This proposal examines how surgical and pharmacological manipulations of the hippocampus or medial prefrontal cortex (MPFC) in rats produce deficits in basic gating and habituation functions that have been linked to schizophrenia. Both prepulse inhibition (PPI) and habituation of startle responses have been used to demonstrate gating and habituation deficits in schizophrenia patients, and in rats with altered corticostriatal circuitry. The hippocampus and MPFC, via connections with the nucleus accumbens (NAC), appear to modulate startle inhibitory processes. Rats having hippocampal or MPFC lesions exhibit a supersensitive response to the PPI-disruptive effects of dopamine (DA) agonists. These inhibitory deficits will be studied to test hypotheses about neural circuitry that is implicated in the pathophysiology of schizophrenia.
Specific Aim 1 will assess critical variables in the development of the """"""""supersensitive"""""""" DA-mediated loss of sensorimotor gating produced by excitotoxin lesions of the hippocampus in rats. Studies will assess behavioral effects of receptor-specific agonists, lesions of hippocampal subregions, and the time-course of lesion effects on both PPI and DA receptor measures in the NAC.
Aim 2 will identify the neural substrates of the """"""""supersensitive"""""""" DA-mediated loss of PPI produced by hippocampal lesions by examining changes in PPI after infusions of DA receptor agonists into the NAC core and shell subregions.
Aim 3 will determine the neural circuitry that mediates the reduction in PPI produced by glutamatergic stimulation of the hippocampal. Studies will examine the ability of manipulations of the NAC, or the hippocampal-accumbens projection, to reverse the PPI disruptive effects of intra-hippocampal infusion of N-methyl-D-Aspartate.
Aim 4 will characterize the """"""""supersensitive"""""""" DA-mediated loss of PPI after excitotoxin lesions of the MPFC, using studies similar to those of Specific Aim 1.
Aim 5 will identify the specific neural substrates of the """"""""supersensitive"""""""" DA-mediated loss of PPI produced by MPFC lesions in rats. Studies will examine MPFC lesion-induced changes in PPI after infusion of DA receptor agonists into the NAC core and shell.
Aim 6 will identify the neural circuitry mediating deficits in PPI produced by reductions in DA function in the MPFC. Studies will test the ability of manipulations of the NAC or ventral tegmentum to reverse the PPI-disruptive effects of MPFC 6-OHDA lesions or intra-MPFC infusion of DA receptor antagonists. In total, these studies will systematically characterize cortico-striatal circuitry regulating critical inhibitory functions that are deficient in schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Psychobiology, Behavior, and Neuroscience Review Committee (PBN)
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University of California San Diego
Schools of Medicine
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Swerdlow, Neal R; Light, Gregory A; Breier, Michelle R et al. (2012) Sensory and sensorimotor gating deficits after neonatal ventral hippocampal lesions in rats. Dev Neurosci 34:240-9
Miller, E J; Saint Marie, L R; Breier, M R et al. (2010) Pathways from the ventral hippocampus and caudal amygdala to forebrain regions that regulate sensorimotor gating in the rat. Neuroscience 165:601-11
Saint Marie, R L; Miller, E J; Breier, M R et al. (2010) Projections from ventral hippocampus to medial prefrontal cortex but not nucleus accumbens remain functional after fornix lesions in rats. Neuroscience 168:498-504
Qu, Ying; Saint Marie, Richard L; Breier, Michelle R et al. (2009) Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague-Dawley and Long-Evans rats. Psychopharmacology (Berl) 207:271-80
Shilling, Paul D; Saint Marie, Richard L; Shoemaker, Jody M et al. (2008) Strain differences in the gating-disruptive effects of apomorphine: relationship to gene expression in nucleus accumbens signaling pathways. Biol Psychiatry 63:748-58
Swerdlow, Neal R; Weber, Martin; Qu, Ying et al. (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 199:331-88
Swerdlow, Neal R; Geyer, Mark A; Shoemaker, Jody M et al. (2006) Convergence and divergence in the neurochemical regulation of prepulse inhibition of startle and N40 suppression in rats. Neuropsychopharmacology 31:506-15
Swerdlow, Neal R; Shoemaker, Jody M; Kuczenski, Ronald et al. (2006) Forebrain D1 function and sensorimotor gating in rats: effects of D1 blockade, frontal lesions and dopamine denervation. Neurosci Lett 402:40-5
Swerdlow, Neal R; Shoemaker, Jody M; Bongiovanni, Michele J et al. (2005) Reduced startle gating after D1 blockade: effects of concurrent D2 blockade. Pharmacol Biochem Behav 82:293-9
Shoemaker, J M; Saint Marie, R L; Bongiovanni, M J et al. (2005) Prefrontal D1 and ventral hippocampal N-methyl-D-aspartate regulation of startle gating in rats. Neuroscience 135:385-94

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