Stress and dopamine dysfunction in the brain: a role for glucose-mediated motivational deficits.
Final Report Abstract
The project centers on the neurobiological mechanisms underlying motivational deficits in depression, focusing on dopamine 2 receptor (D2R) function in the ventral striatum and its interaction with glucose metabolism. Motivational deficits are a hallmark of major depression, characterized by diminished interest in activities, reduced energy, and an imbalance in effort-reward motivation. The mesolimbic dopamine system, plays a critical role in these processes. Evidence from human imaging studies and animal models suggests that disruptions in D2R signaling are linked to motivational impairments. For instance, stress models like chronic social defeat (CSD) in mice demonstrate that D2R dysfunction in the ventral striatum can lead to reward-seeking impairments and other depression-like symptoms. Additionally, disturbances in glucose metabolism appear to interact with D2R dysfunction, exacerbating motivational deficits. Research indicates that chronic stress induces hyperglycemia both peripherally and centrally, including the ventral striatum, which may disrupt the effort-reward balance. In conclusion, striatal D2R signaling may be important for effort-based motivation by directly influencing the mesolimbic dopamine system and glucose metabolism. The project aims to elucidate these interactions using animal models to advance understanding and treatment of depression-related motivational impairments. Our first major observation was that, despite ample evidence that D2R function in the NAc is affected in animal models for CSD, we did not find D2R function to be affected in CSD-exposed mice (based on PET-data and immunohistochemistry). As a result, we focused on other important aspects of the project proposal, namely striatal glucose-metabolism and effort-based motivational aspects after CSD. As we will see later, the lack of impact of CSD on the dopaminergic system may explain some of the findings observed in the study involving effort-based reward motivation. In another study, we investigated hexokinase (HK) 3, an enzyme involved in glucose metabolism in the striatum after CSD. Interestingly, we found that CSD affected glucose metabolism (increased hepatic glycogen and hyperglycemia) and depleted HK3 levels from mitochondria-associated membranes (MAMs). Finally, under control conditions, HK3 levels in the MAMS and in the synaptosomes correlated strongly with peripheral glucose concentrations. However, this connection was lost after CSD. Therefore, CSD may disrupt brain (striatal) glucose metabolism via its impact on HK3. Then, we assessed the impact of CSD on glucose metabolism in the brain (striatum) and peripheral tissue (liver) in detail and employed glucose tracing. We found that CSD strongly altered liver metabolism (rather than the brain) and identified glucagon actions on glycogen phosphorylase as a potential mechanism leading to hyperglycemia (shortly after CSD) and its normalization (3 wks post-CSD). Lastly, we found that CSD impacted effort-based reward motivation only acutely after stress, and that this effects could be mimicked via corticosterone supplementation to the drinking water of the mice.
Link to the final report
https://doi.org/10.4126/FRL01-006510730
Publications
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Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels. Journal of Molecular Medicine, 100(10), 1441-1453.
van der Kooij, Michael A.; Rojas-Charry, Liliana; Givehchi, Maryam; Wolf, Christina; Bueno, Diones; Arndt, Sabine; Tenzer, Stefan; Mattioni, Lorenzo; Treccani, Giulia; Hasch, Annika; Schmeisser, Michael J.; Vianello, Caterina; Giacomello, Marta & Methner, Axel
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Adaptations in hepatic glucose metabolism after chronic social defeat stress in mice. Scientific Reports, 14(1).
Meijboom, Fabiënne S.; Hasch, Annika; Ruiz, de Azua Inigo; Cologna, Camila Takeno; Loopmans, Shauni; Lutz, Beat; Müller, Marianne B.; Ghesquière, Bart & van, der Kooij Michael A.
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Transient impact of chronic social stress on effort-based reward motivation in non-food restricted mice: Involvement of corticosterone. Neurobiology of Stress, 33, 100690.
Evertse, Danina; Alves-Martinez, Pilar; Treccani, Giulia; Müller, Marianne B.; Meye, Frank J. & van, der Kooij Michael A.
