scholarly journals Single-Cell Transcriptional Changes in Hypothalamic Corticotropin-Releasing Factor Expressing Neurons After Early-Life Adversity Inform Enduring Alterations in Vulnerabilities to Stress

Author(s):  
Annabel K. Short ◽  
Christina W. Thai ◽  
Yuncai Chen ◽  
Noriko Kamei ◽  
Aidan L. Pham ◽  
...  
2021 ◽  
Author(s):  
Annabel K Short ◽  
Christina Wilcox ◽  
Yuncai Chen ◽  
Aidan L Pham ◽  
Matthew T Birnie ◽  
...  

AbstractMental 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.


2021 ◽  
Vol 118 (8) ◽  
pp. e2020173118
Author(s):  
Evelyn Ordoñes Sanchez ◽  
Charlotte C. Bavley ◽  
Andre U. Deutschmann ◽  
Rachel Carpenter ◽  
Drew R. Peterson ◽  
...  

Experiencing some early life adversity can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.


2019 ◽  
Author(s):  
Mary Elizabeth Zinn ◽  
Edward Huntley ◽  
Daniel Keating

Introduction. Early life adversity (ELA) can result in negative health-outcomes, including psychopathology. Evidence suggests that adolescence is a critical developmental period for processing ELA. Identity formation, which is crucial to this developmental period, may moderate the effect between ELA and psychopathology. One potential moderating variable associated with identity formation is Prospective Self, a latent construct comprised of future-oriented attitudes and behaviors.Methods. Participants are from the first wave of an ongoing longitudinal study designed to characterize behavioral and cognitive correlates of risk behavior trajectories. A community sample of 10th and 12th grade adolescents (N = 2017, 55% female) were recruited from nine public school districts across eight Southeastern Michigan counties in the United States. Data were collected in schools during school hours or after school via self-report, computer-administered surveys. Structural equation modeling was used in the present study to assess Prospective Self as a latent construct and to evaluate the relationship between ELA, psychopathology, and Prospective Self.Results. Preliminary findings indicated a satisfactory fit for the construct Prospective Self. The predicted negative associations between Prospective Self and psychopathology were found and evidence of moderation was observed for externalizing behavior problems, such that the effects of ELA were lower for individuals with higher levels of Prospective Self. Conclusion. These results support the role of Prospective Self in conferring resilience against externalizing behavior problems associated with ELA among adolescents. Keywords: Adolescence, Adverse Childhood Experiences, Psychopathology, Self-concept, Adolescent Health, Early Life Adversity


Author(s):  
Meg Dennison ◽  
Katie McLaughlin

Early-life adversity is associated with elevated risk for a wide range of mental disorders across the lifespan, including those that involve disruptions in positive emotionality. Although extensive research has evaluated heightened negative emotionality and threat processing as developmental mechanisms linking early-life adversity with mental health problems, emerging evidence suggests that positive emotions play an integral, but complex, role in the association of early-life adversity with psychopathology. This chapter identifies two pathways through which positive emotion influences risk for psychopathology following early-life adversity. First, experiences of early-life adversity may alter the development of the “positive valence system”, which in turn increases risk for psychopathology. Second, the association between adversity and psychopathology may vary as a function of individual differences in positive emotionality. We consider how the development of positive emotionality—measured at psychological, behavioral and neurobiological levels—may be altered by early-life adversity, creating a diathesis for psychopathology. We additionally review evidence for the role of positive emotion, measured at multiple levels, as a protective factor that buffers against the adverse impacts of adversity. In integrating these two roles, it is proposed that characteristics of environmental adversity, including developmental timing, duration, and type of adversity, may differentially impact the development of positive emotionality, leading to a better understanding of risks associated with specific adverse experiences. Methodological issues regarding the measurement of adverse environments as well as implications for early intervention and treatment are discussed.


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