Previous studies of cortical development have demonstrated dynamic patterns of neurotransmitter innervation, which may have functional significance in directing the complex processes of cortical ontogeny. Although acetylcholine (ACh), in particular, has been implicated as a modulator of cortical ontogeny, little is known about the ontogenetic appearance of the receptors through which this system mediates its biological effects. Thus, a detailed characterization of the developmental patterns of cholinergic receptor appearance is essential. By using techniques which permit analysis of the anatomical localization of receptors, cholinoceptive elements within cortex may be identified, and the mechanisms by which ACh influences cortical structure and function may be further elucidated.
The aim of the present proposal is to examine the developmental appearance and functional role of cholinergic receptors in rodent somatosensory cortex. Using receptor autoradiography, in situ hybridization and immunohistochemistry, the laminar and regional distribution of receptors will be examined in somatosensory cortex of rats of defined pre- and post- natal ages. The developmental appearance of cholinergic receptors will be analyzed both within and across individual cortical layers, and will be compared with that of thalamocortical afferents. Particular attention will be paid to the first ten postnatal days, in order to identify those receptors which may modulate crucial aspects of cortical development. Of particular interest will be those receptors which exhibit either a transient appearance and/or a distribution which corresponds to some aspect of the somatotopic map, particularly the whisker barrel field. In order to more accurately predict the possible functional role of such receptors, we shall undertake a detailed examination of their cellular localization. Using quantitative autoradiography, receptor distributions will be examined at appropriate postnatal ages in animals which have received lesions of thalamocortical or serotonergic afferents, or of intrinsic cortical neurons. The timecourse of receptor loss, if any, will be compared with that of cellular loss, as determined by histochemical or autoradiographic techniques. Having identified those receptors which are localized on either thalamocortical afferents or cortical neurons, we shall examine the consequences of their selective pharmacological manipulation on cortical development. We shall first determine whether the receptors of interest are expressed in organotypically cultured thalamocortical slices, and then examine the effects of selective drug treatments on the development of cortical neurons and their thalamocortical innervation in vitro. This will permit analysis of drug effects under carefully controlled experimental conditions. Overall, these studies should provide insight into, not only the cellular localization and physiological role of cholinergic receptors in developing cortex, but also the consequences of their manipulation by the exogenous administration of clinically relevant drugs.
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