Neuronal Nitric Oxide Synthase in Nucleus Accumbens Specifically Mediates Susceptibility to Social Defeat Stress through Cyclin-Dependent Kinase 5

Abstract

Stress-induced depression is common worldwide. NAc, a "reward" center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test, and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we used brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional KO and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, increased protein expression levels, and increased specific enzyme activity, contribute the susceptibility to social defeat and the following depression-like behaviors. NAcSh nNOS does not directly respond to chronic mild stress but facilitates the depression-like behaviors. The increased NAcSh nNOS expression after CSDS leads to the social avoidance and depression-like behaviors in defeated mice, which is dependent on the nNOS enzyme activity and NO production. Moreover, we identify the downstream signal in NAcSh. S-nitrosylation of CDK5 by NO contributes to enhanced CDK5 activity, leading to depression-related behaviors in susceptible mice. Therefore, NAcSh nNOS mediates susceptibility to social defeat stress and the depression-like behaviors through CDK5.

Whole-Brain Afferent Inputs to the Caudate Nucleus, Putamen, and Accumbens Nucleus in the Tree Shrew Striatum

“…The Pu seems to participate in motor learning ( Liebrand et al, 2020 ), auditory responses ( Salisbury et al, 2021 ), cocaine addiction ( Ersche et al, 2021 ), and psychiatric disorders ( Kolomeets and Uranova, 2020 ). In addition, the Acb is involved in motor control ( Sawada et al, 2015 ), reward processing ( Muench et al, 2018 ), motivation ( Baumgartner et al, 2021 ), addiction ( Crofton et al, 2021 ), mental disorders ( Terrillion et al, 2017 ), and social defeat stress ( Yin et al, 2021 ).…”

“NO” Time in Fear Response: Possible Implication of Nitric-Oxide-Related Mechanisms in PTSD

“…The nNOS overexpression, at least in the hippocampus of mice exposed to chronic mild stress, is crucial for the development of stress-induced depressive behavior [ 103 ], suggesting the involvement of nNOS in modulating coping behavior in response to stress. In line with this data, nNOS in the nucleus accumbens, a reward center, regulates susceptibility to social defeat stress and subsequent depression-like behaviors in mice [ 104 ].…”

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

“…Moreover, we found that excitatory neurons in the posterior subregion of the paraventricular thalamic nucleus (pPVT) drive chronic pain-induced anxiety behaviors through the activation of nNOS-expressing neurons in the ventromedial prefrontal cortex (vmPFC), resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons, suggesting that nNOS is involved in chronic pain-induced anxiety behaviors [ 46 ]. More recently, we found that nNOS in the nucleus accumbens of mice specifically mediates susceptibility to social defeat stress through cyclin-dependent kinase 5, which may explain how the brain transduces social stress exposure into depressive symptoms [ 47 ].…”