Differential modulation of GABAergic and glutamatergic neurons in the ventral pallidum by GABA and neuropeptides.

The ventral pallidum (VP) is an integral locus in the reward circuitry and a major target of GABAergic innervation of both D1-medium spiny neurons (MSNs) and D2-MSNs from the nucleus accumbens (NAc). The VP contains populations of GABAergic (VPGABA, GAD2(+) or vGlut(-)) and glutamatergic (VPglutamate, GAD2(-) or vGlut(+)) cells that facilitate positive reinforcement and behavioral avoidance, respectively. MSN efferents to the VP exert opponent control over behavioral reinforcement with activation of D1-MSN afferents promoting and D2-MSN afferents inhibiting reward seeking. How this afferent-specific and cell type-specific control of reward-seeking is integrated remains largely unknown.Besides GABA, D1-MSNs co-release substance P to stimulate NK1 receptors and D2-MSNs co-release enkephalin to activate mu-opioid and delta-opioid receptors. These neuropeptides act in the VP to alter appetitive behavior and reward-seeking.Using a combination of optogenetics and patch-clamp electrophysiology in mice we found that GAD2(-) cells receive weaker GABA input from D1-MSN but GAD2(+) receive comparable GABAergic input from both afferents types. Pharmacological activation of µ-opioid receptors induced an equally strong presynaptic inhibition of GABA and glutamate transmission on both cell types. Interestingly, MOR activation hyperpolarized VPGABA but not vGlut(+). NK1R activation inhibited glutamatergic transmission only on vGlut(+) cells.Our results indicate that the afferent-specific release of GABA and neuropeptides from D1- and D2-MSNs can differentially influence VP neuronal subtypes. Significance Statement Little is known about the cell type-specific modulation of neurotransmission by the neuropeptides co-released with GABA from striatal D1 and D2 synapses. We explored the differential micro-circuitry of the D1 and D2 inputs to the GABAergic and glutamatergic neuronal subpopulations in the ventral pallidum. Based on differential electrophysiological actions of D1 and D2 GABAergic and peptidergic inputs we propose a circuit-based model that partly explains the different actions of D1- and D2-MSN afferents in the ventral pallidum to regulate reward behaviors.