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Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy

Milos Stanojlovic1, Jean Pierre Pallais Yllescas1, Vijaya Mavanji2

  • 1Integrative Biology and Physiology, University of Minnesota , Minneapolis, Minnesota.

American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
|February 7, 2019
PubMed

Insights

Stimulating hypothalamic orexin neurons with designer receptors exclusively activated by designer drugs (DREADD) reversed age-related behavioral and metabolic declines in mice. This suggests orexin neuron activation may combat aging effects on cognition and energy balance.

Area of Science:

  • Neuroscience
  • Aging Research
  • Metabolic Studies

Background:

  • Aging impacts physiological processes and behavior, partly regulated by hypothalamic orexin neurons.
  • Orexin neuron activity may decline with normal aging, contributing to age-related alterations.

Purpose of the Study:

  • To investigate if designer receptors exclusively activated by designer drugs (DREADD) stimulation of orexin neurons can mitigate aging effects on behavior and metabolism.
  • To assess the impact of orexin neuron activation on anxiety-like behavior, locomotion, spontaneous physical activity, and energy expenditure in young and middle-aged mice.

Main Methods:

  • Stereotaxic injection of AAV vectors encoding DREADD in orexin-cre mice (5- and 12-mo old).
  • Confirmation of DREADD targeting via immunohistochemistry for orexin A and mCherry.
  • Behavioral testing (EPM, OFT, NORT) and metabolic monitoring (CLAMS) to assess anxiety, locomotion, SPA, and EE.

Main Results:

  • Orexin neuron activation mitigated age-related reductions in anxiety-like behavior in middle-aged mice.
  • Locomotion was increased in both young and middle-aged mice following orexin neuron activation.
  • Spontaneous physical activity and energy expenditure were increased in middle-aged mice, returning to levels seen in young animals.

Conclusions:

  • Orexin neuron activation ameliorates aging-induced behavioral and metabolic deficits in mice.
  • Orexin neurons represent a potential therapeutic target for age-related cognitive, anxiety, and energy balance impairments.
Keywords:
DREADDOrexinagingenergy expenditurespontaneous physical activity

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