Biomedical Engineering Reference
In-Depth Information
232,262). Ultimately, the energy state of the cell and/or mitochondrial function
may become impaired and normal transport processes may likewise be affected.
In model organisms, protection against degenerative disease can be con-
ferred by over-expression of some members of a family of heat-shock proteins
that keep proteins in a folded state, and are upregulated during cellular stress
conditions (152,194,236). Aging causes these cellular defense proteins to de-
cline, possibly heralding the onset of neurodegenerative disease whose preva-
lence increases with age (152,194,236; see also this volume, Part III, chapter
7.3, by Lipsitz). Molecular systems that keep proteins in a folded state serve as
"capacitors" for cellular evolution (135,205,217,252).
Heritable alterations in gene expression that do not rely on coding or regula-
tory polymorphisms in DNA sequences (e.g., methylation of DNA bases) but on
(a) parental origin of the DNA (epigenetic modifications such as imprinting), (b)
allele specific gene expression not dependent on obvious imprinting, and (c)
variations in gene copy numbers (127,128,136,230) may also contribute to hu-
man variation and neuropsychiatric disease. For example, Down's syndrome,
Turner's syndrome, and Praeder-Willi and Angelman syndromes are neuropsy-
chiatric diseases that can be caused by alterations in gene dosage and/or imprint-
ing rather than by mutations in the DNA itself (17,182,218,245). Such
observations have led to a "rheostat" model for gene expression (17), which acts
as a gain-control to allow rapid and reversible attenuation of gene expression
(over generations and during development). Together, these mechanisms regu-
lating gene expression may contribute to the spectrum nature of psychiatric dis-
eases (e.g., Autism-Asperger's syndrome).
The molecules that serve as the putative gain-control and capacitors for
producing adaptive phenotypic variation function in a substantial and stepwise
fashion rather than an incremental and progressive one. Variations in both sys-
tems may be present in neuropsychiatric diseases such as Rett syndrome
(6,232,262,269). The molecular genetic basis of such neuropsychiatric diseases
may be the outcome of evolutionary events that strike a delicate balance be-
tween minimizing deleterious mutations while allowing phenotypic variations
that are adaptive to a species in a changing environment (17,135,205,217,
233,252,260).
These genetic variations, which may be adaptive or maladaptive in a chang-
ing environment, have the potential to influence brain function at a number of
spatiotemporal scales (Figure 15). The parsimonious description of scales of
brain function and their embedding remains a topic of active discussion (see
56,95). There is also an open question of whether the dynamic principles gov-
erning information processing at one level of organization are applicable to
other levels of organization (i.e., neural scale invariance) (242). For at least one
brain region, the NAc, a qualitative similarity is noted between reports of tran-
scription factor cAMP response element-binding protein (CREB) phosphoryla-
tion in response to aversive and rewarding stimuli (11,278), and the signal
