This application seeks renewed support for MH59803, """"""""Dopaminergic substrates of startle gating across species"""""""". For 20 years, systematic studies in rodents have identified specific neural substrates regulating prepulse inhibition (PPI) of startle. These limbic cortico-striatal-pallido-pontine (CSPP) substrates regulating PPI are relevant to several neuropsychiatric disorders, and are implicated in the reinforcing properties of drugs of abuse. One major challenge is to develop the capacity to probe and understand this PPI-regulatory circuitry in humans, and to identify genes that regulate its function and dysfunction. If neural circuit and genetic information, derived from animal studies, could be translated across species, PPI could become an important, new tool for understanding this biology in normal and neuropsychiatric disordered populations. MH59803 has identified areas of convergence and divergence in the effects of dopamine (DA) and glutamate manipulations on PPI and related measures in rats vs. normal human subjects. These studies also identified both rat and human phenotypes associated with distinct PPI-altering effects of several drugs, including the DA releaser, amphetamine (AMPH). The present proposal extends this translational approach to assess genes associated with PPI-reducing vs. increasing effects of AMPH in inbred rats and normal humans. The expression and its functional consequences of 5 specific genes in three brain regions that regulate PPI -- the nucleus accumbens, medial prefrontal cortex and ventral hippocampus -- will be assessed in inbred rat strains that exhibit PPI-reducing effects of AMPH (""""""""PreA"""""""") vs. PPI-increasing effects of AMPH (""""""""PieA""""""""). Analyses will focus on 5 genes based on their association with both PreA vs. PieA phenotypes in outbred rats and PPI phenotypes in 2 separate schizophrenia cohorts;their expression in these 3 brain regions will facilitate a functional circuit-based analyses of gene effects. Specific genes associated with PPI AMPH- sensitivity in rats, together with others associated with human phenotypes that moderate PPI AMPH sensitivity, will be interrogated as predictors of PPI AMPH effects in normal human subjects, based on their response to placebo vs. 20 mg p.o. AMPH in a double-blind, cross-over design. In total, these studies will leverage new information generated in the past funding period, to discover genetic and neurobiological substrates regulating sensorimotor gating across species. Strong inference would then link these substrates to causative factors in the loss of sensorimotor gating in schizophrenia and other disorders, and to therapeutic interventions to remedy these deficits and their associated functional consequences.

Public Health Relevance

The ability of the human brain to filter or """"""""gate"""""""" irrelevant sensory information is regulated by several neurotransmitters, including dopamine and glutamate, and is impaired in specific inherited brain disorders, including schizophrenia. This application will identify genes in humans and laboratory animals that control the sensitivity to sensorimotor gating changes in response to the dopamine releaser, amphetamine. The findings will inform studies searching for the genes associated with dopamine-linked disorders of impaired sensorimotor gating in humans.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Brady, Linda S
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Swerdlow, Neal R; Light, Gregory A (2018) Sensorimotor gating deficits in schizophrenia: Advancing our understanding of the phenotype, its neural circuitry and genetic substrates. Schizophr Res 198:1-5
Swerdlow, Neal R; Bhakta, Savita G; Talledo, Jo A et al. (2018) Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients. Neuropsychopharmacology 43:708-717
Huang, L; Shum, E Y; Jones, S H et al. (2018) A Upf3b-mutant mouse model with behavioral and neurogenesis defects. Mol Psychiatry 23:1773-1786
Kantrowitz, Joshua T; Swerdlow, Neal R; Dunn, Walter et al. (2018) Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate-Type Glutamate Receptor Function. Biol Psychiatry Cogn Neurosci Neuroimaging 3:581-590
Swerdlow, Neal R; Bhakta, Savita G; Light, Gregory A (2018) Room to move: Plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge. Schizophr Res 199:285-291
Light, Gregory A; Zhang, Wen; Joshi, Yash B et al. (2017) Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia. Neuropsychopharmacology 42:2633-2639
Swerdlow, Neal R; Bhakta, Savita G; Rana, Brinda K et al. (2017) Sensorimotor gating in healthy adults tested over a 15 year period. Biol Psychol 123:177-186
Bhakta, Savita G; Light, Gregory A; Talledo, Jo A et al. (2017) Tolcapone-Enhanced Neurocognition in Healthy Adults: Neural Basis and Predictors. Int J Neuropsychopharmacol 20:979-987
Swerdlow, Neal R; Tarasenko, Melissa; Bhakta, Savita G et al. (2017) Amphetamine Enhances Gains in Auditory Discrimination Training in Adult Schizophrenia Patients. Schizophr Bull 43:872-880
Swerdlow, Neal R; Braff, David L; Geyer, Mark A (2016) Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol 30:1072-1081

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