Mesolimbic Dopamine Neurons in the Brain Reward Circuit Mediate Susceptibility to Social Defeat and Antidepressant Action

Abstract

We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (I h ) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of I h inhibitors ZD7288 (0.1 g) or DK-AH 269 (0.6 g) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.

Jump-starting natural resilience reverses stress susceptibility

“…My studies utilized the well-established social defeat stress mouse model of depression. An increase in the firing rate and bursting events was found in the VTA DA neurons of the brain reward circuitry in susceptible mice, but not in the resilient subgroup ( 16,17). Our work further showed that this hyperactivity was causally linked to the susceptible pehonotype ( 18,19).…”

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…34 The neuronal circuits that underpin stress effects are complex and far from being understood, but an increasing body of literature strongly supports a pivotal role of the DA reward system. 23,24,26,34 SD triggers pronounced increases in VTA DA neuron spontaneous activity, which is causally associated with anhedonia and social aversion. Pre-exposure to stress is also well acknowledged to facilitate self-administration and precipitate relapse, and this is proposed to rely on changes of VTA DA neurons activity.…”

“…[19][20][21] Chronic social defeat stress (SD) parses the enduring behavioral abnormalities induced by stress and is believed to capture features of depressive-like states. 22 SD triggers an increase in DA VTA neuronal activity 23 that drives social avoidance. DA cells exhibit two distinct patterns of in vivo activity-a low-frequency tonic firing and a high-frequency phasic firing-with the possibility of switching amongst these modes.…”

Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress

“…In contrast to the attenuation of the mesocortical dopaminergic pathway, it has been shown that repeated social defeat stress increases firings of VTA dopamine neurons for at least several weeks after the last defeat episode (17,18). This increased excitability is accompanied by augmented Ih currents through hyperpolarizationactivated cyclic nucleotide gated (HCN) channels (18).…”

“…This increased excitability is accompanied by augmented Ih currents through hyperpolarizationactivated cyclic nucleotide gated (HCN) channels (18). Local infusion of HCN-channel blocker at one week following the last defeat episode ameliorates depressive behaviors such as social avoidance and reduced sucrose consumption (18).…”