Neurogenesis is the process by which new neurons are created from neural stem cell populations, then mature, migrate, and integrate into neural circuits. This is necessary for memory, learning, normal tissue maintenance in the brain, and the small degree of regeneration from injury the brain is capable of. Neurogenesis declines with age, for a range of reasons including the usual reduced activity of stem cells that occurs in every tissue, and this is thought to contribute to some degree of the loss of cognitive function observed to occur in later life.
Researchers are interested in finding ways to increase the pace of neurogenesis, as this could partially compensate for the damage and losses of aging and neurodegenerative conditions. It could also enhance cognitive function in younger people. There are many approaches to achieve this end, but the size of the effect is important. Exercise increases neurogenesis (and cognitive performance) at all ages, for example, but one can't exercise one's way out of an Alzheimer's diagnosis, even though fitness maintained over the long term evidently reduces the risk of neurodegenerative conditions. The same is true of other commonly used options, such as antidepressant therapies. If more dramatic outcomes are desired, then much larger increases in neurogenesis are needed than are offered by presently available strategies.
Immature and new neurons in the adult dentate gyrus (DG) play important roles in different forms of learning and memory that depend on the hippocampus. Numerous studies manipulated levels of hippocampal neurogenesis in rodent models and showed an effect of learning and memory. Among others, these studies utilized irradiation, chemical, or genetic manipulation to target neurogenesis. Manipulations that led to reduced or diminished levels of neurogenesis resulted in impaired performance in various cognitive tasks, including contextual discrimination (pattern separation), spatial navigation, long-term spatial memory retention, spatial pattern discrimination, trace conditioning, contextual fear conditioning, clearance of hippocampal memory traces, and reorganization of memory to extra-hippocampal substrates. On the other hand, manipulations that led to the enhancement of neurogenesis, such as environmental enrichment, running, deep brain stimulation, or genetic manipulation, led to improved performance in these tasks. Mounting evidence has linked impaired neurogenesis to cognitive deterioration in Alzheimer's disease (AD).
The identification of signals that are altered in the aging or diseased DG may be possible therapeutic targets or open up new avenues in that regard. For example, imbalance between bone morphogenetic proteins (BMP2 and BMP4) and noggin, where BMP is upregulated is implicated in reduced neurogenesis in depression and aging. One of the homeostatic mechanisms affected in the aged brain that might contribute to the decline in neurogenesis is the Wnt signaling pathway. A downregulation of Wnt ligands and an upregulation of Wnt inhibitors (Dkk1 or sFRP3) has been observed in the aged brain that impairs neurogenesis and the Wnt β-catenin signaling has been proposed as a potential therapeutic target. Endogenous neurotrophic growth factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glia-derived neurotrophic factor (GDNF), and insulin-like growth factor 1 (IGF-1), play vital roles in promoting development, proliferation, and differentiation of neural stem cells (NSCs) in the central nervous system.
Many of these neurotrophic factors activate tropomyosin-related kinase (Trk) receptors, including type A and B, initiating intracellular signaling cascades that govern NSC self-renewal and fate determination. The indispensability of BDNF-TrkB signaling in the enhancement of hippocampal neurogenesis and the survival of newly generated neurons during adult neurogenesis has been unveiled. Considering the significant contributions of neurotrophic factors to neuronal plasticity and function, alterations in levels and expression of their respective receptors are associated with a multitude of psychiatric and neurodegenerative disorders.
Small molecules that can modulate specific neurogenic signals or processes may have a therapeutic potential. For example, protein kinases of the protein kinase C (PKC)-activating diterpene small molecule has been shown to facilitate NSC proliferation in neurogenic niches when injected into cerebral ventricles. PKC stimulates the release of growth factors that stimulate NSC proliferation. ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFkB, Wnt, BDNF, and NPAS3. Combinations of these compounds can potentially transform somatic cells into neurons. This transformation process involves the activation of neuron specific transcription factors such as NEUROD1, NGN2, ASCL1, and SOX2, which subsequently leads to the transcription of downstream genes, culminating in the transformation of somatic cells into neurons.
All classes of antidepressant drugs tested thus far, including 5-HT reuptake inhibitors (SSRIs), tianeptine, and mood stabilizers such as lithium, were shown to increase the proliferation and survival of new neurons in the dentate gyrus. Similarly, under chronic treatment conditions, CRHR1 receptor antagonists and V1b receptor antagonists improved deficits in neurogenesis caused by chronic mild stress. Chronic administration of antidepressants such as fluoxetine, reboxetine, tranylcypromine, and electroconvulsive shock (ECS) enhances neurogenesis in adult rodents, with similar effects observed in non-human primates for fluoxetine and ECS. Antidepressants targeting different neurotransmitter systems, including serotonin and norepinephrine, as well as SSRIs, tricyclics, mood stabilizers, and atypical antidepressants, promote neurogenesis and cell proliferation.
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