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Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons

M Estrella Fernández de Sevilla1,2,3, Jaime Pignatelli4,5, Jonathan A Zegarra-Valdivia1,2,6

  • 1Cajal Institute (CSIC), Madrid, Spain.

Molecular Psychiatry
|February 4, 2022
PubMed

Insights

Insulin-like growth factor I (IGF-I) normalizes post-traumatic stress disorder (PTSD)-like behaviors in mice by regulating orexin neurons. Modulating AMP-kinase (AMPK) offers a potential therapeutic strategy for PTSD.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Molecular Biology

Background:

  • Maladaptive coping behaviors are implicated in post-traumatic stress disorder (PTSD), yet the underlying neurobiological mechanisms remain unclear.
  • Insulin-like growth factor I (IGF-I) signaling pathways are being investigated for their role in stress and anxiety disorders.

Purpose of the Study:

  • To investigate the role of insulin-like growth factor I (IGF-I) signaling in the orexin system of the lateral hypothalamus in the development and amelioration of PTSD-like behaviors.
  • To elucidate the molecular mechanisms by which IGF-I influences neuronal activity and synaptic plasticity in the context of PTSD.

Main Methods:

  • Generation of mice with deficient IGF-I receptors in orexin neurons (Firoc mice) to study the anxiolytic effects of IGF-I.
  • Utilizing a mouse model of PTSD (PTSD mice) and administering systemic IGF-I treatment.
  • Examining synaptic structure modifications in orexin neurons, specifically focusing on GABA(B) receptor dephosphorylation and AMP-kinase (AMPK) activity.
  • Pharmacological inhibition of AMPK to assess its impact on PTSD-like behaviors.

Main Results:

  • Firoc mice exhibited unresponsiveness to IGF-I's anxiolytic effects and displayed PTSD-like behaviors, which were reduced by inhibiting orexin neurons.
  • Systemic IGF-I treatment effectively ameliorated PTSD-like behaviors in wild-type PTSD mice.
  • IGF-I treatment in naïve mice led to increased GABA(B) receptor dephosphorylation in orexin neurons via AMPK inhibition, altering synaptic balance.
  • Pharmacological inhibition of AMPK mimicked IGF-I's effects, normalizing fear behaviors in PTSD mice.

Conclusions:

  • IGF-I plays a crucial role in enabling adaptive coping behaviors by modulating the excitatory/inhibitory (E/I) input onto orexin neurons in a context-dependent manner.
  • The findings suggest that targeting the AMPK pathway within the orexin system presents a novel therapeutic avenue for treating PTSD.

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