Neurogenesis in the adult brain from ballyhoo to sobriety

Sammanfattning: New neurons are spontaneously generated in two regions of the adult brain, the hippocampus and the subventricular zone/olfactory bulb. The objective of this thesis was to study potential implications for adult neurogenesis in Alzheimer's (AD) and Parkinson's diseases (PD). PD is characterized by degeneration of dopaminergic neurons in the substantia nigra. It has been suggested that new dopaminergic neurons are formed in the normal, adult substantia nigra. In contrast, we found no newborn dopamine neurons in the brains of normal or lesioned adult rats and mice. We also noted that some of the methods previously used to identify newborn neurons in the adult substantia nigra were unreliable. We conclude that stimulation of endogenous neurogenesis in the substantia nigra holds little promise as a treatment for PD. In AD, neuropathology is more widespread, with loss of cholinergic neurons in the basal forebrain particularly associated with memory impairment. Intact neurogenesis in the adult hippocampus is suggested to mediate certain memory processes. We investigated the effects on neurogenesis of training in different forms of hippocampus-dependent spatial memory. We discovered that continuous training in a working memory task resulted in decreased neurogenesis. Next, we studied the effects of selective lesions of hippocampal input from the medial septum. We showed that the cholinergic component of the septohippocampal projection is important for proliferation, whereas the GABAergic component regulates survival of hippocampal neural progenitors. Combined lesions dramatically decreased proliferation, survival and differentiation of newborn neurons. Lastly, we demonstrated that continuous infusion of nerve growth factor in adult rats promotes hippocampal neurogenesis. We verified that hippocampal cholinergic activity is increased shortly after initiation of NGF infusion, which likely mediates the increase in neurogenesis. In summary, we demonstrated that acetylcholine and GABA, two neurotransmitter systems affected in AD, are important for intact hippocampal neurogenesis. In addition, we propose that increased hippocampal neurogenesis may contribute to cognitive improvement following NGF treatment.