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.
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