On circuit mechanisms of reward behaviors after early-life adversity

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SUMMARY Early-life adversity (ELA) is associated with vulnerability to mental illnesses that involve disruption of the brain’s reward circuits. These vulnerabilities may manifest as anhedonia, a reduction in reward desire or pleasure that is core feature of major depression. However, whether the association of ELA with anhedonia is causal is difficult to establish in humans, and mechanisms underlying this relationship are not understood. Our well-characterized rodent ELA model reliably leads to reward-circuit disruptions in a sex-dependent manner, yet the circuit nodes and pathways that are most affected remain unclear. In searching for ELA-sensitive reward-circuit components, we discovered and are characterizing a novel projection from basolateral amygdala (BLA) to nucleus accumbens (NAc) that expresses the neuropeptide corticotropin releasing hormone (CRH). Neurons expressing CRH are often stress-sensitive, and our preliminary data suggest this is also the case for the novel CRH+BLA-NAc pathway. Building on these robust data, we will determine the functional roles of the projection in mice and test the hypothesis that ELA- induced plasticity in this pathway contributes to sex-dependent effects of ELA on reward pursuit and consumption, significantly advancing our understanding of the origins of mental illness. Aim 1 will test the hypothesis that the novel CRH+BLA-NAc pathway modulates reward pursuit (motivation) and / or consumption in typically reared male and female mice, capitalizing on the temporal resolution of optogenetics and on formal motivation tasks to probe the specific role of the projection in the motivational vs. consummatory aspects of reward. Aim 2 will use the same technologies to determine the role of the CRH+ BLA-NAc projection in aberrant, sex-specific reward behaviors resulting from ELA. Aim 3 will examine the molecular and cellular mechanisms by which aberrant CRH+ BLA-NAc inputs regulate reward behaviors: we will identify the target cells of the projection following ex vivo optogenetic activation of BLA- origin projection fibers in the NAc, and determine the relative roles of GABA neurotransmission vs CRH receptor activation in the effects of projection stimulation on reward behaviors in male and female mice.