Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine

Cherix, Antoine; Larrieu, Thomas; Grosse, Jocelyn; Rodrigues, João; McEwen, Bruce S.; Nasca, Carla; Gruetter, Rolf; Sandi, Carmen

doi:10.7554/elife.50631

Cited by 51 publications

(55 citation statements)

References 93 publications

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“…L-Carnitine has demonstrated some beneficial effects on axonal development and branching in sensory neurons (Sainath et al, 2017). Furthermore L-Carnitine has anti-depressant effect mediated by an upregulation of metabolic activity (Cherix et al, 2020;Filiou and Sandi, 2019). Our work provides further evidence that L-Carnitine might be of therapeutic interest in correcting mitochondrial disfunction and metabolic imbalance during neurodevelopment.…”

Section: Discussionsupporting

confidence: 52%

The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

Lanfranchi

Meyer-Dilhet

Reis

et al. 2020

Preprint

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The precise regulation of the cellular mechanisms underlying axonal morphogenesis is essential to the formation of functional neuronal networks. We previously identified the autism-candidate kinase NUAK1 as a central regulator of axon branching in mouse cortical neurons through the control of mitochondria trafficking. How does local mitochondrial position or function regulate axon branching during development? Here, we characterized the metabolic regulation in the developing axon and report a marked metabolic decorrelation between axon elongation and collateral branching. We next solved the cascade of event leading to presynaptic clustering and mitochondria recruitment during spontaneous branch formation. Interestingly and contrary to peripheral neurons, mitochondria are recruited after but not prior to branch formation in cortical neurons. Using flux metabolomics and fluorescent biosensors, we observed that NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration. Upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Altogether, our results indicate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondria distribution and activity, and suggest that a mitochondrial-dependent remodeling of local metabolic homeostasis plays a critical role during axon morphogenesis. RESULTS Cortical axon elongation and collateral branching rely on distinct metabolic pathways

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Section: Discussionsupporting

confidence: 52%

The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

Lanfranchi

Meyer-Dilhet

Reis

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…A possible reason for this discrepancy may be the different stress protocols used (i.e., 10-days chronic social defeat 18 vs. the here applied 3-week mCRS). Note, however, that a 3-way chronic restraint protocol results as well in major metabolic changes in the NAc in stress-vulnerable mice 54 . In the future, it will be important to integrate transcriptomic and metabolic analyses in these two brain regions, ideally at the cell-type level, to further our understanding of stress-induced metabolic regulation at the transcriptional level.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, the GR implicated in the mesocorticolimbic dopamine system with chronic stress vulnerability 85 , 86 , and showed that the GR has the capability to translocate into brain mitochondria 68 , 87 , 88 and to bind on the mitochondrial genome 56 , 89 in a glucocorticoid-dependent manner 56 . It will also be important to test whether mitochondrial-targeted interventions known to ameliorate stress and anxiety responses 54 , 90 – 92 would reverse both the behavioral and mtDNA transcriptional changes observed in stress-vulnerable mice.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Weger

Alpern

Cherix

et al. 2020

Sci Rep

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Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

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“…This implies that the power to detect a significant behavior-metabolite association in the occipital lobe was lower, and it would be important in future studies to verify the specificity of the reported associations for the NAc. In this study, only males were included as our prediction for a link between accumbal metabolism and motivated performance was inspired in background studies involving male rodents [59,72,73]. In addition, due to technical challenges mainly associated with scanning at 7 T, our original participant recruitment was reduced to a moderate sample size, which limits the generalization of the obtained results.…”

Section: Discussionmentioning

confidence: 99%

Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

Strasser

Luksys

Xin

et al. 2020

Neuropsychopharmacol.

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Substantial evidence implicates the nucleus accumbens in motivated performance, but very little is known about the neurochemical underpinnings of individual differences in motivation. Here, we applied 1H magnetic resonance spectroscopy (1H-MRS) at ultra-high-field in the nucleus accumbens and inquired whether levels of glutamate (Glu), glutamine (Gln), GABA or their ratios predict interindividual differences in effort-based motivated task performance. Given the incentive value of social competition, we also examined differences in performance under self-motivated or competition settings. Our results indicate that higher accumbal Gln-to-Glu ratio predicts better overall performance and reduced effort perception. As performance is the outcome of multiple cognitive, motor and physiological processes, we applied computational modeling to estimate best-fitting individual parameters related to specific processes modeled with utility, effort and performance functions. This model-based analysis revealed that accumbal Gln-to-Glu ratio specifically relates to stamina; i.e., the capacity to maintain performance over long periods. It also indicated that competition boosts performance from task onset, particularly for low Gln-to-Glu individuals. In conclusion, our findings provide novel insights implicating accumbal Gln and Glu balance on the prediction of specific computational components of motivated performance. This approach and findings can help developing therapeutic strategies based on targeting metabolism to ameliorate deficits in effort engagement.

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Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine

Cited by 51 publications

References 93 publications

The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

The AMPK-related kinase NUAK1 controls cortical axons branching though a local modulation of mitochondrial metabolic functions

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

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