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

Abstract

Maladaptive coping behaviors are probably involved in post-traumatic stress disorders (PTSD), but underlying mechanisms are incompletely understood. We now report that mice lacking functional insulin-like growth factor I (IGF-I) receptors in orexin neurons of the lateral hypothalamus (Firoc mice) are unresponsive to the anxiolytic actions of IGF-I and develop PTSD-like behavior that is ameliorated by inhibition of orexin neurons. Conversely, systemic IGF-I treatment ameliorated PTSD-like behavior in a wild-type mouse model of PTSD (PTSD mice). Further, systemic IGF-I modified the GABA/Glutamate synaptic structure in orexin neurons of naïve wild-type mice by increasing the dephosphorylation of GABA(B) receptor subunit through inhibition of AMP-kinase (AMPK). Significantly, pharmacological inhibition of AMPK mimicked IGF-I, normalizing fear behavior in PTSD mice. Thus, we suggest that IGF-I enables coping behaviors by balancing E/I input onto orexin neurons in a context-dependent manner. These observations provide a novel therapeutic approach to PTSD through modulation of AMPK.

Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons

“…We also showed that Firoc mice under 6 h restricted feeding during the resting phase, a strong food clock entrainment, showed enhanced food anticipatory activity. These results agree with previous ones from our laboratory, showing increased orexinergic activity in Firoc mice undergoing cued behavior paradigms [40]. The FAA phenomenon is independent of the SCN [54][55][56], and only lesions in the DMH abolished it [55].…”

“…Hence, altered orexin activity could be related to IGF-I dysregulation due to aging, diet, or pathology. These results indicate that IGF-I regulates orexin neurons, and, consequently, circadian rhythms and metabolism, extending and confirming previous observations on central actions of IGF-I on mood, metabolism, and wellness [29,40].…”

“…Indeed, orexin neurons have been described as circadian [15,42] and food-entrained oscillators [37]. We previously reported that a loss of IGF-I control on orexin neurons causes abnormal sleep patterns [29] and behavioral disorders [40]. Now, we provide evidence that IGF-I tunes orexin neurons for the proper synchronization of circadian and metabolic systems.…”

“…To confirm the central role of IGF-I signaling on orexin neurons in the regulation of glucose homeostasis, we used a previously described recombinant AAV-HCRT-CRE virus to express CRE recombinase, specifically in orexin neurons of igfrf/f mice [40]. Mice injected with AAV-HCRT-CRE showed glucose intolerance in the glucose tolerance test (Figure S3), as compared to mice injected with an AAV control virus (one-way ANOVA, t(AAV-HCRT-CRE, AAV-control) = −3.56676, p = 0.00442).…”

“…One month later, the GTT was performed, as described above. AAV-HCRT-CRE-EGFP and AAV-HCRT-EGFP viruses were packaged at the Viral Vector Production Unit, UAB-VHIR (Barcelona, Spain), as previously described [40].…”