Disrupted cortical function underlies behavior dysfunction due to social isolation

Abstract

Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress.

Neonatal isolation augments social dominance by altering actin dynamics in the medial prefrontal cortex

“…2B). This result is consistent with other studies demonstrating the glucocorticoid signaling dependence of stress-induced alterations in glutamate transmission (9,28).…”

“…We found that the mEPSCs of socially isolated animals exhibited reduced amplitudes compared with those of nonisolated control rats ( Fig. 2A), similar to the previous finding in the developing barrel cortex (9). Consistent with these electrophysiological results, we detected reduced levels of GluA1 in the postsynaptic density (PSD) fraction of the mPFC from isolated animals compared with nonisolated animals (Fig.…”

“…We have previously shown that neonatal social isolation activates glucocorticoid signaling such that the duration of social isolation and the serum corticosterone levels are positively correlated (9). To determine whether the activation of glucocorticoid signaling mediates isolation-induced social dominance we treated pups undergoing social isolation with RU486, a glucocorticoid receptor antagonist, and then assessed social dominance at 4 wk of age.…”

“…Prolonged exposure to social isolation early in life can affect the formation of neural circuits in the neocortex and result in social dysfunction (2,9,10). Synaptic plasticity driven by experience plays central roles in establishing neural circuits (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

“…The synaptic recruitment of glutamate AMPA receptors (AMPARs) is a crucial mechanism underlying this process (11,(13)(14)(15)(16)(17)(18)(19)(24)(25)(26)(27). We recently showed that neonatal social isolation disrupts the experience-driven synaptic delivery of AMPARs in the developing rat barrel cortex and results in defective sensory processing and altered behaviors (9,10). Other recent studies also suggest that dysfunction of glutamatergic neurotransmission is considered to be a core feature of stressrelated mental illness (28,29).…”