Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function

Ghosal, Sriparna; Gebara, Elias; Ramos-Fernández, Eva; Chioino, Alessandro; Grosse, Jocelyn; Suduiraut, Isabelle Guillot de; Zanoletti, Olivia; Schneider, Bernard L.; Zorzano, António; Astori, Simone; Sandi, Carmen

doi:10.1016/j.celrep.2023.112776

Cited by 13 publications

(4 citation statements)

References 84 publications

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“…Such dysfunction could signal a disruption in the TCA cycle, as suggested by elevated aspartate and glutamate levels 70 , and a compensatory shift towards glycolysis due to impaired oxidative phosphorylation, indicated by increased lactate levels. These disturbances may impair ATP production, amino acids, nucleotides, and bioactive molecules synthesis, essential for neuronal integrity and function 26,27 , as well as neurotransmitter synthesis and signaling pathways 71 . Mitochondrial dysfunction, evidenced in rodent models affecting demanding behavioral tasks 26,72,73 , and metabolic imbalances within the dmPFC/dACC may directly affect energy-intensive cognitive tasks and decision-making processes, further diminishing motivation and cognitive control mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…While initial studies predominantly focused on glucose as a resource-limiting energy source for demanding cognitive processes 19,20 , such as decision-making, evidence has revealed that brain glucose might not be a limited resource for brain processes as was originally proposed [21][22][23][24] . Moreover, neurons utilize various energy substrates, not just glucose, to support both neural structure and function [25][26][27][28][29] and, consequently, meet cognitive demands 18 .…”

Section: Introductionmentioning

confidence: 99%

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A neurometabolic signature in the frontal cortex explains individual differences in effort-based decision-making

Barakat,

Clairis,

Brochard

et al. 2024

Preprint

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Exploring why individuals vary in their willingness to exert effort in decision-making is fundamental for understanding human behavior. Our study focuses on the dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC), a crucial brain region in motivation and decision-making, to uncover the neurobiological factors influencing these individual differences. We utilized 7T proton magnetic resonance spectroscopy (1H-MRS) to analyze metabolite concentrations in the dmPFC/dACC and anterior insula (AI) of 75 participants, aiming to predict individual variability in effort-based decision-making. Employing computational modeling, we identified key motivational parameters and, using machine learning models, pinpointed glutamate, aspartate, and lactate as crucial metabolites predicting decision-making to exert high mental effort, signifying their role as potential biomarkers for mental effort decision-making. Additionally, we examined the relationships between plasma and brain metabolite concentrations. Our findings provide novel insights into the neurometabolic underpinnings of motivated behavior, offering new perspectives in the field of cognitive neuroscience and human behavior.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A neurometabolic signature in the frontal cortex explains individual differences in effort-based decision-making

Barakat,

Clairis,

Brochard

et al. 2024

Preprint

Self Cite

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“…This interpretation is supported by a growing body of work in rodents and humans indicating that mitochondrial OxPhos defects can alter behavior (e.g., refs. 24 , 45 , and 48 ). Social dominance, depressive, and anxiety-related behaviors have been associated with variation in brain mitochondrial OxPhos capacity ( 43 – 46 , 49 ).…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical rodent models, mitochondrial DNA defects alter physiological stress reactivity ( 39 – 41 ) and influence mood-like behaviors ( 40 , 42 ). Alteration in mitochondrial OxPhos in defined brain regions (nucleus accumbens, prefrontal cortex) influences social behavior as well as anxiety-like and depression-like behaviors [( 27 , 43 – 49 ), reviewed in ref. 50 ].…”

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confidence: 99%

Psychosocial experiences are associated with human brain mitochondrial biology

Trumpff,

Monzel,

Sandi

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these “mind-mitochondria” associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.

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The Emerging Role of Brain Mitochondria in Fear and Anxiety

Chioino,

Sandi

2024

Current Topics in Behavioral Neurosciences

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Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function

Cited by 13 publications

References 84 publications

A neurometabolic signature in the frontal cortex explains individual differences in effort-based decision-making

A neurometabolic signature in the frontal cortex explains individual differences in effort-based decision-making

Psychosocial experiences are associated with human brain mitochondrial biology

The Emerging Role of Brain Mitochondria in Fear and Anxiety

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