Biology subjects

Baram, T. Z.

Publications and source records attributed to Baram, T. Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Disrupted neuropeptide-signaling drives enduring reward deficits after early-life stress

Whereas brain systems mediating acute stress are essential for survival, chronic early-life stress (ELA) may lead to poor ability to experience pleasure (anhedonia), a core feature of depression. For decades, the stress neuropeptide corticotropin-releasing hormone (CRH) has been a target for treating depression. However the failure of several clinical trials blocking CRH receptor1 (CRHR1) has left the therapeutic role of CRH signaling a major unresolved mystery. Here, we uncover the signaling plasticity behind this enigma with the use of in vivo G protein-coupled activation-based (GRAB) imaging and viral-genetic and pharmacological mechanistic manipulations. We find that CRH signaling via CRHR1 indeed disrupts reward behaviors in control mice, but is disrupted in anhedonic mice with a history of ELA. Instead, activation of CRH receptor 2 (CRHR2) reverses anhedonia-like behaviors in adult ELA mice. These findings redefine our understanding of stress-mediated anhedonia and provide a precise, novel therapeutic target for stress-related mental illness.

neuroscience↗

bioRxiv2026

A specific computational role for early-life unpredictability, and not lifelong stressful experience, in decision-making under uncertainty.

It has been shown that early-life adversity (ELA) shapes how individuals learn, remember, and make decisions, yet the precise computations altered by these experiences remain unclear. Here, we combine a structured foraging task with computational modeling to test a recently developed theory for how a particular kind of ELA, early-life unpredictability (ELU), specifically influences choice under uncertainty. Adult participants (N=297) performed a sequential foraging task requiring continuous trade-offs between exploiting depleting resources and exploring alternatives. Subsets also completed assessments of early-life unpredictability (QUIC) and for trauma symptoms arising from lifelong stressors (PCL). We fit participants behavior with a Bayesian learning-and-planning model in which uncertainty modulates the valuation of leaving a current resource patch. Critically, the subjective influence of local uncertainty was allowed to vary freely between participants. Consistent with theoretical proposals, computational model fits and mediation analyses revealed a robust indirect pathway: ELU predicted increased discounting in the face of uncertainty, which in turn predicted greater overharvesting. This pattern was consistent across environmental conditions, indicating that early-life unpredictability primarily influences behavior through a general influence on uncertainty processing. Importantly, although PCL scores were also correlated with uncertainty adaptation, these effects were fully accounted for by shared variance with ELU, offering a clear dissociation between developmental unpredictability and lifelong traumatic experience. Together, our results show that early-life unpredictability causes long-lasting changes in decision-making by amplifying the subjective experience of uncertainty.

neuroscience↗

bioRxiv2026

Anhedonia buffers the effects of early-life unpredictability on threat-reward decision-making.

Anhedonia - the diminished capacity to experience or anticipate pleasure - is among the most common consequences of early-life unpredictability, yet how these co-occurring conditions jointly shape real-world decision-making remains unknown. Here, we use a sequential foraging-under-threat task to probe motivational conflict decisions in 357 individuals varying in early-life unpredictability and anhedonia symptoms. We find that unpredictability and anhedonia exert opposing influences on choice: unpredictability shifts behavior away from the survival-optimal policy in a sex-dependent manner, while anhedonia promotes adherence to it, partly through heightened sensitivity to unexpected threatening outcomes. A mediation analysis reveals that anhedonia partially buffers the deleterious effects of unpredictability on decision quality. These results demonstrate that co-occurring conditions can mask one anothers behavioral signatures and suggest that the heterogeneous expression of transdiagnostic constructs like anhedonia may reflect context-dependent adaptations to distinct underlying etiologies.

neuroscience↗

bioRxiv2026

Peptide signaling in the paraventricular thalamus contributes to disrupted adult reward behaviors after early-life adversity

Early-life adversity (ELA) is strongly linked to emotional disorders characterized by dysregulated reward behaviors including diminished motivation for and enjoyment of rewards (anhedonia). However, how transient ELA leads to enduring disruptions of reward behaviors remains unclear. Using activity-dependent genetic labeling during ELA, we previously found that the paraventricular thalamic nucleus (PVT) uniquely distinguishes ELA from typical rearing, and inhibiting ELA-activated PVT cells in adult ELA mice rescued reward behaviors in a sex-specific manner. However, the cellular mechanisms by which ELA alters the function of PVT neurons enduringly, to impact adult reward behaviors is unresolved. Here, we probed potential gene expression mechanisms by assessing reward-induced gene translation selectively in early-life activated (TRAPed) PVT cells, and identified genes regulated by reward in a sex-specific way. Combining data- and hypothesis-driven approaches, we targeted the corticotropin-releasing hormone receptor type 1 (CRHR1) as potentially mediating ELA-induced disruptions of reward behaviors. We find that CRISPR-Cas9-mediated Crhr1 deletion in TRAPed-PVT cells restores typical reward behaviors in ELA mice. Our results provide insight into the developmental origin of mental illness and identify potentially powerful molecular targets for prevention or mitigation of the consequences of ELA on reward behaviors germane to human mental illness.

neuroscience↗

bioRxiv2025

Early life stress induces social behavioral deficits and peripheral biomarker alterations in adolescence that perpetuate intergenerationally

Early life stress (ELS) increases the likelihood of developing chronic health problems including mental illness. In humans, deficits in social behavior often emerge during adolescence and correlate with later-life psychiatric diagnoses. We examined in mice the effects of a limited bedding and nesting (LBN) model of ELS on pup ultrasonic vocalizations (USVs) during postnatal days 3-9 (P3-P9). Then on P30, an adolescent timepoint, we assessed social behavior as well as thymus involution and adrenal hypertrophy, both biomarkers of stress. We found reductions in USVs as early as P3, resembling low levels normally seen later in development. There were few changes in SI, with deficits observed only after restraint stress in female LBN mice. Surprisingly, thymus weights were augmented and adrenal glands were smaller in LBN adolescent mice, opposite to alterations typically observed after chronic adult stress. LBN also produced signs of precocious puberty in both sexes, especially in cohorts of LBN-exposed offspring bred to create second-generation LBN offspring that subsequently underwent LBN, indicating perpetuation across generations. Together, these data suggest that stress in early life has distinct and diverse effects, including accelerating several processes, and that some of these effects persist intergenerationally.

neuroscience↗

bioRxiv2025

A combined neuroanatomy, ex vivo imaging and immunohistochemistry defined MRI mask for the human paraventricular nucleus of the thalamus

The paraventricular nucleus of the thalamus (PVT) is an evolutionarily conserved midline thalamic structure known to contribute to arousal, interoceptive states, and motivated behaviors. Yet, a consensus anatomical definition of the human PVT across tissue-based and MRI-based approaches remains elusive, thereby limiting reliable translation between its cellular characteristics and in vivo functional connectivity. To address this challenge, we describe a histologically-informed PVT segmentation compatible with standard 3T MR imaging pipelines. We performed postmortem anatomical MRI scans on an intact whole brain and an excised thalamic block, manually segmented the PVT at high resolution using ex vivo calretinin staining and neuroanatomical landmarks, registered the resulting image-label pair to a commonly used MRI template space (Montreal Neurological Institutes MNI152), and performed a comparative reanalysis using this newly defined mask. This tissue-grounded PVT mask largely overlaps spatially with existing MRI-based PVT masks, with the exception of additional voxels posteriorly. Importantly, the functional connectivity patterns of this tissue-grounded mask are highly consistent with those previously reported. Collectively, this multimodal definition of the human PVT balances tissue-based ground truth with in vivo MRI features, providing a valuable resource for advancing translation between cellular level features identified by histology and in vivo functional connectivity at the meso/macro scale in the understudied human PVT. Key PointsO_LIAddresses conflict between histological and MRI-based borders of the human PVT. C_LIO_LIHistologically-defined PVT boundaries indicate additional posterior tail to the human PVT as compared to existing human MRI atlases. C_LIO_LIProvided MRI mask demonstrates functional connectivity patterns consistent with prior human and rodent studies. C_LI

neuroscience↗

bioRxiv2025

Unexpected mechanisms of sex-specific memory vulnerabilities to acute traumatic stress

It is increasingly recognized that severe acute traumatic events (e.g., mass shooting, natural disasters) can provoke enduring memory disturbances, and these problems are more common in women. We probed the fundamental sex differences underlying memory vulnerability to acute traumatic stress (ATS), focusing on the role of the sex hormone, estrogen (17{beta}-estradiol) and its receptor signaling in hippocampus. Surprisingly, high physiological hippocampal estrogen levels were required for ATS-induced episodic memory disruption and the concurrent sensitization and generalization of fear memories in both male and female mice. Pharmacological and transgenic approaches demonstrated signaling via estrogen receptor (ER) in males and, in contrast, ER{beta} in females, as the mechanisms for these memory problems. Finally, identify distinct hippocampal chromatin states governed by sex and estrogen levels, which may confer an enduring vulnerability to post-traumatic memory disturbances in females.

neuroscience↗

bioRxiv2024

Sex-and Stress-Dependent Plasticity of a Corticotropin Releasing Hormone / GABA Projection from the Basolateral Amygdala to Nucleus Accumbens that Mediates Reward Behaviors

BackgroundMotivated behaviors are executed by refined brain circuits. Early-life adversity (ELA) is a risk for human affective disorders involving dysregulated reward behaviors. In mice, ELA causes anhedonia-like behaviors in males and augmented reward motivation in females, indicating sex-dependent disruption of reward circuit operations. We recently identified a corticotropin-releasing hormone (CRH) expressing GABAergic projection from basolateral amygdala (BLA) to nucleus accumbens (NAc) that governs reward-seeking deficits in adult ELA males--but not females. MethodsTo probe the sex-specific role of this projection in reward behaviors, adult male and female CRH-Cre mice raised in control or ELA conditions received excitatory or inhibitory Cre-dependent DREADDs in BLA, and then clozapine N-oxide or vehicle to NAc medial shell during reward behaviors. We determined the cell identity of the projection using immunostaining and electrophysiology. Using tissue clearing, light sheet fluorescence microscopy and deep learning pipelines, we mapped brain-wide BLA CRH+ axonal projections to uncover sex differences in innervation. ResultsChemogenetic manipulations in male mice demonstrated inhibitory effects of the CRH+ BLA-NAc projection on reward behaviors, whereas neither excitation nor inhibition influenced female behaviors. Molecular and electrophysiological cell-identities of the projection did not vary by sex. By contrast, comprehensive whole-brain mapping uncovered significant differences in NAc innervation patterns that were both sex and ELA-dependent, as well as selective changes of innervation of other brain regions. ConclusionsThe CRH/GABA BLA-NAc projection that influences reward behaviors in males differs structurally and functionally in females, uncovering potential mechanisms for the profound sex-specific impacts of ELA on reward behaviors.

neuroscience↗

bioRxiv2024

Targeting Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1) Neurons: Validating the Specificity of a Novel Transgenic Crhr1-FlpO Mouse

IntroductionCorticotropin-releasing hormone (CRH) signaling through its cognate receptors, CRHR1 and CRHR2, contributes to diverse stress-related functions in the mammalian brain. Whereas CRHR2 is predominantly expressed in choroid plexus and blood vessels, CRHR1 is abundantly expressed in neurons in discrete brain regions, including the neocortex, hippocampus and nucleus accumbens. Activation of CRHR1 influences motivated behaviors, emotional states, and learning and memory. However, it is unknown whether alterations in CRHR1 signaling contribute to aberrant motivated behaviors observed, for example, in stressful contexts. These questions require tools to manipulate CRHR1 selectively. Here we describe and validate a novel Crhr1-FlpO mouse. MethodsUsing bacterial artificial chromosome (BAC) transgenesis, we engineered a transgenic mouse that expresses FlpO recombinase in CRHR1-expressing cells. We used two independent methods to assess the specificity of FlpO to CRHR1-expressing cells. First, we injected Crhr1-FlpO mice with Flp-dependent viruses expressing fluorescent reporter molecules. Additionally, we crossed the Crhr1-FlpO mouse with a transgenic Flp-dependent reporter mouse. CRHR1 and reporter molecules were identified using immunocytochemistry and visualized via confocal microscopy in several brain regions in which CRHR1 expression and function is established. ResultsExpression of Flp-dependent viral constructs was highly specific to CRHR1-expressing cells in all regions examined (over 90% co-localization). In accord, robust and specific expression of the Flp-dependent transgenic reporter was observed in a reporter mouse, recapitulating endogenous CRHR1 expression. ConclusionsThe Crhr1-FlpO mouse enables selective genetic access to CRHR1-expressing cells within the mouse brain. When combined with Cre-lox or site-specific recombinases, the mouse facilitates intersectional manipulations of CRHR1-expressing neurons.

neuroscience↗

bioRxiv2024

Sex-specific effects of early life unpredictability on hippocampal and amygdala responses to novelty in adolescents

BackgroundUnpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala. MethodsParticipants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes. ResultsExposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally. ConclusionExposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity.

neuroscience↗

bioRxiv2024

PTEN deletion in the adult dentate gyrus induces Epilepsy

Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.

neuroscience↗

bioRxiv2024

Paraventricular Thalamus Neuronal Ensembles Encode Early-life Adversity and Mediate the Consequent Sex-dependent Disruptions of Adult Reward Behaviors

While links between early-life adversity (ELA) and mental illnesses characterized by dysregulated reward behaviors are well-established, the underlying mechanisms remain unclear. In mice, ELA reduces hedonic consumption and interest in sex reward in adult males and, in contrast, augments reward consumption in females. Here, using genetic tagging (TRAPing) we found robust, sex-specific activation of thalamic paraventricular nucleus (PVT) neurons during ELA. Manipulating these neurons in adults normalized reward behaviors: Blocking TRAPed anterior PVT neurons restored hedonic consumption in ELA males and augmented hedonic consumption in control females. In contrast, activation of these neurons reduced consumption in control males and ELA females. For posterior PVT, blocking TRAPed cells attenuated excessive reward consumption in ELA females and reduced it in control males. Thus, PVT is key for adaptive brain plasticity; anterior and posterior PVT carry different functions and contribute to the effects of ELA on adult reward behaviors in a sex-dependent manner.

neuroscience↗

bioRxiv2023

Within-subject changes in DNA-methylome profile identify individual signatures of early-life adversity, with a potential to predict neuropsychiatric outcome.

BackgroundAdverse early-life experiences (ELA), including poverty, trauma and neglect, affect a majority of the worlds children. Whereas the impact of ELA on cognitive and emotional health throughout the lifespan is well-established, it is not clear how distinct types of ELA influence child development, and there are no tools to predict for an individual child their vulnerability or resilience to the consequences of ELAs. Epigenetic markers including DNA-methylation profiles of peripheral cells may encode ELA and provide a predictive outcome marker. However, the rapid dynamic changes in DNA methylation in childhood and the inter-individual variance of the human genome pose barriers to identifying profiles predicting outcomes of ELA exposure. Here, we examined the relation of several dimensions of ELA to changes of DNA methylation, using a longitudinal within-subject design and a high threshold for methylation changes in the hope of mitigating the above challenges. MethodsWe analyzed DNA methylation in buccal swab samples collected twice for each of 110 infants: neonatally and at 12 months. We identified CpGs differentially methylated across time, calculated methylation changes for each child, and determined whether several indicators of ELA associated with changes of DNA methylation for individual infants. We then correlated select dimensions of ELA with methylation changes as well as with measures of executive function at age 5 years. We examined for sex differences, and derived a sex-dependent impact score based on sites that most contributed to the methylation changes. FindingsSetting a high threshold for methylation changes, we discovered that changes in methylation between two samples of an individual child reflected age-related trends towards augmented methylation, and also correlated with executive function years later. Among the tested factors and ELA dimensions, including income to needs ratios, maternal sensitivity, body mass index and sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, an interaction was observed between a measure of high early-life unpredictability and methylation changes, in presaging executive function. InterpretationThese findings establish longitudinal, within-subject changes in methylation profiles as a signature of some types of ELA in an individual child. Notably, such changes are detectable beyond the age-associated DNA methylation dynamics. Future studies are required to determine if the methylation profile changes identified here provide a predictive marker of vulnerabilities to poorer cognitive and emotional outcomes. FundingSupported by NIH P50 MH096889, a Precision Medicine Initiative grant from the State of California (OPR20141) and the Bren Foundation. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIdentification of individuals at risk for cognitive and emotional problems is required for targeted interventions. At the population level, experiencing early-life adversity has been consistently linked to an elevated susceptibility to various mental illnesses. However, recent studies have revealed a significant limitation in the ability of early-life adversity to predict individual-level risk, and there is presently no reliable tool available to determine whether a child experiencing adversity will develop future mental health problems. Promising efforts to discover predictive markers by examining DNA methylation in peripheral cells are challenged by extensive genetic and epigenetic population variability and the rapid methylation changes taking place during childhood, rendering the identification of clinically valuable predictive markers a complex endeavor. Added value of this studyThis study examined neurodevelopmental outcomes following several dimensions of ELA, including a recently identified dimension-unpredictability of parental and environmental signals to the child. It demonstrates changes in DNA methylation in children exposed to a spectrum of ELA dimensions and severity using alternative approaches to those used previously: It employs a longitudinal within-subject design, enabling assessment of DNA changes within an individual over time rather than a cross section comparison of different groups, and focuses on the first year of life, an understudied epoch of development. The study uses reduced representation bisulfite sequencing to measure methylation, an approach compromising between targeted sequencing and a whole genome approach, and sets a high threshold for methylation changes, in consideration of the large changes of DNA methylation during childhood. Finally, in accord with emerging discoveries of the differential effects of ELA on males and females, the study uncovers sex-effects arising already before puberty. Implications of all the available evidenceCollectively, our study, together with a robust existing literature (1) identifies early-life unpredictability as an additional determinant of DNA methylation changes, (2) indicates that within-subject changes in methylation profiles of peripheral cells hold promise as precision medicine tools for predicting risk and resilience to the adverse consequences of early-life hardships on mental health, and (3) suggests that sex-differences should be explored even prior to puberty. Our study contributes significantly to the important goal of early identification of predictive "epigenetic scars" caused by adverse early-life experiences. Such markers are required for targeting interventions to those most at need.

neuroscience↗

bioRxiv2022

Genetic tagging uncovers a robust, selective activation of the thalamic paraventricular nucleus by adverse experiences early in life

BackgroundEarly-life adversity (ELA) is associated with increased risk for mood disorders including depression and substance use disorders. These are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we have identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits. MethodsEmploying TRAP2 male and female mice, in which neurons activated within a defined timeframe are permanently tagged, we compared ELA and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native cFos labeling, we defined the molecular identity of this population of activated neurons. ResultsWe uniquely demonstrate that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus (PVT) is robustly and almost exclusively activated by ELA and is the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated PVT neurons express CRFR1, the receptor for the stress-related peptide, corticotropin-releasing hormone (CRH), but these neurons do not express CRH itself. ConclusionsWe show here that the PVT, an important component of reward circuits which is known to encode remote, emotionally salient experiences to influence future motivated behaviors, encodes adverse experiences as remote as those occurring during the early postnatal period and is thus poised to contribute to the enduring deficits in reward-related behaviors consequent to ELA.

neuroscience↗

bioRxiv2022

Stress-induced plasticity of a novel CRH GABA projection disrupts reward behaviors

Disrupted operations of the reward circuit are thought to underlie major emotional disorders including depression and drug abuse1-3. These disorders commonly arise following early life stress4,5; however, how stress early in life enduringly impacts reward circuit functions to promote disease remains unclear. Here, we discover and characterize a novel stress-sensitive reward-circuit projection connecting the basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We then identify a crucial role for this projection in executing the disrupted reward behaviors provoked by early-life adversity (ELA): Chemogenetic and optogenetic stimulations of the CRHGABA BLA[->]NAc projection in typically reared mice suppressed several reward seeking behaviors, recapitulating deficits resulting from ELA and demonstrating a key contribution of this pathway in the normal operations of the reward circuit. Next, inhibition of the CRHGABA BLA[->]NAc projection in adult mice that experienced ELA restored typical reward behaviors in these mice, and, in contrast, had little effect in typically reared mice, indicating a selective ELA-induced maladaptive plasticity of this reward-circuit projection. We discover a novel, stress-sensitive, reward inhibiting projection from the BLA[->]NAc with unique molecular features, which may provide targets for intervention in disabling mental illnesses.

neuroscience↗

bioRxiv2021

Single-Cell transcriptional changes in hypothalamic CRH-expressing neurons after early-life adversity inform enduring alterations in responses to stress

Mental and cognitive health, as well as vulnerability to neuropsychiatric disorders, involve the interplay of genes with the environment, particularly during sensitive developmental periods. Early-life stress / adversity (ELA) promotes vulnerabilities to stress-related affective disorders, yet it is unknown how a transient ELA dictates life-long neuroendocrine and behavioral reactions to stress. The population of hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons that regulate stress-responses is a promising candidate to mediate the enduring influences of ELA on stress-related behavioral and hormonal responses via enduring transcriptional and epigenetic mechanisms. Capitalizing on a well-characterized model of ELA, we examined here the ELA-induced changes in gene expression profiles of stress-sensitive CRH-neurons in the hypothalamic paraventricular nucleus (PVN) of male mice. Given the known heterogeneity of these neuronal populations, we employed single-cell RNA sequencing (RNA-seq) approaches. The use of single-cell transcriptomics identified distinct CRH-expressing neuronal populations characterized by both their gene expression repertoire and their neurotransmitter profiles. Expression changes provoked by ELA clustered around genes involved in neuronal differentiation, synapse formation, altered energy metabolism and the cellular responses to stress and injury. Notably, the ELA-induced transcriptional changes took place primarily in subpopulations of glutamatergic CRH cells. Finally, ELA-induced transcriptional reprogramming of hypothalamic CRH-expressing neurons heralded significant, enduring disruptions of both hormonal and behavioral responses to stress throughout life.

neuroscience↗

bioRxiv2021

Early Life Adversity in Male Mice Sculpts Reward Circuits.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA- NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.

neuroscience↗

bioRxiv2021

Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

neuroscience↗