The function of GABA/glutamate co-release in the habenula

ABSTRACT: Balance of excitation and inhibition is critical for proper function of the nervous system. In many brain regions, there is feedforward and feedback inhibition from interneurons that release the inhibitory transmitter GABA to balance the release of excitatory glutamate from long-range inputs. However, in the lateral habenula (LHb) - a key component of the brain's reward system – there is little, if any, feedforward or feedback inhibition and few inhibitory neurons. Instead, our work suggests that excitatory/inhibitory balance is achieved, at least partly, by co-release of GABA with glutamate from individual inputs arising from the globus pallidus (GPi), a major input to the LHb. The activity of GPi inputs to the LHb and the activity of LHb neurons affect motivational vigor. They are also phasically excited by negative environmental feedback and phasically inhibited by positive environmental feedback, which guide learning. Rats with low motivation and negatively biased feedback sensitivity have elevated LHb activity and unbalanced GABA and glutamate signaling from the GPi to LHb. Based on these observations, we believe that GABA/glutamate balance from GPi to the LHb is important for (1) regulating tonic (basal) LHb activity and motivational vigor, and (2) bidirectional phasic signaling of negative and positive feedback in the LHb and behavioral sensitivity to negative and positive feedback. The objective of this grant is to test these hypotheses by artificially manipulating GABA/glutamate balance from GPi to LHb in mice and measuring (1) tonic LHb activity and motivation, and (2) phasic LHb responses and behavioral sensitivity to negative feedback (reward omission) and positive feedback (reward). Based on studies of GABA/glutamate co- release in the hippocampus, we further hypothesize that long-term changes in tonic and/or phasic LHb activity will induce homeostatic plasticity of GABA/glutamate co-transmission from the GPi to LHb. We believe this study is significant because it will reveal the relationship between excitatory/inhibitory balance and fundamental motivational and learning processes that are affected in many psychiatric disorders, while also investigating the function of GABA/glutamate co-transmission.