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.

Does maternal separation accelerate maturation of perineuronal nets and parvalbumin-containing inhibitory interneurons in male and female rats?

“…In another recent study, again, not explicitly designed to assess the stress acceleration hypothesis, Guadagno et al (2020) reported a number of effects of early life adversity. Of most direct relevance to the current study, Guadagno and colleagues reported that early life adversity increased the density of PV-labelled interneurons with a PNN, an effect that we did not observe.…”

An Extracellular Perspective on CNS Maturation: Perineuronal Nets and the Control of Plasticity

“…Interestingly, early-life adverse experiences have been associated with aberrant PNN density and intensity in the adult prefrontal cortex [ 104 ], basolateral amygdala [ 105 ], and hippocampus [ 106 , 107 ], suggesting that early life stress affects PNN organization throughout the brain. It is also noteworthy that infant rats reared in stressful conditions exhibit longer retention of fear memories than standard-reared rats (for a review, see [ 7 ]), where this is accompanied by earlier maturation of GABAergic neurons and PNNs in the amygdala in male individuals [ 108 ].…”

Impact of Perineuronal Nets on Electrophysiology of Parvalbumin Interneurons, Principal Neurons, and Brain Oscillations: A Review

“…However, it is important to also recognize the rapidly-growing body of work supporting changes in PNNs themselves (or their key components) in response to physiological stimuli, such as stress, exercise, environmental enrichment, diet, circadian rhythms, and normal aging processes. Short term and chronic stress lead to brain region-dependent changes in PV cells and PNNs both in early life (Castillo-Gómez et al, 2017 ; Ueno et al, 2018 ; Murthy et al, 2019 ; Guadagno et al, 2020 ; Soares et al, 2020 ; Yu et al, 2020 ) and in adults (Pesarico et al, 2019 ; Yu et al, 2020 ). Exercise also alters PNNs, and the effects are dependent on the brain region examined (Smith et al, 2015 ; Briones et al, 2021 ).…”