KRISTEN A KEEFE portrait
  • Assistant Vice President, Office for Faculty, U of U Health
  • Associate Dean, Faculty Affairs, College Of Pharmacy
  • Professor, Pharmacology And Toxicology
801-585-7989

Research Statement

My laboratory is interested in the structure and function of the basal ganglia, a group of subcortical nuclei in the brain involved in the control of movement and cognition. The importance of the basal ganglia for normal behavior is highlighted by the profound deficits observed in patients with Parkinson's disease, Huntington's disease, schizophrenia, and drug addiction -- diseases that are associated with dysfunction in the basal ganglia. Our work determines the influence of both endogenous and exogenous chemicals on the function of neurons in the basal ganglia in an attempt to better understand:

1)  the role that glutamate (via NMDA receptors) and monoamines (dopamine and serotonin) play in regulating the activity of basal ganglia nuclei;

2)  the mechanisms by which drugs of abuse that affect the basal ganglia exert both their acute and long-lasting adverse effects, with a particular emphasis on how the function of astrocytes at the tripartite synapse are altered in the setting of drug addiction and contribute to development of habitual control over behavior; and

3)  the mechanisms by which the function of the basal ganglia can be beneficially altered by drugs to better treat sequelae associated with dysfunction in these nuclei.

We use numerous techniques to examine the effects of both endogenous and exogenous drugs on basal ganglia function.

These techniques include:

1)  Neurochemical approaches in the brain of awake animals to examine changes in the release of amino acid, monoamine, and neuropeptide neurotransmitters.

2)  In situ hybridization histochemistry to measure changes in the levels of messenger RNAs in brain neurons to examine short- and long-term changes in gene expression in neurons of the basal ganglia.

3)  Immunohistochemistry and western blotting to examine changes in protein expression in defined basal ganglia neurons and nuclei.

4)  Behavioral analyses of learning and memory processes mediated by corticostriatal circuits.

5)  Electrophysiology and imaging in collaboration with the Wilcox and West laboratories to assess changes in neuron and astrocyte functions.

Coupling these techniques, we can begin to understand how neurotransmitters and drugs acutely affect the function of basal ganglia neurons and the neuroadaptive changes that occur in response to neural injury in the basal ganglia and exposure to therapeutic and abused drugs.

Presentations

  • Scranton Brain and Behavior Conference, Invited Keynote Speaker, “"Consequences of methamphetamine-induced neurotoxicity on basal ganglia-mediated learning and memory processes, Scranton, PA. Invited Talk/Keynote, Presented, 03/05/2022.
  • 2019 Addictions Update: Science, Policy & Treatment, Invited speaker, “’Choosing’ To Use: Insights Into The Neurobiology Of Behavioral Choice,” Salt Lake City, UT . Invited Talk/Keynote, Presented, 06/13/2019.
  • International Behavioral Neuroscience Society meeting, Invited speaker in symposium, "Basic and Translational Aspects of Drug Addiction," British Columbia, Canada. Invited Talk/Keynote, Presented, 06/2015.
  • Dept. of Biology, Eastern Washington University, "Consequences of methamphetamine-induced neurotoxicity on molecular and behavioral functions of the basal ganglia" . Invited Talk/Keynote, Presented, 01/16/2015.
  • American Association of Colleges of Pharmacy, participant in session entitled, "Succession Planning in Academic Pharmacy," AACP Annual Meeting. Invited Talk/Keynote, Presented, 07/29/2014.
  • Dept. of Molecular Pharmacology, Rosalind Franklin University of Medicine and Science. Invited seminar speaker, "What a METH: Long-term consequences of METH-induced partial DA loss on phasic DA neurotransmission and basal ganglia-mediated learning and memory processes". Invited Talk/Keynote, Presented, 09/27/2012.
  • Dept. of Neurosciences, College of Medicine, The University of Toledo. Invited seminar speaker, "What a METH: Long-term consequences of METH-induced partial DA loss on phasic DA neurotransmission and basal ganglia-mediated learning and memory processes". Invited Talk/Keynote, Presented, 08/15/2012.
  • Dept. of Physiology and Developmental Biology, Brigham Young University. Invited seminar speaker, "Consequences of Methamphetamine-Induced Neurotoxicity on Molecular and Behavioral Functions of the Basal Ganglia". Invited Talk/Keynote, Presented, 09/15/2011.
  • 2011 Gordon Research Conference on Catecholamines, Invited speaker in session on Catecholamines in Neuropsychiatric/Neurological Disorders. Invited Talk/Keynote, Presented, 08/12/2011.
  • 44th Winter Conference on Brain Research, invited presenter in session entitled "Becoming addicted: The transition to dorsal striatum mediated drug-seeking behavior ", Keystone, CO. Invited Talk/Keynote, Presented, 01/27/2011.
  • Translational Research in Methamphetamine Addiction meeting. Session Chair (Pharmacology and Toxicology of Methamphetamine) and invited presentation entitled "Methamphetamine and basal ganglia dysregulation", Chico Hot Springs and Day Spa, Pray, Montana . Invited Talk/Keynote, Presented, 07/21/2010.
  • Dept. of Pharmacology and Toxicology Seminar Series, University of Utah, "Long-term consequences of methamphetamine-induced neurotoxicity on cellular, systems, and behavioral function of the basal ganglia" . Invited Talk/Keynote, Presented, 03/15/2010.
  • 2010 Society of Toxicology Meeting, "How to Identify your skills and passions". Invited presentation in panel entitled "Where do I go now? Rational career development planning for early-career scientists", Salt Lake City, UT. Invited Talk/Keynote, Presented, 03/09/2010.
  • 2009 National Meeting of Directors of Graduate Study in Pharmacology, “Selecting for Success in Graduate School and Beyond”, New Orleans, LA. Invited Talk/Keynote, Presented, 04/24/2009.
  • 42nd Winter Conference on Brain Research. Organizer and presenter in workshop entitled "One Model Doesn’t Fit All—Partial DA Loss and Striatal Function", Copper Mtn, CO. Invited Talk/Keynote, Presented, 01/30/2009.
  • Neurology Residents Lecture Series, University of Utah, “Introduction to the Autonomic Nervous System I and II”. Invited Talk/Keynote, Presented, 12/18/2008.
  • 2008 Bioscience Symposium, University of Utah, “Long-term consequences of methamphetamine-induced neurotoxicity on cellular, systems, and behavioral function of the dorsal striatum". Invited Talk/Keynote, Presented, 09/23/2008.
  • Dept. of Neuroscience, Medical University of South Carolina, “Long-term consequences of methamphetamine-induced neurotoxicity on cellular, systems, and behavioral function of the dorsal striatum". Invited Talk/Keynote, Presented, 05/01/2008.
  • 23rd Annual Spring Meeting, Center for Neurobiology of Learning and Memory, University of California, Irvine. "Long-term consequences of methamphetamine-induced neurotoxicity on cellular, systems, and behavioral function of the dorsal striatum". Invited Talk/Keynote, Presented, 04/18/2008.
  • 41st Winter Conference on Brain Research, invited presenter in scientific panel entitled "Learning and Plasticity: What’s Arc Got To Do with It?", Snowbird, UT. Invited Talk/Keynote, Presented, 02/01/2008.
  • 40th Winter Conference on Brain Research, invited presenter in scientific panel entitled “Skating on Thin “Ice”: Neurobiological and Behavioral Consequences of High Dose Methamphetamine.” Snowmass, CO. Invited Talk/Keynote, Presented, 01/2007.
  • 40th Winter Conference on Brain Research, organizer and presenter in scientific panel entitled “The glass ski boot: Fitting thalamic afferents into striatal anatomy and function.” Snowmass, CO. Invited Talk/Keynote, Presented, 01/2007.

Research Groups

  • Ashley Fricks-Gleason, Postdoc. 01/2010 - present.
  • Melissa Barker-Haliski, Graduate Student. 08/2009 - 04/2012.
  • Danielle Friend, Graduate Student. 07/2009 - present.
  • Amber Frye, Technician. 07/2009 - 08/2011.
  • Elissa Pastuzyn, Graduate Student. 07/2009 - present.
  • Jong-Hyun Son, Postdoc. 05/2009 - present.

Grants, Contracts & Research Gifts

  • Illudalic acid analogs as chemical probes for PTPRD activity in substance use disorders. PI: Barrios, Keefe, Dudley MPI. NIDA/NIH, 07/01/2022 - 06/30/2026. Total project budget to date: $1,999,354.00
  • Training in the Development of Novel Interventions for the Treatment of Neurological and Neurobehavioral Disorders. PI: Keefe, KA. NINDS/NIH, 07/15/2020 - 07/14/2025. Total project budget to date: $1,044,304.00
  • Exploring steroid-based therapies to reduce opioid abuse. PI: Bortolato/Peterson . NIDA/NIH, 04/15/2020 - 03/31/2022. Total project budget to date: $275,000.00
  • Astrocyte-mediated glutamate transport in dorsal striatum associated with habitual cocaine seeking. PI: Keefe, KA & Wilcox, KS. NIDA/NIH , 02/01/2019 - 01/31/2022. Total project budget to date: $377,438.00
  • Screening of Investigational Compounds to Treat, Modify, or Prevent Epilepsy for the NINDS Epilepsy Therapy Screening Program (ETSP): Addendum (Track three). PI: Wilcox, KW. NIH/NINDS, 10/01/2018 - 09/30/2019. Total project budget to date: $77,129.00
  • Exploring nucleocytoplasmic IEG mRNA export in striatal neuron subpopulations. PI: Keefe, K.A. NIDA/NIH, 04/01/2015 - 03/31/2018. Total project budget to date: $372,500.00
  • Opioid modulation of neural encoding of motivation and reward. PI: Keefe, K.A. NIMH/NIH, 03/01/2014 - 02/28/2018. Total project budget to date: $1,117,500.00
  • HPLC System with Electrochemical Detector for Analysis of Central Neurotransmitters. PI: Keefe, K.A. Univ. of Utah Research Instrumentation Fund Grant, 01/2013 - 12/2013. Total project budget to date: $38,000.00
  • Predoctoral Interdepartmental Training Program in Neuroscience. PI: Keefe, K.A. NINDS/NIH, 07/01/2012 - 06/30/2016. Total project budget to date: $859,204.00
  • Hippocampus and relapse associated with drug addiction. PI: Kesner, RP & Keefe, KA. NIDA/NIH , 01/2012 - 12/2015. Total project budget to date: $410,670.00
  • Arc, Phasic Dopamine, and Methamphetamine-Induced Striatal Learning Deficits. PI: Pastuzyn. NIDA/NIH, 01/2011 - 12/2014. Total project budget to date: $70,359.00
  • nNOS-containing striatal interneurons and methamphetamine-induced neurotoxicity. PI: Fricks-Gleason. post-doctoral NRSA Training Fellowship, NIDA/NIH, 01/2011 - 12/2013. Total project budget to date: $117,161.00
  • Long-term consequences of methamphetamine toxicity. PI: Keefe, K.A. NIDA/NIH , 01/2008 - 12/2014. Total project budget to date: $1,657,282.00
  • Neural Substrates of Stimulus-Induced Drug Seeking. PI: Keefe, K.A. NIDA/NIH, 01/2007 - 12/2010. Total project budget to date: $408,613.00
  • Cued Drug-seeking Behavior and Synaptic Plasticity in Striatal Efferent Neurons. PI: Keefe, K.A. Univ. of Utah Research Foundation, 01/2004 - 12/2005. Total project budget to date: $29,000.00
  • Regulation of striatal neurons by NMDA receptor subtypes. PI: Keefe, K.A. NINDS/NIH, 01/2002 - 12/2007. Total project budget to date: $1,406,428.00
  • Differential Effects of Methamphetamine and Cocaine. PI: Keefe, K.A. NIDA/NIH, 01/2001 - 12/2012. Total project budget to date: $1,654,599.00

Languages

  • English, fluent.

Publications

  • Gibson, A. & Keefe, K.A. (2021). Consequences of Neurotoxin-induced Dopamine Loss on Striatal Synaptic Plasticity. Handbook of Neurotoxicity, Springer. Published, 01/2021.
  • Keefe, K.A. & Gibson, A. (2021). Models of Methamphetamine-induced Neurotoxicity. Handbook of Neurotoxicity, Springer. Published, 01/2021.
  • Keefe, K.A. & Horner, K.A. (2017). Neurotransmitter Regulation of Striatal Gene Expression (Chapter 30). Handbook of Basal Ganglia Structure and Function 2e, Elsevier, Inc. Published, 01/2017.
  • Garris, P.A. & Keefe, K.A. (2015). Voltammetric Analysis of Loss and Gain of Dopamine Function (Chapter 13). Compendium of In Vivo Monitoring in Real-Time Molecular Neuroscience Volume 1: Fundamentals and Applications, World Scientific Publishing Co.. Published, 01/2015.
  • Keefe, K.A. & Horner, K.A. (2010). Neurotransmitter Regulation of Basal Ganglia Gene Expression (Chapter 27). Handbook of Basal Ganglia Structure and Function, a Decade of Progress, Elsevier, Inc.. Published, 01/2010.
  • Keefe, K.A. (2003). Sympathomimetic drugs . Remington: The Science and Practice of Pharmacy, Mack Publishing Co.. Published, 01/2003.
  • Zigmond, M.J. and Keefe, K.A. (1997). 6-Hydroxydopamine as a tool for studying catecholamines in adult animals: Lessons from the neostriatum. Highly Selective Neurotoxins: Basic and Clinical Applications, Humana Press. Published, 01/1997.
  • Gerfen, C.R. & Keefe, K.A., and Steiner H. (1996). D1 and D2 dopamine receptor-mediated gene regulation in the striatum. Pharmacological Regulation of Gene Expression in the CNS, CRC Press, Boca Rotan. Published, 01/1996.
  • Friend, D.M. & Fricks-Gleason, A.N., Keefe, K.A. (2014). Is There A Role for Nitric Oxide in Methamphetamine-Induced Dopamine Terminal Degeneration?. Neurotoxicity Research. Published, 01/2014.
  • Giangrasso DM, Veros, K, West PJ, Wilcox KS, Keefe, KA (2023). Glutamate dynamics in the dorsolateral striatum of rats with goal-directed and habitual cocaine-seeking behavior. Front. Mol. Neurosci. Published, 05/11/2023.
  • Gibson AS & West PJ, Keefe KA (2022). Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation. Psychopharmacology. Published, 01/2022.
  • Bosse, GD & Cadeddu, R, Floris, G, Farero, RD, Vigato, E, Lee, SJ, Zhang, T, Gaikwad, NW, Keefe, KA, Philips, PEM, Bortolato, M, Peterson, RT (2021). The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder. Journal of Clinical Investigation. Published, 05/17/2021.
  • Gibson, AS & Keefe, KA, Furlong, TM (2020). Accelerated habitual learning resulting from L-dopa exposure in rats is prevented by N-acetylcysteine. Pharmacology, Biochemistry, and Behavior. Published, 11/2020.
  • Henchey, C & Keefe, KA, Munger, MA, Witt, DM (2020). Fostering PharmD Student Research and Quality Improvement with Mentored Projects. American Journal of Pharmaceutical Education. Published, 04/2020.
  • Giangrasso, DM & Furlong, TM, Keefe, KA (2020). Characterization of striatum-mediated behavior and neurochemistry in the DJ-1 knock-out rat model of Parkinson’s disease. Neurobiology of Disease. Published, 02/2020.
  • Tandon S & Keefe KA, Taha SA (2017). Mu opioid receptor signaling in the nucleus accumbens shell increases responsiveness of satiety-modulated lateral hypothalamus neurons. European Journal of Neuroscience. Published, 04/10/2017.
  • Sheth, C & Furlong, TM, Keefe, KA, Taha, SA (2017). The lateral hypothalamus to lateral habenual projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption. Behavioral Brain Research. Published, 04/18/2017.
  • Tandon S & Keefe KA, Taha SA (2017). Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion. Journal of Physiology, J Physiol. Published, 02/15/2017.
  • Sheth, C & Furlong, TM, Keefe, KA, Taha, SA (2016). Lesions of the rostromedial tegmental nucleus increase voluntary ethanol consumption and accelerate extinction of ethanol-induced conditioned-taste aversion. Psychopharmacology (Berl). Published, 01/2016.
  • Kesner, RP & Kirk, RA, Clark, JK, Keefe, K (2016). Naloxone injections into CA3 disrupt pattern completion associated with relapse from cocaine seeking. Hippocampus. Published, 01/2016.
  • Furlong, TM & Leavitt, LS#, Keefe, KA, Son, J-H (2016). Methamphetamine-, d-amphetamine-, and p-chloroamphetamine-induced neurotoxicity differentially effect impulsive responding on the stop-signal task in rats. Neurotoxicity Research. Published, 01/2016.
  • Fricks-Gleason, AN & German, CL, Hoonakker, AJ, Friend, DM, Ganesh, KK, Carver, AS, Hanson, GR, Fleckenstein, AE, Keefe, KA (2016). An acute, epitope-specific modification in the dopamine transporter associated with methamphetamine-induced neurotoxicity. Synapse. Published, 01/2016.
  • Robinson JD & Howard CD, Pastuzyn ED, Byers DL, Keefe KA, Garris PA (2014). Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum. Neurotoxicity Research. Published, 01/2014.
  • Pastuzyn ED and Keefe, KA (2014). Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss. Neuropsychopharmacology. Published, 01/2014.
  • Friend, DM and Keefe, KA (2013). A role for D1 DA receptors in striatal methamphetamine-induced neurotoxicity. Neuroscience Letters. Published, 01/2013.