Biology subjects

Short, A. K.

Publications and source records attributed to Short, A. K..

10 recordsLinked to original sources

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.

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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.

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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.

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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.

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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.

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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.

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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.

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bioRxiv2020

Sex-dependent effects of chronic exercise on cognitive flexibility in aging mice

Cognitive impairments associated with advanced age are a growing concern in our aging society. Such impairments are associated with alterations in brain structure and function, especially in the hippocampus, which changes to experience throughout life. It is well-known that regular exercise can maintain hippocampus volume. The hippocampus is critical for cognitive flexibility involved with extinction and reinstatement of conditioned fear. Therefore, we asked whether voluntary chronic exercise in middle-aged mice can improve extinction and/or reinstatement of conditioned fear compared to standard housing. Eight-month-old male and female C57Bl/6J mice had access to a running wheel or remained in standard housing until 11 months of age. Alongside control standard-housed young adult (3-month-old) mice, they received tone-footshock pairings, which were subsequently extinguished with tone-alone presentations the next day. Half of the mice then received a reminder treatment in the form of a single footshock. Both male and female 11-month-old mice housed in standard conditions exhibited impaired reinstatement compared to young adult mice. However, for males that had access to a running wheel from 8 months of age, the reminder treatment rescued reinstatement ability. This was not observed in females. Additionally, exercise during middle age in both sexes increased expression of Bdnf mRNA in the hippocampus, specifically exon 4 mRNA. These results show that, at least for males, physical exercise is beneficial for reducing age-related decline in cognitive abilities. Despite not rescuing their impaired reinstatement, exercise also increased Bdnf gene expression in the female hippocampus, which could potentially benefit other forms of hippocampal-dependent cognition.

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bioRxiv2019

Short-term block of CRH receptor in adults mitigates age-related memory impairments provoked by early-life adversity

In humans, early-life adversity (ELA) is associated with impairments in learning and memory that may emerge later in life. In rodent models, ELA directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of ELA on hippocampal structure and memory-function. Early-life adversity increases CRH production and levels, and blocking CRH receptor type 1 (CRHR1) within the hippocampus immediately following adversity prevented the memory and LTP problems caused by ELA. Here we queried if blocking CRHR1 during adulthood ameliorates the adverse impact of ELA on memory in middle age. Blocking CRHR1 for a week in two month old male rats prevented ELA-induced deficits in object recognition memory that emerge during middle age. The intervention failed to mitigate the reduction of spatial memory at 4 and 8 months, but restored hippocampus-dependent location memory in ELA-experiencing rats during middle age (12 months of age).\n\nNotably, neither ELA nor blocking CRHR1 influenced anxiety- or depression-related behaviors These findings suggest a sensitive period during which interventions can fully prevent long-lasting effects of ELA, yet indicate that interventions later in life offer significant benefits.

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bioRxiv2018

NRSF-mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction

Repression of target genes by the transcriptional repressor neuronal restrictive silencing factor (NRSF)/repressor element 1 silencing transcription factor (REST) contributes to enduring plasticity in the developing brain. However, the cofactor(s) interacting with NRSF to enable target gene repressor are not well understood, and may vary among neuronal populations and brain regions as well as with different contexts. Here we employed the novel designer drug mS-11 to block the interactions of the cofactor Sin3 with NRSF. We tested if NRSF-Sin3 interaction is required for repression of NRSF target genes in developing hypothalamus after activity-dependent modulation of NRSF function. In the hypothalamus in vitro, blocking glutamatergic neurotransmission robustly increased NRSF binding to the target gene Crh, resulting in its repression. Blocking the binding of NRSF to the chromatin with decoy NRSE-oligodeoxynucleotides abrogated this repression. In contrast, mS-11 at several concentrations did not impede Crh repression. NRSF-mediated repression may underlie disease processes such as the onset of epilepsy. Therefore, identifying small-molecule antagonists of NRSF is crucial for the development of disease-preventing or modifying interventions.

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