The major thrust of our research is to understand the molecular and cellular mechanisms underlying cognitive function, such as learning and memory. In particular, we are interested in elucidating the function of individual brain-subarea networks in the limbic and neocortices. Toward this goal, we set up an experimental system that utilizes three individual core technologies, (1) molecular genetics using the Cre/loxP and/or other drug-induced gene manipulation system to create conditional mutant mice, (2) in vivo neural activity monitoring using multi-electrode recording techniques, and (3) rodent behavioral analysis of transgenic animals. The rationale for using the Cre/loxP system and inducible transgenic is to allow genetic manipulation during a certain time window, only in a specific brain region. To uncover cognitive deficits in genetically-altered mice, it is generally desired that such an animal would have measurable deficits in cognitive function, while basic sensory and motor functions indispensable for displaying behavioral output are intact. Inducible gene expression/suppression in a particular brain region would be the most convincing method for investigate causal relations of the function of gene product in the particular region with behavioral and neuronal phenotypes in the mutants. Furthermore, the combination of in vivo monitoring of neural activity with behavioral manipulation is a powerful approach for identifying neural mechanisms that underlie behavioral phenotypes following gene manipulation. Recent experience analyzing CA3-NMDA receptor knockout mice using the hippocampus place cell monitoring in awake-behaving mice has led us to the above combined strategy to increase our understanding of cognitive function.

     Using these experimental strategies, this Unit is focusing upon two fundamental questions of modern neuroscience. The first question is to clarify the functional roles of particular brain regions, including hippocampal CA3, in learning and memory, and to identify neural substrates underlying these functions. Initial analyses of CA3-NMDA receptor knockout mice revealed CA3 NMDA receptor involvement in memory acquisition of one-time experience and in pattern completion during memory recall under partial cue conditions. Simultaneous in vivo tetrode recording from subfield CA1 and CA3 in the mutant animals during particular behavioral paradigms, under conditions that reveal behavioral impairments in the mutants, would provide some clues to clarify the mechanistic roles of area CA3 in these behaviors. Generation of other genetically-engineered mice is also underway, in which region-specific and inducible manipulations of any genes of interest will be possible in specific brain regions.

     Our second primary research focus will be to develop new conditional mutant mice in which attention or consciousness is modified. It is generally accepted that the hippocampus is a site of awareness or conscious recollection. Damage to the hippocampus formation in humans produced an intergraded amnesia, which strongly impairs the acquisition of new episodic information about individual events and experiences accessible to conscious control. In rodents, while some classical conditioning tasks such as cued-fear conditioning and eye-blink conditioning are known to be hippocampus-independent, intervention of temporal incontinency, “a trace period”, between conditioned stimulus and unconditioned stimulus during its acquisition phase makes these tasks hippocampus-dependent. This suggests that trace conditioning is closely related to awareness of the stimulus contingencies. The hippocampus is also thought to be involved in attention mechanisms. Lesions of the hippocampal formation, as well as lesions of the nucleus accumbens or the mesolimbic dopaminergic projection from ventral tegmental area to the nucleus accumbens, lead to an impairment in latent inhibition, which is defined as an increased associative strength between an elemental stimulus paired with an unconditioned stimulus following non-reinforced pre-exposure to the tone. Impairment in latent inhibition has been considered to reflect an acquisition deficit that interferes with normal “decremental attention”, and has become a popular paradigm for the study of the neurobiological basis of schizophrenia. Recent evidence suggests that schizophrenic patients indeed do not display latent inhibition. The ultimate goal of this project is to understand the neural basis of mental states of animals during behavior, such as consciousness, awareness or attention, using genetically-engineered mice.

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