Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-0QUANTITATIVE STRUCTURAL CHANGES IN THE AGEING BRAIN 47Potential Regeneration of the Ageing BrainStephen B. DunnettSchool of Biosciences, Cardiff University, Wales, UKThe brain does not spontaneously regenerate. As long ago as1928, Cajal recorded that ‘‘once development was ended, thefounts of growth and regeneration of axons and dendrites driedup irrevocably. In adult centres . . . everything may die, nothingmay be regenerated’’ 1 . Although it remains the case that thedamaged mammalian central nervous system (CNS) does notgenerally generate new nerve cells in response to disease or injury,the intervening 70 years have identified a considerable plasticity ofaxons to remodel nerve connections and a limited degree ofneurogenesis, which opens new opportunities for promotingregeneration and repair in the damaged, diseased or ageingnervous system (see Figure 1).COLLATERAL SPROUTINGThe first clear evidence that Cajal’s dictum was overly pessimisticin relation to the mammalian CNS came from the demonstrationthat if a septal cell loses some of its normal axonal inputs, thenother afferent axons can sprout into the vacated spaces to formFigure 1. Schematic illustration of examples of regeneration and repair in the septo–hippocampal system of rats. (A) Normal synaptic inputs onto septalcells arising in the hippocampus and brainstem locus coeruleus. (B) Collateral sprouting of afferents from hippocampus following removal of afferentsfrom the brainstem by a lesion of the medial forebrain bundle. (C) Normal septal projections into the hippocampus via dorsal and ventral pathways. (D)Compensatory collateral sprouting of ventral afferents following lesion of afferents to the dorsal hippocampus by transection of the fimbria-fornix bundle.(E) Implantation of hippocampal or glial grafts provides a substrate for regenerative growth of host septal axons back to the hippocampus. (F)Implantation of septal grafts provides a cholinergic reinnervation of the deafferented hippocampus. (G) Chronic injection of NGF molecules (triangles)diffusing via the lateral ventricles provides trophic support of cholinergic septo–hippocampal neurones in aged animals. (H) Implantation of cellsengineered to secrete NGF provides similar neuroprotection in aged animals. (J) Neuronal stem cells in subventricular zone have the capacity to divide anddifferentiate in the adult brain. Whether they can also migrate to repopulate areas of cell loss in the aged brain remains speculative. ff, fimbria-fornix; h,hippocampus; Ic, locus coeruleus; s, septum; small circles, neurones; small triangles, neuronal stem cells; asterisks, growth factor molecules