The Pallidohabenular System in Parkinsonism - SUMMARY The basal ganglia serve many behavioral functions, ranging from the regulation of movements and cognition to the modulation of valence and mood. This functional heterogeneity is reflected in the composition of the principal output nucleus of the primate basal ganglia, the internal pallidal segment (GPi). This nucleus contains two distinct populations of projection neurons. A major group of cells in the core of GPi projects to the ventral thalamus (and other targets) and is known to be involved in motor functions. Much less explored is a second population of neurons that is confined to the GPi periphery and projects exclusively to the lateral habenula (LHb). Studies in monkeys and rodents have shown that this group of cells communicates negative valence signals to the LHb which, in turn, regulates the activity of dopaminergic and serotonergic brainstem areas that are involved in the control of reward responses and mood. Based on literature evidence and our preliminary data, we hypothesize that pallidohabenular neurons differ from the pallidothalamic cells in terms of their synaptic connectivity, neurotransmitter content and electrophysiological responses to dopamine depletion in the parkinsonian state. To test this hypothesis, the following studies are proposed: In aim 1, we will analyze the synaptic connectivity and prevalence of cortical glutamatergic inputs to pallidohabenular neurons, and study their anatomical relationship to other afferents in normal and MPTP-treated parkinsonian rhesus monkeys. In aim 2, we will compare the neurotransmitter phenotype and synaptic architecture of pallidohabenular terminals in these animals. To achieve these goals, we will combine high-resolution 3D immuno-electron microscopy with viral vector tracing methods. These anatomical experiments will generate in-depth knowledge of the microcircuits that regulates the activity and synaptic transmission of primate pallidohabenular neurons in the normal and parkinsonian states. Studies under aim 3 will functionally assess parkinsonism-associated activity changes in pallidohabenular neurons and probe their impact upon LHb neurons, using state-of the art optotagging approaches to identify these cells in vivo. The available evidence leads us to hypothesize that the activity of pallidohabenular neurons is increased in the parkinsonian state, resulting in a pathological increase of LHb neurons activity. It is possible that these rate changes are associated with oscillatory synchrony, as is the case for other GPi neurons. Increased activity along the pallidohabenular axis could specifically contribute to the emergence of parkinsonism-associated depression and other psychiatric features of Parkinson's disease. Given the importance of Deep Brain Stimulation (DBS) therapy for the treatment of parkinsonism, we will also examine whether electrical stimulation in the subthalamic nucleus alters the firing of LHb neurons, and whether such changes correlate with the emergence of depressive-like behaviors. Taken together, the results of this project will increase our knowledge of the anatomy and function of the primate pallidohabenular system under healthy conditions, and elucidate changes within this system in the parkinsonian state.
