Does the Regeneration of Hippocampal Neurons Offer Hope for the Treatment of Cognitive Deficits?

Abstract

A number of pathological conditions including, but not limited to, Alzheimer’s disease, Parkinson’s disease, stroke, epilepsy and chronic stress can result in substantial loss of neurons throughout the brain. Neuronal loss in the cerebral cortex associated with several of these condition causes lasting deficits in cognition. Of direct relevance to the work discussed here is that many of these conditions lead to permanent deficits in long-term memory, most often caused by damage to the hippocampus. A key goal in the field of neuroscience continues to be the promotion of the functional recovery of damaged brain circuitry in an attempt to potentially reverse or attenuate these deficits. The regrowth of functional neurons within the adult brain is an exciting avenue of research made possible by a number of relatively recent discoveries and there are promising early results using at least one animal model. Treatment strategies aimed at the restoration of function as a result of pathology have often employed neuroprotective drugs [1] or the transplantation of exogenous stem cells [2–4]. Although the early findings for regenerating brain circuitry were promising, the long-term results have been unimpressive. There is a lack of evidence for longterm survival of grafted neurons [2,3,5] and for normal functional, synaptic integration into an existing neural network [2,3,6]. In summary, these approaches have generated some limited success. As an alternative approach, we manipulated a naturally occurring neurogenic system that normally, continually results in the functional integration of new neurons into an existing network within the adult animal. It is now well established that at least two discrete brain regions naturally and continuously produce neurons throughout adulthood, a process referred to as adult neurogenesis [7,8]. The specific functions of adult-born neurons are unclear, but an important question is whether ongoing neurogenesis may support repair of a given area after damage. The focus of this editorial is the stem cell niche located within the subgranular zone of the dentate gyrus of the hippocampus [8], a structure known to be involved in memory processes [9–11]. Using a rat model, we have focused on examining whether increasing the proliferation and survival of new neurons in the dentate gyrus may support repair in the event of an injury to dentate gyrus circuitry. The model that we have developed involves slow neural degeneration in the hippocampus leading to the onset of cognitive symptoms, similar to those experienced by people suffering from hippocampal damage as a result of a variety of pathological disorders. Our model capitalizes on the interesting pheno menon that bilateral removal of the adrenal glands (ADX) results in the selective and gradual death of hippocampus granule cells [12]. The selective loss of granule cells is caused by the elimination of circulating corticosterone, specifically a lack of stimulation of type 1 glucocorticoid receptors [13].