Synaptic Mechanisms Regulating Mood State Transitions in Depression

Parekh, Puja K.; Johnson, Shane B.; Liston, Conor

doi:10.1146/annurev-neuro-110920-040422

Cited by 55 publications

(28 citation statements)

References 159 publications

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“…Ketamine is primarily an NMDAR antagonist and therefore has direct action on glutamatergic receptors in the brain. There is a growing consensus that the therapeutic effects of ketamine depend critically on its influence on glutamatergic signaling. − By contrast, psychedelics such as psilocybin are serotonin receptor agonists, and therefore studies of the drugs’ effect on neural plasticity have mostly focused on the pharmacology of serotonin. − , The exploratory analyses in this study revealed a correlation between Htr2a transcript levels and psilocybin-evoked c-Fos expression, consistent with the known receptor interaction. However, we also observed robust relationships for glutamatergic receptors including Grin2a and Grin2b , particularly for cortical regions, which means that the presence of glutamatergic receptors is an even stronger indicator for whether a cortical region is sensitive to psilocybin-evoked neural plasticity.…”

Section: Discussionsupporting

confidence: 67%

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin

Davoudian

Shao

Kwan

2023

ACS Chem. Neurosci.

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Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.

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Section: Discussionsupporting

confidence: 67%

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin

Davoudian

Shao

Kwan

2023

ACS Chem. Neurosci.

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“…Ketamine is primarily a NMDAR antagonist, and therefore has direct action on glutamatergic receptors in the brain. There is growing consensus that the therapeutic effects of ketamine depend critically on its influence on glutamatergic signaling [69][70][71][72] . By contrast, psychedelics such as psilocybin are serotonin receptor agonists, and therefore studies of the drugs' effect on neural plasticity have mostly focused on the pharmacology of serotonin [12][13][14]64 .…”

Section: Discussionmentioning

confidence: 99%

Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin

Davoudian

Shao

Kwan

2022

Preprint

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Background: Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. Methods: Whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. Results: Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe, lateral habenula, and insular cortex for psilocybin and retrosplenial cortex for ketamine. Correlation of psilocybin's effects with gene expression highlighted potential roles of 5-HT2A and GluN2B subunit of NMDA receptors. Conclusions: The systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a valuable resource that highlights previously underappreciated regions for future investigations. By identifying regions with similar and disparate effects, the results provide insights into how psilocybin and ketamine may produce their rapid-acting and long-lasting therapeutic effects.

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“…In our study, we found that resveratrol administration can improve anxiety-like behavior and reduce the increase of dendritic spines in the NAc induced by social isolation, suggesting that resveratrol plays a region-specific regulatory effect on dendritic spines. Moreover, many studies have shown that the regulatory effect of stress on synaptic remodeling is different in brain regions [ 48 ]. It was reported that the number and morphology of spines are connected to synaptic plasticity and circuit remodeling in the NAc [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Resveratrol on Adolescent Social Isolation-Induced Anxiety-Like Behaviors via Modulating Nucleus Accumbens Spine Plasticity and Mitochondrial Function in Female Rats

Zhao

Liu

et al. 2022

Nutrients

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Social isolation (SI) is a major risk factor for mood disorders in adolescents. The nucleus accumbens (NAc) is an important reward center implicated in psychiatric disorders. Resveratrol (RSV) is one of the most effective natural polyphenols with anti-anxiety and depression effects. However, little is known about the therapeutic effects and mechanisms of RSV on behavioral abnormality of adolescent social stress. Therefore, this study aimed to investigate the underlying mechanism of RSV on the amelioration of SI-induced behavioral abnormality. We found that SI induced anxiety-like behavior and social dysfunction in isolated female rats. Moreover, SI reduced mitochondrial number and ATP levels and increased thin spine density in the NAc. RNA sequencing results showed that SI changed the transcription pattern in the NAc, including 519 upregulated genes and 610 downregulated genes, especially those related to mitochondrial function. Importantly, RSV ameliorated behavioral and spine abnormalities induced by SI and increased NAc ATP levels and mitochondria number. Furthermore, RSV increased the activity of cytochrome C oxidase (COX) and upregulated mRNA levels of Cox5a, Cox6a1 and Cox7c. These results demonstrate that the modulation of spine plasticity and mitochondrial function in the NAc by RSV has a therapeutic effect on mood disorders induced by social isolation.

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Synaptic Mechanisms Regulating Mood State Transitions in Depression

Cited by 55 publications

References 159 publications

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin

Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin

Protective Effects of Resveratrol on Adolescent Social Isolation-Induced Anxiety-Like Behaviors via Modulating Nucleus Accumbens Spine Plasticity and Mitochondrial Function in Female Rats

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