The long-term objective of this proposal is to characterize neurobiological processes that contribute to behavioral recovery from cortical injury. Injury to the prefrontal area termed medial agranular (AGm) cortex of rats results in a well-characterized neglect of stimuli, in which animals fail to orient toward visual, auditory, or tactile stimuli on the side contralateral to the lesion. These symptoms are similar to neglect in humans. However, rats show a remarkable spontaneous recovery from this neglect, and by several weeks postoperatively they typically respond to stimuli on either body side. While the processes responsible for this recovery are only beginning to be understood, current evidence indicates that adaptations within striatal dopaminergic synapses contribute importantly to time-dependent restoration of orientation. The effects of striatal dopaminergic neurotransmission on recovery from cortical neglect will be interpreted with reference to a neurobiological model of the striatum in which corticostriatal (excitatory amino acid- using) and nigrostriatal (dopaminergic) afferents converge on individual medium spiny neurons. This proposal will investigate neurobiological compensations occurring within the striatum of animals given unilateral AGm ablations. The overall strategy is to study indexes of dopaminergic or excitatory amino acid transmission, or of medium spiny neurons' responses, within the striatum of rats given AGm ablations, comparing short-term (5 days post surgery) effects in animals with neglect to long-term (greater than or equal to 3 weeks) changes in recovered animals. Specific experiments will investigate whether recovery from AGm injury is associated with presynaptic, postsynaptic, or intracellular adaptations occurring within striatum by examining: (1) extracellular dopamine, glutamate, or aspartate concentrations, (2) numbers or affinities of dopamine or excitatory amino acid receptors, (3) dopamine-stimulated adenylate cyclase activity and G(olf) immunoreactivity, or (4) immediate early gene expression stimulated by dopamine or NMDA agonists. A role for striatal excitatory amino acid transmission in recovery from neglect will be tested further by determining the effects on orientation of intrastriatal infusion of NMDA or non-NMDA antagonists in recovered AGm- lesioned rats. Finally, studies will examine changes in immediate early gene expression of non-striatal regions (superior colliculus, subthalamus, and thalamus) in relation to recovery from AGm ablations.
