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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.

SUBMITTER: Quessy F

PROVIDER: S-EPMC8154906 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute stress is thought to reduce goal-directed behaviour, an effect purportedly associated with stress-induced release of catecholamines. In contrast, experimentally increased systemic catecholamine levels have been shown to increase goal-directed behaviour. Whether experimentally increased catecholamine function can modulate stress-induced reductions in goal-directed behaviour and its neural substrates, is currently unknown.AimTo assess whether and how experimentally induced increases in dopamine and noradrenaline contribute to the acute stress effects on goal-directed behaviour and associated brain activation.MethodsOne hundred participants underwent a stress induction protocol (Maastricht acute stress test; MAST) or a control procedure and received methylphenidate (MPH) (40 mg, oral) or placebo according to a 2 × 2 between-subjects design. In a well-established instrumental learning paradigm, participants learnt stimulus-response-outcome associations, after which rewards were selectively devalued. Participants' brain activation and associated goal-directed behaviour were assessed in a magnetic resonance imaging scanner at peak cortisol/MPH concentrations.ResultsThe MAST and MPH increased physiological measures of stress (salivary cortisol and blood pressure), but only MAST increased subjective measures of stress. MPH modulated stress effects on activation of brain areas associated with goal-directed behaviour, including insula, putamen, amygdala, medial prefrontal cortex, frontal pole and orbitofrontal cortex. However, MPH did not modulate the tendency of stress to induce a reduction in goal-directed behaviour.ConclusionOur neuroimaging data suggest that MPH-induced increases in dopamine and noradrenaline reverse stress-induced changes in key brain regions associated with goal-directed behaviour, while behavioural effects were absent. These effects may be relevant for preventing stress-induced maladaptive behaviour like in addiction or binge eating disorder.

Project description:Background: The ventral tegmental area (VTA), containing mesolimbic and mesocortical dopaminergic neurons, is implicated in processes involving reward, addiction, reinforcement, and learning, which are associated with a variety of neuropsychiatric disorders. Electrical stimulation of the VTA or the medial forebrain bundle and its projection target the nucleus accumbens (NAc) is reported to improve depressive symptoms in patients affected by severe, treatment-resistant major depressive disorder (MDD) and depressive-like symptoms in animal models of depression. Here we sought to determine the neuromodulatory effects of VTA deep brain stimulation (DBS) in a normal large animal model (swine) by combining neurochemical measurements with functional magnetic resonance imaging (fMRI). Methods: Animals (n = 8 swine) were implanted with a unilateral DBS electrode targeting the VTA. During stimulation (130 Hz frequency, 0.25 ms pulse width, and 3 V amplitude), fMRI was performed. Following fMRI, fast-scan cyclic voltammetry in combination with carbon fiber microelectrodes was performed to quantify VTA-DBS-evoked dopamine release in the ipsilateral NAc. In a subset of swine, the blood oxygen level-dependent (BOLD) percent change evoked by stimulation was performed at increasing voltages (1, 2, and 3 V). Results: A significant increase in VTA-DBS-evoked BOLD signal was found in the following regions: the ipsilateral dorsolateral prefrontal cortex, anterior and posterior cingulate, insula, premotor cortex, primary somatosensory cortex, and striatum. A decrease in the BOLD signal was also observed in the contralateral parahippocampal cortex, dorsolateral and anterior prefrontal cortex, insula, inferior temporal gyrus, and primary somatosensory cortex (Bonferroni-corrected < 0.001). During neurochemical measurements, stimulation time-locked changes in dopamine release were recorded in the NAc, confirming that mesolimbic dopaminergic neurons were stimulated by DBS. In the parametric study, BOLD signal changes were positively correlated with stimulation amplitude. Conclusions: In this study, the modulation of the neural circuitry associated with VTA-DBS was characterized in a large animal. Our findings suggest that VTA-DBS could affect the activity of neural systems and brain regions implicated in reward, mood regulation, and in the pathophysiology of MDD. In addition, we showed that a combination of fMRI and electrochemically-based neurochemical detection platform is an effective investigative tool for elucidating the circuitry involved in VTA-DBS.

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Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways.

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