Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum

Abstract

The ventral pallidum (VP) lies at the interface between sensory, motor, and cognitive processing—with a particular role in mounting behavioral responses to rewards. Though the VP is predominantly GABAergic, glutamate neurons were recently identified, though their relative abundances and respective roles are unknown. Here, we show that VP glutamate neurons are concentrated in the rostral ventromedial VP and project to qualitatively similar targets as do VP GABA neurons. At the functional level, we used optogenetics to show that activity in VP GABA neurons can drive positive reinforcement, particularly through projections to the ventral tegmental area (VTA). On the other hand, activation of VP glutamate neurons leads to behavioral avoidance, particularly through projections to the lateral habenula. These findings highlight cell-type and projection-target specific roles for VP neurons in behavioral reinforcement, dysregulation of which could contribute to the emergence of negative symptoms associated with drug addiction and other neuropsychiatric disease.

Complementary roles for ventral pallidum cell types and their projections in relapse

“…We studied the cellular and circuit architecture for relapse control in ventral striatopallidal pathways, showing how different forms of relapse are assembled from VP cell populations and their projections. Our findings add to an emerging literature showing that the functional diversity in the ventral striatopallidal system can be resolved by analyses of different families of VP neurons and their projection targets (Richard et al, 2016;Knowland et al, 2017;Faget et al, 2018;Tooley et al, 2018). In the context of relapse to drug seeking, our findings raise the possibility that treatments targeting these different ventral striatopallidal pathways may provide one approach to tailored interventions for different forms of relapse.…”

“…The role of VP vGlut2 neurons in promoting or preventing relapse remains to be determined. These neurons have been implicated in aversion and behavioral avoidance via their projections to the lateral habenula (Knowland et al, 2017;Faget et al, 2018) and this same projection acts to constrain reward seeking (Tooley et al, 2018). One common feature of tests in both the extinction and training contexts here was that the reinforcer was absent and these tests were under extinction conditions.…”

“…A VP àVTA pathway is a second plausible candidate for VP PV contributions to relapse. VP PV provide monosynaptic input to VTA dopamine and GABAergic neurons (Knowland et al, 2017;Faget et al, 2018). VP inputs to VTA are recruited during different forms of relapse (Mahler and Aston-Jones, 2012;Mahler et al, 2014;Prasad and McNally, 2016), and non-selective chemogenetic disconnection of VP neurons from VTA reduces relapse (Mahler et al, 2014;Prasad and McNally, 2016) To determine whether VP PV contributions to relapse depend on VTA, we used the three group chemogenetic disconnection design (PV-Cre+ Contra n = 9 , PV-Cre-Contra n = 7 , PV-Cre+ Ipsi n = 6) (Figure 4D, E).…”

“…Further, VP neurons form multiple output pathways, including to lateral hypothalamus, subthalamic nucleus, lateral habenula, and ventral tegmental area as well as prefrontal cortex, amygdala, and nucleus accumbens (Haber et al, 1985;Zahm et al, 1987;Root et al, 2015). Recent work has begun to show how this cell-type and projection heterogeneity relates to different behavioral states (Knowland et al, 2017;Faget et al, 2018;Tooley et al, 2018). Yet, how the role for VP in relapse relates to this cell-type and projection heterogeneity remains poorly understood.…”

Opposite responses to aversive stimuli in lateral habenula neurons

“…Remarkably, the LHb receives afferents from diverse brain regions involved in aversion processing (Tan et al, 2012) and containing GABAergic cells (Meye, Lecca, Valentinova, & Mameli, 2013). Particularly, neurons in the VTA, Lateral hypothalamus (LH), Lateral Preoptic Area (LPO) and Ventral Pallidum (VP) project GABAergic axons to the medial portion of the LHb (Barker et al, 2017;Faget et al, 2018;Lammel et al, 2012;Root, Mejias-Aponte, Qi, & Morales, 2014;Root, Mejias-Aponte, Zhang, et al, 2014;Stamatakis et al, 2016). Therefore, any of these regions may drive Fs-mediated inhibition.…”