Vol 6 n° 2 - Neuroplasticity
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1 1 7 I n   t h i s   i s s u e . . . For many of us, a central tenet of our neurobiological train- ing was that the structure of the brain was fixed, as was the number of neurons in the adult brain. This belief was not only incorrect, but also restricted our understanding of a variety of fundamental processes including learning, adap- tation and maladaptation to stress, development of sus- ceptibility to disease, and resilience. This issue of Dialogues in Clinical Neuroscience describes the flexible, adaptive responses of the brain—neuroplasticity—and the relevance of neuroplastic changes to the pathophysiology of neu- ropsychiatric  illness,  the  mechanism  of  action  of  psy- chotropic medications, and the transduction of environ- mental factors to changes in brain function. In the State of the art article, Bruce S. McEwen (page 119) provides  an  introduction  to  allostasis—adaptation  to stress—and an overview of the structural and cellular con- sequences of stress, its molecular mediators in altering brain structure, and the kinetics of stress-induced structural remodeling. The compelling models described make appar- ent the complexity and dynamic nature of adaptation, as well as the ontogeny of susceptibility to psychiatric illness. In the first Basic research article, Fred H. Gage (page 135) reviews an element of neuroplasticity, neurogenesis, ie, the generation of new neurons, and describes the multiple steps involved in the process of neurogenesis: differentia- tion, commitment, survival, and functional integration. This capacity for self-repair represents one of the therapeutic frontiers in the treatment of neuropsychiatric illness. In the second Basic research article, Jing Du and col- leagues (page 143) review the evidence suggesting the role of glutamatergically mediated synaptic plasticity in both the pathophysiology and treatment of affective ill- ness. While focusing on AMPA (a-amino-3-hydroxy-5- methyl-4-isoxazolepropionate) and GluR1 (glutamate) receptor trafficking, these authors provide an excellent introduction to glutamate receptor pharmacology and intracellular signaling as a way of demonstrating both the mechanisms of action of mood stabilizers and targets for subsequent drug development. In one of the Pharmacological aspects articles, Ronald S. Duman (page 157) discusses the effects of stress and antidepressants on neuroplasticity, particularly as these effects relate to depression. He focuses on two mediating systems that appear to link, at a molecular level, neuro- plasticity, stress, depression, and pharmacotherapy: the neurotrophin BDNF (brain-derived neurotrophic factor), and the cAMP-CREB (cyclic adenosine monophosphate [cAMP]–cAMP-response element binding protein) cas- cade. He suggests that the cellular and molecular under- pinnings  of  structural  and  functional  plasticity  offer promising clues to the pathophysiology of depression and targets for drug development. In the other Pharmaco- logical aspects article, Eberhard Fuchs and Gabriele Flügge (page 171) describe the pharmacology of the stress response by focusing on changes in monoamines and monoamine receptors in several animal stress mod- els. They provide a basis for understanding depression as an impairment of synaptic and structural plasticity, with consequent implications for its treatment. In the first Clinical research article, Craig A. Stockmeier and Grazyna Rajkowska (page 185) describe in detail the neural and glial abnormalities identified in several critical brain regions in affective illness. This comprehensive review of postmortem studies discusses the possible functional implications of abnormalities of cell morphology and dis- tribution and introduces the circuitry that is described in more detail in the second article by Wayne C. Drevets (page 199). While focusing on neuroimaging studies, he provides a synthesis of identified neuropathological and imaging abnormalities in affective illness, highlighting those neural circuits strongly implicated as dysfunctional in affective disorder. Elucidation of this circuitry at functional and structural levels will also help illuminate substrates for component processes common to a variety of neuropsy- chiatric disorders. Indeed, in the last article, Dennis S. Charney and his col- leagues (page 217) suggest that studies of neuroplastici- ty will result in a new psychiatric nosology, as well as new therapeutic targets. Thus, not only will the therapeutic armamentarium be expanded as we better understand the mechanics of neuroplasticity, but this better under- standing will also lead to a reconceptualization of how psychiatric illness is acquired, how it is optimally treated (with attention to both structural and functional ele- ments), and, perhaps most importantly, how resilience is expressed at cellular and organismic levels. David R. Rubinow, MD