Defective daily temperature regulation in a mouse model of amyotrophic lateral sclerosis

Exp Neurol. 2019 Jan;311:305-312. doi: 10.1016/j.expneurol.2018.07.008. Epub 2018 Jul 18.


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.

Keywords: Circadian; G93A; SOD1; Scholander curves; Suprachiasmatic nucleus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Body Temperature Regulation / physiology*
  • Circadian Rhythm / physiology*
  • Disease Models, Animal*
  • Humans
  • Locomotion / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Superoxide Dismutase-1 / biosynthesis
  • Superoxide Dismutase-1 / genetics


  • SOD1 protein, human
  • Superoxide Dismutase-1