Deletion of Rictor in catecholaminergic neurons alters locomotor activity and ingestive behavior

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.

Comparison of chronic physical and emotional social defeat stress effects on mesocorticolimbic circuit activation and voluntary consumption of morphine

“…Voluntary drinking was assessed by a two-bottle choice test using 50 ml plastic conical tubes fitted with standard sipper tops following established procedures 51 . Briefly, bottle placements (left or right side of standard home-cage) were switched daily to account for individual side-preference.…”

Behavioral effects of SGK1 knockout in VTA and dopamine neurons

“…For example, decreased VTA dopamine receptor 2 (D 2 R) expression and sensitivity has been observed following psychostimulant self-administration 36,37 ; however, VTA knockdown of D 2 R did not alter the number of sucrose or cocaine rewards earned during operant self-administration, though D 2 R knockdown did increase motivation to earn rewards when rats were tested under a progressive ratio 38 . Similarly, chronic social defeat stress has been shown to decrease AKT phosphorylation in the VTA and overexpression of AKT mutants alters stress susceptibility 39 , however genetic knockdown of the kinase responsible for AKT phosphorylation did not increase susceptibility to stress 40 . Together these studies demonstrate the potential for disconnect between stimuli-induced gene and protein regulation in the VTA and effects of experimenter manipulation.…”

“…Viral-mediated gene transfer. Stereotaxic surgeries were completed following established procedures 6,40 .…”

“…To assess voluntary drinking, mice were singly housed with access to two 50 mL conical tubes fitted with sipper tops following established procedures 40,57 . Briefly, every morning fluid consumption was measured, and bottle placement was switched to account for individual side bias.…”

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson’s Disease

“…It remains unclear, however, to what extent these motor and non-motor features of PD have truly discernible neuroanatomical or molecular substrates, as effects of changes in mRNA expression in the “behavioral areas” VTA, VM, and PFC on motor function of our animals cannot be excluded. For example, a recent paper reported that VTA-specific knockout of RICTOR in mice may affect cognition and mood, but also results in hyperactivity in the open field [ 83 ]. In addition, it has been suggested that during exercise, the mesolimbic pathway (including the VTA and VM) may provide a compensatory functional activation of the motor loop [ 84 ].…”