The NGF saga: From animal models of psychosocial stress to stress-related psychopathology

The role of the neurotrophins Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) has been expanding over the last years from trophic factors involved in brain growth and differentiation, to much more complex messengers, involved in psycho–neuro-endocrine adaptations. Much of this research stems from a series of studies inspired by the life-long work of the Nobel laureate Rita Levi-Montalcini. A new field of research started when NGF was found to be released in the bloodstream as a result of psychosocial stressors in male mice. Subsequent studies have shown that, in humans, highly arousing situations also result in increased blood levels of NGF, underlying the unique role of this neurotrophin, compared to other neuroendocrine effectors, and its sensitivity to environmental variables endowed by a social nature. Data are reviewed to support the hypothesis that this neurotrophic factor, together with BDNF, could be involved in the neurobiological changes underlying physiological and pathological reactions to stress that can result in increased vulnerability to disease in humans, including risk for anxiety disorders, or in the complex pathophysiology associated with mood disorders. Indeed, numerous data indicate that neurotrophins are present in brain hypothalamic areas involved in the regulation of hypothalamic-pituitary–adrenal axis, circadian rhythms and metabolism. In addition, there is now evidence that, in addition to the nervous system, neurotrophins exert their effects in various tissue compartments as they are produced by a variety of non-neuronal cell types such as endocrine and immune cells, adipocytes, endothelial cells, keratinocytes, thus being in a position to coordinate brain and body reactions to external challenges. Aim of this review is to discuss the evidence suggesting a role for neurotrophins as multifunctional signaling molecules activated during allostatic responses to stressful events and their involvement in the complex pathophysiology underlying stress-related psychopathology.