What is adult neurogenesis? The term refers to a complex process, starting, at the least, with the division of a precursor cell and ending with the existence of a new functional neuron. It also involves securing the survival of the new cell and the sending out the cellular processes of dendrites and axons, thereby creating new synaptic connections. Neurogenesis is considered a prominent part of a wider process called neuroplasticity; it is part of the continuous, far-reaching process of neuroplasticity. The two neurogenic regions in the adult mammalian brain are: the olfactory bulb and the hippocampus. Both forms of adult neurogenesis originate from different precursor cell populations, are regulated independently, and serve entirely different functions. Stress is a prominent regulator of neurogenesis, as well as of neuroplasticity in general.
The initial research on adult neurogenesis involved the effects of stress on the brain (see the research of Elizabeth Gould and Bruce McEwen). Gerd Kempermann (2006-see his volume Adult Neurogenesis: Stem Cells and Neuronal Development in the Adult Brain, published by Oxford University Press), director of the research group for neural stem cells at the Max Delbrück Center for Molecular Medicine in Berlin-Buch, Germany, noted:
“...stress downregulates cell proliferation in the dentate gyrus and the consecutive stages of neuronal development...Prenatal stress has been found to have long-lasting effects on adult neurogenesis and appears to lower the baseline level of adult hippocampal neurogenesis. It is not known how persistent the effects of stress in adulthood are, but negative effects of even prolonged stress on adult hippocampal neurogenesis are reversible” (p.263).
Acute psychosocial stress, which is severe, significantly reduces cell proliferation in the adult hippocampal dentate gyrus. However, many situations associated with mild to moderate forms of stress actually appear to augment adult neurogenesis, e.g., physical activity and environmental enrichment (both of which have proved to be protective factors in epidemiological research on Alzheimer’s disease). Chronic mild stress has down-regulating effects on cell proliferation. Therefore, stress and adult neurogenesis are in a dose-response relationship which follows an inverted-U curve. As is well known. elevated stress levels lead to chronically high levels of glucocorticoid secretion (e.g., cortisol) and over time to a failure of feedback processes that control glucocorticoid secretion on the one hand and glucocorticoid receptor expression on the other. Stress can attenuate the number of sphere-forming cells that can be derived from the brain. Postnatal handling and stroking, a paradigm with well-known positive effects on reducing stress, reverses this decline in sphere-forming cells.
Depression, for example, is correlated with disturbed cortisol levels, resulting in altered circadian patterns of hormone secretion and chronically elevated glucocorticoid levels. Glucocorticoids are regulators of adult neurogenesis. Depression is also associated with hippocampal atrophy (antidepressant medication, such as fluoxetine, is associated with stimulation of adult neurogenesis) in MRI research as well as postmortem studies. Barry Jacobs from Princeton University first proposed the viewpoint of the neurogenesis hypothesis of depression. Depression may therefore be associated with disturbed cellular plasticity, including adult hippocampal neurogenesis. A neuroplasticity hypothesis of affective disorders, associated with loss, various traumas (e.g., physical, emotional and sexual abuse), social isolation, and profound stress/fear/anxiety, may be reasonably extended to the schizophrenias. The most robust neuroimaging findings in the schizophrenias seem to be ventriculomegaly (20-30% enlargement in the lateral and third ventricles), and temporal-hippocampal/parahippocampal (6% reduction), prefrontal (2-8% reduction) and amygdalar (10% reduction) atrophy and white matter deficits (about a 2% reduction) observed on diffusion tensor imaging (DTI) comparing fractional anisotropy maps (FA)- (the extent to which these are reversible is still being researched). I do not believe we need to fall back upon purely physico-chemical explanations and neurogenetics to explain these findings (parenthetically some of this research is conducted with medication-naive patients, often the research is with first episode patients). The most conspicuous factor, which correlates with subjective/phenomenological experience, as well as neurochemical and neurobiological studies, is profound and chronic stress. The role of genetics may very well prove to be one of epigenetic suppression of gene expression through DNA methylation, associated with traumatic social-environmental experience as well as social isolation. This is not to say that stress is the primary 'cause' of the schizophrenias. The latter are complex conditions in which the self and relational factors, across development, and the collective culture (transgenerationally) also play significant roles.
Brian Koehler PhD
New York University
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