell-type-specific differences in the cilia-genes expression during mouse and human corticogenesis. Then, to dissect their role, we provoked their ectopic overexpression or silencing in the developing mouse cortex or in human brain organoids. Our findings suggest that cilia genes manipulation alters both the numbers and the position of NPCs and neurons in the developing cortex. Interestingly, primary cilium morphology is disrupted, as we find changes in their length, orientation and number that lead to disruption of the apical belt and altered delamination profiles during development. Our results give insight into the role of primary cilia in human cortical development and address fundamental questions regarding the diversity and convergence of gene function in development and disease manifestation. It has the potential to uncover novel pharmacological targets, facilitate personalized medicine, and improve the lives of individuals affected by NDDs through targeted cilia-based therapies.

Mitochondrial diversity in the mouse and human brain

The basis of the mind, of mental states, and complex behaviors is the flow of energy through microscopic and macroscopic brain structures. Energy flow through brain circuits is powered by thousands of mitochondria populating the inside of every neuron, glial, and other nucleated cell across the brain-body unit. This seminar will cover emerging approaches to study the mind-mitochondria connection and present early attempts to map the distribution and diversity of mitochondria across brain tissue. In rodents, I will present convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct behaviorally-relevant mitochondrial phenotypes exist across large-scale mouse brain networks. Extending these findings to the human brain, I will present a developing systematic biochemical and molecular map of mitochondrial variation across cortical and subcortical brain structures, representing a foundation to understand the origin of complex energy patterns that give rise to the human mind.

Thalamocortical feedback circuits selectively control pyramidal neuron excitability

Roles of inhibition in stabilizing and shaping the response of cortical networks

Inhibition has long been thought to stabilize the activity of cortical networks at low rates, and to shape significantly their response to sensory inputs. In this talk, I will describe three recent collaborative projects that shed light on these issues. (1) I will show how optogenetic excitation of inhibition neurons is consistent with cortex being inhibition stabilized even in the absence of sensory inputs, and how this data can constrain the coupling strengths of E-I cortical network models. (2) Recent analysis of the effects of optogenetic excitation of pyramidal cells in V1 of mice and monkeys shows that in some cases this optogenetic input reshuffles the firing rates of neurons of the network, leaving the distribution of rates unaffected. I will show how this surprising effect can be reproduced in sufficiently strongly coupled E-I networks. (3) Another puzzle has been to understand the respective roles of different inhibitory subtypes in network stabilization. Recent data reveal a novel, state dependent, paradoxical effect of weakening AMPAR mediated synaptic currents onto SST cells. Mathematical analysis of a network model with multiple inhibitory cell types shows that this effect tells us in which conditions SST cells are required for network stabilization.

Stability of visual processing in passive and active vision

The visual system faces a dual challenge. On the one hand, features of the natural visual environment should be stably processed - irrespective of ongoing wiring changes, representational drift, and behavior. On the other hand, eye, head, and body motion require a robust integration of pose and gaze shifts in visual computations for a stable perception of the world. We address these dimensions of stable visual processing by studying the circuit mechanism of long-term representational stability, focusing on the role of plasticity, network structure, experience, and behavioral state while recording large-scale neuronal activity with miniature two-photon microscopy.

Behavioral and Neuronal Correlates of Exploration and Goal-Directed Navigation

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Biological-plausible learning with a two compartment neuron model in recurrent neural networks

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Chronic optogenetic stimulation has the potential to shape the collective activity of neuronal cell cultures

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Computational analysis of optogenetic inhibition of a pyramidal CA1 neuron

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Computing in neuronal networks with plasticity via all-optical bidirectional interfacing

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Is the cortical dynamics ergodic? A numerical study in partially-symmetric networks of spiking neurons

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Cross-correlation--response relation for spike-driven neurons

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Plastic Arbor: a modern simulation framework for synaptic plasticity – from single synapses to networks of morphological neurons

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Excitatory and inhibitory neurons exhibit distinct roles for task learning, temporal scaling, and working memory in recurrent spiking neural network models of neocortex.

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Exploring behavioral correlations with neuron activity through synaptic plasticity.

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Newly Formed Synapses Between VTA Projections and ACC Pyramidal Neurons in Response to Chronic Social Defeat Stress Differentiate Stress Susceptible From Stress Resilient Mice

A new framework for modeling innate capabilities in network with diverse types of spiking neurons: Probabilistic Skeleton

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Identifying patterns across brains from 10 years of human single-neuron recordings

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Improving the Neuronal Classification Capacity with Nonlinear Parallel Synapses

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Inhibitory columnar feedback neurons are required for peripheral visual processing

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Learning neuronal manifolds for interacting neuronal populations

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Local E/I Balance and Spontaneous Dynamics in Neuronal Networks

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Migraine mutation of a Na+ channel induces a switch in excitability type and energetically expensive spikes in an experimentally-constrained model of fast-spiking neurons

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Neuronal bursting from an interplay of fast voltage and slow concentration dynamics mediated by the Na+/K+-ATPase

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A neuronal central pattern generator to control the REM/non-REM sleep cycle

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Neuronal degeneracy: an information-energy trade-off?

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Neuronal Heterogeneity Enhances Sensory Integration and Processing

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Neuronal spike generation via a homoclinic orbit bifurcation increases irregularity and chaos in balanced networks

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Neurons learn by predicting their synaptic inputs

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Optimizing Trajectories via Replay in a Closed-Loop Spiking Neuronal Network Model of Navigation

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Spatial integration properties in MT neurons affect spatiotemporal motion discrimination

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Probing right-hemispheric neuronal representations in the language network of an individual with aphasia

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Psychedelic space of neuronal population activity: emerging and disappearing contrastive dimensions

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Pyramidal Interneuron Next-Generation Neural Mass Model: Synaptic Properties and Stimulation Response

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Response Characteristics of V4 Neurons to Angled Stimuli

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The role of gap junctions and clustered connectivity in emergent synchronisation patterns of spiking inhibitory neuronal networks

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The role of multi-neuron temporal spiking patterns on stable encoding of natural movie presentations

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Semantic Embodiment: Decoding Action Words through Topographic Neuronal Representation with Brain-Constrained Network

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Synaptic Upscaling Amplifies Chaotic Dynamics in Recurrent Networks of Rate Neurons

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Task choice influences single-neuron tuning predictions in connectome-constrained modeling

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Top-down modulation shapes timescales via synaptic plasticity in cortical circuits with multiple interneuron types

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Utilizing Random Forest for Multivariate Analysis: Exploring the Influence of Dopaminergic Neurons on Drosophila Larvae Locomotion

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Variability in Self-Organizing Networks of Neurons: Between Chance and Design

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What should a neuron aim for? Designing local objective functions based on information theory

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Activity-Dependent Network Development in Silico: The Role of Inhibition in Neuronal Growth and Migration

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