Compensatory actions of orexinergic neurons in the lateral hypothalamus during metabolic or cortical challenges may enable the coupling of metabolic dysfunction and cortical dysfunction

Tight linkages between metabolic states and cerebral cortical excitability have been observed and may be enabled by orexinergic neurons in the lateral hypothalamus (LH). However, despite reports of the close relationship between “dysfunction” in metabolism and “dysfunction” in cerebral cortical excitability, a mechanism has yet to be proposed to explain this coupling. We propose that the “compensatory actions” of orexinergic neurons in the LH may enable the coupling of metabolic and cortical dysfunction. When metabolites are inefficiently utilized during metabolic dysfunction with insulin/leptin resistance, orexinergic neurons can be activated to initiate negative feedback by triggering sympathetic innervation to elevate compromised catabolism. Activated orexinergic neurons as an intentional metabolic compensation, however, may unintentionally cause cortical dysfunction in the end by making the cortex, thalamus, and hippocampus hyperexcitable. Similarly, during cortical dysfunction, activated orexinergic neurons can trigger negative feedback on unstably high cortical rhythms by increasing food intake, which can potentially relieve cortical excitability via hypothalamic satiety modulation mechanisms. However, hyperphagia, an intentional cortical compensation, metabolically challenges bodies and eventually may result in metabolic dysfunction. Our model proposes a new therapeutic rationale for metabolic and cortical disorders. We suggest that by maintaining the negative feedback loop mediated by orexinergic neurons intact and pharmacologically blocking unintentional branches that may give rise to new types of dysfunction, the vicious cycle of metabolic and cortical dysfunction can be avoided.