Studies of the plasticity of startle responses elicited by intense stimuli offer unusual opportunities for cross-species explorations of the gating abnormalities characteristic of schizophrenic patients. Schizophrenic patients exhibit deficits in both prepulse inhibition (PPI) and habituation of startle. In animal studies, these forms of startle plasticity provide operational measures of the attentional inhibitory deficits that have been demonstrated in schizophrenia spectrum patients. In rats, dopaminergic, serotonergic, and related neurotransmitter systems modulate startle plasticity via neural circuitry including the hippocampus, nucleus accumbens, subpallidum, and pedunculopontine nucleus. The new thrust of the proposed work is to assess the influences of a developmental manipulation, isolation rearing, on PPI and habituation functions in adult rats. A major goal of this work is to develop an animal model of the inhibitory deficits exhibited by schizophrenic patients that does not rely upon the administration of a drug or the introduction of a lesion. When tested as adults, rats reared in social isolation post- weaning exhibit deficits in startle PPI and habituation relative to rats reared in social groups. The deficit in PPI does not appear before puberty or in rats placed in social isolation as adults.
Aim 1 will characterize behavioral and developmental aspects of the effects of isolation rearing on PPI and habituation, by identifying the particular developmental period responsible for these delayed effects of isolation rearing, determining the degree to which these emergent effects of an early developmental manipulation reflect enduring changes in adulthood, and testing whether adult resocialization of isolation-reared rats reverses the deficits in PPI or habituation.
Aim 2 will use pharmacological studies to identify the neurochemical substrates responsible for the effects of isolation rearing on startle plasticity. Appropriate agonists and antagonists will be used to test the hypotheses that overactivity of D2 dopaminergic and/or 5-HT2 serotonergic systems contribute to the isolation-rearing-induced deficits in PPI and habituation. Related studies will assess the predictive validity of this isolation-rearing paradigm for the detection of both typical and atypical antipsychotic drugs.
In Aim 3, intracranial microinjections will be used to specify the anatomical substrates of the gating deficits seen in adult rats reared in isolation. Based on the cortico-striato-pallido-pontine circuit that modulates gating, microinjections of specific agonists and/or antagonists will be used to identify the components of this circuit in which isolation rearing produces changes in neurotransmission that disrupt PPI or reduce startle habituation. These studies will test the hypothesis that overactivity of dopaminergic and/or serotonergic systems in the nucleus accumbens or hippocampus is responsible for the PPI and habituation deficits produced by isolation rearing.
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