This K02 proposal is for renewed career development support for Dr. Neal Swerdlow, to extend 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 regulating aspects of behavioral plasticity in animals and humans. For over 20 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 three exciting new lines of inquiry - two 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 the genetic regulation of this circuitry, and will make substantive progress towards understanding 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 acumens. 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 use strain differences in PPI sensitivity to understand the genetic regulation of CSPT circuitry in rats. A third line of inquiry will assess the dopaminergic regulation of PPI in normal humans. Bilateral eye blink startle and PPI will be measured after administration of several different dopaminergic agents, in dose-response and agonist-antagonist studies. This proposal 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 at the levels of their underlying neural and genetic substrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH001436-09
Application #
6846309
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Meinecke, Douglas L
Project Start
1997-02-01
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
9
Fiscal Year
2005
Total Cost
$114,696
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
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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