Transcriptomic signature of early life stress in male rat prefrontal cortex

Abstract

Early life stress (ELS) is associated with adverse mental health outcomes including anxiety, depression and addiction-like behaviours. While ELS is known to affect the developing brain, leading to increased stress responsiveness and increased glucocorticoid levels, the molecular mechanisms underlying the detrimental effects of ELS remain incompletely characterised. Rodent models have been instrumental in beginning to uncover the molecular and cellular underpinnings of ELS. Limited nesting (LN), an ELS behavioural paradigm with significant improvements over maternal separation, mimics human maternal neglect. We have previously shown that LN leads to an increase in one of the behavioural measures of anxiety like-behaviours in rats (percent of entries in the EPM open arm). Here we assessed gene expression changes induced by ELS in rat prefrontal cortex by RNA-sequencing. We show that LN leads primarily to transcriptional repression and identify a molecular signature of LN in rat PFC that is observed across ELS protocols and replicable across rodent species (mouse and rat).

Effects of Psychosocial Intervention on the Level of Stress: A Pre-ExperimentalResearchonSchoolChildrenWho Experienced Displacement in Marawi City, Philippines

“…After 13 months in inadequate evacuation camps, adjusting to a new environment may have been stressful. Consistent with other research, it has been discovered that prolonged stress has the most detrimental impacts on children, such as altering brain chemistry and function and decreasing illness resistance (Battaglia et al, 2023;Green et al, 2021;Kim et al, 2021).…”

Impact of Early Life Stress on Reward Circuit Function and Regulation

“…RNA-seq provides an opportunity not only to look for gene expression changes in an unbiased manner, but also to examine broad patterns of change that would be impossible to observe when sampling only a few candidate genes. ELS consistently induces changes in reward circuitry gene expression that last into adulthood in male and female mice ( 94 , 95 , 100 , 124 , 153 ). Interestingly, two studies comparing male and female transcriptomic responses to ELS (using different types of stress and at different juvenile states) have found around twice as many genes altered in female than male NAc ( 95 , 124 ).…”

“…The pattern of increased transcriptional changes in response to adult stress given prior ELS from P10-17 was also observed in female (but not male) VTA and PFC which both send inputs to NAc ( 95 ). In male PFC, ELS alone predominately down-regulated gene expression, which may blunt response to future stimuli ( 153 ). Similarly in hippocampus, early postnatal stress (from P2-12) and adolescent stress (from P38-49) blunted transcriptomic response to acute adult stress in mice and rats ( 157 , 158 ).…”

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

“…However, ELS appears to alter these normal fear and anxiety-related processes, disrupting conditioned fear as well as decreasing exploration of open arms in an elevated plus maze (Nisar et al, 2019;Oldham Green et al, 2021;Toda et al, 2014). While recent work has provided tremendous ex vivo insight into the genetic, epigenetic, and molecular bases for these differences particularly in the PFC (Oldham Green et al, 2021;Torres-Berrío et al, 2019), surprisingly little is known about how mature in vivo neurons in ELS-experienced animals encode information about threat and safety during behavior. Using limited experience with wet bedding as variant of a limited bedding model of ELS (Léonhardt et al, 2007;Molet et al, 2014;Walker et al, 2017), we assessed behavioral and in vivo neural activity in vmPFC in adulthood of these ELS subjects (along with unstressed Controls) in a conditioned suppression task.…”

“…Conversely, pharmacological or optical silencing of this IL pathway in fear extinction learning results in increased freezing behavior and reduced extinction rates (Adhikari et al, 2015;Gutman et al, 2017;Laurent and Westbrook, 2009). However, ELS appears to alter these normal fear and anxiety-related processes, disrupting conditioned fear as well as decreasing exploration of open arms in an elevated plus maze (Nisar et al, 2019;Oldham Green et al, 2021;Toda et al, 2014). While recent work has provided tremendous ex vivo insight into the genetic, epigenetic, and molecular bases for these differences particularly in the PFC (Oldham Green et al, 2021;Torres-Berrío et al, 2019), surprisingly little is known about how mature in vivo neurons in ELS-experienced animals encode information about threat and safety during behavior.…”