Impact of neonatal cell-specific silencing of AR, MAGL or DAGL on adolescent play.

Abstract

Endocannabinoids and the innate immune system are two early signaling systems that influence brain development. During a unique critical period in the neonatal amygdala of the rat, innate immune cells of the brain, microglia, actively engulf and kill newborn cells that would have gone on to become astrocytes. This mechanism determines the future density of astrocytes in the amygdala. The optimal density is lower for males than females, which is responsible for increased neuronal activity during epochs of adolescent social play. Increased phagocytic activity of microglia in the male amygdala is a direct consequence of a higher EDC tone, which is programmed by elevated androgens in neonatal males. Changes to either androgen levels or EDC tone, including by exposure to THC, during the critical period permanently alters the neuronal/astrocytic population and playfulness during adolescence. Marijuana use during pregnancy and breastfeeding is increasing, and the potential consequences to the fetal and newborn brain are still unknown. Advances in transcriptomics and adeno-associated virus (AAV) techniques provide new tools for exploration in rats. The aim of this study is to establish a larger framework for understanding development THC exposure that converges on inhibitory neurons in brain regions regulating sex-typic social behaviors. For this, Sprague Dawley rat pups (PN 0) will selectively reduced androgen receptor and endocannabinoid degradative or synthetic enzyme expression in one cell type, using AAV techniques. Then, animals will be reared to adolescence. Beginning ~PN26, animals will be assigned a "play mate" that they meet in a neutral arena for a 10 min "play date", daily for 5-7 days. Videotapes will quantified the timing and frequency of various components of the play. The results of this study will provide important insight on how this behavior develops, and how it does so differently in males versus females.