Mitofusin-2 in the Nucleus Accumbens Regulates Anxiety and Depression-like Behaviors Through Mitochondrial and Neuronal Actions.
Anxiety
Coping behavior
Depression
Medium spiny neurons
Mitochondria
Mitofusin
Motivation
Nucleus Accumbens
Reward
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
received:
04
06
2020
revised:
11
11
2020
accepted:
02
12
2020
pubmed:
16
2
2021
medline:
29
6
2021
entrez:
15
2
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33583561
pii: S0006-3223(20)32110-7
doi: 10.1016/j.biopsych.2020.12.003
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1033-1044Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.