Biology subjects

Ramakrishnan, A.

Publications and source records attributed to Ramakrishnan, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Polyimide-Based Flexible Multi-Electrode Arrays: Synthesis, Microfabrication, and in-vivo Validation

Neurological disorders such as epilepsy, Parkinsons disease, are rising globally, with conditions like drug-resistant epilepsy affecting millions of patients for whom traditional pharmacological treatments are ineffective. Implantable neural devices have shown great promise in managing these conditions, but their accessibility is limited due to high costs and the availability of suitable biocompatible materials.Thin film implantable neural interfaces hold immense promise over conventional clinical electrodes, offering higher resolution, flexibility, and improved integration with neural tissue. However, their widespread use, especially for flexible interfaces, is limited by the lack of customizable and medical grade materials. We report a novel synthesis method for ISO 10993-11 compliant polyamic acid that enables the fabrication of biocompatible polyimide films tailored for neural implants. Using this material, we developed 4 and 32 channel depth and surface electrodes, including custom whole brain ECoG arrays. These were implanted in the laforin knockout mice, a validated model of drug-resistant epilepsy, to monitor spontaneous seizures. Both acute and 12 day recordings demonstrated mechanical flexibility, long term stability, and excellent biocompatibility. This study presents a clinically safe material platform and a complete fabrication pathway for building thin film neural interfaces, paving the way for broader clinical use in applications such as epilepsy monitoring and stereo EEG.

bioengineering↗

bioRxiv2023

Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling, and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice exposed to early life stress (ELS) or to chronic social defeat stress (CSDS) in adulthood displayed increased enrichment of H3K27me1, and transient decreases in H3K27me2, in the nucleus accumbens (NAc), a key brain-reward region. Stress induction of H3K27me1 was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which is induced by chronic stress and controls H3K27 methylation patterns. Overexpression of the VEFS domain led to social, emotional, and cognitive abnormalities, and altered excitability of NAc D1 mediums spiny neurons. Together, we describe a novel function of H3K27me1 in brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.

neuroscience↗

bioRxiv2023

ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A - a transcriptional regulator of astrocyte reactivity - as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress - a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability.

neuroscience↗

bioRxiv2023

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress-induced gene expression and behavior

BackgroundMajor depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. MethodsWe employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. ResultsWe found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. ConclusionsThese findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

neuroscience↗

bioRxiv2023

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNAseq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following prolonged abstinence, and heroin-primed drug-seeking (i.e., "relapse"). Bioinformatics analysis of this rich dataset identified numerous patterns of molecular changes, transcriptional regulation, brain-region-specific involvement in various aspects of OUD, and both region-specific and pan-circuit biological domains affected by heroin. Integrating RNAseq data with behavioral outcomes using factor analysis to generate an "addiction index" uncovered novel roles for particular brain regions in promoting addiction-relevant behavior, and implicated multi-regional changes in affected genes and biological processes. Comparisons with RNAseq and genome-wide association studies from humans with OUD reveal convergent molecular regulation that are implicated in drug-taking and relapse, and point to novel gene candidates with high therapeutic potential for OUD. These results outline broad molecular reprogramming that may directly promote the development and maintenance of OUD, and provide a foundational resource to the field for future research into OUD mechanisms and treatment strategies.

neuroscience↗

bioRxiv2022

Histone monoaminylation dynamics are regulated by a single enzyme and promote neural rhythmicity

Histone H3 monoaminylations at glutamine(Q) 5 represent an important family of epigenetic markers in neurons that play critical roles in the mediation of permissive gene expression (1, 2). We previously demonstrated that H3Q5 serotonylation(ser) and dopaminylation(dop) are catalyzed by the Transglutaminase 2 (TGM2) enzyme and alter both local and global chromatin states (3, 4). Here, we found that TGM2 additionally functions as an "eraser" of H3 monoaminylations that is capable of "re-writing" these epigenetic marks in cells, including a new class of this modification, H3Q5 histaminylation(his), which displays dynamic diurnal expression in brain and contributes to neural rhythmicity. We found that H3Q5his inhibits binding of the MLL1 complex to the H3 N-terminus and attenuates its methyltransferase activity on H3 lysine(K) 4. We determined that H3Q5 monoaminylation dynamics are dictated by local monoamine concentrations, which are utilized by TGM2. Taken together, we present here a novel mechanism through which a single chromatin regulatory enzyme is capable of sensing chemical microenvironments to affect the epigenetic states of cells. One sentence summaryA single enzyme, TGM2, bidirectionally controls H3 monoaminylation dynamics, which, in turn, facilitate neural rhythmicity.

molecular biology↗

bioRxiv2022

Cell-Type-Specific Epigenetic Priming of Gene Expression in Nucleus Accumbens by Cocaine

A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe a novel epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled to increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relates to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaines rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2-MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior.

molecular biology↗

bioRxiv2022

ATAC and histone H3K9me3 landscapes revealed the altered epigenome by fetal-neonatal iron deficiency in the adult male rat hippocampus

Iron deficiency during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive and widespread hippocampal gene dysregulation. Globally, fetal-neonatal iron deficiency produces both long-term activation and repression of hundreds of loci in the adult rat hippocampus. Prenatal choline (a methyl donor) supplementation can partially reverse these effects, suggesting an interaction between iron and choline in regulating the hippocampal transcriptome. To gain insights into the underlying epigenetic signatures, we integrate hippocampal transcriptomes and epigenetic marks of active (transposase accessible chromatin/ATAC) and repressed (H3K9me3 enrichment) genes in adult rats that had been exposed to fetal-neonatal iron deficiency with or without prenatal choline supplementation. Rats were made iron-deficient during fetal and neonatal period by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Choline (5.5 g/kg) was given to half of the pregnant dams during G11-18. This paradigm produced four comparison groups (Iron-sufficient [IS], Iron-deficient [ID], IS+choline [ISch], and ID+choline [IDch]). Hippocampi were collected from P65 males and analyzed for changes in chromatin conformation and histone H3K9me3 enrichment. ATAC-seq results accounted for 22% and 24%, whereas H3K9me3 enrichment accounted for 1.7% and 13% of differences in ID- and IDch-altered gene expression. These epigenetic changes were annotated onto gene networks regulating synaptic structure and plasticity, neuroinflammation, and reward circuits. The low correlation between gene dysregulation and changes in ATAC or H3K9me3 signatures indicate involvements of other epigenetic modifications. This study provides a genome-wide findings of stable epigenetic changes and lays a foundation for further analyses to elucidate more fully iron-dependent epigenetic mechanisms that underlie iron deficiency, choline supplementation, and their interactions in mediating long-term neural gene dysregulation. SIGNIFICANCE STATEMENTEarly-life iron deficiency can lead to long-term neurocognitive dysfunction and persistent neural gene dysregulation, despite prompt iron replenishment, suggesting that iron deficiency results in long-term neuroepigenomic changes. This study combined RNA-seq, ATAC-seq, and ChIP-seq to provide the epigenetic basis for gene dysregulation due to fetal-neonatal iron deficiency and prenatal choline supplementation. We found that early-life iron deficiency alters epigenetic regulation of genes involved in neuronal development, cell signaling, neuroinflammation, and reward-related cognition. While choline supplementation to iron-deficient animals partially reverses these effects, it also leads to dysregulation of genes in iron-sufficient animals. The patterns of gene dysregulation were positively correlated with differences in chromatin accessibility and negatively correlated with repressive histone H3K9me3 modification. Our results indicate that these changes at the epigenetic level partially account for the long-term hippocampal gene dysregulation.

neuroscience↗

bioRxiv2022

epiAneufinder: identifying copy number variations from single-cell ATAC-seq data

Single-cell open chromatin profiling via the single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) assay has become a mainstream measurement of open chromatin in single-cells. Here we present a novel algorithm, epiAneufinder, that exploits the read count information from scATAC-seq data to extract genome-wide copy number variations (CNVs) for individual cells, allowing to explore the CNV heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show how epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNV profiles. These profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. epiAneufinder allows the addition of single-cell CNV information to scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored.

bioinformatics↗

bioRxiv2022

Spatial patterning and immunosuppression of glioblastoma immune contexture in hypoxic niches

Glioblastoma (GBM), a highly lethal brain cancer, is notorious for its immunosuppressive microenvironment, yet current immunotherapies are ineffective. Thus, understanding the immune contexture and governing factors of immunosuppression is crucial. Here, we identified a highly dynamic temporospatial patterning of tumor-associated macrophages (TAMs) corresponding to vascular changes in GBM: as tumor vessels transition from an initial dense regular network to later scant engorged vasculature, CD68+ TAMs shift away from perivascular regions to poorly vascularized areas. Remarkably, this process is heavily influenced by the immunocompetency of host animal, as tumor vessels in immunodeficient hosts remained dense and regular while TAMs evenly distributed. Utilizing a sensitive fluorescent reporter to track tumor hypoxia, we revealed that hypoxic niche controls immunosuppression by at least two mechanisms: first, attracting and sequestering activated TAMs in hypoxic zones, and second, reprograming entrapped TAMs towards an immunotolerant state. Indeed, entrapped TAMs also experience hypoxia and upregulate phagocytic marker Cd68 and immunotolerant genes Mrc1 and Arg1, thereby facilitating debris clearing, inflammatory containment, and immunosuppression in hypoxic zones. Mechanistically, we identified Ccl8 and IL-1{beta} as two hypoxic niche factors released by TAMs in response to cues from hypoxic GBM cells, functioning to reinforce TAM retainment. Reciprocally, niche factors also shape the transcriptional responses of hypoxic tumor cells that exhibit quiescence and mesenchymal shift. Moreover, hypoxic niche factors are highly enriched in human GBMs, particularly mesenchymal subtype, and predict poor survival. Importantly, perturbing hypoxic niches resulted in reduced TAM sequestration and better tumor control. Together, understanding the mutual influence of immune contexture and metabolic landscape has important ramifications for improving efficacy of immunotherapies against GBM.

cancer biology↗

bioRxiv2021

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

neuroscience↗

bioRxiv2021

DeepRegFinder: Deep Learning-Based Regulatory Elements Finder

MotivationEnhancers and promoters are important classes of DNA regulatory elements that control gene expression. Identifying them at the genomic scale is a critical and challenging task in bioinformatics. The most successful method so far is to train machine learning models on known enhancer and promoter sites and predict them at other genomic regions using ChIP-seq and related data. ResultsWe have developed a highly customizable program called DeepRegFinder which automates data processing, model training and genome-wide prediction of enhancers and promoters using convolutional and recurrent neural networks. Our program further classifies the enhancers and promoters into active and poised states to facilitate downstream analysis. Based on mean average precision scores of different classes across multiple cell types, our method significantly outperforms the existing algorithms. Availabilityhttps://github.com/shenlab-sinai/DeepRegFinder

bioinformatics↗

bioRxiv2021

Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium

Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD), and a histologic hallmark of SFD is a thick layer of extracellular deposits beneath the retinal pigment epithelium (RPE). Previous studies of SFD patient-induced pluripotent stem cell (iPSC) derived RPE differ as to whether these cultures recapitulate this key clinical feature by forming increased drusenoid deposits. The primary purpose of this study is to examine whether SFD patient-derived iPSC-RPE form basal deposits similar to what is found in affected family member SFD globes and to determine whether SFD iPSC RPE may be more oxidatively stressed. We performed a careful comparison of iPSC RPE from three control individuals, multiple iPSC clones from two SFD patients iPSC RPE, and post-mortem eyes of affected SFD family members. We also examined the effect of CRISPR-Cas9 gene correction of the S204C TIMP3 mutation on RPE phenotype. Finally, targeted metabolomics analysis with liquid chromatography and mass spectrometry analysis and stable isotope-labeled metabolite analysis was performed to determine whether SFD RPE are more oxidatively stressed. We found that SFD iPSC-RPE formed significantly more sub-RPE deposits ([~]6-90 m in height) compared to control RPE at 8 weeks. These deposits were similar in composition to the basal laminar drusen found in SFD family member globes by immunofluorescence staining and TEM imaging. S204C TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in significantly reduced basal laminar and sub-RPE calcium deposits. We detected a [~]18-fold increase in TIMP3 accumulation in the extracellular matrix (ECM) of SFD RPE, and targeted metabolomics showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE, suggesting increased ECM turnover. Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress. Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms.

cell biology↗

bioRxiv2020

Gap junction protein INNEXIN2 modulates the period of free-running rhythms in Drosophila melanogaster

The circadian neuronal circuit of Drosophila melanogaster is made up of about 150 neurons, distributed bilaterally and distinguished into 7 clusters. Multiple lines of evidence suggest that coherent rhythms in behaviour are brought about when these clusters function as a network. Although chemical modes of communication amongst circadian neurons have been well-studied, there has been no report of communication via electrical synapses made up of gap junctions. Here, we report for the first time that gap junction proteins - Innexins play crucial roles in determining the period of free-running activity rhythms in flies. Our experiments reveal the presence of gap junction protein INNEXIN2 in the ventral lateral neurons. RNA-interference based knockdown of its expression in circadian pacemakers slows down the speed of locomotor activity rhythm. Concomitantly, we find alterations in the oscillation of a core-clock protein PERIOD and in the output molecule Pigment Dispersing Factor in the circadian pacemaker neuron network.

neuroscience↗

bioRxiv2020

Decomposing Loss Aversion from Gaze Allocation and Pupil Dilation

Loss-averse decisions, in which one avoids losses at the expense of gains, are highly prevalent. However, the underlying mechanisms remain controversial. The prevailing account highlights a valuation bias that overweighs losses relative to gains, but an alternative view stresses a response bias to avoid choices involving potential losses. Here we couple a computational process model with eye-tracking and pupillometry to develop a physiologicallygrounded framework for the decision process leading to accepting or rejecting gambles with equal odds of winning and losing money. Overall, loss-averse decisions were accompanied by preferential gaze towards losses and increased pupil dilation for accepting gambles. Using our model, we found gaze allocation selectively indexed valuation bias, and pupil dilation selectively indexed response bias. Finally, we demonstrated that our computational model and physiological biomarkers can identify distinct types of loss-averse decision-makers who would otherwise be indistinguishable using conventional approaches. Our study provides an integrative framework for the cognitive processes that drive loss-averse decisions and highlights the biological heterogeneity of loss aversion across individuals. Significance StatementWe revisit the concept of loss aversion by synthesizing distinct views into an integrative framework and by probing physiological biomarkers associated with the behavior. The framework decomposes loss aversion into a valuation bias, which weighs losses over gains, and a response bias, which avoids loss-related choices altogether. Further, we revealed a double dissociation in physiology underlying the decision process. Valuation bias was associated with preferential gaze allocation to losses whereas response bias was associated with pupillary dilation. Our framework exposed biological heterogeneity underlying loss aversion and distinguishes different loss-averse decision makers who are otherwise indistinguishable using conventional approaches. Our integrative approach provides a deeper analysis of the mechanisms underlying loss aversion and incorporates distinct views within a unified biological framework.

neuroscience↗

bioRxiv2020

Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward

Adolescence is a sensitive window for reward- and stress-associated behavior. Although stress during this period causes long-term changes in behavior in males, how females respond is relatively unknown. Here we show that social isolation stress in adolescence, but not adulthood, induces persistent but opposite effects on anxiety- and cocaine-related behaviors in male vs. female mice, and that these effects are reflected in transcriptional profiles within the adult medial amygdala (meA). By integrating differential gene expression with co-expression network analyses, we identified crystallin mu (Crym), a thyroid-binding protein, as a key driver of these transcriptional profiles. Manipulation of Crym specifically within adult meA neurons recapitulates the behavioral and transcriptional effects of social isolation and re-opens a window of plasticity that is otherwise closed. Our results establish that meA is essential for sex-specific responses to stressful and rewarding stimuli through transcriptional programming that occurs during adolescence.

neuroscience↗

bioRxiv2019

A machine learning approach to identifying objectivebiomarkers of anxiety and stress

Anxiety and stress-related disorders are highly prevalent and debilitating conditions that impose an enormous burden on society. Sensitive measurements that can enable early diagnosis could mitigate suffering and potentially prevent onset of these conditions. Self-reports, however, are intrusive and vulnerable to biases that can conceal the true internal state. Physiological responses, on the other hand, manifest spontaneously and can be monitored continuously, providing potential objective biomarkers for anxiety and stress. Recent studies have shown that algorithms trained on physiological measurements can predict stress states with high accuracy. Whether these predictive algorithms generalize to untested situations and participants, however, remains unclear. Further, whether biomarkers of momentary stress indicate trait anxiety - a vulnerability foreshadowing development of anxiety and mood disorders - remains unknown. To address these gaps, we monitored skin conductance, heart rate, heart rate variability and EEG in 39 participants experiencing physical and social stress and compared these measures to non-stressful periods of talking, rest, and playing a simple video game. Self-report measures were obtained periodically throughout the experiment. A support vector machine trained on physiological measurements identified stress conditions with ~96% accuracy. A decision tree that optimally combined physiological and self-report measures identified individuals with high trait anxiety with ~84% accuracy. Individuals with high trait anxiety also displayed high baseline state anxiety but a muted physiological response to acute stressors. Overall, these results demonstrate the potential for using machine learning tools to identify objective biomarkers useful for diagnosing and monitoring mental health conditions like anxiety and depression.

neuroscience↗

bioRxiv2019

Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brains transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

neuroscience↗