This K02 proposal is for carer development support for Dr. Neal Swerdlow, to permit a period of intensive focus on his longstanding research goal: to increase our understanding of the substrates of specific mental disorders by elucidating the neural circuitry relating aspects of behavioral plasticity in animals and humans. For over 15 years, the PI has studied functional and anatomical interactions in limbic cortico- striato-pallido-thalamic (CSPT) circuitry that regulate sensorimotor gating of the startle reflex. This proposal describes two exciting new lines of inquiry - one in laboratory animals and one in humans - that provide the focus for the next phase of his evolving career. These studies will enhance the convergence of animal and human studies of sensorimotor gating, and will thereby maximize the full power of this cross-species approach to neurobehavioral analysis. Ultimately, this work will help to delineate the functional connections within limbic CSPT circuitry, and to test hypotheses regarding the contributions of CSPT dysfunctions to the pathophysiology of certain neuropsychiatric disorders. In one line of inquiry, the PI will examine functional interactions between regions of limbic cortex and ventral striatum that regulate sensorimotor gating in rats. Prepulse inhibition (PPI) of acoustic startle will be measured in rats after surgical and pharmacological manipulations of the hippocampus, medial prefrontal cortex and nucleus accumbens. These studies will test the hypothesis that changes in sensorimotor gating of the startle reflex after manipulations of the limbic cortex in rats reflect identifiable changes in dopaminergic and glutamatergic activity within the nucleus accumbens. A second line of inquiry will examine specific variables of fundamental importance in human studies of sensorimotor gating: sex, menstrual cyclicity and laterality. Bilateral eyeblink startle and PPI will be measured in men, and in women during follicular and luteal phases of the menstrual cycle. Findings from this work will direct future animal studies aimed at understanding the neural bases for the hormonal and lateralized regulation of sensorimotor gating. These studies will provide critical new information that will facilitate the design and interpretation of future studies of sensorimotor gating in psychiatric populations, and will help us to interpret sensorimotor gating abnormalities in psychiatric patients in terms of underlying neural substrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH001436-03
Application #
2873022
Study Section
Psychobiology, Behavior, and Neuroscience Review Committee (PBN)
Program Officer
Meinecke, Douglas L
Project Start
1997-02-01
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Weber, Martin; Chang, Wei-Li; Breier, Michelle R et al. (2010) The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats. Eur Neuropsychopharmacol 20:421-5
Nasrallah, Henry A; Keshavan, Matcheri S; Benes, Francine M et al. (2009) Proceedings and data from The Schizophrenia Summit: a critical appraisal to improve the management of Schizophrenia. J Clin Psychiatry 70 Suppl 1:4-46
Swerdlow, Neal R; Breier, Michelle; Mora, Adrienne B et al. (2008) A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating. Pharmacol Biochem Behav 88:280-90
Weber, M; Swerdlow, N R (2008) Rat strain differences in startle gating-disruptive effects of apomorphine occur with both acoustic and visual prepulses. Pharmacol Biochem Behav 88:306-11
Swerdlow, Neal R; Sprock, Joyce; Light, Gregory A et al. (2007) Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia. Schizophr Res 92:237-51
Harte, M K; Powell, S B; Swerdlow, N R et al. (2007) Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats. J Neural Transm 114:893-8
Swerdlow, Neal R; Shoemaker, Jody M; Bongiovanni, Michele J et al. (2007) Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration. Pharmacol Biochem Behav 87:1-10
Swerdlow, Neal R; Blumenthal, Terry D; Sutherland, Ashley N et al. (2007) Effects of prepulse intensity, duration, and bandwidth on perceived intensity of startling acoustic stimuli. Biol Psychol 74:389-95
Braff, David L; Light, Gregory A; Swerdlow, Neal R (2007) Prepulse inhibition and P50 suppression are both deficient but not correlated in schizophrenia patients. Biol Psychiatry 61:1204-7
Metzger, Kayla L; Shoemaker, Jody M; Kahn, Jonathan B et al. (2007) Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits. Psychopharmacology (Berl) 190:201-11

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