Biology subjects

Carlson, D.

Publications and source records attributed to Carlson, D..

18 recordsLinked to original sources

bioRxiv2026

Sleep spindles stabilize human thalamocortical networks, inhibiting pathological disruptions

The thalamus coordinates sleep-dependent brain function including memory consolidation, sensory gating, and network stability through spindle oscillations. Thalamocortical circuits are also affected in many neurological and neuropsychiatric disorders. Yet how human thalamocortical circuits respond to pathological disruptions remain poorly understood. Here, we leveraged interictal epileptiform discharges (IEDs) as spontaneous perturbations to probe spindle-generating circuits and thalamocortical dynamics in vivo. Using multi-night intracranial recordings spanning multiple thalamic nuclei and cortical regions in 55 individuals with epilepsy, we investigated interactions between sleep spindles and epileptic activity across timescales from milliseconds to days. Sleep spindles were associated with IED suppression, whereas IEDs increased subsequent spindle probability, revealing bidirectional interactions between physiological and pathological activity. Nights with lower IEDs corresponded to increased spindle occurrence, longer duration, and faster frequency, reflecting a more stable thalamocortical state. These findings propose sleep spindles as potential regulators of thalamocortical networks that actively respond to and regulate pathological activity.

neuroscience↗

bioRxiv2026

A protective hybrid protein vaccine informed by mapping major histocompatibility class II epitopes in Cryptococcus neoformans chitin deacetylases that stimulate CD4+ T cell responses

Infections due to Cryptococcus species are estimated to cause over 100,000 deaths a year. No cryptococcal vaccines are approved for human use. We have shown that vaccine formulations consisting of C. neoformans chitin deacetylase (Cda)2 and Cda1 adjuvanted with Cationic Adjuvant Formulation 01 (CAF01) protect mice against experimental cryptococcosis by a mechanism dependent upon CD4+ T cells. Here, using overlapping peptide libraries, we mapped epitopes in Cda2 and Cda1 that stimulated interferon-gamma (IFN{gamma}) release from splenocytes of C57BL/6 and DR4 mice immunized with these proteins. DR4 mice lack mouse major histocompatibility class II (MHC-II) proteins and express chimeric MHC-II proteins with the specificity of the human HLA-DR allele, HLA-DRB1*04:01. Experimental results were then compared with MHC-II binding predictions using the Immune Epitope Database (IEDB) NetMHCIIpan 4.1 BA MHC-II epitope prediction tool. Unique epitopes in Cda2 and Cda1 were discovered for each mouse strain, some of which were not predicted to bind well to MHC-II. CD4+ T cells were responsible for cytokine release as IFN{gamma} production was lost if CD4+ T cells were depleted from the splenocyte population. Finally, we tested a hybrid recombinant protein that consisted of portions of Cda2 and Cda1 containing the MHC-II/CD4+ T cell epitopes which induce CD4+ T cells in DR4 mice. When administered as a CAF01-adjuvanted vaccine, the hybrid protein protected DR4 mice from an otherwise lethal C. neoformans pulmonary challenge. These results provide a proof of principle regarding the utility of MHC-II/CD4+ T cell epitope mapping in cryptococcal vaccine development.

immunology↗

bioRxiv2026

Therapy-induced senescent-like cancer cells drive macrophage-mediated immunosuppression in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a lethal biliary cancer in which chemoresistance is nearly universal, and its tumor immune microenvironment is dominated by immunosuppressive tumor-associated macrophages (TAMs) that exclude cytotoxic CD8+ T cells. How tumor cells sustain this immunosuppressive state during chemotherapy is undefined. Here we demonstrate that therapy-induced senescent-like (Sen-L) cancer cells accumulate after gemcitabine/cisplatin in human and murine CCA, are predominantly cancer cells, and predict shorter survival. Genetic elimination of Sen-L cancer cells reduces tumor burden, lowers TAM abundance, and restores intratumoral CD8+ T cells, establishing them as causal drivers. Growth differentiation factor 15 (GDF-15) is the dominant Sen-L-secreted factor and reprograms macrophages to suppress CD8+ T cells through the non-canonical receptor TGFBR2 and STAT6, and p16-restricted Gdf15 silencing phenocopies Sen-L elimination. Combined with chemotherapy, Sen-L elimination improves survival beyond chemotherapy alone. These findings establish Sen-L cancer cells and their GDF-15 output as causal, targetable drivers of macrophage-mediated immune evasion in CCA. SIGNIFICANCE STATEMENTTherapy-induced senescent-like cancer cells, not stromal cells, are the dominant senescent-like and immunosuppressive population in cholangiocarcinoma, and their elimination restores antitumor immunity. GDF-15 is their dominant secreted effector and engages a non-canonical macrophage receptor, TGFBR2, identifying a cancer-cell-to-macrophage axis and a Sen-L-elimination strategy to restore chemosensitivity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/734341v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@7d3fd8org.highwire.dtl.DTLVardef@ea9efborg.highwire.dtl.DTLVardef@16ba16borg.highwire.dtl.DTLVardef@132b821_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. Senescent-like CCA cells promote tumor immunosuppression through TAMs polarization by GDF-15 C_FIG

Cancer Biology↗

bioRxiv2026

A widespread internal brain state for fentanyl withdrawal

Opioid addiction is characterized by escalating drug use, driven in part by negative reinforcement from withdrawal, but the neural processes linking withdrawal to increased drug-taking remain poorly understood. Here, we use multisite local field potential recordings and interpretable machine learning to identify large-scale brain networks engaged by repeated opioid exposure and withdrawal. After discovering that repeated fentanyl exposure induces a progressively ramping network of widespread high beta and low gamma oscillations, we then identified a distinct brain network that selectively encodes the emergence and severity of opioid withdrawal. This network, termed EN-Withdrawal, is characterized by regional gamma oscillations and widely synchronized delta/theta oscillations. Its activity patterns predict the emergence of spontaneous and naloxone-precipitated withdrawal across multiple independent cohorts, generalizing across mice, sex, opioids, and dosing regimens, while persisting over multiple days of withdrawal. Using a novel, data-driven severity index, we find that network activity scales with individual behavioral severity without simply reflecting ongoing somatic behaviors or general aversion, suggesting that EN-Withdrawal underlies a withdrawal-induced internal state. Strikingly, network activity predicts the escalation of fentanyl self-administration on a mouse-by-mouse basis in experienced, but not drug-naive, animals. These findings reveal a neurophysiological substrate of the negative reinforcement cycle of addiction that shapes individual vulnerability.

neuroscience↗

bioRxiv2025

Swine reporter model for preclinical evaluation and characterization of gene delivery vectors

Delivery of gene therapy vectors targeted to any somatic cell remains a key barrier for the development of genetic medicines. While rodent models provide insights into vector biodistribution and cellular tropism, their anatomical and physiological differences from humans limit their translational potential and studies in large animal models are often required. In this study, we developed a swine reporter model (SRM-1) to evaluate both viral and nonviral vector delivery in a large animal system. The SRM-1 model harbors a Cre- and CRISPR-activated tdTomato reporter at the Rosa26 locus that allows for tracing of cell-specific delivery and expression of gene therapy vectors in vivo. To evaluate this model, we administered adeno-associated virus serotype 9 (AAV9) and lipid nanoparticles (LNPs) carrying mRNA systemically and found successful in vivo reporter activation across a variety of tissues. Intracerebroventricular (ICV) administration of LNP-Cre mRNA was also performed and demonstrated localized activation in cortical brain cells. In addition to biodistribution studies, this model has utility for testing safety and clinically relevant administration methods, surgical and non-surgical, of delivery vectors. Our findings support the SRM-1 model as a valuable tool for advancing gene therapies from preclinical testing to clinical application.

genetics↗

bioRxiv2025

Frequent EPHA2 receptor mutations in cholangiocarcinoma disrupt receptor forward signaling supporting a tumor suppressor role

EPHA2 is a receptor tyrosine kinase highly expressed in many cancers. By analyzing cancer patient databases for mutations in the EPHA2 coding sequence, we found that cholangiocarcinoma (a hepatobiliary cancer with dismal prognosis) exhibits a uniquely high incidence of EPHA2 mutations. To deUine the functional signiUicance of these mutations, we generated representative EPHA2 mutants and monitored major receptor autophosphorylation sites as indicative of kinase activity-dependent signal transduction (known as forward signaling). We found that missense mutations in the ligand-binding domain abrogate ligand binding and ligand-induced EPHA2 tyrosine phosphorylation, while most missense mutations in the kinase domain abrogate kinase activity. We detected less pronounced effects of missense mutations in other domains, which vary depending on the phosphosite, suggesting that these EPHA2 mutations might differentially affect (or bias) different downstream signaling pathways. Other EPHA2 mutations introduce early stop codons and encode receptor truncated forms lacking all or part of the kinase domain. We also found that an EPHA2 secreted truncated form, a transmembrane truncated form, and a full-length kinase inactive mutant can inhibit tyrosine phosphorylation of co-expressed EPHA2 wild-type. Taken together, these data suggest that mutations interfering with EPHA2 forward signaling facilitate cholangiocarcinoma development. We indeed obtained evidence that an EPHA2 kinase inactive mutant, but not EPHA2 wild-type, can induce proliferative masses consistent with well differentiated cholangiocarcinoma in a validated mouse model of cholangiocarcinogenesis. Taken together, our Uindings suggest that EPHA2 is a driver gene in cholangiocarcinoma and that its forward signaling has tumor suppressor activity.

biochemistry↗

bioRxiv2025

CD4+ Mucosal-associated Invariant T (MAIT) cells express highly diverse T cell receptors

Mucosal-associated invariant T cells are highly conserved innate-like T cells in mammals recognized for their high baseline frequency in human blood and cytotoxic effector functions during infectious diseases, autoimmunity, and cancer. While the majority of these cells express a conserved CD8{beta}+ TRAV1-2 T cell receptor recognizing microbially-derived Vitamin B2 intermediates presented by the evolutionarily conserved major histocompatibility complex I-related molecule, MR1, there is an emerging appreciation for diverse subsets that may be selected for in humans with distinct functions, including subpopulations that co-express CD4. Prior work has not examined T cell receptor (TCR) heterogeneity in CD4+ MAIT cells, largely due to bias of identifying human MAIT cells as CD8+ TRAV1-2+ cells. In this study, we adopted an unbiased single-cell TCR-sequencing approach of total MR1-5-OP-RU-tetramer-reactive T cells and discovered that CD4+ MAIT cells express highly diverse TRAV1-2 negative TCRs. To specifically characterize this TCR repertoire, we analyzed VDJ sequences of single MR1-5-OP-RU tetramer+ MAIT cells across two datasets and identified distinct TCR usage among CD4+ MAIT cells including TRAV21, TRAV8 (TRAV8-1, TRAV8-2, TRAV8-3), and TRAV12 families (TRAV12-2, TRAV12-3), as well as more variable J chain and CDR3 sequences. Non-TRAV1-2 MAIT cell TCRs were also enriched after in vitro expansion, including with Mycobacterial tuberculosis. These results indicate that mature human CD4+ MAIT cells adopt distinct TCR usage from the canonical TRAV1-2+ CD8+ subset and suggest that alternative MR1 ligands in addition to riboflavin intermediates may select them.

genomics↗

bioRxiv2024

Sleep-wake states are encoded across emotion-regulation regions of the mouse brain

Emotional dysregulation is highly comorbid with sleep disturbances. Sleep is comprised of unique physiological states that are reflected by conserved brain oscillations. Though the role of these state-dependent oscillations in cognitive function has been well established, less is known regarding the nature of state-dependent oscillations across brain regions that strongly contribute to emotional function. To characterize these dynamics, we recorded local field potentials simultaneously from multiple cortical and subcortical regions implicated in sleep and emotion-regulation and characterize widespread patterns of spectral power and synchrony between brain regions during sleep/wake states. First, we showed that these brain regions encode sleep state, albeit to various degrees of accuracy. We then identified network-based classifiers of sleep based on the combination of features from all recorded brain regions. Spectral power and synchrony from brain networks allowed for automatic, accurate and rapid discrimination of wake, non-REM sleep (NREM) and rapid eye movement (REM) sleep. When we examined the impact of commonly prescribed sleep promoting medications on neural dynamics across these regions, we found disparate alterations to both cortical and subcortical activity across all three states. Finally, a we found that a stress manipulation that disrupts circadian rhythm produced increased sleep fragmentation without altering the underlying average brain dynamics across sleep-wake states. Thus, we characterized state dependent brain dynamics across regions canonically associated with emotions. Significance StatementSleep and emotion regulation are known to be intertwined at the level of behavior and in neuropsychiatric illnesses. Here, we examined how brain regions involved in emotion regulation encode wake and sleep states by performing multi-site electrophysiological recordings in mice. We developed sleep-wake state classifiers that rapidly labeled sleep-wake states from brain activity alone. We then identified how commonly prescribed sleep-inducing medications have unique impacts on brain activity throughout these emotion-regulation regions. Finally, we explored the impact of circadian rhythm disruption on sleep architecture and brain activity. Together, these data shed light on how brain regions which regulate emotion behave during sleep so that one day, treatments to improve both sleep and emotional well-being may be developed.

neuroscience↗

bioRxiv2024

A widespread electrical brain network encodes anxiety in health and depressive states

In rodents, anxiety is characterized by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system is fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, multiple translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.

neuroscience↗

bioRxiv2024

Immunological correlates of protection mediated by a whole organism Cryptococcus neoformans vaccine deficient in chitosan

The global burden of infections due to the pathogenic fungus Cryptococcus is substantial in persons with low CD4+ T cell counts. Previously, we deleted three chitin deacetylase genes from C. neoformans to create a chitosan-deficient, avirulent strain, designated cda1{Delta}2{Delta}3{Delta} which, when used as a vaccine, protected mice from challenge with virulent C. neoformans strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8+ T cells. In contrast, protection was lost in mice lacking /{beta} T cells or CD4+ T cells. Moreover, CD4+ T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4+ T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4+ T cells after vaccination, but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in IFN{gamma}, TNF, or IL-23p19. A robust influx of leukocytes and IFN{gamma}- and TNF-expressing CD4+ T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFN{gamma} production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8+ T cells are dispensable, IFN{gamma} and CD4+ T cells have overlapping roles in generating protective immunity prior to cda1{Delta}2{Delta}3{Delta} vaccination. However, once vaccinated, protection becomes less dependent on CD4+ T cells, suggesting a strategy for vaccinating HIV+ persons prior to loss of CD4+ T cells. ImportanceThe fungus Cryptococcus neoformans is responsible for >100,000 deaths annually, mostly in persons with impaired CD4+ T cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of C. neoformans, designated cda1{Delta}2{Delta}3{Delta}. When used as a vaccine, cda1{Delta}2{Delta}3{Delta} protects mice against a subsequent challenge with a virulent C. neoformans strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8+ T cells were dispensible, protection was lost in mice genetically deficient in CD4+ T cells, and the cytokines IFN{gamma}, TNF, or IL-23. A robust influx of cytokine-producing CD4+ T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4+ T cells following vaccination, suggesting a strategy to protect persons who are at risk for future CD4+ T cell dysfunction.

immunology↗

bioRxiv2024

Loss of circulating CD8α+ NK cells during human Mycobacterium tuberculosis infection

Natural Killer (NK) cells can recognize and kill Mtb-infected cells in vitro, however their role after natural human exposure has not been well-studied. To identify Mtb-responsive NK cell populations, we analyzed the peripheral blood of healthy household contacts of active Tuberculosis (TB) cases and source community donors in an endemic region of Port-au-Prince, Haiti by flow cytometry. We observed higher CD8 expression on NK cells in putative resistors (IGRA-contacts) with a progressive loss of these circulating cells during household-associated latent infection and disease. In vitro assays and CITE-seq analysis of CD8+ NK cells demonstrated enhanced maturity, cytotoxic gene expression, and response to cytokine stimulation relative to CD8- NK cells. CD8+ NK cells also displayed dynamic surface expression dependent on MHC I in contrast to conventional CD8+ T cells. Together, these results support a specialized role for CD8+ NK cell populations during Mtb infection correlating with disease resistance.

immunology↗

bioRxiv2023

Molecular mechanisms of seasonal brain shrinkage and regrowth inSorex araneus

To meet the challenge of wintering in place many high-latitude small mammals reduce energy demands through hibernation. In contrast, short-lived Eurasian common shrews, Sorex araneus, remain active and shrink, including energy-intensive organs in winter, regrowing in spring in an evolved strategy called Dehnels phenomenon. How this size change is linked to metabolic and regulatory changes to sustain their high metabolism is unknown. We analyzed metabolic, proteomic, and gene expression profiles spanning the entirety of Dehnels seasonal cycle in wild shrews. We show regulatory changes to oxidative phosphorylation and increased fatty acid metabolism during autumn-to-winter shrinkage, as previously found in hibernating species. But in shrews we also found upregulated winter expression of genes involved in gluconeogenesis: the biosynthesis of glucose from non-carbohydrate substrates. Co-expression models revealed changes in size and metabolic gene expression interconnect via FOXO signaling, whose overexpression reduces size and extends lifespan in many model organisms. We propose that while shifts in gluconeogenesis meet the challenge posed by high metabolic rate and active winter lifestyle, FOXO signaling is central to Dehnels phenomenon, with spring downregulation limiting lifespan in these shrews.

genetics↗

bioRxiv2023

Suprabasal cells retaining stem cell identity programs drive basal cell hyperplasia in eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH) and loss of differentiation. Although BCH correlates with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that despite the presence of BCH in all EoE patients examined, no increase in basal cell proportion was observed by scRNA-seq. Instead, EoE patients exhibited a reduced pool of KRT15+ COL17A1+ quiescent cells, a modest increase in KI67+ dividing epibasal cells, a substantial increase in KRT13+ IVL+ suprabasal cells, and a loss of differentiated identity in superficial cells. Suprabasal and superficial cell populations demonstrated increased quiescent cell identity scoring in EoE with the enrichment of signaling pathways regulating pluripotency of stem cells. However, this was not paired with increased proliferation. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these findings were not observed in GERD. Thus, our study demonstrates that BCH in EoE results from an expansion of non-proliferative cells that retain stem-like transcriptional programs while remaining committed to early differentiation.

molecular biology↗

bioRxiv2021

Vocal tract allometry in a mammalian vocal learner

Acoustic allometry occurs when features of animal vocalisations can be predicted from body size measurements. Despite this being considered the norm, allometry sometimes breaks, resulting in species sounding smaller or larger than expected for their size. A recent hypothesis suggests that allometry-breaking mammals cluster into two groups: those with anatomical adaptations to their vocal tracts and those capable of learning new sounds (vocal learners). Here we test which mechanism is used to escape from acoustic allometry by probing vocal tract allometry in a proven mammalian vocal learner, the harbour seal (Phoca vitulina). We test whether vocal tract structures and body size scale allometrically in 68 young individuals. We find that both body length and body mass accurately predict vocal tract length and one tracheal dimension. Independently, body length predicts vocal fold length while body mass predicts a second tracheal dimension. All vocal tract measures are larger in weaners than in pups and some structures are sexually dimorphic within age classes. We conclude that harbour seals do comply with anatomical allometric constraints. However, allometry between body size and vocal fold length seems to emerge after puppyhood, suggesting that ontogeny may modulate the anatomy-learning distinction previously hypothesised as clear-cut. We suggest that seals, like other species producing signals that deviate from those expected from their vocal tract dimensions, may break allometry without morphological adaptations. In seals, and potentially other vocal learning mammals, advanced neural control over vocal organs may be the main mechanism for breaking acoustic allometry.

animal behavior and cognition↗

bioRxiv2020

Prenatal Environmental Stressors Impair Postnatal Microglia Function and Adult Behavior in Males

Gestational exposure to environmental toxins and socioeconomic stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism. We modeled these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activated the maternal immune system. Only male offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminished microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Genetic ablation of microglia during the same critical period mimicked the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.

neuroscience↗

bioRxiv2020

YASS: Yet Another Spike Sorter applied to large-scale multi-electrode array recordings in primate retina

Spike sorting is a critical first step in extracting neural signals from large-scale multi-electrode array (MEA) data. This manuscript presents several new techniques that make MEA spike sorting more robust and accurate. Our pipeline is based on an efficient multi-stage "triage-then-cluster-then-pursuit" approach that initially extracts only clean, high-quality waveforms from the electrophysiological time series by temporarily skipping noisy or "collided" events (representing two neurons firing synchronously). This is accomplished by developing a neural network detection and denoising method followed by efficient outlier triaging. The denoised spike waveforms are then used to infer the set of spike templates through nonparametric Bayesian clustering. We use a divide-and-conquer strategy to parallelize this clustering step. Finally, we recover collided waveforms with matching-pursuit deconvolution techniques, and perform further split-and-merge steps to estimate additional templates from the pool of recovered waveforms. We apply the new pipeline to data recorded in the primate retina, where high firing rates and highly-overlapping axonal units provide a challenging testbed for the deconvolution approach; in addition, the well-defined mosaic structure of receptive fields in this preparation provides a useful quality check on any spike sorting pipeline. We show that our pipeline improves on the state-of-the-art in spike sorting (and outperforms manual sorting) on both real and semi-simulated MEA data with > 500 electrodes; open source code can be found at https://github.com/paninski-lab/yass.

neuroscience↗

bioRxiv2017

A convergent depression vulnerability pathway encoded by emergent spatiotemporal dynamics

Fluctuations in brain local field potential (LFP) oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these LFP oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional processes at the network level. Here we use machine learning to integrate LFP activity acquired concurrently from seven cortical and subcortical brain regions into an analytical model that predicts the emergence of depression-related behavioral dysfunction across individual mice subjected to chronic social defeat stress. We uncover a spatiotemporal dynamic network in which activity originates in prefrontal cortex (PFC) and nucleus accumbens (NAc, ventral striatum), relays through amygdala and ventral tegmental area (VTA), and converges in ventral hippocampus (VHip). The activity of this network correlates with acute threat responses and brain-wide cellular firing, and it is enhanced in three independent molecular-, physiological-, and behavioral-based models of depression vulnerability. Finally, we use two antidepressant manipulations to demonstrate that this vulnerability network is biologically distinct from the networks that signal behavioral dysfunction after stress. Thus, corticostriatal to VHip-directed spatiotemporal dynamics organized at the network level are a novel convergent depression vulnerability pathway.

neuroscience↗

bioRxiv2017

YASS: Yet Another Spike Sorter

Spike sorting is a critical first step in extracting neural signals from large-scale electrophysiological data. This manuscript describes an efficient, reliable pipeline for spike sorting on dense multi-electrode arrays (MEAs), where neural signals appear across many electrodes and spike sorting currently represents a major computational bottleneck. We present several new techniques that make dense MEA spike sorting more robust and scalable. Our pipeline is based on an efficient multi-stage \"triage-then-cluster-then-pursuit\" approach that initially extracts only clean, high-quality waveforms from the electrophysiological time series by temporarily skipping noisy or \"collided\" events (representing two neurons firing synchronously). This is accomplished by developing a neural network detection method followed by efficient outlier triaging. The clean waveforms are then used to infer the set of neural spike waveform templates through nonparametric Bayesian clustering. Our clustering approach adapts a \"coreset\" approach for data reduction and uses efficient inference methods in a Dirichlet process mixture model framework to dramatically improve the scalability and reliability of the entire pipeline. The \"triaged\" waveforms are then finally recovered with matching-pursuit deconvolution techniques. The proposed methods improve on the state-of-the-art in terms of accuracy and stability on both real and biophysically-realistic simulated MEA data. Furthermore, the proposed pipeline is efficient, learning templates and clustering much faster than real-time for a [~=] 500-electrode dataset, using primarily a single CPU core.

neuroscience↗