The role of anterior cingulate leptin signaling in modulating effortful reward seeking - PROJECT SUMMARY Depression and metabolic syndrome are frequently comorbid and bidirectionally linked, yet our understanding of how metabolic dysfunction impacts features of depression is limited. Anhedonia is a core symptom of depression which encompasses deficits in reward processing including effort valuation, or the weighing of a reward’s value against the effort necessary to obtain it. Due to the intrinsic relationship between effort and energy expenditure, effort valuation represents a behavior that is both relevant to anhedonia and likely to be subject to metabolic regulation. While studies exploring this possibility are lacking, several lines of evidence indicate that the adipokine leptin, whose regulation is altered in metabolic syndrome, may serve as a metabolic input to neural circuits supporting effortful valuation. For example, previous studies have demonstrated that leptin levels correspond to adiposity and, on the basis of stored energy levels, regulate other processes tied to energy intake and expenditure, such as appetite, fertility, and thermoregulation. Further, treatment of mice with chronic corticosterone (CORT) induces effort valuation deficits while concomitantly increasing leptin levels and inducing a leptin resistant phenotype that mirrors metabolic syndrome. Notably, CORT’s effects on effortful valuation are associated with reduced activity in the anterior cingulate cortex (ACC), a brain region required for effort valuation that contains a sparse population of excitatory neurons that express the leptin receptor (Lepr). Lastly, this putative function of leptin is supported by our preliminary data which shows a CORT-induced downregulation of Lepr expression in layer 2/3 excitatory neurons in the ACC, an effect that is reversed after treatment with ketamine, a rapid-acting antidepressant. This result indicates a link between the CORT-induced hyperleptinemia and local changes in ACC leptin signaling. Based on these data, we hypothesize that ACC leptin signaling, through changing the activity of Lepr+ neurons, supports effortful reward seeking and mediates the effects of CORT- induced metabolic dysfunction on effort valuation. In this proposal, we will first fully characterize the extent and time course of CORT’s metabolic effects using metabolic chambers. This will then allow appropriately timed viral manipulations of Lepr levels in the ACC neurons of transgenic mice, which will be used to determine whether altered ACC leptin signaling is necessary and sufficient for the effects of CORT on effortful reward seeking behavior. Next, we will use transgenic mice and viral expression of a fluorescent calcium indicator to determine the effect of leptin signaling on the spontaneous activity of Lepr+ neurons in both control and CORT mice. Finally, we will evaluate the role of Lepr+ neurons in supporting effortful reward seeking by recording and manipulating their activity with fiber photometry and optogenetics, respectively, in behaving mice engaged in an effort valuation task. Completion of the research proposed here will determine the role of ACC leptin signaling on effort valuation, thereby improving our understanding of mechanisms mediating the relationship between metabolic dysfunction and hedonic behavior.
