A Role for SIRT-1 in Dendritic and Spine Morphology of Medium Spiny Neurons in the Nucleus Accumbens

Major depressive disorders affect 350 million people globally and are the leading cause of disability worldwide. Chronic or prolonged stress can trigger development of depression. Key symptoms of depression are anhedonia, helplessness, and decreased socialization. These behavioral outcomes suggest a dysfunction within the brain’s reward system, the mesolimbic system. The nucleus accumbens (NAc) is regarded as the brain’s reward hub, integrating signals from multiple brain regions to influence motivated behavioral output. The NAc consists of medium spiny neurons (MSNs) which represent 95% of the cellular landscape. These neurons can be separated into two distinct groups, dopamine receptor-1 (DR1 or D1) and dopamine receptor-2 (DR2 or D2). Differentiating between these two cell types is ideal as activation results in opposing outcomes. One protein of interest sirtuin-1 (SIRT1) has been found to alter dendritic morphology in brain regions involved in stress. Discovery that SIRT1, a histone deacetylase (HDAC), has cell-type-specific action in the NAc in a mouse model of depression and resulting behavioral changes suggest possible underlying morphological changes. Neuronal morphology includes measurement of the dendritic arbor and dendritic spines, small protrusions from the dendritic shaft. These studies seek to elucidate morphological changes following knockout or overexpression of SIRT1 in either D1-or D2-MSNs in both male and female mice. Results show that SIRT1 overexpression in male D1-MSNs results in a significant increase in stubby spines and a decrease in mushroom spines. Conversely, in female mice with SIRT1 OVEXP in D1-MSNs, there was found a significant increase in mushroom spines accompanied by a significant decrease in stubby spines. The D2-targeted mice also showed significant changes across spine types. In both treatment types, D2- males had a significant increase in stubby spines, filopodia, and thin spines. Females with SIRT1 knocked out had a significant decrease in filopodia and thin spines. SIRT1 overexpression in D2- females showed a significant decrease in stubby spines. These results suggest SIRT1 has a regulatory role in the density of spine type and possibly the maturation of spines. This discovery of an increase in stubby spines in male D1-MSNs overexpressing mice establishes a role for SIRT1 in stubby spine formation.