Project Summary/AbstractMajor depressive disorder (MDD) is a leading cause of disability with ~20% of individuals suffering fromclinical depression during their lifetime. Depression is a heterogeneous syndrome consisting of severalsubtypes and abnormalities in multiple brain regions. Despite the prevalence of depression and itsconsiderable impact knowledge about its pathophysiology is limited. Thus there is an urgent need to discovernovel signaling pathways contributing to the development of depression so that better diagnostic teststreatments and preventive measures can be attained. A recent ground breaking report revealed SIRT1 as oneof the first two genes successfully linked to MDD in a genome-wide study. SIRT1 a member of the sirtuinfamily is characterized as a Class III histone deacetylase (HDAC) which regulates the acetylation state ofhistones and non-histone proteins and thereby influences gene expression and cellular physiology. Preliminarydata from our lab show that chronic social defeat stress (CSDS) an ethologically validated model ofdepression and other stress-related disorders regulates SIRT1 levels in the NAc a key brain reward region.Additionally we demonstrate that SIRT1 overexpression in the NAc increases anxiety and despair-likebehaviors. What is not understood is how SIRT1 influences anxiety and despair-like behaviors in a cell andcircuit-specific manner. This is of particular importance due to the opposing role of D1 medium spiny neurons(MSNs) and D2 MSNs in reward- and depression-related behaviors. A central hypothesis of this project is thatSIRT1 signaling acts through the D1 pathway to mediate anxiety- and despair-like behaviors. To test thishypothesis first we will use Cre-inducible RiboTag (RT) mice which have been crossed with D1-Cre and D2-Cre bacterial artificial chromosome (BAC) transgenic mice allowing for the cell-type specific isolation ofmRNA from D1 or D2 MSNs. Following CSDS we will measure SIRT1 mRNA from D1 and D2 MSN isolatedfrom RiboTag-D1 Cre and RiboTag-D2 Cre mice. Second to determine through which MSN subtype SIRT1acts to mediate anxiety- and depressive- like behaviors we will selectively overexpress SIRT1 in D1 or D2MSNs in the NAc and third we will utilize electrophysiology and morphological approaches to uncover cell-typespecific SIRT1 dependent neural circuits that mediate depression-like behaviors. If successful this study willhave several positive impacts: 1) it would have identified the SIRT1-signaling pathway as a potential target inthe development of urgently needed novel antidepressants; 2) it will provide additional support for thedevelopment of non-monoaminergic medications to treat depression; and 3) it will identify the neural circuit andcell-type specific mechanisms through which SIRT1 mediates depression-like behaviors.