Circuit Mechanisms Underlying Early Life Adversity-Induced Reward Deficits

About This Grant

Two-third of individuals worldwide experience chronic adversity during childhood such as abuse, neglect or similar highly-stressful events. Such early-life adversity (ELA) is one of the best-characterized risk factors for developing psychiatric disorders associated with reward deficits including depression, substance use disorders and schizophrenia later in life. ELA related reward deficits are even observed in healthy individuals suggesting a link between pre-existing reward deficits and ELA-induced vulnerability to psychopathology. Mice exposed to ELA also show reward deficits later in life, however how ELA produces sustained changes at the neural circuit level to induce persistent reward-deficits is unknown. Reward processing is complex involves several aspects, governed by overlapping but still distinct reward circuits. A major challenge in studying circuit mechanisms underlying ELA-induced reward deficits have been a lack of dissection of the affected reward constructs. Our preliminary data suggest that ELA produces enduring deficits in hedonia in mice. Ventral pallidum (VP) and nucleus accumbens (Nac) have been implicated in reward processes, the historical view is that VP receives the reward-related information from Nac and modulates behavior through interactions with downstream targets. However recent findings challenge this view and show that VP encodes reward value and learned cue value more accurately and faster than Nac. Moreover, our preliminary findings show that the optogenetic stimulation of VP-Nac projection rescues reward deficits in ELA mice while the inhibition of this projection mimics the effects of ELA on hedonia. This proposal will test whether VP-Nac afferent activity is prominent in governing hedonia and whether disruptions of this circuit mediate the ELA-induced persistent reward-deficits. By employing fiber- photometry, Aim 1 will examine if ELA produces deficits in reward-related activity of VP cell populations, while Aim 2 will determine whether particularly the reduction of VP-Nac core activity is associated with ELA-induced hedonic deficits. Finally, Aim 3 will use pathway-specific optogenetic manipulations to test the role of VP-Nac afferents in ELA-related hedonic deficits such that if the inhibition of VP neurons projecting to different subregions of Nac suffices to induce hedonic deficits or the stimulation of the same circuit activity rescues the ELA effects on reward. We will also test the role of this pathway in hedonic encoding during cue-reward associations or instrumental learning in ELA. By combining these approaches, we will establish a pathway specific understanding of how ELA impairs reward processes with the goal of developing novel treatments for reward deficits.