Hormesis is defined operationally as responses of cells or organisms to an exogenous or intrinsic factor (chemical, temperature, psychological challenge, etc.) in which the factor induces stimulatory or beneficial effects at low doses and inhibitory or adverse effects at high doses. The compendium of articles by Calabrese entitled "Neuroscience and Hormesis" provides a broad range of examples of neurobiological processes and responses to environmental factors that exhibit biphasic dose responses, the signature of hormesis. Nerve cell networks are the "first responders" to environmental challenges-they perceive the challenge and orchestrate coordinated adaptive responses that typically involve autonomic, neuroendocrine, and behavioral changes. In addition to direct adaptive responses of neurons to environmental stressors, cells subjected to a stressor produce and release molecules such as growth factors, cytokines, and hormones that alert adjacent and even distant cells to impending danger. The discoveries that some molecules (e.g., carbon monoxide and nitric oxide) and elements (e.g., selenium and iron) that are toxic at high doses play fundamental roles in cellular signaling or metabolism suggest that during evolution, organisms (and their nervous systems) coopted environmental toxins and used them to their advantage. Neurons also respond adaptively to everyday stressors, including physical exercise, cognitive challenges, and dietary energy restriction, each of which activates pathways linked to the production of neurotrophic factors and cellular stress resistance proteins. The development of interventions that activate hormetic signaling pathways in neurons is a promising new approach for the preventation and treatment of a range of neurological disorders.
COMMENTARY ON NEUROSCIENCE AND HORMESISThe biphasic nature of responses to neurotransmitters, neurotrophic factors, cytokines, drugs of abuse, and treatments for a range of neurological disorders is underappreciated and often ignored in basic and applied neuroscience research. Calabrese demonstrates a broad understanding of basic principles of neuroscience, to which he applies his expertise in toxicology and hormesis to catalog hundreds of examples of "toxins," pharmacological agents, intrinsic signaling molecules, and behavioral factors that exhibit biphasic dose responses. The focus throughout the series of articles in "Neuroscience and Hormesis" is on the results of cell culture and in vivo experiments in which the effects of increasing doses of exogenous agents (toxins, neurotransmitters, peptide, hormones, drugs of abuse, etc.) on neuronal survival or plasticity or on animal behavior has been investigated. Calabrese aptly explores the existence of hormesis in most of the major areas of the field of neuroscience, ranging from developmental mechanisms (cell survival and neurite outgrowth) to synaptic plasticity to behavior to