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1.7 Neurogenetics

indicate that patients with chronic fatigue syndrome may be hypocortisolemic because of impaired activation of the hypotha- lamic–pituitary–adrenal axis. Although an acute viral infection frequently precedes the onset of chronic fatigue syndrome, no infectious agent has been causally associated with it. In contrast, Lyme disease, in which sleep disturbances and depression are also common, is clearly caused by infection with the tick-borne spirochete Borrelia burgdorferi, which can invade the CNS and cause encephalitis and neurological symptoms. Lyme disease is remarkable because it appears to produce a spectrum of neuro- psychiatric disorders, including anxiety, irritability, obsessions, compulsions, hallucinations, and cognitive deficits. Immunopa- thology of the CNS may be involved, because symptoms can persist or reappear even after a lengthy course of antibiotic treat- ment, and the spirochete is frequently difficult to isolate from the brain. Gulf War syndrome is a controversial condition with inflammatory and neuropsychiatric features. The condition has been attributed variously to combat stress, chemical weapons (e.g., cholinesterase inhibitors), infections, and vaccines. Given the impact of stress on neurochemistry and immune responses, these pathogenic mechanisms are not mutually exclusive. Therapeutic Implications The bidirectional nature of CNS–immune system interactions implies the therapeutic possibility that agents known to posi- tively alter stress system activity might benefit immune func- tioning and, conversely, that agents that modulate immune functioning may be of potential benefit in the treatment of neu- ropsychiatric disturbance, especially in the context of medical illness. Increasing evidence supports both hypotheses. Antidepressants and the Immune System Emerging data indicate that in animals and humans, antide- pressants attenuate or abolish behavioral symptoms induced by inflammatory cytokine exposure. For example, pretreatment of rats with either imipramine or fluoxetine (a tricyclic antidepres- sant and selective serotonin reuptake inhibitor, respectively) for 5 weeks prior to endotoxin administration significantly attenu- ated endotoxin-induced decrements in saccharine preference (commonly accepted as a measure for anhedonia), as well as weight loss, anorexia, and reduced exploratory, locomotor, and social behavior. Similarly, several studies in humans suggest that antidepressants can ameliorate mood disturbances in the con- text of chronic cytokine therapies, especially if given prophy- lactically before cytokine exposure. For example, the selective serotonin reuptake inhibitor paroxetine significantly decreased the development of major depression in patients receiving high doses of interferon- a (IFN- a ) for malignant melanoma. Behavioral Interventions and Immunity It has been known for years that psychosocial factors can miti- gate or worsen the effects of stress, not only on immune func- tioning but also on the long-term outcomes of medical conditions in which the immune system is known to play a role. Therefore, behavioral interventions aimed at maximizing protective psycho- social factors might be predicted to have a beneficial effect, not only in terms of mitigating the effect of stress on immune func-

tioning but perhaps also on diminishing emotional disturbances that arise in the context of immune system dysregulation. Two factors that have been repeatedly identified as protec- tive against stress-induced immune alterations are social sup- port and the ability to see stressors as being to some degree under the individual’s control. In this regard, a recent study that conducted a genome-wide scan to assess gene expression activ- ity in socially isolated versus nonisolated individuals found that social isolation was associated with increased activation of a number of proinflammatory, cytokine-related pathways and reduced activity in anti-inflammatory cytokine pathways, as well as in the glucocorticoid receptor, which plays an important role in neuroendocrine control of inflammatory processes. Of interest, the two types of psychotherapy most often examined in illnesses associated with immune dysregulation are group therapy, which provides social support, and cognitive behavioral therapy, which provides cognitive reframing techniques aimed at enhancing one’s sense of agency (and hence control). R eferences Bajramovic J. Regulation of innate immune responses in the central nervous sys- tem. CNS Neurol Disord Drug Targets. 2011;10:4. Capuron L, Miller AH. Immune system to brain signaling: Neuropsychopharma- cological implications. Pharmacol Ther. 2011;130(2):226. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 2008;65:409. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflamma- tion to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46. Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH. Interferon- a effects on diurnal hypothalamic-pituitary-adrenal axis activity: Relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010;15:535. Raison CL, Cowles MK, Miller AH. Immune system and central nervous system interactions. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Com- prehensive Textbook of Psychiatry. 9 th edition. Philadelphia: Lippincott Williams &Wilkins; 2009:175. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012;122(4):1164. Steiner J, Bernstein HG, Schiltz K, Müller UJ, Westphal S, Drexhage HA, Bogerts B. Immune system and glucose metabolism interaction in schizophrenia:A chicken– egg dilemma. Prog Neuropsychopharmacol Biol Psychiatry . 2014;48:287–294. Wilson EH, Weninger W, Hunter CA. Trafficking of immune cells in the central nervous system. J Clin Invest. 2010;120(5):1368. Yousef S, Planas R, Chakroun K, Hoffmeister-Ullerich S, Binder TM, Eiermann TH, Martin R, Sospedra M. TCR bias and HLA cross-restriction are strategies of human brain-infiltrating JC virus-specific CD4 + T cells during viral infec- tion. J Immunol. 2012;189(7):3618. ▲▲ 1.7 Neurogenetics Starting from the rediscovery of Gregor Mendel’s basic concepts at the turn of the 20 th century, the field of genetics has matured into an essential cornerstone not only of the biological sciences but of all of medicine. The discovery of the basic structure and properties of deoxyribonucleic acid (DNA) in the middle of the century led to an exponential acceleration in our understand- ing of all aspects of the life sciences, including deciphering the complete sequence of the human genome, and those of myriad other species. Massive databases of such sequences now provide 21st-century biologists with the task of decoding the functional significance of all this information. In particular, attention has turned to determining how sequence variations contribute to the phenotypic variation between species and between individuals