AFFERENT REGULATION OF BASAL FOREBRAIN CHOLINERGIC SYSTEM

基底前脑胆碱能系统的传入调节

• 批准号: 3847082
• 负责人: LASZLO ZABORSZKY
• 金额: --
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3847082
• 关键词: acetylcholine; afferent nerve; brain mapping; brain stem; choline acetyltransferase; dopamine receptor; electron microscopy; gamma aminobutyrate; glutamate decarboxylase; immunocytochemistry; interneurons; laboratory rat; light microscopy; muscarinic receptor; neuroanatomy; neurons; neuropeptide Y; prosencephalon; serotonin receptor; somatostatin; tissue /cell culture

Multiple dementing illnesses share the common neuropathological substrate of loss in the basal forebrain of large neurons, many of which are cholinergic. Hypotheses about the mechanism of cholinergic cell loss in Alzheimer's disease, and related disorders must include the observation that monoaminergic cell groups which project to the basal forebrain also suffer moderate to marked loss. A recently developed idea is that cholinergic cell loss in AD and related disorders is not primary, but results from degeneration mediated by transneuronal pathways. The overall goal of this project to acquire anatomical and functional neurochemical data in support of this idea by obtaining a systematic and detailed understanding of how the basal forebrain cholinergic system is modulated by monoaminergic afferents. In order to achieve this goal, specific attempts will be made to assess whether projections from different brainstem serotoninergic and dopaminergic cell groups terminate on cholinergic forebrain neurons. As a logical extension of these experiments we will identify the sources of monoaminergic (noradrenergic, dopaminergic and serotonergic) afferents to local GABAergic and peptidergic (NPY and somatostatin) neurons which are connected to cholinergic neurons. These studies will be aided by using in vivo anterograde (PHA-L) and in vitro (Lucifer Yellow) tracer techniques, immunocytochemical methods and the Golgi technique in various combinations at both the light and EM level, supplemented by 3-D reconstruction of cholinergic neurons and their putative terminals. We will also characterize how the disruption of monoaminergic afferent systems affects expression of mRNAs for neurotransmitter enzymes (ChAT, GAD), neuropeptides (NPY, somatostatin) and receptors (5-HT[1C], D2 and M2) in basal forebrain neurons. Finally, we will test the hypothesis whether the decrease of ChAT activity after monoaminergic deprivation is mediated through the forebrain GABAergic system by monitoring forebrain GABAergic activity and cortical acetylcholine release. Defining the precise anatomy and regulatory mechanisms in specific basal forebrain circuits will be essential in our understanding of the deficiencies in the information processing in these systems in disease states. Moreover our study may provide additional clues to the pathophysiology of cognitive disorders as to whether neuronal metabolism and/or degeneration in this brain region is due at least in part to anterograde transneuronal mechanisms.

多种痴呆症有共同的神经病理基础