Damage to the human hippocampal formation following surgical ablation, cerebral ischemia or neurodegenerative conditions such as Alzheimer's disease results in a profound impairment of memory characterized by an enduring inability to recreate a record of day-to-day events. Experimental studies in the monkey indicate that the hippocampal formation is but one component of a distributed memory system. Recent neuroanatomical and behavioral studies conducted under this research program have determined that other temporal lobe structures, such as the perirhinal and parahippocampal cortices, also make important contributions to normal memory. Moreover, it appears that the perirhinal cortex may carry out its memory function independently of the hippocampal formation. We propose to investigate the efferent connections of the perirhinal cortex in order to determine whether it interacts with other brain regions, such as the mediodorsal nucleus of the thalamus or the frontal cortex, that are nonhippocampal components of the memory system. Since modern attempts at developing a unified neurobiology of memory rely on rat, monkey and human models, it is problematic that there is relatively little neuroanatomical information about the rat perirhinal region. We propose to fill this gap in essential information by carrying out a series of cytoarchitectonic and connectional studies in the rat perirhinal region that parallels our ongoing work in the monkey. Neuroanatomical and clinical evidence suggest that the retrosplenial area of the cingulate cortex may be yet another important memory-related region. It may contribute to memory by acting as an interface between working memory regions of the frontal lobe and the long term memory mechanisms of the medial temporal lobe. We have previously discovered strong projections from the monkey retrosplenial cortex to the hippocampal formation and to the parahippocampal cortex. We propose here to conduct additional neuroanatomical studies and initiate a new program of behavioral studies to investigate the functional organization of the monkey retrosplenial cortex. While it is important to investigate new components of the brain's memory system, there remain substantial gaps in our understanding of the functional circuitry of the primate hippocampal formation. We propose to use the sensitive anterograde tracer PHA-L to study the patterns of intrinsic connections of the monkey hippocampal formation. The results of these studies will be compared with similar studies already completed in the rat. We will also study the intralaminar and inter-areal organization of local circuits in the monkey entorhinal cortex. These data will provide insight into the level of sensory integration and input/output relations that take place in this pivotal cortical region. Taken together, these studies will provide important new information concerning the functional organization of memory systems in the rat and monkey brains.
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