Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood

Abstract

Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.

N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury

“…At the same time, we observed an increase in CD86+ immunostaining in the CA3 hippocampal region, while synaptamide administration did not reduce the activity of pro-inflammatory microglia in this area five weeks post-surgery. Given that the CA3 region is the most susceptible to changes under various stressful conditions [ 50 , 51 ], activation of microglia may in this case be not only a consequence of pain pathology, but also a consequence of chronic stress associated with hypothalamo-pituitary-adrenal (HPA) axis activation and the development of a maladaptive response [ 52 ]. In this case, the administration of synaptamide reduces the intensity of these changes, preventing them from leading to fatal neuronal dendritic tree structural abnormalities and the impairment of cognitive processes.…”

The mechanism of enriched environment repairing the learning and memory impairment in offspring of prenatal stress by regulating the expression of activity-regulated cytoskeletal-associated and insulin-like growth factor-2 in hippocampus

“…Furthermore, prenatal stress can alter in early postnatal development of the hippocampal functions and structures that may implicate the mechanisms of cognitive deficits in children. Many studies show that chronic early-life stressors are associated with the structure and function impairments in hippocampus of adulthood [41]. Hippocampal synaptic plasticity, particularly the long-term potentiation (LTP) and long-term depression (LTD), is believed to be the underlying mechanism of learning and memory functions.…”

Translatomic profiling of the acute stress response: It’s a TRAP

“…More recently, several studies have begun to address cell-type specificity of the stress response. Three pioneering studies have employed translating ribosome affinity purification (TRAP) technology [6] to characterize which genes are actively translated in CA3 pyramidal neurons of the hippocampus in response to stress [7][8][9]. These studies suggest that acute stress alters the translation of thousands of genes in CA3 pyramidal neurons, and that this response is strongly modulated by factors such as sex, genotype and a history of early life stress.…”

“…However, our re-analysis indicates that, most likely due to the low number of replicates (6 independent samples for 4 groups) and high technical variability ( Figure 1C), this does not replicate in samples from the second dataset ( Figure 1B). A follow-up study [8] reports that early life stress (ELS) changes the translational response of a large number of genes to an acute stress challenge later in life. To demonstrate this, the sets of genes that were (significantly) changed in response to acute stress in the ELS group were subtracted from those changed in the non-ELS control group.…”