School of Medicine and Health Sciences Poster Presentations

Title

Behavioral impact of the disinhibition of the dopaminergic neurons in the VTA via inhibition of VTA GABAergic neurons using the subchronical variable stress paradigm

Poster Number

289

Document Type

Poster

Status

Staff

Abstract Category

Neuroscience

Keywords

stress, depression, VTA, GABA, Dopamine

Publication Date

Spring 2018

Abstract

Depression is the leading cause of disability worldwide, with over 300 million people affected by the disorder (World Health Organization, 2018). Women are twice as likely to be diagnosed with depression as men, yet most animal research into the disorder and its symptoms is performed in only males. This creates a gap between preclinical experiments and their potential clinical use. Females display different neurobiological, behavioral and transcriptional responses when dealing with stress that leads to depressive phenotypes (Dalla et al., Physiology and Behavior , 2008; Hodes et al., Journal of Neuroscience , 2015; La Plant et al., Biol Psychiatry , 2009). Subchronic variable stress (SCVS) is a stress paradigm that induces depression and anxiety like symptoms in female mice, and leaves male mice behaviorally unaffected. The ventral tegmental area (VTA) is a crucial hub in the mesolimbic reward pathway, sending dopaminergic projections to regions like the nucleus accumbens (NAc) and prefrontal cortex. Due to its role in reward seeking behavior and motivation, dysregulation of the VTA circuitry has been implicated in mood disorders. The function of dopaminergic neurons within the VTA is controlled by the GABAergic networks both locally, in the VTA, and by inputs from outside the VTA. In the VTA, GABAergic neurons are activated by stress and inhibit the dopaminergic VTA neurons that are involved in reward seeking and motivation. In addition, several studies using animal models of depression have found that there is altered activity of the dopaminergic neurons of the VTA (Nestler, E., Carlezon, W A., Biol Psychiatry , 2006). The role of VTA GABAergic neurons in stress-induced depressive behavior has not been studied. In this project, we used SCVS to study the effect of chemogenetic inhibition of local GABAergic neurons in the VTA on the behavioral responses to stress. AAVs encoding Cre-dependent inhibitory designer receptors exclusively activated by designer drugs (DREADDs) were injected into the VTA of VGAT-cre mice, allowing VTA GABA neurons to be selectively inhibited by the otherwise-inert ligand CNO. The impact of this manipulation was tested through a variety of behavioral tests that assayed for anxiety and depressive-like phenotypes. We hypothesized that disinhibition of the dopaminergic neurons in the VTA via inhibition of VTA GABAergic neurons will alleviate the behavioral effects of SCVS in female mice.

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Behavioral impact of the disinhibition of the dopaminergic neurons in the VTA via inhibition of VTA GABAergic neurons using the subchronical variable stress paradigm

Depression is the leading cause of disability worldwide, with over 300 million people affected by the disorder (World Health Organization, 2018). Women are twice as likely to be diagnosed with depression as men, yet most animal research into the disorder and its symptoms is performed in only males. This creates a gap between preclinical experiments and their potential clinical use. Females display different neurobiological, behavioral and transcriptional responses when dealing with stress that leads to depressive phenotypes (Dalla et al., Physiology and Behavior , 2008; Hodes et al., Journal of Neuroscience , 2015; La Plant et al., Biol Psychiatry , 2009). Subchronic variable stress (SCVS) is a stress paradigm that induces depression and anxiety like symptoms in female mice, and leaves male mice behaviorally unaffected. The ventral tegmental area (VTA) is a crucial hub in the mesolimbic reward pathway, sending dopaminergic projections to regions like the nucleus accumbens (NAc) and prefrontal cortex. Due to its role in reward seeking behavior and motivation, dysregulation of the VTA circuitry has been implicated in mood disorders. The function of dopaminergic neurons within the VTA is controlled by the GABAergic networks both locally, in the VTA, and by inputs from outside the VTA. In the VTA, GABAergic neurons are activated by stress and inhibit the dopaminergic VTA neurons that are involved in reward seeking and motivation. In addition, several studies using animal models of depression have found that there is altered activity of the dopaminergic neurons of the VTA (Nestler, E., Carlezon, W A., Biol Psychiatry , 2006). The role of VTA GABAergic neurons in stress-induced depressive behavior has not been studied. In this project, we used SCVS to study the effect of chemogenetic inhibition of local GABAergic neurons in the VTA on the behavioral responses to stress. AAVs encoding Cre-dependent inhibitory designer receptors exclusively activated by designer drugs (DREADDs) were injected into the VTA of VGAT-cre mice, allowing VTA GABA neurons to be selectively inhibited by the otherwise-inert ligand CNO. The impact of this manipulation was tested through a variety of behavioral tests that assayed for anxiety and depressive-like phenotypes. We hypothesized that disinhibition of the dopaminergic neurons in the VTA via inhibition of VTA GABAergic neurons will alleviate the behavioral effects of SCVS in female mice.