The Repairable Brain: An Anatomists View

Many neurological disorders result from progressive degeneration of specific anatomical pathways in the central nervous system (CNS). These include, but are not restricted to diseases such as Parkinson's (PD), amyotrophic lateral sclerosis, Alzheimer's, Huntington's, and many others. Also, CNS trauma can result in paralysis, and cognitive decline, motor disability and neuroendocrine imbalance are common. The identification of neurotransmitters in the 1960's with the advent of monoamine histochemistry followed by immunohistochemical staining for neuropeptides a decade later made it possible to correlate loss of transmitters such as dopamine (DA) with specific diseases such as PD. Beginning in the 1980's we and other laboratories began to test whether cell replacement was possible in the CNS and discovered that endocrine, motor, visual, and cognitive functions could be improved in rodent models of neurological disorders. We then extended our PD studies to the non‐human primate and demonstrated that the functional integrity of the nigrostriatal DA pathway from the substantia nigra (SN) of the mesencephalon to the neostriatum could be restored by the implantation of embryonic DA neurons into DA‐deficient regions. Optimal results were obtained by knowledge of the anatomy and migratory pattern of the newly generated DA neurons during precise stages of ontogeny. Grafted neurons survived implantation, extended DA rich neurites into the host neuropil and released DA as measured biochemically in microdissected punches in the region of grafts. Animals improved for over a year and were studied morphologically to assess survival characteristics. These proof of principle studies led to clinical trials that showed efficacy and the value of a translational model closely related to humans. We next demonstrated the positive effect of concurrent gene therapy via the delivery of growth factors as well as the potential to reconstruct the nigrostriatal pathway with the use of helper co‐grafts of embryonic target tissue. Axons extended from DA rich neuronal grafts in the region of the substantia nigra to the neostriatum by placement of growth factor‐laden “stepping stones.” More recently, we studied another mechanism of potential brain repair, i.e. neurogenesis. In DA‐depleted monkeys we discovered a population of DA neurons that increases significantly in number and invades the caudate nucleus, most likely from the subventricular zone, a known neurogenic niche. Because vertebrates like the salamander can regenerate DA neurons in response to insult this wave of putative neurogenesis may represent a conserved biological mechanism in the primate brain. Research next will focus on mechanisms to stimulate and maintain these new DA neurons for neural repair. Support or Funding Information Supported by NINDS, various foundations and with collaborators identified during the lecture.