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Deletion of Rictor in catecholaminergic neurons alters locomotor activity and ingestive behavior
Sophia Kaska1, Rebecca Brunk2, Vedrana Bali3
1Dept. of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States.
Abstract:
While the etiology of depression is not fully understood, increasing evidence from animal models suggests a role for the ventral tegmental area (VTA) in pathogenesis. In this paper, we investigate the potential role of VTA mechanistic target of rapamycin 2 (TORC2) signaling in mediating susceptibility to chronic social defeat stress (CSDS), a well-established mouse model of depression. Utilizing genetic and viral knockout of Rictor (rapamycin-insensitive companion of target of rapamycin), a requisite component of TORC2, we demonstrate that decreasing Rictor-dependent TORC2 signaling in catecholaminergic neurons, or within the VTA specifically, does not alter susceptibility to CSDS. Opiate abuse and mood disorders are often comorbid, and previous data demonstrate a role for VTA TORC2 in mediating opiate reward. Thus, we also investigated its potential role in mediating changes in opiate reward following CSDS. Catecholaminergic deletion of Rictor increases water, sucrose, and morphine intake but not preference in a two-bottle choice assay in stress-naïve mice, and these effects are maintained after stress. VTA-specific knockout of Rictor increases water and sucrose intake after physical CSDS, but does not alter consummatory behavior in the absence of stress. These findings suggest a novel role for TORC2 in mediating stress-induced changes in consummatory behaviors that may contribute to some aspects of mood disorders.
Insights
The ventral tegmental area's TORC2 pathway does not affect depression susceptibility. However, it influences stress-induced changes in consummatory behaviors, potentially impacting mood disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Science
Background:
- The precise causes of depression remain unclear, but the ventral tegmental area (VTA) is implicated in its development.
- Mechanistic target of rapamycin 2 (TORC2) signaling is a key cellular pathway.
- Chronic social defeat stress (CSDS) is a validated model for studying depression-like behaviors in mice.
Purpose of the Study:
- To investigate the role of VTA TORC2 signaling in depression susceptibility using a CSDS mouse model.
- To explore the involvement of VTA TORC2 in modulating opiate reward following CSDS.
- To understand how TORC2 signaling in catecholaminergic neurons impacts stress-related behaviors.
Main Methods:
- Genetic and viral knockout of Rictor, a crucial component of TORC2, in specific neuronal populations (catecholaminergic neurons and VTA).
- Assessment of susceptibility to CSDS in mice with altered TORC2 signaling.
- Evaluation of consummatory behaviors (water, sucrose, and morphine intake and preference) in both stress-naïve and stressed mice.
Main Results:
- Disrupting Rictor-dependent TORC2 signaling in catecholaminergic neurons or the VTA did not alter susceptibility to CSDS.
- Deletion of Rictor in catecholaminergic neurons increased intake of water, sucrose, and morphine in stress-naïve mice, effects that persisted after stress.
- VTA-specific Rictor knockout elevated water and sucrose intake following CSDS, but did not affect consummatory behavior without stress.
Conclusions:
- VTA TORC2 signaling is not a primary mediator of depression susceptibility in the CSDS model.
- TORC2 signaling plays a role in stress-induced alterations in consummatory behaviors, which may be relevant to aspects of mood disorders.
- These findings highlight a novel function of TORC2 in the brain's response to stress and its potential link to mood regulation.
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