1.4 Neurophysiology and Neurochemistry
35
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.
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eferences
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▲▲
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.
