Mitofusin-2 in the Nucleus Accumbens Regulates Anxiety and Depression-like Behaviors Through Mitochondrial and Neuronal Actions

Elias Gebara; Olivia Zanoletti; Sriparna Ghosal; Jocelyn Grosse; Bernard L Schneider; Graham Knott; Simone Astori; Carmen Sandi

doi:10.1016/j.biopsych.2020.12.003

Mitofusin-2 in the Nucleus Accumbens Regulates Anxiety and Depression-like Behaviors Through Mitochondrial and Neuronal Actions

Biol Psychiatry. 2021 Jun 1;89(11):1033-1044. doi: 10.1016/j.biopsych.2020.12.003. Epub 2020 Dec 8.

Authors

Elias Gebara¹, Olivia Zanoletti¹, Sriparna Ghosal¹, Jocelyn Grosse¹, Bernard L Schneider², Graham Knott³, Simone Astori¹, Carmen Sandi⁴

Affiliations

¹ Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
² Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne, Geneva, Switzerland.
³ Biological Electron Microscopy Facility, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁴ Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Electronic address: carmen.sandi@epfl.ch.

PMID: 33583561
DOI: 10.1016/j.biopsych.2020.12.003

Abstract

Background: Emerging evidence points to 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 about how they impact neuronal structure and function. Here, we investigated 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 assessed how individual differences in anxiety-like (measured via the elevated plus maze and open field tests) and depression-like (measured via the forced swim and saccharin preference tests) behaviors in outbred rats relate to mitochondrial morphology (electron microscopy and 3-dimensional reconstructions) and function (mitochondrial respirometry). Mitochondrial molecules were measured for protein (Western blot) and messenger RNA (quantitative reverse transcriptase polymerase chain reaction, RNAscope) content. Dendritic arborization (Golgi Sholl analyses), spine morphology, and MSN excitatory inputs (patch-clamp electrophysiology) were characterized. MFN2 overexpression in the NAc was induced through an AAV9-syn1-MFN2.

Results: Highly anxious animals showed increased depression-like behaviors, as well as reduced expression of the mitochondrial GTPase MFN2 in the NAc. They also showed alterations in mitochondria (i.e., respiration, volume, and interactions with the endoplasmic reticulum) and MSNs (i.e., dendritic complexity, spine density and typology, and excitatory inputs). Viral MFN2 overexpression in the NAc reversed all of 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.

Keywords: Anxiety; Coping behavior; Depression; Medium spiny neurons; Mitochondria; Mitofusin; Motivation; Nucleus Accumbens; Reward.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety
Depression*
Mice
Mice, Inbred C57BL
Mitochondria
Neurons / metabolism
Nucleus Accumbens* / metabolism
Rats