Early life trauma increases threat response of peri‐weaning rats, reduction of axo‐somatic synapses formed by parvalbumin cells and perineuronal net in the basolateral nucleus of amygdala

Abstract

Early life trauma is a risk factor for life-long disorders related to emotional processing, but knowledge underlying its enduring effect is incomplete. This study was motivated by the hypothesis that early life trauma increases amygdala-dependent threat responses via reduction in inhibition by parvalbumin (PV) interneurons and perineuronal nets (PNN) supporting PV cells, thus increasing excitability of the basolateral amygdala (BLA). From postnatal day (PN) 8-12, rat pups of both sexes were reared under normal bedding or under insufficient nest-building materials to induce maternal-to-infant maltreatment trauma (Scarcity-Adversity Model, SAM). At weaning age of PN23, the SAM group exhibited increased threat responses to predator odor. The SAM-induced increase in threat response was recapitulated in normally reared PN22-23 rats that were unilaterally depleted of PNN in the BLA by the enzymes, chondroitinase-ABC plus hyaluronidase at PN19-20. Light and electron microscopic analysis of the BLA revealed that anterior-to-mid levels of SAM group's BLAs exhibited decreased PNN intensity and decreased axo-somatic synapses between PV-to-principal pyramidal-like neurons and PV-to-PV. PV and PNN densities (cells/mm ) in the BLA of both control (CON) and SAM groups were still low at PN12 and SAM delayed the ontogenetic rise of PV intensity and PNN density. Moreover, PV cell density in the anterior-to-mid BLA correlated negatively with threat response of CON animals, but not for SAM animals. Thus, reduction of PNN-supported, PV-mediated somatic inhibition of pyramidal cells provides a mechanistic support for the enduring effect of early life maltreatment manifested as increasing innate threat response at weaning.

Early life adversity decreases pre-adolescent fear expression by accelerating amygdala PV cell development

“…PV-positive neuronal activity in the BLA has been shown to be capable of modulating fear expression ( Davis et al, 2017 ; Wolff et al, 2014 ). In addition, PV-positive cell density has previously been shown to be negatively correlated with innate threat responses in post-weanling rats ( Santiago et al, 2018 ). Consistent with the previously described role of PV-positive cells in BLA, we found that mice reared under LB conditions had a decreased fear response, as indexed by lower freezing to a tone previously paired with a shock at PND 21.…”

Perineuronal Nets, Inhibitory Interneurons, and Anxiety-Related Ventral Hippocampal Neuronal Oscillations Are Altered by Early Life Adversity

“…Experience has been shown to alter PNN expression but the effects are complex, depending on the type of experience, the developmental stage examined and the brain region. For example, early life trauma has been shown to reduce PNN expression in the basolateral amygdala (31), enriched environment rearing reduces PNNs in the cerebellum (32) but increases them in the CA2 region of the hippocampus (33), while enriched environment exposure in adulthood increases or decreases PNN expression depending on the brain region and presence of other experiences (34). PNNs have been linked to the transcription factor orthodenticle homeobox protein 2 (OTX2) (35), the expression of which coincides with the maturation of PV+ cells and the closure of the critical period of plasticity in mice.…”

Decreased Density of Perineuronal Net in Prelimbic Cortex Is Linked to Depressive-Like Behavior in Young-Aged Rats

“…Chronic stress during early life or adulthood alters the density of PNNs in the medial prefrontal cortex, and affects the structure and plasticity of inhibitory neurons, especially PV-expressing interneurons (Castillo-Gómez et al, 2017;de Araújo Costa Folha et al, 2017;Pesarico et al, 2019). Early life maltreatment or maternal immune activation caused developmental abnormalities in PNNs in the prefrontal cortex and basolateral amygdala (Paylor et al, 2016;Page and Coutellier, 2018;Santiago et al, 2018), which may be associated with the increased vulnerability to neuropsychiatric disorders such as anxiety. Chronic antidepressant treatments such as fluoxetine and venlafaxine have also been shown to alter PV-and PNN-positive cell density in cortical and hippocampal regions in adults (Ohira et al, 2013;Alaiyed et al, 2019) and these effects may be relevant to their antidepressant efficacy.…”