The crosstalk between brain and periphery: Implications for brain health and disease

Mounting evidence indicates that signaling molecules identified primarily in the peripheral circulation can affect cognitive function in physiological and pathological conditions, including in the development of several neurological diseases. However, considering the properties of the vascular blood-brain barrier (BBB), circulating lipophobic molecules would not be expected to cross this vascular structure. Thus, if and how peripheral lipophobic molecules, such as hormones and cytokines, reach the brain to exert their reported effects remains to be better established. In this review, we will discuss evidence for and against the ability of molecules in the circulation, such as insulin, cytokines, and irisin to reach the brain and mediate the crosstalk between peripheral tissues and the central nervous system (CNS). We hypothesize that in addition to entering the brain via receptor-mediated transcytosis, these circulating molecules can have their transport facilitated by extracellular vesicles or under pathological conditions when the BBB is disrupted. We also discuss the possibility that these circulating molecules access the brain by acting directly on circumventricular organs, which lack the BBB, by local synthesis in the choroid plexus, and via activation of afferent vagal nerves. Advancing the understanding of mechanisms implicated in the transport of blood-borne molecules to the CNS will help us elucidate the contribution of peripheral factors to brain health and disease, and will enable the development of minimally invasive strategies to deliver therapeutic drugs to the brain in neurological disorders. This article is part of the special Issue on 'Cross Talk between Periphery and the Brain'.