Abstract
Social hierarchies are present in most mammalian species. In nature, hierarchies offer a tradeoff between reduction of in-group fighting between males, at the expense of an asymmetric sharing of resources. Early life experiences and stress are known to influence the rank an individual attains in adulthood, but the associated cellular and synaptic alterations are poorly understood. Using a maternal separation protocol, we show that care-deprived mice display a long-lasting submissive phenotype, increased social recognition, and enhanced explorative behavior. These alterations are consistent with an adaptation that favors exploration rather than confrontation within a group setting. At the neuronal level, these animals display dendritic atrophy and enhanced inhibitory synaptic inputs in medial prefrontal cortex (mPFC) neurons. To determine what could underlie this synaptic modification, we first assessed global gene expression changes via RNAseq, and next focused on a smaller subset of putatively altered synaptic receptors that could explain the changes in synaptic inhibition. Using different cohorts of maternally deprived mice, we validated a significant increase in the expression of Npy1r, a receptor known to play a role in maternal care, anxiety, foraging, and regulation of group behavior. Using electrophysiological recordings in adult mice while blocking NPY1R signaling, we determined that this receptor plays a key role in enhancing GABAergic currents in mice that experience maternal deprivation. Taken together, our work highlights the potential of regulating NPY1R in social anxiety disorders and the alterations induced in brain circuitry as a consequence of early life stress and adversity.
Highlights
Individuals from gregarious species experience social stressors emanating from isolation, agonistic encounters, overcrowding, or from the relative rank in their social hierarchy [1,2,3,4]
Early life adversity induces social subordination and increased explorative behavior To address the consequences of early life stress (ELS), we subjected C57BL/6 pups to unpredictable maternal separation and maternal stress between postnatal day (PND) 2 and PND 14 (Fig. 1a)
We found no alteration in sociability as measured by the percentage of time control animals (CTR) and ELS mice spent interacting with a stranger animal versus an empty cage (Fig. 2l), since both groups presented equal preference to interact with a stranger animal (Preference for Social1, CTR: 59 ± 2.992%, n = 20; ELS: 57.72 ± 2.31%; p = 0.7367)
Summary
Individuals from gregarious species experience social stressors emanating from isolation, agonistic encounters, overcrowding, or from the relative rank in their social hierarchy [1,2,3,4]. Persistent activation of the hypothalamic-pituitary-adrenal axis produces a remodeling in the mPFC that impacts decision-making [10] This brain area is critical in processing social and moral reasoning in humans [7, 11] and, in rodents, damaging the mPFC lowers social dominance and induces deficits in recognizing social rank [12, 13]. Recent studies have demonstrated that manipulation of synaptic strength in this area alone is sufficient to provide direct and bidirectional control over social rank [6, 14] Together, these data indicate that mPFC circuitry is reciprocally involved in biological aspects pertaining to the control of social dominance and in the integration of stress response
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