It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress

Abstract

Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons in vitro in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms.SIGNIFICANCE STATEMENT Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders.

Keywords: LTP; amygdala; early life stress; juvenile; perineuronal net; sex.