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, 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) In vivo microdialysis 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 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. 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.
Keefe, K.A. and Horner, K.A. (2010) Neurotransmitter Regulation of Basal Ganglia Gene Expression (Chapter 27). In Handbook of Basal Ganglia Structure and Function, a Decade of Progress (H. Steiner and K.Y. Tseng, Eds.), Elsevier, Inc., pp 461-490.
Howard, C.D., Keefe, K.A., Garris, P.A., and Daberkow, D.P. (2011) Methamphetamine-induced neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum. The Journal of Neurochemistry, Aug;118(4):668-676. PMID: 21668447 [PubMed - indexed for MEDLINE]
Son, J-H, Latimer, C., and Keefe, K.A. (2011) Impaired formation of stimulus-response, but not action-outcome, associations in rats with methamphetamine-induced neurotoxicity. Neuropsychopharmacology, Nov;36(12): 2441-2451. PMID: 21775980 [PubMed - indexed for MEDLINE]
Pastuzyn, E.D., Chapman, D.E., Wilcox, K.S., Keefe, K.A. (2012) Altered learning and Arc-regulated consolidation of learning in striatum by methamphetamine-induced neurotoxicity.. Neuropsychopharmacology, Mar;37(4):885-95. PMID: 22071872 [PubMed - indexed for MEDLINE
Barker-Haliski, M.L., Pastuzyn, E.D., Keefe, K.A. (2012) Expression of the core exon-junction complex factor eukaryotic initiation factor 4A3 is increased during spatial exploration and striatally-mediated learning. Neuroscience, 226: 51-61. PMID: 22982623 [PubMed - indexed for MEDLINE]
Barker-Haliski, M.L., Oldenberger, K., Keefe, K.A. (2012) Disruption of subcellular Arc/Arg 3.1 mRNA expression in striatal efferent neurons following partial monoamine loss induced by methamphetamine. The Journal of Neurochemistry, 123(5): 845-855. PMID: 22978492 [PubMed - indexed for MEDLINE]
Son, J.H., Kuhn, J., Keefe, K.A. Perseverative behavior in rats with methamphetamine-induced neurotoxicity. Neuropharmacology, 67: 95-103. PMID: 23159331 [PubMed - indexed for MEDLINE]
Friend, D.M., Son, J.H., Keefe, K.A., Fricks-Gleason, A.N. (2013) Expression and activity of nitric oxide synthase isoforms in methamphetamine-induced striatal dopamine toxicity. Journal of Pharmacology and Experimental Therapeutics. 344(2): 511-521. PMID: 23230214 [PubMed - indexed for MEDLINE]
Friend, D.M., Keefe, K.A. (2013) Glial reactivity in resistance to methamphetamine-induced neurotoxicity. Journal of Neurochemistry, 125(4): 566-574. PMID: 23414433 [PubMed - indexed for MEDLINE]
Howard, C.D., Keefe, K.A., Daberkow, D.P., Ramsson, E., Garris, P.A. (2013) Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine transient activity in the striatum of freely moving rats. European Journal of Neuroscience, 38(1):2078-2088, PMID: 23574406 [PubMed - indexed for MEDLINE]
Howard, C.D., Pastuzyn, E.P., Barker-Haliski, M.L., Garris, P.A., Keefe, K.A. (2013) Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation. The Journal of Neurochemistry, 125(4):555-565, PMID: 23480199 [PubMed - indexed for MEDLINE]
Friend, D.M., Keefe, K.A. (2013) A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity. Neuroscience Letters, 555:243-247. PMID: 23994061 [PubMed - indexed for MEDLINE]
Fricks-Gleason, A.N., Keefe, K.A. (2013) Evaluating the role of neuronal nitric oxide synthase-containing striatal interneurons in methamphetamine-induced dopamine neurotoxicity. Neurotoxicity Research, 24(2): 288-297. PMID: 23575992 [PubMed - indexed for MEDLINE]
Riedy, M.D. Keefe, K.A. (2013) Lack of increased immediate early gene expression in rats reinstating cocaine-seeking behavior to discrete sensory cues. PLOS One, 8(9):e72883. PMID 24069163 [PubMed – indexed for MEDLINE]
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, 25(2) 153-160. PMID: 23918001 [PubMed - indexed for MEDLINE]
Pastuzyn, E.D., Keefe, K.A. (2014) Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss. Neuropsychopharmacology, 39(4):963-p972. PMID: 24150570 [PubMed – indexed for MEDLINE]
Robinson, J.D., Howard, C.D., Pastuzyn, E.D., Byers, D.L., Keefe K.A., Garris P.A. (2014) Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum. Neurotoxicity Research. 226(2):152-167. PMID: 24562969 [PubMed - in process]