Alcohol, neural stem cells, and adult neurogenesis

Recent research demonstrates that neural stem cells divide throughout life and give rise to new neurons, a process known as neurogenesis. This article addresses two principal questions concerning alcohol and adult neurogenesis: To what extent are neurogenesis in the adult brain and the risk for alcoholism governed by similar factors? And, to what extent and through what mechanisms do alcohol use and alcoholism affect adult neurogenesis? This article also discusses genetic and environmental influences on risk for alcoholism and on regulation of neurogenesis; the possibility that modulation of neurogenesis contributes to alcoholic pathology; and the evidence that alcohol disrupts neurogenesis in the adult brain, and the neurochemical processes by which this may occur. KEY WORDS: neural cell; stem cell; cell growth and differentiation; neurobiological theory of AODU (alcohol and other drug use); genetic theory of AODU; biological regulation; environmental factors; stress; neurochemistry; glutamate receptors; serotonin receptors; limbic system; hippocampal formation; chronic AODE (alcohol and other drug effects); brain; morphology; adult

For decades, the majority of neuroscientists believed, and physicians were taught, that the number of nerve cells (i.e., neurons) in the adult brain was fixed early in life and that learning and other flexible (i.e., plastic) processes in the brain must be related to changes in the existing neurons. Doctors postulated that nervous system plasticity was achieved by "strengthening synapses" without adding new neurons. The theoretical understanding of plastic processes such as learning, memory, mood, and other features of adult behavior is entrenched in this concept of a fixed number of neurons in the adult brain. As a result, research on brain plasticity has long focused on alterations in neurotransmitter receptors, numbers of synapses, structure of synapses, and transmitter release mechanisms.

The seminal discoveries on the formation of new neurons (i.e., neurogenesis) in adulthood were made in the 1960s. Until recently, dogma and insufficient technology prevented acceptance of these findings as an additional process influencing brain plasticity. This area remains controversial, with researchers currently debating how extensive neurogenesis is in the adult brain. Recent research clearly establishes that neural stem cells (NSCs) divide throughout life and give rise to new neurons in at least two regions of the adult brain: in the dentate gyrus of the hippocampus, a brain region important for learning and memory, and in the subventricular zone (SVZ) of the anterior lateral ventricles, the site of origin for olfactory bulb neurons. The function of adult NSCs is not known, but they are associated with complicated brain functions such as learning, mood, and association of sensory information. The discovery of NSCs and adult neurogenesis provides a new theoretical framework for understanding processes regulating brain plasticits. As addiction is thought to represent maladaptive changes in brain plasticity, understanding the role of alcohol-induced changes in the brain and exploiting the new research findings on brain plasticity should be included in scientists' schema for understanding, treating, and curing alcoholism.

This article addresses two principal questions concerning the connection between alcohol and adult neurogenesis. First, to what extent are neurogenesis in the adult brain and the risk for alcoholism governed by similar genetic and environmental factors? Second, do alcohol use and alcoholism affect adult neurogenesis, and if so, what are the mechanisms underlying those effects?

GENETIC AND ENVIRONMENTAL REGULATION OF ADULT NEUROGENESIS AND ALCOHOLISM

The components of neurogenesis--the proliferation of NSCs and their survival and differentiation into neurons and other brain cells--are heavily regulated by genetics but also respond to environmental factors. Indeed, many of the environmental factors that regulate adult neurogenesis also are affected in people with chronic alcoholism. Thus, the regulation of NSCs is similar to some aspects of alcohol abuse and alcoholism. Alcoholism is a progressive disease associated with maladaptive changes in behavior that are mediated by environmental and genetic factors, as well as by physiological changes that take place in the brain as a result of exposure to alcohol. Interestingly, genetics and specific environmental factors play an important role in regulating neurogenesis, and these same environmental factors (discussed below) are key factors in the risk of developing alcoholism. Given the overlapping genetic and environmental factors that appear to be involved in both adult neurogenesis and alcoholism, we argue that understanding the commonalities between these two plastic processes may provide new clues to the treatment and prevention of chronic alcoholism.

Genetic Regulation

Animal genetic studies; classic twin, family, and adoption studies; and systematic searches of the entire human genetic makeup (i.e., the genome) have demonstrated that genetics plays a significant role in the risk of developing alcohol dependence and excessive alcohol consumption. Furthermore, animal studies clearly have indicated that genetic factors influence many responses to alcohol use, including sensitivity to alcohol intoxication, alcohol withdrawal seizures, and preference for drinking alcohol over water.

Environmental Regulation

Adult neurogenes also is regulated by environmental factors. Research indicates that animals placed in an enriched environment (in particular, one that promotes physical activity and learning) show a significant increase in neurogenesis compared with animals in normal housing conditions. For example, running and hippocampal-dependent learning (such as spatial learning, or learning how to find something in an area) increase NSC survival and differentiation. Furthermore, inhibiting neurogenesis with a drug that prevents cell division disrupts associative learning. Interestingly, this disruption only is observed 1 to 2 weeks after administering the drug, when newborn cells--now functional neurons--would be expected to begin contributing to learning . Research comparing different strains of mice indicates that NSCs' response to environmental stimulation is, at least to some degree, under genetic control. For example, C57BL/6 mice, which have a high innate rate of NSC proliferation, are competent in learning tasks, whereas 129/SvJ mice, which produce fewer neurons than other mouse strains, do not perform well on learning tasks. Thus genetic factors and environmental factors overlap in this new mechanism of brain plasticity.

An important environmental factor is stress. Stress reduces neurogenesis and also is known to precipitate depression and increase drinking. As this environmental factor plays an important role in both neurogenesis and addiction, a more in-depth discussion of this point is included in a later section.