Retired- no longer accepting undergraduate or graduate students in the lab

Overall Research Area:

Preclinical Neuropsychopharmacology. The use of animal models to study the psychobiology of attentional dysfunctions and cognitive flexibility, particularly as these impairments contribute to the cognitive deficits seen in schizophrenia. We utilize these animal models to test hypotheses about the etiologies of schizophrenia as well as to develop translational models to test the efficacy of novel pharmacotherapeutics for the enhancement of cognitive function in this disorder.

Current Research:

Our laboratory currently focuses on the development of animal models to study the neurobiological bases of cognitive impairments in schizophrenia. Collectively, these studies are designed to provide insights into possible etiologies of these cognitive symptoms as well as to design valid preclinical screens for the development of novel, more efficacious pharmacotherapies. We are particularly interested in the psychobiology of two cognitive operations (attentional processing and cognitive flexibility/set-shifting) as they are expressed in normal animals and in those animals designed to model various aspects of schizophrenia. Deficits in attention and cognitive flexibility can significantly impair the detection and processing of relevant stimuli as well as the ability to adjust behavior in light of changing events.

The anatomical mediation of attention and cognitive flexibility involves a distributed neural system that includes the hippocampus, nucleus accumbens, basal forebrain, and prefrontal cortex. Research in our laboratory, as well as others, has demonstrated the importance of interactions among cholinergic, glutamatergic, and dopaminergic transmitter systems, throughout these brain regions, in the mediation of attentional processing and set-shifting behavior. Moreover, dysregulations in these transmitter systems have been linked to the cognitive deficits seen in schizophrenia.

We utilize several different animal models (reversible and non-reversible inactivation of hippocampal outflow during sensitive developmental periods; pharmacological disruption of astrocyte-mediated regulation of alpha7 nicotine receptors in prefrontal cortex and accumbens; acute and chronic administration of NMDA antagonists) to simulate the neurochemical dysfunctions believed to underlie several of the cognitive deficits seen in schizophrenia. The impact of these manipulations on ACh, glutamate, and dopamine release are determined using state-of-the-art neurochemical methods (high temporal resolution electrochemistry using enzyme-based microelectrodes; in vivo microdialysis) in animals as they perform behavioral tasks designed to assess attentional processing or set-shifting behavior. These experimental protocols then provide a sensitive platform for assessing the efficacy of novel pharmacotherapeutic compounds.

Representative Publications

Alexander, K.S., Wu, H-Q., Schwarcz, R., Bruno, J.P. Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine. Psychopharmacology, 220, 627-637, (2012). DOI.

Brooks, J.M., Sarter, M., Bruno, J.P. Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia. Neuropsychopharmacology, 36, 2477-2487, (2011). DOI.

St. Peters, M., Demeter, E., Lustig, C., Bruno, J.P., Sarter, M. Enhanced top-down control of attention by stimulating mesolimbic-corticopetal cholinergic circuitry. Journal of Neuroscience, 31(26), 9760-9771, (2011). DOI.

Konradsson-Geuken, A., Wu, H-Q., Gash, C.R., Alexander, K., Campbell, A., Sozeri, Y., Pellicciari, R., Schwarcz, R., Bruno, J.P. Cortical kynurenic acid bi-directionally modulates prefrontal glutamate levels as assessed by microdialysis and rapid electrochemistry. Neuroscience, 169, 1848-1859, (2010). DOI.

Wu, H-Q., Pereira, E.F.R., Bruno, J.P., Pellicciari, R., Albuquerque, E.X., Schwarcz, R. Kynurenic Acid: an astrocyte-derived, neuromodulatory alpha7 nicotinic receptor antagonist with links to schizophrenia. Journal of Molecular Neuroscience, 40, 204-210, (2010). DOI.

Konradsson-Geuken, A., Gash, C.R., Alexander, K., Pomerleau, F., Huettl, P., Gerhardt, G.A., Bruno, J.P. Second-by-second analysis of alpha 7 nicotine receptor regulation of glutamate release in the prefrontal cortex of awake rats. Synapse, 2009. DOI.

Wu, H-Q., Pereira, E.F.R., Bruno, J.P., Pellicciari, R., Albuquerque, E.X., Schwarcz, R. Kynurenic acid: an astrocyte-derived neuromodulatory alpha 7 nicotinic receptor antagonist with links to schizophrenia. Journal of Molecular Neuroscience, 2009. DOI. 

Alexander, K.A., Brooks, J.M., Sarter, M., Bruno, J.P. Disruption of mesolimbic regulation of prefrontal cholinergic transmission in an animal model of schizophrenia and normalization by chronic clozapine treatment. Neuropsychopharmacology, 2009. DOI.

Zmarowski, A., Wu, H-Q., Brooks, J.M., Potter, M., Pellicciari, R., Schwarcz, R., Bruno, J.P. Astrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine release. European Journal of Neuroscience, 29, 529-538, 2009. DOI.

Burmeister, J.J., Pomerleau, F., Huettl, P., Gash, C.R. Werner, C.E., Bruno, J.P., Gerhardt, G.A. Ceramic-based multisite microelectrode arrays for simulltaneous measures of choline and acetylcholine in CNS. Biosensors and Bioinstrumentation, 23, 1382-1389, 2008. DOI.

Kozak, R., Martinez, V., Young, D., Brown, H., Bruno, J.P., and Sarter, M.  Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia:  disruptionn of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing rats.  Neuropsychopharmacology, 32, 2074-2086, 2007. DOI.

Brooks, J.M., Sarter, M., and Bruno, J.P.  D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex.  Neuropharmacology, 57, 455-463, 2007. DOI.

Zmarowski, A., Sarter, M., and Bruno, J.P.  Glutamate receptors in nucleus accumbens mediate regionally selective increases in cortical acetylcholine release.  Synapse, 61, 115-123, 2007. DOI.

Bruno, J.P., Gash, C., Martin, B., Zmarowski, A., Pomerleau, F., Burmeister, J., Huettl, P., and Gerhardt, G. Second-by-second measurement of acetylcholine release in prefrontal cortex. European Journal of Neuroscience24, 2749-2757, 2006. DOI.

Bruno, J.P., Sarter, M., Gash, C., and Parikh, V. Choline- and acetylcholine-sensitive microelectrodes. In GA. Grimes and E. Dickey (Eds), Encyclopedia of Sensors, American Scientific Publishers (Stevenson Ranch, CA), ,2006. DOI.

Kozak, R., Bruno, J.P., and Sarter, M.  Augmented prefrontal acetylcholine release during challenged attentional performance.  Cerebral Cortex, 16, 9-17, 2006. DOI.

Zmarowski, A., Sarter, M., and Bruno, J.P.  NMDA and dopamine interactions in the nucleus accumbens modulate cortical acetylcholine release.  European Journal of Neuroscience, 22, 1731-1740, 2005. DOI.

Bruno, J.P., Sarter, M., Gash, C.R., and Parikh, V.  Choline- and acetylcholine-sensitive microelectrodes.  Encyclopedia of Sensors, In Press, 2005. DOI.

Nelson, C.L., Sarter, M., and Bruno, J.P.  Prefrontal cortical modulation of acetylcholine release in posterior parietal cortex.  Neuroscience, 132, 347-359, 2005. DOI.

Sarter, M., Hasselmo, M.E., Bruno, J.P., and Givens, B.  Unraveling the attentional functions of cortical cholinergic inputs:  interactions between signal-driven and cognitive modulation of signal detection.  Brain Research Reviews, 48, 98-111, 2005. DOI.

Sarter, M., Nelson, C.L., and Bruno, J.P.  Cortical cholinergic transmission and cortical information processing in schizophrenia.  Schizophrenia Bulletin, 31, 117-138, 2005. DOI.

Sarter, M. and Bruno, J.P.  Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities.  Neurobiology of Aging, 25, 1127-1139, 2004. DOI.

Parikh, V., Pomerleau, F., Huettle, P., Gerhardt, G.A., Sarter, M. and Bruno, J.P.  Amperometric measurement of extracellular choline:  a method for the detection of rapid changes in cholinergic transmission.  European Journalof Neuroscience, 20, 1545-1554, 2004. DOI.

Neigh, G.N., Arnold, H.M., Rabenstein, R.L., Sarter, M. and Bruno, J.P.  Neuronal activity in the nucleus accumbens is necessary for performance-related increases in cortical acetylcholine release. Neuroscience, 123, 635-645, 2004. DOI.

Sandstrom, M.I., Nelson, C.L. and Bruno, J.P. Mechanisms underlying spontaneous recovery from motor deficits in rats depleted of striatal dopamine as weanlings.  Developmental Psychobiology, 43, 373-383, 2003. DOI.

Herzog, C.D., Nowak, K.A., Sarter, M. and Bruno, J.P. Microdialysis without acetylcholinesterase inhibition reveals an age-related attenuation in stimulated cortical acetylcholine release.  Neurobiology of Aging, 24, 861-863, 2003. DOI.

Arnold, H.M., Nelson, C.L., Sarter, M. and Bruno, J.P. Sensitization of cortical acetylcholine release by repeated administration of nicotine.  Psychopharmacology, 164, 346-358, 2003. DOI.

Neigh-McCandless, G., Kravitz, B. Adar, Sarter, M. and Bruno, J.P.  Stimulation of cortical acetylcholine release following blockade of ionotropic glutamate receptors in nucleus accumbens. European Journal of Neuroscience, 16, 1-9, 2002.  DOI.

Bruno, J.P. and Sarter, M.  Aminergic transmitter systems in cognitive disorders.  In D. D'haenen, J.A. Den Boer, H. Westenberg and P. Willner (Eds)  Textbook of Biological Psychiatry, John Wiley & Sons (Boston), 235-245, 2002. DOI.

Sarter, M. and Bruno, J.P.  The neglected constituent of the basal forebrain corticopetal projection system:  GABAergic projections.  European Journal Neuroscience, 15, 1867-1873, 2002. DOI.

Nelson, C.L., Burk, J.A., Bruno, J.P. and Sarter, M.  Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats.  Psychopharmacology, 161, 168-179, 2002.  DOI.

Himmelheber, A.M., Sarter, M., and Bruno, J.P.  The effects of manipulations of attentional demand on cortical acetylcholine release.  Cognitive Brain Research, 12, 353-370, 2001. DOI.

Sarter, M., Givens, B., and Bruno, J.P.  The cognitive neuroscience of sustained attention:  where top-down meets bottom-up. Brain Research Reviews, 35, 146-160, 2001. DOI.

Neigh, G.N., Arnold, H.M., Sarter, M., and Bruno, J.P.  Dissociations between the effects of intra-accumbens administration of amphetamine and exposure to a novel environment on accumbens dopamine and cortical acetylcholine release.  Brain Research, 894, 354-358, 2001. DOI.

Arnold, H.M., Fadel, J., Sarter, M., and Bruno, J.P. Amphetamine-stimulated cortical acetylcholine release:  role of the basal forebrain. Brain Research, 894, 74-87, 2001. DOI.

Fadel, J., Sarter, M., and Bruno, J.P. Basal forebrain glutamatergic modulation of cortical acetylcholine release. Synapse, 39, 2001. DOI.

Sarter, M., and Bruno, J.P.  Cortical cholinergic inputs mediating arousal, attentional processing and dreaming:  differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents.  Neuroscience, 95, 933-952, 2000. DOI.

Nelson, C.L., Sarter, M., and Bruno, J.P. Repeated pre-treatment with amphetamine sensitizes increases in cortical acetylcholine release. Psychopharmacology, 151, 2000. DOI.

Himmelheber, A.M., Sarter, M., and Bruno, J.P.  Increases in cortical acetylcholine release during sustained attentional performance in rats.  Cognitive Brain Research, 9, 313-325, 2000. DOI.

Arnold, M.H., Nelson, C.L., Neigh, G.N., Sarter, M., and Bruno, J.P.  Systemic and intra-accumbens administration of amphetamine differentially affect cortical acetylcholine release.  Neuroscience, 96,  675-685, 2000. DOI.

Sarter, M. and Bruno, J.P.  Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders.  Trends in Neuroscience, 22, 67-74, 1999. DOI.

Fadel, J., Sarter, M., and Bruno, J.P.  Age-related attenuation of stimulated cortical acetylcholine release in basal forebrain-lesioned rats.   Neuroscience, 90, 793-802, 1999. DOI.

Bruno, J.P.,Sarter, M., Arnold, H.M., and. Himmelheber, A.M.   In vivo neurochemical markers of cognitive processes: methodological and conceptual challenges. Reviews in the Neuroscience, 10, 25-49, 1999. DOI.

Sarter, M., Bruno, J.P. and Turchi, J.  Ventral striatal-basal forebrain mechanisms modulating cortical acetylcholine, attention, and implications for neuropsychiatric disorders.  Annals New York Academy Sciences, 22, 368-382, 1999. DOI.

Moore, H., Fadel, J., Sarter, M., and Bruno, J.P.  Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release.  Neuroscience, 88,  811-822, 1998. DOI.

Sarter, M. and Bruno, J.P.  Cortical acetylcholine, reality distortion, schizophrenia and Lewy Body dementia: too much or too little  acetylcholine?  Brain and Cognition,38, 297-316, 1998. DOI.

Sarter, M. and Bruno, J.P.  Age-related changes in rodent cortical acetylcholine and cognition: main effects of age versus age as an intervening variable.  Brain Research Reviews, 27, 143-156, 1998. DOI.

Himmelheber, A.M., Sarter, M., and Bruno, J.P.  Operant performance and  cortical acetylcholine release: role of response rate, reward density, and non-contingent stimuli.  Cognitive Brain Research,6, 23-36, 1997. DOI.