Biology subjects

Ressler, K. J.

Publications and source records attributed to Ressler, K. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Adrenal remodeling encodes stress axis memory to shape fentanyl seeking

The hypothalamic-pituitary-adrenal (HPA) axis is implicated in substance use disorders, yet the features of this circuit that contribute to addiction vulnerability remain unclear. Here, we show that fentanyl engages with different components of the HPA axis, and this engagement varies across timescales. Within minutes, fentanyl activated corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVNCRH) and transiently increased adrenocorticotropic hormone (ACTH) levels. Hours to days later, fentanyl suppressed PVN activity, reduced adrenal size, and impaired corticosterone release. Conversely, ACTH-induced adrenal hypertrophy, increased corticosterone, suppressed fentanyl-evoked PVNCRH activity, and elevated fentanyl-seeking behavior. These findings identify adrenal remodeling as a physiological record of stress history that shapes neuroendocrine and behavioral responses to fentanyl, mechanistically linking stress and addiction while revealing treatment targets for opioid dependence.

neuroscience↗

bioRxiv2026

Stressor Identity Shapes Reactivity To Subsequent Stress

Extensive work has established that exposure to a single acute stressor can have profound impacts on future reactivity to new stressors, including enhanced acquisition of new fear. The impact of stressor type on development of stress sensitization, however, remains unclear. We investigated whether fundamentally different acute stressors (shock, social defeat, or restraint stress) differ in ability to sensitize acquisition of a new, contextually distinct fear memory in adult male mice two weeks following stress exposure. Stressor subtype differentially sensitized new fear learning; specifically, shock and social defeat - but not restraint stress - led to enhanced recall of a new shock-paired fear memory. We also compared how stressor subtypes differentially engage the brain-periphery interactions that regulate stress responsivity. Notably, restraint stress, which did not lead to fear sensitization to foot shock, drove similar or even greater corticosterone release than other stressors, suggesting that the neuroendocrine response to the original stressor is dissociable from development of a behavioural fear sensitization response. Using the immediate-early gene FOS as a marker of neural activity, all conditions - including the context-only control condition - activated a similar number of neurons in the basolateral amygdala. In contrast, only stressful conditions activated the paraventricular nucleus of the hypothalamus, and restraint stress selectively spared activation of the dorsal hippocampus. These data collectively suggest that future responses to stress depend critically on the identity of previously experienced stressors, rather than simply on prior exposure to stress, establishing a powerful comparative model for investigating the specific mechanisms underlying stress-enhanced fear learning.

neuroscience↗

bioRxiv2026

Fine mapping of PTSD GWAS reveals a role for amygdala Foxp2 in regulation of fear and threat responses

Post-traumatic Stress Disorder (PTSD) is a debilitating psychiatric condition caused by severe trauma exposure and characterized by ongoing dysregulation of fear processing, hyperarousal, and amygdala activation, but with limited effective treatments. Recent large-scale genome-wide association studies (GWAS) of PTSD have identified the transcription factor FOXP2 as a highly-significant, top putative risk gene. Both fine-mapping of the PTSD GWAS with amygdala-specific expression quantitative trait loci (eQTL) data, and transcriptome-wide association analyses, show that altered expression of FOXP2 is associated with increased PTSD risk. In vertebrates, FOXP2 mRNA is most densely expressed in the intercalated cells (ITCs) of the amygdala. ITC neurons receive excitatory input from external regulatory and sensory brain regions, as well as the basolateral amygdala, and send inhibitory projections to the central amygdala, which regulates downstream fear responses. While ITCs are critical for conditioned fear acquisition and extinction, the role of the FOXP2 gene in modulating fear-related behaviors remains unknown. Here, we used complementary bioinformatic, molecular, circuit, behavioral, and electrophysiological approaches to characterize the function of mouse (Foxp2) and human (FOXP2) orthologs in amygdala-mediated fear learning. To assess Foxp2 function in vivo, we first used shRNA-mediated knockdown (KD) of Foxp2 in ITC neurons of adult mice. Targeted Foxp2 KD robustly and significantly reduced freezing (threat/fear expression) during and after auditory fear conditioning. Whole-cell recordings from individual ITC neurons revealed that Foxp2 KD increased their intrinsic membrane excitability and action potential frequency, consistent with hypothesized enhanced inhibitory output to the central amygdala and thus reduced fear expression. This hyperexcitability was associated with reduced potassium channel conductance. Bulk RNA sequencing (RNA-seq) of mouse amygdala after ITC Foxp2 KD confirmed decreased potassium channel transcription and revealed broader Foxp2-dependent regulation of multiple genes implicated in fear learning, including Wnt, Crh (which encodes corticotropin-releasing hormone), and neurokinin signaling pathways. Consistent with these findings, bulk RNA-seq of medial amygdala postmortem tissue from humans with PTSD versus neurotypical controls showed decreased potassium channel transcription in samples with low FOXP2 expression. Downstream transcriptional changes following Foxp2 KD in the mouse amygdala also showed marked enrichment of genes identified in PTSD risk loci from the largest PTSD GWAS to date. Specifically, downregulated genes were enriched for mouse orthologs of Tier 1 PTSD GWAS risk genes. This enrichment appears to reflect subcortical Foxp2 signaling within the amygdala, driven predominantly by decreased expression of genes lacking promoter-anchored chromatin loops. This finding suggests that Foxp2 may directly bind regulatory elements of multiple top PTSD risk genes, acting as a key regulatory node for fear-related pathways in the amygdala. Collectively, our findings establish FOXP2 as a central transcriptional regulator of fear-related gene networks in the amygdala and potential regulatory hub for PTSD genetic risk.

neuroscience↗

bioRxiv2026

A critical role for the murine anterior insula in male social avoidance after early life maltreatment.

Maltreatment in children and adolescents poses a major public health crisis as a primary factor for the development of adult psychiatric disorders. However effective treatments for symptoms resulting from early life maltreatment are lacking, in part due to a lack of understanding of how neural circuits are disrupted in adulthood after childhood and adolescent abuse. We used a novel model of developmental maltreatment (early adolescent chronic social defeat stress, eaCSDS) in C57/B6J mice to examine behavioral and circuit-level effects in the adult anterior insula (AI). We combined chemogenetics, whole brain c-fos imaging and multi-site LFP to investigate the role of the AI and related circuitry in adult behavioral dysfunction after early life maltreatment. Behavioral analysis in adult animals reveals that males, but not females, show robust generalized social avoidance after social defeat in early adolescence. Chemogenetic silencing of AI neurons in males, but not females, reduces social avoidance in adulthood after eaCSDS. In males, whole brain c-fos imaging and multi-site LFP recordings further reveal circuit-level disruptions in connectivity to AI, implicating AI dysregulation as a driver of adult male social avoidance after adolescent maltreatment. Together these findings reveal AI as a novel circuits-level target whose activity normalization may reduce fear-based symptoms of adolescent maltreatment in adulthood specifically in males.

neuroscience↗

bioRxiv2026

Acute Ethanol Exposure Induces Stage-Specific Bioenergetic, Mitochondrial and Neurodevelopmental Transcriptional Remodeling in Human Forebrain Progenitors

Prenatal alcohol exposure (PAE) is associated with long-term neurodevelopmental risk, yet how neuronal progenitor metabolism responds to alcohol across developmental stages remains unclear. Here, we integrated brain-isoform-focused analysis of public datasets with targeted transcriptional, translational, and functional mitochondrial assessments in human iPSC-derived cortical progenitor models representing distinct bioenergetic states. Re-analysis of prior PAE studies revealed broad metabolic gene downregulation in embryonic systems, whereas neurodevelopmental models showed limited and non-coherent transcriptional signatures. In vitro, acute ethanol exposure (AEE) induced stage-dependent transcriptional remodeling in iPSC-derived neuronal progenitor cells. Early progenitors exhibited selective upregulation of mitochondrial-associated transcripts alongside increased neuronal lineage markers. In contrast, late progenitors showed broader increases in glycolytic, lipid, and mitochondrial gene expression. Despite these transcriptional changes, mitochondrial ATP production and mitochondrial protein abundance remained unchanged in both models with altered dynamics being restricted to late progenitors. These findings indicate that ethanol exposure is associated with developmental stage-dependent neuronal remodeling of bioenergetic genes. Measurements of mitochondrial-neural frameworks after AEE showed no major alterations in either model. Overall, our results reveal a dissociation between transcriptional, translational, and functional bioenergetic outputs in models of early human neurodevelopment and highlight that transcriptional alterations of mitochondria and cellular bioenergetics under AEE should be interpreted in the context of developmental stage rather than in isolation as evidence of energetic dysfunction.

neuroscience↗

bioRxiv2025

Cognition-centric brain activity across diverse imaging tasks constrains the representation of mental health in task-evoked brain function

Large-scale neuroimaging studies best powered to investigate mental health biomarkers continue to administer a set of in-scanner tasks that, to date, yield weak brain-mental health associations. Triangulating the source of these weak associations is critical to directing the focus of future work. Using these tasks strong brain-cognition associations as a positive control, we analyzed potential sources of weak brain-mental health associations across five popular fMRI tasks and dozens of task-evoked brain networks. Across tasks and networks, latent mental health factors showed substantially weaker brain associations than cognition despite comparable measurement reliability and greater interindividual variability. Moreover, increasing brain-feature dimensionality improved cognitive but not mental health signal, and task-evoked network profiles were 1.8-2.3 times more homogeneous and 3.5 times lower-dimensional than mental health profiles. Findings implicate a signal evocation bottleneck: common fMRI tasks elicit little interindividual variation in mental health-related brain activity relative to the diversity of mental health itself. Overall, these findings motivate a shift in focus to the development and use of tasks in large-scale studies more explicitly designed to evoke mental health-relevant brain activity. Significance StatementIdentification of robust individual-specific mental health-related brain signals from fMRI remains elusive, limiting the clinical utility of brain imaging. To investigate why, we systematically evaluated brain signals evoked by tasks used by the Human Connectome Project-Young Adult study, which are now commonly included in many large-scale neuroimaging studies. Our findings suggest that, more so than analytical or measurement constraints on detecting these signals, a primary limitation is a failure of these prevalent fMRI tasks to evoke mental health-relevant brain signals in the first place. These findings suggest that progress in psychiatric neuroimaging may require tasks more explicitly designed to evoke mental health-relevant brain activity.

neuroscience↗

bioRxiv2025

Correspondence between sleep patterns and anhedonia in adult male mice exposed to early-life stress

Early-life stress (ELS) can produce long-lasting effects that increase the risk for mood and anxiety disorders. Transdiagnostic symptoms include anhedonia (reduced reward sensitivity) and sleep disruption, both of which are quantifiable via objective endpoints that can be utilized across species. Here we used a mouse model for ELS--exposure to juvenile chronic social defeat stress (jCSDS)--together with translationally-applicable endpoints to examine correspondence between sleep patterns and anhedonia. These initial studies focused on males, which typically show robust defeat-induced anhedonia phenotypes. Exposure to jCSDS produced reductions in open-field social behavior, an endpoint commonly used in mice to quantify stress effects, during adulthood. Mice were then implanted with wireless transmitters that enable continuous EEG-derived analysis of sleep architecture. Following assessment of baseline sleep patterns, mice were tested in a rodent version of the Probabilistic Reward Task (PRT), a procedure used to quantify reward responsiveness in humans, during the light phase of their diurnal cycle. These studies revealed significant associations between baseline sleep architecture and anhedonic phenotypes in jCSDS-exposed mice: higher anhedonia correlated with less time awake and more time in slow wave sleep (SWS) during the light phase, and more time awake and less time in rapid eye movement (REM) sleep and SWS during the dark (active) phase. Our findings suggest that sleep patterns represent a biomarker that can predict stress-susceptible (higher anhedonia) and resilient (lower anhedonia) phenotypes. This work enhances our understanding of relationships between sleep and anhedonia, and may provide a basis for precision approaches to treat ELS-induced pathophysiology.

animal behavior and cognition↗

bioRxiv2025

A Clinically Aligned Murine Model of Electroconvulsive Stimulation Reverses Social Aversion and Displays Fear Memory Impairment After Chronic Social Defeat Stress

Electroconvulsive therapy (ECT) is the most effective treatment for patients with major depression, bipolar depression, mania, catatonia, and schizophrenia. Nonetheless, the mechanisms underlying its therapeutic effects largely remain unknown. While previous preclinical studies have noted a role for neurotropic signaling, neurogenesis, and alterations in monoamine neurotransmitter systems, these models were largely conducted using procedures that deviate from clinical practice. Therefore, we sought to develop a clinically relevant murine model of ECT, referred to as electroconvulsive stimulation (ECS) in animals, which more closely aligns with current clinical approaches to better explore its mechanisms. Using the well-established chronic social defeat stress (CSDS) paradigm, known to negatively impact reward processes, we investigated whether the behavioral changes after CSDS could be reversed following a clinically related course of ECS. Additionally, we observed induction of plasticity-related genes in the nucleus accumbens (NAcc) and amygdala, regions responsible for reward and fear-related memory, respectively. Lastly, we investigated ECS-related changes in the NAcc with bulk RNA-sequencing. Pathway analysis demonstrated cellular changes primarily involved in neuroplasticity and regulating cell migration and differentiation. Therefore, utilizing our novel and clinically relevant model of ECS, we have begun to elucidate mechanisms that contribute to ECTs therapeutic outcomes by examining murine behavior and RNA from brain regions associated with stress-induced states that model anxiety and depression and the effects of ECS.

neuroscience↗

bioRxiv2025

Childhood Maltreatment and Brain Aging During Adulthood

ImportanceChildhood maltreatment (CM) is associated with the early onset of psychiatric and medical disorders and accelerated biological aging. ObjectiveTo identify types of maltreatment and developmental sensitive periods that are associated with accelerated adult brain aging. DesignParticipants were mothers of infants recruited from the community into a study assessing the effects of CM on maternal behavior, infant attachment, and maternal and infant neurobiology. Data were collected from July 2015 to November 2019 and were analyzed from July 2023 to October 2024. SettingAcademic medical centers. ParticipantsHigh-quality MRI scans were obtained on 92 of 150 mothers enrolled in the study. The main exclusion criteria for neuroimaging were histories of head trauma with loss of consciousness or concussion, psychotropic use before age 18, pregnancy, and customary MRI exclusions (e.g., metal implant). The primary reasons for non-completion of the neuroimaging study were unwillingness to be scanned, inability to attend the MRI study visit due to work and/or childcare, metal implants, or pregnancy. Main Outcome(s) and Measure(s)The Maltreatment and Abuse Chronology of Exposure scale was used to retrospectively assess the annual severity of exposure to ten types of CM from birth to age 18 years. Brain age was calculated from T1-weighted 3T MRI Scans using a previously published machine learning algorithm. Sensitive periods were identified using random forest regression with conditional inference trees. ResultsForty-nine (53.3%) of the 92 mothers (mean [SD] age, 32.4 [4.3] years) reported experiencing one or more types of CM. Total CM severity was associated with accelerated brain aging ({beta}=0.05, 95% CI, 0.02 to 0.09, p<.005). The most robust type/time risk factors for accelerated brain aging were parental physical abuse between ages 4 to 6 years, witnessing sibling violence between ages 4 to 15 years, parental verbal abuse between ages 10 to 12 years, and parental emotional neglect between ages 16 to 18 years. Conclusions and RelevanceSeveral types of CM between ages 4-18 years were associated with accelerated brain aging. Understanding how these specific types and ages of exposure contribute to accelerated brain aging may provide important insights into preventing key clinical consequences of CM. SUMMARYQuestion: How does childhood adversity relate to brain aging in adulthood, and are there sensitive periods for this association? Findings: In this cohort-based study of adult women, we observed sensitive periods for the association between adult brain aging and five classes of childhood maltreatment: parental physical abuse, parental verbal abuse, parental emotional neglect, and witnessing sibling violence. Meaning: These findings suggest that maltreatment subtype and age at exposure may be important factors contributing to the impact of childhood adversity on brain aging later in life.

neuroscience↗

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗

bioRxiv2024

Concurrent large-scale brain dynamics during the emotional face matching task and their relation to behavior and mental health

Prior investigations of emotion processings neural underpinnings rely on a priori models of brain response, obscuring detection of task-relevant neurobiological processes with complex temporal dynamics. To overcome this limitation, we applied unsupervised machine learning to functional magnetic resonance imaging data acquired during the emotional face matching task (EFMT) in healthy young adults from the Human Connectome Project (n=413; n=416 replication). Tensorial independent component analysis showed that the EFMT engages 10 large-scale brain networks - each recruiting visual association cortex in distinct temporal fashions and in tandem with diverse non-visual regions - that collectively recruit 74% of cortex, posterior cerebellum, and amygdala. Despite prominent use of the EFMT to probe negative affect and related psychopathology, EFMT-recruited networks strongly reflected individual differences in cognition but not internalizing/negative affect. Overall, we characterize a richer-than-expected tapestry of concurrent EFMT-recruited brain processes, their diverse activation dynamics, and their relations to task performance and latent mental health phenotypes.

neuroscience↗

bioRxiv2024

Intra-amygdala circuits of sleep disruption-induced anxiety in female mice

Combining mouse genetics, electrophysiology, and behavioral training and testing, we explored how sleep disruption may affect the function of anxiety-controlling circuits, focusing on projections from the basolateral nucleus of the amygdala (BLA) to CRF-positive cells in the lateral division of the central amygdala (CeL). We found in Crh-IRES-Cre::Ai14(tdTomato) reporter female mice that 6 hours of sleep disruption during their non-active (light) cycle may be anxiogenic. Notably, the AMPAR/NMDAR EPSC amplitude ratio at the BLA inputs to CRF-CeL cells (CRFCeL), assessed with whole-cell recordings in ex vivo experiments, was enhanced in slices from sleep-disrupted mice, whereas paired-pulse ratio (PPR) of the EPSCs induced by two closely spaced presynaptic stimuli remained unchanged. These findings indicate that sleep disruption-associated synaptic enhancements in glutamatergic projections from the BLA to CRF-CeL neurons may be postsynaptically expressed. We found also that the excitation/inhibition (E/I) ratio in the BLA to CRFCeL inputs was increased in sleep-disrupted mice, suggesting that the functional efficiency of excitation in BLA inputs to CRFCeL cells has increased following sleep disruption, thus resulting in their enhanced activation. The latter could be translated into enhanced anxiogenesis as activation of CRF cells in the CeL was shown to promote anxiety-like behaviors.

neuroscience↗

bioRxiv2024

Acute sleep deprivation reduces fear memories in male and female mice

Sleep problems are a prominent feature of mental health conditions including post-traumatic stress disorder (PTSD). Despite its potential importance, the role of sleep in the development of and/or recovery from trauma-related illnesses is not understood. Interestingly, there are reports that sleep deprivation immediately after a traumatic experience can reduce fear memories, an effect that could be utilized therapeutically in humans. While the mechanisms of this effect are not completely understood, one possible explanation for these findings is that immediate sleep deprivation interferes with consolidation of fear memories, rendering them weaker and more sensitive to intervention. Here, we allowed fear-conditioned mice to sleep immediately after fear conditioning during a time frame (18 hr) that includes and extends beyond periods typically associated with memory consolidation before subjecting them to 6 hr of sleep deprivation. Mice deprived of sleep with this delayed regimen showed dramatic reductions in fear during tests conducted immediately after sleep deprivation, as well as 24 hr later. This sleep deprivation regimen also increased levels of mRNA encoding brain-derived neurotrophic factor (BDNF), a molecule implicated in neuroplasticity, in the basolateral amygdala (BLA), a brain area implicated in fear and its extinction. These findings raise the possibility that the effects of our delayed sleep deprivation regimen are not due to disruption of memory consolidation, but instead are caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear. Treatments that safely reduce expression of fear memories would have considerable therapeutic potential in the treatment of conditions triggered by trauma.

neuroscience↗

bioRxiv2023

Single nucleus transcriptomics of human and monkey striatum implicates DNA damage, neuroinflammation, and neurodegeneration signaling in opioid use disorder

The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are involved in altered reward processing, formation of habits, and development of negative affect states associated with OUD. Using single nuclei RNA-sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g., dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2-hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We also identified sex-dependent differences in the expression of stress-induced transcripts among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.

neuroscience↗

bioRxiv2023

PACAP-mediated gating of anxiety-controlling circuits

Combining the use of ex vivo and in vivo optogenetics, viral tracing, electrophysiology and behavioral testing, we show that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) gates anxiety-controlling circuits by differentially affecting synaptic efficacy at projections from the basolateral amygdala (BLA) to two different subdivisions of the dorsal subdivision of the bed nucleus of the stria terminalis (BNST), modifying the signal flow in BLA-ovBNST-adBNST circuits in such a way that adBNST is inhibited. Inhibition of adBNST is translated into the reduced firing probability of adBNST neurons during afferent activation, explaining the anxiety-triggering actions of PACAP in BNST, as inhibition of adBNST is anxiogenic. Our results reveal how innate, fear-related behavioral mechanisms may be controlled by neuropeptides, PACAP specifically, at the level of underlying neural circuits by inducing long-lasting plastic changes in functional interactions between their different structural components.

neuroscience↗

bioRxiv2023

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1{beta} release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1{beta} release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimers disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimers disease, providing new mechanistic insight into the biology of neuroinflammation.

neuroscience↗

bioRxiv2023

Early life stress in male mice blunts responsiveness in a translationally-relevant reward task

Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety disorders. In humans, myriad forms of ELS--including childhood abuse, bullying, poverty, and trauma--are increasingly prevalent. Understanding the signs of ELS, including those associated with psychiatric illness, will enable improved treatment and prevention. Here we developed a novel procedure to model human ELS in mice and identify translationally-relevant biomarkers of mood and anxiety disorders. We exposed male mice (C57BL/6J) to an early-life (juvenile) chronic social defeat stress (jCSDS) and examined social interaction and responsivity to reward during adulthood. As expected, jCSDS-exposed mice showed a socially avoidant phenotype in open-field social interaction tests. However, sucrose preference tests failed to demonstrate ELS-induced reductions in choice for the sweetened solution, suggesting no effect on reward function. To explore whether other tasks might be more sensitive to changes in motivation, we tested the mice in the Probabilistic Reward Task (PRT), a procedure often used in humans to study reward learning deficits associated with depressive illness. In a touchscreen PRT variant that was reverse-translated to maximize alignment with the version used in human subjects, mice exposed to jCSDS displayed significant reductions in the tendency to develop response biases for more richly-rewarded stimuli, a hallmark sign of depression (anhedonia) when seen in humans. Our findings suggest that translationally-relevant procedures that utilize the same endpoints across species may enable the development of improved model systems that more accurately predict outcomes in humans.

neuroscience↗

bioRxiv2023

Dysregulation of Prefrontal Oligodendrocyte Lineage Cells Across Mouse Models of Adversity and Human Major Depressive Disorder

Animal models of adversity have yielded few molecular mechanisms that translate to human stress-related diseases like major depressive disorder (MDD). We congruently analyze publicly available bulk-tissue transcriptomic data from prefrontal cortex (PFC) in multiple mouse models of adversity and in MDD. We apply strategies, to quantify cell-type specific enrichment from bulk-tissue transcriptomics, utilizing reference single cell RNA sequencing datasets. These analyses reveal conserved patterns of oligodendrocyte (OL) dysregulation across animal experiments, including susceptibility to social defeat, acute cocaine withdrawal, chronic unpredictable stress, early life stress, and adolescent social isolation. Using unbiased methodologies, we further identify a dysregulation of layer 6 neurons that associate with deficits in goal-directed behavior after social isolation. Human post-mortem brains with MDD show similar OL transcriptome changes in Brodmann Areas 8/9 in both male and female patients. This work assesses cell type involvement in an unbiased manner from differential expression analyses across animal models of adversity and human MDD and finds a common signature of OL dysfunction in the frontal cortex.

neuroscience↗