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Publication
Defective daily temperature regulation in a mouse model of amyotrophic lateral
sclerosis.
Authors Braun MC, Castillo-Ruiz A, Indic P, Jung DY, Kim JK, Brown RH, Swoap SJ,
Schwartz WJ
Submitted By Submitted Externally on 9/10/2018
Status Published
Journal Experimental neurology
Year 2018
Date Published 7/1/2018
Volume : Pages Not Specified : Not Specified
PubMed Reference 30031021
Abstract Current understanding of the pathogenesis of the familial form of amyotrophic
lateral sclerosis has been aided by the study of transgenic mice that
over-express mutated forms of the human CuZn-superoxide dismutase (SOD1) gene.
While mutant SOD1 in motor neurons determines disease onset, other non-cell
autonomous factors are critical for disease progression, and altered energy
metabolism has been implicated as a contributing factor. Since most energy
expended by laboratory mice is utilized to defend body temperature (Tb), we
analyzed thermoregulation in transgenic mice carrying the G93A mutation of the
human SOD1 gene, using implantable temperature data loggers to continuously
record Tb for up to 85?days. At room (22?°C) ambient temperature, G93A mice
exhibited a diminished amplitude of the daily Tb rhythm compared to C57BL/6J
controls, secondary to decreased Tb values during the dark (behaviorally active)
phase of the light-dark cycle. The defect arose at 85-99?days of age, around the
age of symptom onset (as assessed by grip strength), well before observable
weakness and weight loss, and could not be accounted for by decreased levels of
locomotor activity or food consumption. Housing under thermoneutral (29?°C)
ambient temperature partially rescued the defect, but age-dependently (only in
animals >100?days of age), suggesting that the deficit in older mice was due in
part to inadequate thermogenesis by "peripheral" thermogenic organs as the
disease progressed. In younger mice, we found that cold-induced thermogenesis
and energy expenditure were intact, hinting that an initial "central" defect
might localize to the subparaventricular zone, involving neural output pathways
from the circadian clock in the hypothalamic suprachiasmatic nucleus to
forebrain thermoregulatory circuitry.




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