Impairments in laterodorsal tegmentum to VTA projections underlie glucocorticoid-triggered reward deficits.

Bárbara Coimbra,Sónia Borges,Carina Soares-Cunha,Nuno Sousa,Ana João Rodrigues,Nivaldo Ap Vasconcelos

doi:10.7554/elife.25843

Abstract

Ventral tegmental area (VTA) activity is critical for reward/reinforcement and is tightly modulated by the laterodorsal tegmentum (LDT). In utero exposure to glucocorticoids (iuGC) triggers prominent motivation deficits but nothing is known about the impact of this exposure in the LDT-VTA circuit. We show that iuGC-rats have long-lasting changes in cholinergic markers in the LDT, together with a decrease in LDT basal neuronal activity. Interestingly, upon LDT stimulation, iuGC animals present a decrease in the magnitude of excitation and an increase in VTA inhibition, as a result of a shift in the type of cells that respond to the stimulus. In agreement with LDT-VTA dysfunction, we show that iuGC animals present motivational deficits that are rescued by selective optogenetic activation of this pathway. Importantly, we also show that LDT-VTA optogenetic stimulation is reinforcing, and that iuGC animals are more susceptible to the reinforcing properties of LDT-VTA stimulation.

Highlights

The ventral tegmental area (VTA) is an heterogeneous brain region containing distinctive neuronal populations essential for the expression of motivated behaviors and reinforcement (Berridge and Robinson, 1998; Wise, 2004; Bayer and Glimcher, 2005; Fields et al, 2007; Berridge, 2007; van Zessen et al, 2012)
We quantified ChAT+ cells in the laterodorsal tegmentum (LDT) of 3, 30 and 90 days old animals (Figure 1a–c) and observed an effect of In utero exposure to glucocorticoids (iuGC) treatment (Two-way analysis of variance (ANOVA); F(1,25) = 19.31, p=0.0002). iuGC animals had a significant increase in the density of the cholinergic population of the LDT at 30 days of age (post-hoc Bonferroni; control group (CTR)(30 days) vs. iuGC(30 days): t(25) = 2.616, p=0.0446) that persisted until adulthood (post-hoc Bonferroni; CTR(90 days) vs. iuGC(90 days): t(25) = 3.971, p=0.0016)
We found a significant effect of iuGC treatment in ChAT (Two-way ANOVA; F(1,24) = 26.27, p

Summary

Introduction

The ventral tegmental area (VTA) is an heterogeneous brain region containing distinctive neuronal populations essential for the expression of motivated behaviors and reinforcement (Berridge and Robinson, 1998; Wise, 2004; Bayer and Glimcher, 2005; Fields et al, 2007; Berridge, 2007; van Zessen et al, 2012). Several studies have shown that exposure to unexpected rewards, or cues that predict rewards, can activate VTA dopaminergic neurons culminating in the release of dopamine in the nucleus accumbens (NAc) (Roitman et al, 2004; Stuber et al, 2005; Stuber et al, 2008; Schultz et al, 1997; Bromberg-Martin et al, 2010) This activity is tightly modulated by cholinergic projections (Omelchenko and Sesack, 2005; Omelchenko and Sesack, 2006), with an additional contribution of glutamatergic projections, arising from the LDT (Cornwall et al, 1990; Oakman et al, 1999; Lammel et al, 2012). Recent studies have shown that optogenetic stimulation of LDT neurons that project to the VTA enhances conditioned place preference (Lammel et al, 2012) and operant responses in rodents (Steidl and Veverka, 2015)

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