Mitofusin-2 in nucleus accumbens regulates anxiety and depression-like behaviors through mitochondrial and neuronal actions

Background Emerging evidence points at a central role of mitochondria in psychiatric disorders. However, little is known about the molecular players that regulate mitochondria in neural circuits regulating anxiety and depression, and how they impact on neuronal structure and function. Here, we investigate the role of molecules involved in mitochondrial dynamics in medium spiny neurons (MSNs) from the nucleus accumbens (NAc), a hub of the brain’s motivation system. Methods We assess how individual differences in anxiety (elevated plus maze and open field tests) and depression-like (forced swim and saccharin preference tests) behaviors in outbred rats relate to mitochondrial morphology (electron microscopy and 3D reconstructions) and function (mitochondrial respirometry). Mitochondrial molecules are measured for protein (Western blot) and mRNA (qRT-PCR, RNAscope) content. Dendritic arborization (Golgi sholl analyses), spine morphology, and MSNs excitatory inputs (path-clamp electrophysiology) are characterized. Mitofusin 2 (Mfn2) overexpression in the NAc is induced through an AAV9-syn1-MFN2. Results High anxious animals show increased depression-like behaviors, as well as reduced expression of the mitochondrial GTPase Mfn2 in the NAc. They also show alterations in mitochondria (i.e., respiration, volume, interactions with the endoplasmic reticulum) and MSNs (i.e., dendritic complexity, spine density and typology, excitatory inputs). Viral Mfn2 overexpression in the NAc reverses all these behavioral, mitochondrial and neuronal phenotypes. Conclusions Our results implicate a causal role for accumbal Mfn2 on the regulation of anxiety and depression-like behaviors through actions on mitochondrial and MSN structure and function. Mfn2 is posited as a promising therapeutic target to treat anxiety and associated behavioral disturbances.