Abstract
Early-life experiences influence brain structure and function long-term, contributing to resilience or vulnerability to stress and stress-related disorders. Therefore, understanding the mechanisms by which early-life experiences program specific brain cells and circuits to shape life-long cognitive and emotional functions is crucial. We identify the population of corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN) as a key, early target of early-life experiences. Adverse experiences increase excitatory neurotransmission onto PVN CRH cells, whereas optimal experiences, such as augmented and predictable maternal care, reduce the number and function of glutamatergic inputs onto this cell population. Altered synaptic neurotransmission is sufficient to initiate large-scale, enduring epigenetic re-programming within CRH-expressing neurons, associated with stress resilience and additional cognitive and emotional outcomes. Thus, the mechanisms by which early-life experiences influence the brain provide tractable targets for intervention.
Highlights
The origins of mental health outcomes are early in life (Kessler et al, 2005; Insel, 2009)
Mechanistic studies have revealed that reduction of excitatory neurotransmission onto paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons is sufficient to diminish their expression of CRH, among other important neuronal genes related to synaptic function (Singh-Taylor et al, 2018)
Largescale changes in repressive histone modifications of neuronal genes like CRH were initiated by increases in function of the transcriptional repressor, neuron-restrictive silencer factor (NRSF) (Singh-Taylor et al, 2018), the same transcription factor that is implicated in programming LBN-induced cognitive vulnerabilities (Schulmann et al, 2018)
Summary
The origins of mental health outcomes are early in life (Kessler et al, 2005; Insel, 2009). Mechanistic studies have revealed that reduction of excitatory neurotransmission onto PVN CRH neurons is sufficient to diminish their expression of CRH, among other important neuronal genes related to synaptic function (Singh-Taylor et al, 2018) These alterations in gene expression following optimal early-life experiences can be maintained long-term by epigenetic mechanisms. Largescale changes in repressive histone modifications of neuronal genes like CRH were initiated by increases in function of the transcriptional repressor, NRSF (Singh-Taylor et al, 2018), the same transcription factor that is implicated in programming LBN-induced cognitive vulnerabilities (Schulmann et al, 2018) These results provide a causal link between neonatal experience, synaptic refinement and induction of epigenetic processes within specific neuronal populations. Patterns of maternal sensory signals may exert bidirectional influence over the maturation of the reward/pleasure system—a hypothesis that warrants further exploration
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