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Early life adversity in male mice sculpts reward circuits

ABSTRACT: 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, associated with deficient reward seeking behaviors 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 a social anhedonia-like phenotype in adulthood with decreased direct social approach and time spent with peers in the three-chamber task, and no overt differences in sucrose preference. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may reflect enduring reward deficits.

SUBMITTER: Wendel K

PROVIDER: S-EPMC8554344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mental and cognitive health, as well as vulnerability to neuropsychiatric disorders, involve the interplay of genes with the environment during sensitive developmental periods. Genetic and environmental factors contribute to the development and maturation of neurons, synapses, and the resulting brain circuits. Within the hypothalamus, early-life experiences cause changes in the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN). Further, such synaptic changes suffice to induce enduring epigenomic changes within these cells, influencing programs of gene expression. However, the epigenetic mechanisms by which early-life experiences orchestrate transcriptional programs within individual CRH-expressing neurons, with enduring functional consequences, remain unknown. We utilize animal models of an impoverished environment and unpredictable maternal care (in a limited bedding and nesting [LBN] paradigm), which provokes major alterations in cognitive and emotional outcomes. We are focused on the change in gene expression profiles of stress-sensitive CRH-neurons in the PVN following early-life adversity (ELA). Because of the known heterogeneity of CRH-expressing neuronal populations, we are using single-cell RNA sequencing (RNA-seq) to determine differential gene expression associated with early-life adversity and establish the upstream mechanisms and downstream consequences. We found that CRH-expressing populations of neurons in the PVN can be clustered by both their gene expression profiles as well as by their neurotransmitter phenotype. ELA significantly modified gene expression programs in some neuronal clusters more than others, reducing programs of neuronal development and differentiation and enhancing gene families involved in responses to stress and inflammation. The use of single-cell transcriptomics revealed that ELA impacts gene expression profiles in a cell-type specific manner, with distinctive influence on the different clusters and subpopulations of CRH neurons.

Project description:BackgroundAnhedonia, the diminished ability to experience pleasure, is an important dimensional entity linked to depression, schizophrenia, and other emotional disorders, but its origins and mechanisms are poorly understood. We have previously identified anhedonia, manifest as decreased sucrose preference and social play, in adolescent male rats that experienced chronic early-life adversity/stress (CES). Here we probed the molecular, cellular, and circuit processes underlying CES-induced anhedonia and tested them mechanistically.MethodsWe examined functional brain circuits and neuronal populations activated by social play in adolescent CES and control rats. Structural connectivity between stress- and reward-related networks was probed using high-resolution diffusion tensor imaging, and cellular/regional activation was probed using c-Fos. We employed viral-genetic approaches to reduce corticotropin-releasing hormone (Crh) expression in the central nucleus of the amygdala in anhedonic rats, and tested for anhedonia reversal in the same animals.ResultsSucrose preference was reduced in adolescent CES rats. Social play, generally considered an independent measure of pleasure, activated brain regions involved in reward circuitry in both control and CES groups. In CES rats, social play activated Crh-expressing neurons in the central nucleus of the amygdala, typically involved in anxiety/fear, indicating aberrant functional connectivity of pleasure/reward and fear circuits. Diffusion tensor imaging tractography revealed increased structural connectivity of the amygdala to the medial prefrontal cortex in CES rats. Crh-short hairpin RNA, but not control short hairpin RNA, given into the central nucleus of the amygdala reversed CES-induced anhedonia without influencing other emotional measures.ConclusionsThese findings robustly demonstrate aberrant interactions of stress and reward networks after early-life adversity and suggest mechanistic roles for Crh-expressing amygdala neurons in emotional deficits portending major neuropsychiatric disorders.

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Early life adversity in male mice sculpts reward circuits

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