Stewart Clark PhD

The goal of my research is the elucidation of the role of brainstem systems in motivated behaviors. My current focus is the function of neuropeptide systems, specifically urotensin II (UII). Ultimately I would like to exploit this system to better treat people with neuropsychiatric disorders.

Currently my lab is pursuing the following:

1) Determine the role of UIIR activation and the UIIR expressing neurons in reward-related behaviors:. Our results support the need for further investigation of the UII-system as a therapeutic target for treating drug abuse disorders. In addition, we are investigating the i) bias-signaling properties of the endogenous UIIR ligands, and ii) the impact of UIIR single-nucleotide polymorphisms on receptor signaling.

2) Establish the contribution of cholinergic PPT to Parkinsonism-related behaviors: We designed a toxin that selectively targets UIIR expressing neurons (cholinergic PPT). In rats the toxin-mediated lesion mimics Progressive Supranuclear Palsy (the most common atypical parkinsonism) on multiple fronts: selective ablation of cholinergic PPT neurons, impaired motor function, and deficits in acoustic startle reaction (MacLaren et al, 2014a; MacLaren et al, 2014b). Similarly, the collection of deficits found after non-selective manipulations of the PPT overlap with that of Parkinson’s Disease [e.g. reduced prepulse inhibition, impaired attention, cognitive deficits, sleep disturbances]. Traditional dopamine-depletion models do not produce similar sensorimotor and cognitive deficits. Therefore, PPT lesions as an adjunct or stand alone preclinical models of Parkinsonism may be useful in identifying non-dopaminergic pharmacotherapeutics. We are pursuing further studies utilizing our selective cholinergic depletion and a viral-mediated tauopathy method with support from the CurePSP Foundation.