Glutamatergic VP neurons constitute a noncanonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons and adaptively constrain reward seeking.

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A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

AMPA receptors (AMPARs) are present throughout the CNS and mediate the majority of fast excitatory neurotransmission. AMPARs are implicated in CNS diseases such as Alzheimer's, Parkinson's, and epilepsy. Recently, the first AMPAR-selective drug was approved in the form of perampanel for treatment of epilepsy. Perampanel is a negative allosteric modulators (NAMs), inhibiting AMPAR activity via a poorly understood mechanism.Little is known about the location and structure of binding sites for perampanel or other prototypical AMPAR NAMs such as GYKI-53,655 and CP-465,022. Identifying NAM binding sites and binding modes is prerequisite to understanding the molecular mechanism that underlies negative allosteric modulation of AMPAR function and is important for future development of other NAMs. This project aims to characterize the binding sites and binding modes of perampanel and other NAMs. AMPARs are tetrameric assemblies of subunits with a highly modular structure comprising two large extracellular domains -the amino-terminal domain and the ligand-binding domain -connected to the transmembrane domain via three flexible linkers (denoted S1-M1, S2-M3, and S2-M4). Previous work has identified positions within these linkers to control NAM potency (Balannik et al., 2005, Neuron). To identify additional residues that participate in NAM interaction, mutational scanning was performed of the S1-M1 and S2-M4 linker regions. 48 point mutants were functionally characterized using an intracellular calcium imaging assay. For the 37 mutants with intact receptor function, IC 50 was determined for four prototypical NAMs, including perampanel, to identify mutant effects on NAM potency. Several mutants were found having >5-fold change in IC 50 of one or more NAMs and further characterized by two-electrode voltage clamp electrophysiology. The mutational dataset will be used to guide molecular modeling studies of NAM binding modes to the receptor.

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