Impact of mitofusin 2 on accumbens-associated behaviors and underlying neurobiological mechanisms

Mitochondrial dysfunction has been implicated in psychiatric disorders, yet the specific cellular and molecular mechanisms remain elusive. Previous research has identified a connection between high trait anxiety and low levels of mitofusin 2 (Mfn2), a mitochondrial fusion protein, in the nucleus accumbens (NAc), a brain region crucial for motivation and goal-directed behavior. To assess the implications of Mfn2 in a cell-type specific manner, in this study we selectively manipulated Mfn2 in NAc dopamine receptor 1-expressing medium spiny neurons (D1-MSNs) using a viral vector (AAV1-Dyn-CRE) in the Mfn2lox/lox mouse line. Behavioral assessments demonstrated that deleting Mfn2 in NAc D1-MSNs resulted in reduced motivation to seek rewards and increased passive coping behavior during exposure to inescapable stress. Moreover, during the latter, cFos mapping indicated altered neuronal engagement in NAc shell neurons. Consistent with our previous results, Mfn2 downregulation reduced mitochondrial complexity and volume, indicating organelle fragmentation, as shown by correlative-light electron microscopy. Ex vivo electrophysiological recordings and RNA sequencing from Mfn2-deleted D1-MSNs revealed a decreased ratio between excitatory and inhibitory inputs, reduced dendritic complexity, and altered gene expression related to synaptic physiology, axonal guidance, and neurite growth. Notably, the expression of genes and proteins associated with the structure of primary cilia were also reduced, which was accompanied by a shortening of the cilia by ~25%, suggesting an impact of Mfn2 in ciliary function in D1-MSNs. Overall, our findings identify Mfn2 as a key regulator of accumbal D1-MSN structure, excitability and organelle function, and as a potential target to tackle motivational disorders.