Age-related damage to neurons in the brain results in a rearrangement of synaptic contacts, and the partial or total isolation of a cortical region from other areas of the brain. Decreased synaptic activity appear to contribute to the initiation of the age-related neuronal damage by decreasing the stability of the cytoskeleton of affected neurons, but there are few animal models in which the mechanisms of the gradual, age- related reorganization of cortical neurons can be examined. Our recent studies indicate that the apical dendrites of the layer II neurons in the retrosplenial granular cortex may provide a useful model in which to uncover some of these mechanisms. In the mature rat, apical dendrites of the layer II neurons arborize and receive innervation primarily in layer Ia of the cortex, the zone in which three afferent to this cortex are selectively located, i.e., a major excitatory projection (from the anterior ventral thalamic nucleus) and two neuromodulator inputs (the alpha2 adrenoceptor related, noradrenergic innervation and the m2 muscarinic receptor related, cholinergic input). In aged rats the apical dendrites of the layer II, retrosplenial granular cortex neurons lose their distal dendritic tufts, i.e., many (>50%) of them no longer reach their terminal field in layer Ia. In contrast, the basal dendrites of the layer II neurons increase in length, and the apical dendrites of deeper neurons extend into layer Ia (where they normally are not present). Thus, during the period of age-related regression of the apical dendrites of the layer II neurons in this cortex, neurons actively reorganize their synaptic relationships. The initial focus of the proposed studies is to determine the mechanisms that lead to the instability of apical dendrites of the layer II neurons. The second focus is to characterize the ability of the axons and dendrites in this cortex to reorganize their synaptic relationships in response to the change in the apical dendrites. our general hypothesis concerning these age-related changes in retrosplenial granular cortex is that the age- related regression of apical dendrites of layer II neurons in the retrosplenial granular cortex from their normal terminal field in layer Ia is the result of a chronically decreased synaptic activation of these dendrites, i.e., an use-dependent alteration. We hypothesize that three mechanisms contribute to the activity-dependent changes in the apical dendrites in this model. 1) In aged rats, decreased synaptic activity from the primary excitatory input results in a regression of apical dendrites. 2) Neuromodulatory inputs to the apical dendrites, but in aged rats this neuromodulation decreases, thereby contributing to a decline in synaptic activation of the layer Ia dendrites. 3) The decrease in excitatory stimulation results in a re-expression of forms of cytoskeletal proteins (especially microtubule associated proteins) that normally are found in immature neurons and in the phosphorylation of these proteins, resulting in a depolymerization of the microtubules in the dendrites and a destabilization of the postsynaptic receptors on these dendrites. Further, we will test the hypothesis that the regression of the apical dendrites of the layer II neurons leads to a reorganization of the thalamocortical circuit in this cortical region.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurology B Subcommittee 2 (NEUB)
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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van Groen, Thomas; Kadish, Inga; Wyss, J Michael (2004) Retrosplenial cortex lesions of area Rgb (but not of area Rga) impair spatial learning and memory in the rat. Behav Brain Res 154:483-91
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