Limbic pallidal circuits linked to apathy in Parkinson’s disease during subthalamic deep brain stimulation

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PROJECT SUMMARY/ABSTARCT Parkinson’s disease (PD) is a neurodegenerative disease that presents both motor and non-motor disturbances. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficacious in treating cardinal motor features of PD. In contrast, non-motor symptoms typically do not improve and may even worsen with DBS. Electrode placement in the STN is targeted to the motor subregion, but off-target activation of limbic and associative circuits, and the resultant adaptations in circuit activity after DBS, likely lead to non-motor adverse effects. The long-term goals of our Research Program are to i) identify biomarkers that can be used to predict when DBS may result in disorders of mood and cognition, and ii) improve DBS stimulation paradigms to reduce non-motor adverse effects. Apathy is a prevalent non-motor symptom of PD that frequently worsens after STN- DBS to significantly impair quality of life. Thus, the current R21 Study will focus on apathy. Accordingly, the overall objective of the Study is to determine the mechanism(s) and anatomical substrate(s) of apathy after STN-DBS in a rat model of PD. Highly selective optogenetic stimulation approaches will be used to isolate the contribution of STN outputs known to regulate apathy; i.e., STN glutamatergic efferents to the ventral pallidum (VP). The Study central hypotheses are that i) apathy-like behaviors during STN-DBS treatments in a rat model of PD reflect neuroplasticity in downstream limbic structures that regulate motivation, and ii) activation of STN- VP glutamatergic efferents in a rat model of PD is sufficient to mediate apathy-like behaviors and circuit changes. Specific Aim 1 will assess the temporal development and persistence of apathy-like and motor behaviors in chronic optogenetic STN-DBS. Specific Aim 2 will assess whether selective activation of glutamatergic STN-VP projections during STN-DBS is sufficient to produce apathy-like behaviors. Comprehensive behavioral assessments will include PD-like motor and apathy profiles. Circuit consequences will be revealed by measuring post mortem markers of neuronal activity. The proposed research is innovative as these studies will combine established techniques to decipher a currently undescribed pathogenic circuit that likely underpins non-motor behaviors associated with STN-DBS. The research is significant for outcomes are expected to i) determine the role of specific STN glutamatergic projections to the VP in PD-like behaviors, ii) indicate the potential of STN-VP circuits to serve as biomarkers for apathy during DBS, and iii) form the basis for future NIH-funded projects that will lead to the design of novel DBS protocols that improve outcomes.