Stewart Clark PhD
Stewart Clark
PhD
Associate Professor
Department of Pharmacology and Toxicology
Jacobs School of Medicine & Biomedical Sciences
Specialty/Research Focus
Behavioral Neuroscience; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Neuroscience
Professional Summary:
The goal of my research is to elucidate the endogenous role of two neuropeptide systems and their potential as therapeutic targets; urotensin II (UII) and neuropeptide S (NPS). Both of these peptides regulate basal ganglia function through G protein-coupled receptor (GPCR) mediated intracellular signals. The basal ganglia are critical in motivated behavior (e.g. food seeking), voluntary movement, and the expression of habits (e.g. compulsions). Basal ganglia dysfunction results in neurological disorders as diverse as Parkinsonism and drug addiction. GPCRs are proven to be amenable to drug development and are targeted by over 30 percent of present day pharmaceuticals. My goal is to exploit the UII and NPS systems to improve the medical treatment of neurological 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) 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). Our selective cholinergic depletion and a viral-mediated tauopathy rat models are the first to specifically model PSP, and we are further characterizing these models in hope of using them for future drug discovery.
3) During my graduate and post-doctoral training it was found that the central brain administration of neuropeptide S (NPS) in mice enhances memory, is anxiolytic-like (reduced anxiety) and produces hyperlocomotor (increased movement) (Xu et al., 2004; Jungling et al., 2008; Duangdao et al., 2009; Okamura et al., 2011). This is a highly unique behavioral profile. Typically drugs that induce activity and arousal increase anxiety-like behaviors, while drugs that are anxiolytic generally have sedative effects and impair memory. Therefore, the NPS-system could be a therapeutic target for disorders for which fast-acting anxiolytics that augment memory formation would be beneficial (e.g. post-traumatic stress disorder (PTSD)).
In collaboration with the Drug Discovery Center at Research Triangle Institute, we are testing new small molecule NPSR-targeted drug-like compounds.
4) In addition to Drug Discovery for new anxiolytics (#3 above), my lab is also actively testing NPSR ligands for their ability to curb the intake and seeking of drugs of abuse. Current work centers on testing NPSR biased agonists in models of the relapse of drug taking behavior.
Education and Training:
- Fellowship, Post-Doctoral, University of California, Irvine (2011)
- Fellowship, Post-Doctoral, Center for Addiction and Mental Health (2006)
- PhD, Molecular Neuropharmacology, University of California, Irvine (2003)
- BS, Biology/Psychology, McMaster University (1997)
Employment:
- Associate Professor, Pharmacology and Toxicology, University at Buffalo (2019-present)
- Assistant Professor, Pharmacology and Toxicology, University at Buffalo (2011–2019)
Awards and Honors:
- Distinguished Research Mentor Award (2022)
- President Emeritus and Mrs. Meyerson Award for Distinguished Undergraduate Teaching and Mentoring (2022)
- Young Investigator Travel Award (2012)
- NIDA Travel Award (2010)
- Post-Doctoral Fellowship (2007)
- Travel Award (2005)
- Post-Doctoral Fellowship (2004)
Grants and Sponsored Research:
- August 2020–August 2024
Tau accumulation in the pedunculopontine tegmentum as an early node in Progressive Supranuclear Palsy pathogenesis.
NINDS
Role: Principal Investigator - December 2019–October 2023
Small molecule biased agonists of the NPS receptor
NIMH
Role: Principal Investigator - February 2019–February 2022
Dissecting the Paradox of the Neuropeptide S System
NIDA
Role: Principal Investigator
Journal Articles:
- Costa PC, Salinas B, Wojciechowski A, Wood SK, Runyon S, Clark SD. (2024) The Influence of the Estrous Cycle on Neuropeptide S Receptor-Mediated Behaviors. The Journal of pharmacology and experimental therapeutics (Nov), 391(3): 460-471. doi:10.1124/jpet.124.002415
- Angelakos CC, Girven KS, Liu Y, Gonzalez OC, Murphy KR, Jennings KJ, Giardino WJ, Zweifel LS, Suko A, Palmiter RD, Clark SD, Krasnow MA, Bruchas MR, de Lecea L. (2023) A cluster of neuropeptide S neurons regulates breathing and arousal. Current biology : CB (Dec), 33(24): 5439-5455.e7.
- Huang Y, Wojciechowski A, Feldman K, Ettaro R, Veros K, Ritter M, Carvalho Costa P, DiStasio J, Peirick JJ, Reissner KJ, Runyon SP, Clark SD. (2023) RTI-263, a biased neuropeptide S receptor agonist that retains an anxiolytic effect, attenuates cocaine-seeking behavior in rats. Neuropharmacology (Dec), 241: 109743.
- Park J, Moon JH, O'Shea H, Shin D, Hwang SU, Li L, Lee H, Brimble E, Lee J, Clark S, Lee SK, Jeon S. (2023) The patient-specific mouse model with Foxg1 frameshift mutation uncovers the pathophysiology of FOXG1 syndrome. Research square (Jun). doi:10.21203/rs.3.rs-2953760/v1
- King G, Veros KM, MacLaren DAA, Leigh MPK, Spernyak JA, Clark SD. (2021) Human Wildtype Tau Expression in Cholinergic Pedunculopontine Tegmental Neurons is Sufficient to Produce PSP-like Behavioral Deficits and Neuropathology. The European journal of neuroscience (Oct)
- Zarkin A, Jahan R, Uprety R, Zhang Y, McElhinny C, Snyder R, Gay E, Jewula G, Bool H, Clark SD, Runyon S. (2021) Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core. Pharmaceuticals (Basel, Switzerland) (Sep), 14(10) doi:10.3390/ph14101024
- Chambers NE, Coyle M, Sergio J, Lanza K, Saito C, Topping B, Clark SD, Bishop C. (2021) Effects of pedunculopontine nucleus cholinergic lesion on gait and dyskinesia in hemiparkinsonian rats. The European journal of neuroscience (Jan), 53(8): 2835-2847.
- Ettaro R, Laudermilk L, Clark SD, Maitra R. (2020) Behavioral assessment of rimonabant under acute and chronic conditions. Behavioural brain research (Jul), 390: 112697. doi:10.1016/j.bbr.2020.112697
- Ettaro R, Markovic T, Daniels D, MacLaren DA, Clark SD. (2020) Microinjection of urotensin II into the pedunculopontine tegmentum leads to an increase in the consumption of sweet tastants. Physiology & behavior (Mar), 215: 112775.
- MacLaren DAA, Ljungberg TL, Griffin ME, Clark SD. (2018) Pedunculopontine tegmentum cholinergic loss leads to a progressive decline in motor abilities and neuropathological changes resembling progressive supranuclear palsy. The European journal of neuroscience (Dec), 48(12): 3477-3497.
- Clark SD, Kenakin TP, Gertz S, Hassler C, Gay EA, Langston TL, Reinscheid RK, Runyon SP, Clark S. (2017) Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation. Neuropharmacology (May), 118: 69-78.
- Mueller LE, Kausch MA, Markovic T, MacLaren DA, Dietz DM, Park J, Clark SD, Clark S. (2015) Intra-ventral tegmental area microinjections of urotensin II modulate the effects of cocaine. Behav Brain Res (Feb), 278: 271-279.
- MacLaren DA, Markovic T, Daniels D, Clark SD, Clark S. (2015) Enhanced consumption of salient solutions following pedunculopontine tegmental lesions. Neuroscience (Jan), 284: 381-399.
- Santollo J, Whalen PE, Speth RC, Clark SD, Daniels D, Clark S. (2014) Properly timed exposure to central ANG II prevents behavioral sensitization and changes in angiotensin receptor expression. Am J Physiol Regul Integr Comp Physiol (Dec), 307(12): 1396-1404.
- MacLaren DA, Markovic T, Clark SD, Clark S. (2014) Assessment of sensorimotor gating following selective lesions of cholinergic pedunculopontine neurons. Eur J Neurosci (Nov), 40(10): 3526-3537.
- MacLaren DA, Santini JA, Russell AL, Markovic T, Clark SD, Clark S. (2014) Deficits in motor performance after pedunculopontine lesions in rats--impairment depends on demands of task. Eur J Neurosci (Oct), 40(8): 3224-3236.
- Belaid H, Adrien J, Laffrat E, Tandé D, Karachi C, Grabli D, Arnulf I, Clark SD, Drouot X, Hirsch EC, François C, Clark S. (2014) Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion. J Neurosci (Jul), 34(27): 9124-9133.
- Cyr M, Parent MJ, Mechawar N, Rosa-Neto P, Soucy JP, Aliaga A, Kostikov A, Maclaren DA, Clark SD, Bedard MA, Clark S. (2014) PET imaging with [¹8F]fluoroethoxybenzovesamicol ([¹8F]FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat. Nucl Med Biol (Jan), 41(1): 96-101.
- Clark SD, Duangdao DM, Schulz S, Zhang L, Liu X, Xu YL, Reinscheid RK. (2011) Anatomical characterization of the neuropeptide S system in the mouse brain by in situ hybridization and immunohistochemistry. J Comp Neurol (Jul), 519(10): 1867-1893.
- Okamura N, Garau C, Duangdao DM, Clark SD, Jüngling K, Pape HC, Reinscheid RK, Clark S. (2011) Neuropeptide S enhances memory during the consolidation phase and interacts with noradrenergic systems in the brain. Neuropsychopharmacology (Mar), 36(4): 744-752.
- Si W, Aluisio L, Okamura N, Clark SD, Fraser I, Sutton SW, Bonaventure P, Reinscheid RK. (2010) Neuropeptide S stimulates dopaminergic neurotransmission in the medial prefrontal cortex. J Neurochem (Oct), 115(2): 475-482.
- Gill RS, Hsiung MS, Sum CS, Lavine N, Clark SD, Van Tol HH. (2010) The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2. Cell Signal (Feb), 22(2): 285-290.
- Clark SD, Tran HT, Zeng J, Reinscheid RK. (2010) Importance of extracellular loop one of the neuropeptide S receptor for biogenesis and function. Peptides (Jan), 31(1): 130-138.
- Duangdao DM, Clark SD, Okamura N, Reinscheid RK. (2009) Behavioral phenotyping of neuropeptide S receptor knockout mice. Behav Brain Res (Dec), 205(1): 1-9.
- Nagasaki H, Chung S, Dooley CT, Wang Z, Li C, Saito Y, Clark SD, Houghten RA, Civelli O. (2009) The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries. Eur J Pharmacol (Jan), 602(2-3): 194-202.
- Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu YL, Reinscheid RK, Pape HC, Clark S. (2008) Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron (Jul), 59(2): 298-310.
- Clark SD, Alderson HL, Winn P, Latimer MP, Nothacker HP, Civelli O. (2007) Fusion of diphtheria toxin and urotensin II produces a neurotoxin selective for cholinergic neurons in the rat mesopontine tegmentum. J Neurochem (Jul), 102(1): 112-120.
- Nothacker HP, Clark S. (2005) From heart to mind. The urotensin II system and its evolving neurophysiological role. FEBS J (Nov), 272(22): 5694-5702.
- Clark SD, Nothacker HP, Blaha CD, Tyler CJ, Duangdao DM, Grupke SL, Helton DR, Leonard CS, Civelli O. (2005) Urotensin II acts as a modulator of mesopontine cholinergic neurons. Brain Res (Oct), 1059(2): 139-148.
- Huitron-Resendiz S, Kristensen MP, Sánchez-Alavez M, Clark SD, Grupke SL, Tyler C, Suzuki C, Nothacker HP, Civelli O, Criado JR, Henriksen SJ, Leonard CS, de Lecea L, Clark S. (2005) Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons. J Neurosci (Jun), 25(23): 5465-5474.
- Van Craenenbroeck K, Clark SD, Cox MJ, Oak JN, Liu F, Van Tol HH. (2005) Folding efficiency is rate-limiting in dopamine D4 receptor biogenesis. J Biol Chem (May), 280(19): 19350-19357.
- Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, Civelli O. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron (Aug), 43(4): 487-497.
- Clark SD, Nothacker HP, Wang Z, Saito Y, Leslie FM, Civelli O. (2001) The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat. Brain Res (Dec), 923(1-2): 120-127.
Professional Memberships:
- American Society for Pharmaceutical and Experimental Therapeutics (ASPET); Member (2012–present)
- Member, Society for Neuroscience (1996–present)
Presentations:
- "My Path to Faculty" UB Biology Honors Program (2025)
- "An Orphan Grows Up: The Urotensin II System Leads to a Preclinical Model of Progressive Supranuclear Palsy" Research Triangle Institute (2024)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects" Rutgers University (2024)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects." University of North Carolina, Chapel Hill, (2024)
- "My Path to Faculty" UB Biology Honors Program (2024)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects" University of South Carolina (2024)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects." Pharmaceutical Sciences Seminar Series, University at Buffalo (2023)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects." Pharmaceutical Sciences Seminar Series (2023)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects." Psychology Department Brown Bag (2023)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects." MD-PhD Seminar class, University at Buffalo (2023)
- "Neuropeptide S: progress towards the development of a fast-acting non-sedative anxiolytic with memory enhancing effects." Psychology Department Brown Bag, University at Buffalo (2023)
- "The Role of the Cholinergic Pedunculopontine in Parkinsonisms" Rossy Progressive Supranuclear Palsy Center Research Meeting (2021)
- "An Orphan Grows-Up: The Characterization of the Urotensin II System Leads to Insights into Parkinsonism." Pharmacology and Toxicology Seminar Series (2018)
- "A Preclinical Model of Progressive Supranuclear Palsy." CurePSP Annual International Research Symposium (2017)
- "Development of Neuropeptide S Receptor Targeted Compounds as Potential Therapies for Anxiety-Related Disorders." Department of Psychiatry, Erie County Medical Center (2017)
- "Progress Toward an Animal Model of PSP" PSP/CBD Family Conference (2017)
- "Development of Neuropeptide S Receptor Targeted Compounds as Potential Therapies for Anxiety-Related Disorders." Upstate New York Pharmacology Society Annual Meeting (2017)
- "A Work in Progress: A Model of Progressive Supranuclear Palsy" PSP/Lewy Body Disease Think Tank - Symposium VI (2017)
- "An Orphan Grows-Up: The Characterization of the Urotensin II System Leads to Insights into Parkinsonism" Binghamton University (2016)
- "An Orphan Grows-Up: The Characterization of the Urotensin II System Leads to Insights into Parkinsonism" Pharmacology and Toxicology Seminar Series (2016)
- "Two Neuropeptides, One Strategy. University of Strathclyde" Institute of Pharmacy and Biomedical Sciences (2010)
Service Activities:
- Behavioural Brain Research; Reviewer (2025)
- Search Committee - Associate Dean of Undergraduate Education and Undergraduate Research and Scholarship; Member (2024–present)
- SURF 2024 Networking Event; Host (2024)
- ASPET Program Committee (National); Member (at-large) (2024–present)
- Special Emphasis Panel/Scientific Review Group 2023/01 AGCD-1; Reviewer (Standing Member) (2024–present)
- NIH, National Institute on Drug Abuse Drug Supply Program; Reviewer (2024)
- Post-Doctoral Showcase, Neuropharmacology division, ASPET; Presentation Judge (2024)
- Special Emphasis Panel administered by National Center for Advancing Translational Sciences (NCATS); Reviewer (2024)
- JPET; Reviewer (2024)
- Admissions Committee for UB MD-PhD Program; Member (2023–present)
- CSTEP Research Symposium Judge; Judge (2023)
- Faculty Search Committee; Member (2022–2023)
- Lecturer Search Committee; Member (2022–2023)
- Selection Committee for the 2023 President Emeritus and Mrs. Meyerson Award for Distinguished Undergraduate Teaching and Mentoring; Reviewer (2022–2023)
- Special Emphasis Panel/Scientific Review Group AGCD-1; Reviewer (Ad Hoc) (2022–2024)
- CSTEP Research Symposium Judge; Judge (2022)
- Western University, London, ON, Canada. Neuroscience graduate student Faraj Haddad’s PhD defense – Mentor: Susanne Schmid; External Reviewer (2022)
- Leiboff Award Selection Committee, Behavioral Neuroscience Program - Department of Psychology; Reviewer (2022)
- LAF-BEB Supervisor Search Committee; Reviewer (2022)
- ACS Chemical Neuroscience Journal; Reviewer (2021–present)
- Reviewed Letters of Intent for the CTSI diversity supplements; ad hoc Reviewer (2021)
- Frontiers Cellular Neuroscience Journal; Reviewer (2021–present)
- PMY 405/406 Curriculum Committee; Member (2021)
- University Faculty Senate; Member (2020–2022)
- Frontiers Pharmacology; Reviewer (2020–present)
- Neurotherapeutics; Reviewer (2020–present)
- Review the ASPET-SURF Applicants (for CLIMB-UP); ad hoc Reviewer (2020–present)
- Neuropharmacology Executive Committee of the American Society for Pharmacology and Experimental Therapeutics (ASPET); Member (2016–2020)
- Admissions Committee; Co-Chair (2011–present)