Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways

Abstract

Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidence suggests that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical dopaminergic pathways. Yet, the molecular interactions underlying these changes are still poorly understood, and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and mesocortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of activity-dependent markers pERK and c-fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Our results show that social stress decreases the density of TH+ dopaminergic axonal projections in the deep layers of the mPFC in susceptible but not resilient male and female mice. Consistently, our analyses suggest that pERK expression is decreased in the mPFC but increased in the NAc following CSDS in males and females, with no change in c-fos expression in both sexes. Overall, our findings indicate that social defeat stress impacts the mesolimbic and mesocortical pathways by altering the molecular interactions regulating somatic and axonal plasticity in males and females.

Functional Contribution of the Medial Prefrontal Circuitry in Major Depressive Disorder and Stress-Induced Depressive-Like Behaviors

“…These afferences follow a precise topological organization. For instance, inputs from the LC concentrate mainly in layers I and II/III, dopaminergic nerve terminals from the VTA populate preferentially layers V and VI ( Vander Weele et al, 2018 ; Quessy et al, 2021 ), the amygdala innervates mainly layers II and V ( Aggleton et al, 2015 ; McGarry and Carter, 2016 ), serotonergic inputs arrive mainly in layers I and V/VI and sparser proportions in layer II/III ( Linley et al, 2013 ), and projections from the hippocampus are located in layers II/III and V ( Liu and Carter, 2018 ; Figure 2 ).…”

“…The mPFC receives various afferences from cortical, subcortical and brainstem areas ( Zhang et al, 2010 ; Gabbott et al, 2012 ; Linley et al, 2013 ; Vander Weele et al, 2018 ; Quessy et al, 2021 ) which have been shown to control several fundamental behavioral features such as memory formation, emotional processing, decision-making, attention and behavioral flexibility ( Beversdorf et al, 1999 ; Gunaydin et al, 2014 ; Mitchell, 2015 ; Sharp, 2017 ; Phillips et al, 2019 ). With this in mind, recent studies investigating the contributions of these afferences in the elaboration and consolidation of stress responses address more specifically their roles in modulating anxiety, behavioral despair, social avoidance, and anhedonia-like behavioral features in males and females ( Table 1 ).…”

“…Interestingly, the VTA-mPFC firing rate was significantly reduced in susceptible animals but not in resilient and control, suggesting that decreased activity of this pathway causes social avoidance in susceptible males ( Chaudhury et al, 2013 ). Moreover, the density of dopamine axon terminals in the layers V and VI of the mPFC is reduced in male and female mice after CSDS ( Quessy et al, 2021 ). Additionally, repeated optogenetic stimulation of mPFC-projecting VTA neurons in mice that underwent CSDS reversed social avoidance ( Friedman et al, 2014 ).…”

Distinct cell populations of ventral tegmental area process motivated behavior

“…Depending on the pre- and post-regions of dopamine, four distinct pathways exist: the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways ( Fig. 1 ) [ 1 - 3 ]. The mesolimbic pathway represents dopamine traveling from the VTA to the nucleus accumbens (NAc).…”

Inactivation of Zona Incerta Blocks Social Conditioned Place Aversion and Modulates Post-traumatic Stress Disorder-Like Behaviors in Mice

“…Repeated exposures to social defeat stress has been reported to cause a variety of molecular, physiological, and behavioral changes ( Bondar et al, 2018 ; Miyanishi et al, 2021 ; Quessy et al, 2021 ). In particular, animals suffered with RSDS exhibit loss of self-esteem, robust and sustained social avoidance, cognitive deficit, anxiety-, and depression-like phenotypes ( Björkqvist, 2001 ; Wagner et al, 2013 ; Kosuge et al, 2021 ).…”