The broad, long-term objectives of this project are to provide physiological and pharmacological analyses of the synaptic organization of efferent, afferent, and intrinsic connections of the rat subicular complex and entorhinal cortex. First, physiological studies of efferent projections from these structures will be continued. Work will concentrate on projections from the subicular complex and entorhinal cortex to the prefrontal cortex. In order to achieve this objective, the subicular complex and entorhinal cortex will be stimulated electrically, and synaptic potentials in response to this stimulation will be recorded intracellularly in the prefrontal cortex. Target neurons in the prefrontal cortex will be injected intracellularly with horseradish peroxidase (HRP) in order to establish their dendritic and axonal morphology. Second, a pharmacological analysis of projections from the subicular complex to the entorhinal cortex will be conducted, using multibarrel iontophoretic techniques. The pharmacological studies will be designed to test the hypothesis that the excitatory responses in entorhinal principal and inhibitory cells are mediated by glutamatergic transmission; and that inhibitory responses are mediated by GABAergic transmission, secondary to glutamatergic excitation of local inhibitory neurons (feedforward inhibition). Specific antagonists of GABA A and GABA B receptors will be used in order to determine the receptor subtype(s) responsible for the inhibitory responses. Third, a pharmacological analysis of the projections from the subicular complex and entorhinal cortex to the amygdala and to the prefrontal cortex will be conducted. It is hypothesized that glutamatergic and GABAergic receptors mediate feedforward inhibition within these targets, and effort will be concentrated on establishing the roles of receptor subtypes. Fourth, the physiological action of projections to the subicular complex and entorhinal cortex from the prefrontal cortex will be determined. In particular, it is proposed 1) to establish whether inhibitory responses to prefrontal stimulation are mediated by inhibitory neurons located within the subicular complex and entorhinal cortex and 2) to establish the dendritic morphology and pattern of axonal projections of responsive target neurons by injecting them intracellularly with HRP. The proposed intracellular and pharmacological studies attack problems that can best be studied at the systems level in the intact, in vivo preparation. The subicular complex and entorhinal cortex participate in medically-refractory temporal lobe seizures, and appear to be early targets of cell death in Alzheimer's disease. Accordingly, a better understanding of these neuronal systems can provide insight into the pathophysiology associated with these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS016721-07
Application #
3397081
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1981-07-01
Project End
1992-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Mello, L E; Tan, A M; Finch, D M et al. (1996) Fos-like immunoreactivity after status epilepticus and spontaneous seizures in rats. Epilepsy Res Suppl 12:205-13
Mello, L E; Kohman, C M; Tan, A M et al. (1996) Lack of Fos-like immunoreactivity after spontaneous seizures or reinduction of status epilepticus by pilocarpine in rats. Neurosci Lett 208:133-7
Handforth, A; Finch, D M; Peters, R et al. (1994) Interictal spiking increases 2-deoxy[14C]glucose uptake and c-fos-like reactivity. Ann Neurol 35:724-31
Gigg, J; Tan, A M; Finch, D M (1994) Glutamatergic hippocampal formation projections to prefrontal cortex in the rat are regulated by GABAergic inhibition and show convergence with glutamatergic projections from the limbic thalamus. Hippocampus 4:189-98
Mello, L E; Cavalheiro, E A; Tan, A M et al. (1993) Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 34:985-95
Gigg, J; Tan, A M; Finch, D M (1992) Glutamatergic excitatory responses of anterior cingulate neurons to stimulation of the mediodorsal thalamus and their regulation by GABA: an in vivo iontophoretic study. Cereb Cortex 2:477-84
Mello, L E; Cavalheiro, E A; Tan, A M et al. (1992) Granule cell dispersion in relation to mossy fiber sprouting, hippocampal cell loss, silent period and seizure frequency in the pilocarpine model of epilepsy. Epilepsy Res Suppl 9:51-9;discussion 59-60
Mello, L E; Tan, A M; Finch, D M (1992) Convergence of projections from the rat hippocampal formation, medial geniculate and basal forebrain onto single amygdaloid neurons: an in vivo extra- and intracellular electrophysiological study. Brain Res 587:24-40
Mello, L E; Tan, A M; Finch, D M (1992) GABAergic synaptic transmission in projections from the basal forebrain and hippocampal formation to the amygdala: an in vivo iontophoretic study. Brain Res 587:41-8
Lingenhohl, K; Finch, D M (1991) Morphological characterization of rat entorhinal neurons in vivo: soma-dendritic structure and axonal domains. Exp Brain Res 84:57-74

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