In 2015, 4% of U.S. adults aged 18 or older experienced a serious mental illness that interfered with daily functioning, and this percentage increases to almost 18% when adults with any mental illness are considered. Major depression in particular is one of the most common psychiatric disorders in the U.S., and has the highest disability burden among all mental disorders. Despite the social and economic costs of depression, relatively little is known about its neurobiological basis.

Anhedonia, or the inability to experience pleasure from activities usually found to be enjoyable, is a key feature of depression, and suggests that there may be a deficit in the reward circuitry of the brain in this disorder. Dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain that project to the nucleus accumbens (NAc) have been implicated in reward recognition and initiation of reward utilization. Alterations in the function of this pathway could potentially underlie some of the behavioral deficits seen in people with depression.

Two in vivo firing patterns have been identified in dopaminergic VTA neurons: 1) low frequency tonic firing, and 2) high frequency phasic firing. Previously, phasic firing was shown to be upregulated by repeated social-defeat stress (a mouse model of depression) in susceptible mice, whereas mice resilient to the effects of repeated social-defeat showed no firing rate change.

Dr. Eric Nestler’s lab at Icahn School of Medicine at Mount Sinai in New York used optogenetic techniques to drive different firing patterns in dopaminergic VTA neurons in order to assess whether phasic firing patterns could induce depression-like behaviors in mice. They injected double floxed Cre-dependent AAV virus expressing channelrhodopsin-2 fused with enhanced yellow fluorescent protein (ChR2-eYFP) into the VTA of tyrosine hydroxylase (TH)-Cre mice to target expression of ChR2-eYFP to dopaminergic VTA neurons. VTA neurons were driven via activation of ChR2 at either a low frequency tonic pattern or a high frequency phasic pattern during a subthreshold social-defeat stress paradigm. Mice that received phasic stimulation showed a significant increase in depression-like behavior compared to mice receiving tonic stimulation. The depression-like phenotype was characterized by decreased social interaction with another mouse and decreased sucrose preference.


Chaudhury et al. (2013) then assessed whether phasic firing in VTA neurons could confer susceptibility in mice resilient to the social-defeat paradigm. A standard 10-day social-defeat paradigm was performed in wild-type mice, and a social-interaction test was then performed to identify resilient mice. HSV-ChR2-eYFP virus was injected into the VTA of resilient mice, and a second social-interaction test was then performed while undergoing optogenetic phasic stimulation of VTA neurons. The behavioral phenotype of these mice switched from resilient to susceptible, as shown by a decrease in social interaction and a decrease in sucrose preference 12 hours after optogenetic activation of VTA neurons. VTA neurons exhibited sustained alterations in excitability 12 hours after optogenetic activation, evidenced by increased spontaneous and evoked activity. This increased excitability may explain the decreased sucrose preference seen 12 hours after VTA neuronal stimulation in the social-interaction test.

Given that VTA dopamine neurons project to numerous brain areas, they wanted to test the role of the VTA-NAc pathway specifically in mediating the depression-related phenotype. Replication-defective pseudorabies virus expressing Cre (PRV-Cre) was injected into the NAc, and the Cre-dependent AAV ChR2-eYFP virus was injected into the VTA. This combination caused expression of ChR2 in only NAc-projecting VTA neurons. Mice were subjected to the subthreshold social-defeat paradigm, and then 24 hours later optogenetic stimulation of VTA neurons was performed during the social-interaction test. This manipulation reliably induced the depression-related phenotype of increased social avoidance and decreased sucrose preference. Similar methodology was employed when testing the effects of inhibiting this pathway, but an AAV halorhodopsin-eYFP virus was injected into the VTA instead. Inhibition of VTA neurons during the social-interaction test induced resilience to the depression-related phenotype, with increased social interaction and increased sucrose preference.


Manipulation of firing rates in VTA neurons projecting to the medial prefrontal cortex (mPFC) were also performed in this study using ChR2 and halorhodopsin, and the same methodologies that were used to study the VTA-NAc pathways were employed. Optogenetically induced phasic firing of VTA-mPFC neurons had no effect on social interaction and sucrose preference after subthreshold social defeat. Inhibition of VTA-mPFC neuronal activity via halorhodopsin activation during the social-interaction test induced a susceptible phenotype (decreased social interaction) after subthreshold social defeat, but no difference in sucrose preference was observed.

The results of these studies delineate neural circuitry involved in the induction of depression-like behavior after social-defeat stress, specifically the VTA-NAc pathway mediating anhedonia-like behavior. As we begin to unravel the neurobiological complexity of depression and other psychiatric illnesses, new therapeutic strategies can be created to more selectively target pathways responsible for the behavioral abnormalities seen in these disorders.

To learn more about the work conducted in Dr. Nestler’s lab, please attend his talk this Tuesday, February 28, at 4:00pm in the Center for Neural Circuits and Behavior.

Molly Kwiatkowski is a third year MD/PhD student in the Young lab located in the Consortium for Translational Research in Neuropsychopharmacology. Her work focuses on elucidating neural mechanisms underlying psychiatric disorders such as bipolar disorder.



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