Early-Life Experience Reduces Excitation to Stress-Responsive Hypothalamic Neurons and Reprograms the Expression of Corticotropin-Releasing Hormone

Abstract

Increased sensory input from maternal care attenuates neuroendocrine and behavioral responses to stress long term and results in a lifelong phenotype of resilience to depression and improved cognitive function. Whereas the mechanisms of this clinically important effect remain unclear, the early, persistent suppression of the expression of the stress neurohormone corticotropin-releasing hormone (CRH) in hypothalamic neurons has been implicated as a key aspect of this experience-induced neuroplasticity. Here, we tested whether the innervation of hypothalamic CRH neurons of rat pups that received augmented maternal care was altered in a manner that might promote the suppression of CRH expression and studied the cellular mechanisms underlying this suppression. We found that the number of excitatory synapses and the frequency of miniature excitatory synaptic currents onto CRH neurons were reduced in "care-augmented" rats compared with controls, as were the levels of the glutamate vesicular transporter vGlut2. In contrast, analogous parameters of inhibitory synapses were unchanged. Levels of the transcriptional repressor neuron-restrictive silencer factor (NRSF), which negatively regulates Crh gene transcription, were markedly elevated in care-augmented rats, and chromatin immunoprecipitation demonstrated that this repressor was bound to a cognate element (neuron-restrictive silencing element) on the Crh gene. Whereas the reduced excitatory innervation of CRH-expressing neurons dissipated by adulthood, increased NRSF levels and repression of CRH expression persisted, suggesting that augmented early-life experience reprograms Crh gene expression via mechanisms involving transcriptional repression by NRSF.

Paternal social enrichment effects on maternal behavior and offspring growth

“…These phenotypic effects may be achieved through maternal epigenetic programming of offspring gene expression, inducing individual differences that persist into adulthood (29,30,34). Thus, the paternally induced alterations in maternal behavior we observe could affect multiple developmental outcomes.…”

“…Enriching the postnatal and/or postweaning environment can increase levels of BDNF (25-27), whereas maternal neglect and postweaning social isolation lead to reduced levels of BDNF in the brain (28,29). CRH expression is similarly sensitive to experiential factors (30). Although stressinduced levels of CRH potentiate anxiety-like responses, in the absence of stressors, basal levels of CRH in the hippocampus (and other extrahypothalamic regions) have been associated with hypervigilance and arousal (31).…”

Influence of housing variables on the development of stress-sensitive behaviors in the rat

“…A robust literature highlights the importance of early life environmental variables that inuence stress responsivity in adult offspring, primarily using the laboratory rat as a model [1,28,[36][37][38][39]. One environmental variable demonstrated to inuence offspring development is the material on which rodents are housed [40].…”

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

“…The nature of these networks is not fully known, but they include amygdala-ventromedial prefrontal cortex circuitry implicated in the regulation of emotion (Burghy et al, 2012). Thus, abnormal maternal care and chronic early-life stress have been shown to result in increased number and function of excitatory synapses to stress-sensitive neurons in hypothalamus (Gunn et al, 2013), whereas reduced excitatory synapse number and function have been reported after augmented maternal care (Korosi et al, 2010). Increased excitatory input may sensitize the central components of the neuroendocrine stress system to subsequent stress, predisposing to stress-related emotional disorders.…”

“…Other structural changes including stunting, atrophy, or hypertrophy of dendritic structure and altered synapse number and function might take place in amygdala and hippocampus (Ivy et al, 2010). The resulting changes in intracellular signaling, potentially via calcium-dependent changes, might provide a signal for downstream gene expression effects, maintained via epigenetic alterations of the chromatin (Korosi et al, 2010;Hornung and Heim, 2014;Lewis and Olive, 2014;Turecki, 2014;Szyf, 2015).…”