Cannabinoid Modulation of Development and Neuroprotection in African Naked Mole-Rats

Naked mole-rats display typical subterranean features, but also has unusual characteristics even among subterranean mammals due to unusually large colony sizes. The naked mole-rat provides insights into the complex interplay of evolutionary adaptations to the constraints of subterranean living, the hallmark of which is extreme hypoxia tolerance. Many of the known naked mole-rat adaptations are based in systems modulated by the endocannabinoid (eCB) system. This project characterized the three most relevant to naked mole-rat adaptations: neoteny, low oxygen tolerance, and attenuated hypercapnic pain response. I found that naked mole-rat expression of the endocannabinoid system is delayed in the hippocampus and prefrontal cortex. Additionally, the eCB system has developmentally dependent effects on behavior and physiology. I found novel effects in locomotion, synaptic facilitation, and synaptic plasticity. I also characterized the C-fiber pathway in naked mole-rats and investigating the attenuation of pain through the eCB system. I found that there is a functional purinergic response in naked mole-rats which cannabinoids attenuate, but not inflammatory response after activation. The final aim of the project was to assess the role of endocannabinoids in naked mole-rat hypoxia tolerance. In an analysis of naked mole-rat expression after 5 hours of hypoxia, there is a global decrease in multiple endocannabinoids which is not seen in mice. I looked at the effect of the eCB system on the hippocampus when exposed to anoxia. In immature animals, antagonizing the eCB system was protective. In another age-dependent response, adult animals responded equally to both agonism and antagonism of the eCB system to improve the time to depolarization. In both plasticity and anoxic protection, the adult response may be caused by a species dependent change in the balance of CB1r localization compared to excitatory and inhibitory synapses. Therefore, like other neonatally retained traits, the retention of an immature endocannabinoid system may be due to a need for adult naked mole-rats to mediate neuroprotection through the endocannabinoid system. This project identified multiple areas of interest for therapeutic potential in development, pain, and neuroprotection and reinforced the dynamic potential of the endocannabinoid system to modulate a vast array of functions.