Kaplan + Sadock's Synopsis of Psychiatry, 11e

35

1.4 Neurophysiology and Neurochemistry

R eferences DiCicco-Bloom E, Falluel-Morel A. Neural development and neurogenesis. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Text- book of Psychiatry. 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009. Eisch AJ, Petrik D. Depression and hippocampal neurogenesis: A road to remis- sion? Science. 2012;338:72. Hsieh J, Eisch AJ. Epigenetics, hippocampal neurogenesis, and neuropsychiat- ric disorder: Unraveling the genome to understand the mind. Neurobiol Dis. 2010;39:73. Kobayashi M, Nakatani T, Koda T, Matsumoto KI, Ozaki R, Mochida N, Keizo T, Miyakawa T, Matsuoka I. Absence of BRINP1 in mice causes increase of hip- pocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders. Mol Brain . 2014;7:12. Levenson CW, Morris D. Zinc and neurogenesis: Making new neurons from devel- opment to adulthood. Adv Nutr. 2011;2:96. Molina-Holgado E, Molina-Holgado F. Mending the broken brain: Neuroimmune interactions in neurogenesis. J Neurochem. 2010;114:1277. Sanes DH, Reh TA, Harris WA. Development of the Nervous System. 3 rd ed. Burlington, MA: Academic Press; 2011. Sek T, Sawamoto K, Parent JM, Alvarez-Buylla A, eds. Neurogenesis in the Adult Brain I: Neurobiology. NewYork: Springer; 2011. Sek T, Sawamoto K, Parent JM, Alvarez-Buylla A, eds. Neurogenesis in the Adult Brain II: Clinical Implications. NewYork: Springer; 2011. Shi Y, Zhao X, Hsieh J, Wichterle H, Impey S, Banerjee S, Neveu P, Kosik KS. MicroRNA regulation of neural stem cells and neurogenesis. J Neurosci. 2010;30:14931. ▲▲ 1.4 Neurophysiology and Neurochemistry The study of chemical interneuronal communication is called neurochemistry, and in recent years there has been an explosion of knowledge in understanding chemical transmission between neurons and the receptors affected by those chemicals. Simi- larly, advances in the science of physiology as applied to the brain and how the brain functions have been equally influenced. This chapter focuses on the complex heterogeneity of both these areas to help explain the complexity of thoughts, feelings, and behaviors that make up the human experience. Monoamine Neurotransmitters The monoamine neurotransmitters and acetylcholine have been historically implicated in the pathophysiology and treatment of a wide variety of neuropsychiatric disorders. Each monoamine neurotransmitter system modulates many different neural path- ways, which themselves subserve multiple behavioral and phys- iological processes. Conversely, each central nervous system (CNS) neurobehavioral process is likely modulated by multiple interacting neurotransmitter systems, including monoamines. This complexity poses a major challenge to understanding the pre- cise molecular, cellular, and systems level pathways through which various monoamine neurotransmitters affect neuropsychiatric disor- ders. However, recent advances in human genetics and genomics, as well as in experimental neuroscience, have shed light on this question. Molecular cloning has identified a large number of genes that regulate monoaminergic neurotransmission, such as the enzymes, receptors, and transporters that mediate the synthesis, cellular actions, and cellular reuptake of these neurotransmitters, respectively. Human genetics stud- ies have provided evidence of tantalizing links between allelic variants in specific monoamine-related genes and psychiatric disorders and trait abnormalities, whereas the ability to modify gene function and cellular activity in experimental animals has clarified the roles of specific genes and neural pathways in mediating behavioral processes.

in the striatum stimulates adjacent SVZ neurogenesis with neurons migrating to the injury site. Furthermore, in a highly selective paradigm not involving local tissue damage, degenera- tion of layer 3 cortical neurons elicited SVZ neurogenesis and cell replacement. These studies raise the possibility that newly produced neurons normally participate in recovery and may be stimulated as a novel therapeutic strategy. However, in contrast to potential reconstructive functions, neurogenesis may also play roles in pathogenesis: In a kindling model of epilepsy, newly generated neurons were found to migrate to incorrect positions and participate in aberrant neuronal circuits, thereby reinforc- ing the epileptic state. Conversely, reductions in neurogenesis may contribute to several conditions that implicate dysfunction or degeneration of the hippocampal formation. Dentate gyrus neurogenesis is inhibited by increased glucocorticoid levels observed in aged rats and can be reversed by steroid antagonists and adrenalectomy, observations potentially relevant to the cor- relation of elevated human cortisol levels with reduced hippo- campal volumes and the presence of memory deficits. Similarly, stress-induced increases in human glucocorticoids may contrib- ute to decreased hippocampal volumes seen in schizophrenia, depression, and posttraumatic stress disorder. A potential role for altered neurogenesis in disease has gained the most support in recent studies of depression. A number of studies in ani- mals and humans suggest a correlation of decreased hippocampal size with depressive symptoms, whereas clinically effective antidepressant therapy elicits increased hippocampal volume and enhanced neurogen- esis, with causal relationships still being defined. For example, postmor- tem and brain imaging studies indicate cell loss in corticolimbic regions in bipolar disorder and major depression. Significantly, mood stabiliz- ers, such as lithium ion and valproic acid, as well as antidepressants and electroconvulsive therapy activate intracellular pathways that promote neurogenesis and synaptic plasticity. Furthermore, in a useful primate model, the adult tree shrew, the chronic psychosocial stress model of depression elicited ∼ 15 percent reductions in brain metabolites and a 33 percent decrease in neurogenesis (BrdU mitotic labeling), effects that were prevented by coadministration of antidepressant, tianeptine. More importantly, although stress exposure elicited small reductions in hip- pocampal volumes, stressed animals treated with antidepressant exhib- ited increased hippocampal volumes. Similar effects have been found in rodent models of depression. In addition to the foregoing structural relationships, recent evidence has begun defining the roles of relevant neurotransmitter systems to antidepressant effects on behavior and neurogenesis. In a most excit- ing finding, a causal link between antidepressant-induced neurogen- esis and a positive behavioral response has been demonstrated. In the serotonin 1A receptor null mouse, fluoxetine, a selective serotonin reuptake inhibitor [SSRI], produced neither enhanced neurogenesis nor behavioral improvement. Furthermore, when hippocampal neuro- nal precursors were selectively reduced (85 percent) by X-irradiation, neither fluoxetine nor imipramine induced neurogenesis or behavioral recovery. Finally, one study using hippocampal cultures from normal and mutant rodents strongly supports a neurogenetic role for endog- enous NPY, which is contained in dentate gyrus hilar interneurons. NPY stimulates precursor proliferation selectively via the Y1 (not Y2 or Y5) receptor, a finding consistent with the receptor-mediating antidepressive effects of NPY in animal models and the impact of NPY levels on both hippocampal-dependent learning and responses to stress. In aggregate, these observations suggest that volume changes observed with human depression and therapy may directly relate to alterations in ongoing neu- rogenesis. More generally, the discovery of adult neurogenesis has led to major changes in our perspectives on the regenerative capacities of the human brain.