Adolescence is a critical period of brain development in humans as well as in other mammalian species. The match-mismatch hypothesis of brain development postulates that early life adversity can promote an adaptive phenotype later in life, allowing individuals to cope with certain adverse situations in adulthood. Preliminary results from our lab show that chronic stress during adolescence makes animals resilient to the deleterious impact of traumatic stress (single prolonged stress) (SPS) in adulthood. SPS is a stress paradigm used to model post-traumatic stress disorder (PTSD) symptoms in rodents, as it impairs extinction of conditioned fear. In humans, PTSD is linked to reduced activation of area 25, homologous to the infralimbic (IL) prefrontal cortex in the rodent (PFC). Rodent studies indicate that extinction of fear memory requires plasticity in the IL and its downstream connections to the basolateral amygdala (BLA). It has been shown that parvalbumin interneurons (PV INs) in the IL play a role in mediating fear responses. Activation of PV INs in the IL mPFC inhibits pyramidal cell output in the IL-BLA circuit, enhancing fear reinstatement. PV INs undergo remarkable maturation during adolescence and are affected by stress during this time period, making them potential targets for modulating IL-BLA circuit function following adolescent stress. The objective of this proposal is to test the hypothesis that adolescent stress promotes stress resilience by modifying PV IN activity in the IL-BLA circuit.
Specific Aim 1 which will use an optogenetic and electrophysiological approach to elucidate the effects of adolescent stress on synaptic inhibition within the IL-PFC.
Specific Aim 2 which will use a chemogenetic approach to identify the IL-PFC interneurons that promote stress resilience following adolescent stress. We expect that adolescent stress will block the SPS-induced enhancement of PV IN mediated GABAergic signaling in the IL-BLA circuit, and demonstrate that PV INs are necessary and sufficient for promoting stress resilience. Overall, the findings of these studies will contribute to the understanding of the mechanisms through which stress during development can control reactivity to stressors in adulthood, and are anticipated to define a central role for IL PV INs in stress resilience.
This innovative proposal will study the complex relationship between developmental stress, single prolonged stress (a model for PTSD symptoms) and stress resiliency by exploring synaptic plasticity and behavior at the cellular and whole organism levels. The results of these multi-faceted experiments will significantly enhance our understanding of the mechanisms underlying developmental stress-induced changes in the brain and provide insights into mechanisms underlying stress resiliency. The results will provide novel information that can be used to develop better therapies for stress-related pathologies such as PTSD and depression.
