Constitutive accessibility of circulating proteins to hippocampal neurons in physiologically normal rats

Abstract

Introduction Although the hippocampus (HIP) is thought impermeable to blood‐borne proteins because of the integrity of the blood–brain barrier (BBB), it was recently suggested to be susceptible to hydrophilic hormones. The present study determined the accessibility of blood‐borne signal molecules such as hormones to hippocampal neurons in physiologically normal rats. Methods As a probe for accessibility, Evans blue dye (EB) that rapidly binds to albumin (Alb), which is impermeable to the BBB, was injected intravenously. To increase the vascular permeability of the BBB, a daily single administration of angiotensin II (Ang II) was applied intravenously for seven consecutive days. Results Fifteen minutes after the injection of EB, histological observation revealed that a number of neurons had entrapped and accumulated EB into their cell bodies in the hippocampal dentate gyrus in all rats. Of these, relatively large oval neurons (>15 µm) in the hilus and molecular layer showed parvalbumin immunopositivity, indicating they are GABAergic interneurons. The population of EB‐accumulating neurons (approximately 10 µm) were localized in the inner margin of the granule cell layer, suggesting they were granule cells. However, the number of EB‐positive neurons did not change in rats treated with Ang II compared with vehicle injection. Conclusions These findings suggest an intriguing possibility that blood‐derived proteins such as hormones have access to hippocampal neurons constitutively in the absence of stimuli that increase the vascular permeability of the BBB in a physiologically normal state.

Internal state dependent control of feeding behaviour via hippocampal ghrelin signalling

“…Given the tight regulation of substance entry across the blood-brain barrier (BBB), one important question is whether ghrelin and other hormones mediate their effects on vS circuitry by directly binding hippocampal neurons, or are instead signalled indirectly via upstream synaptic inputs that themselves have access to peripheral ghrelin. The hippocampus is situated adjacent to circulating cerebrospinal fluid (CSF) in the ventricles, and has a rich surrounding blood supply from the choroid plexus (Lathe, 2001) that facilitates transfer of molecules across the BBB (Hamasaki et al, 2020), including ghrelin (Banks et al, 2002; Diano et al, 2006). This is consistent with a vast array of peripheral ghrelin mediated structural and functional effects on hippocampal neurons (Diano et al, 2006; Ribeiro et al, 2014), but also the role of hippocampal ghrelin in influencing behaviour (Diano et al, 2006; Hsu et al, 2015; Kanoski et al, 2013).…”

“…More specifically to hunger, the hippocampus expresses the receptor for the peripheral hunger hormone ghrelin (GHSR1a) in both rodents (Diano et al, 2006; Guan et al, 1997; Hsu et al, 2015; Mani et al, 2014; Zigman et al, 2006) and non-human primates (Mitchell et al, 2001). Interestingly, many peripherally circulating hormones are able to gain access to the hippocampus (Hamasaki et al, 2020), and there is evidence to support the entry of peripheral ghrelin into the hippocampus through the blood-brain barrier (Banks et al, 2002; Diano et al, 2006, but see Furness et al, 2011). Once present in the hippocampus, ghrelin is capable of not only inducing structural and functional plasticity (Diano et al, 2006; Ribeiro et al, 2014), but also influencing anticipatory behaviour and influencing choice (Diano et al, 2006; Hsu et al, 2015, 2016; Kanoski et al, 2013, Yang et al, 2020).…”

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

“…Here, the oscillating or even retrograde flow along VRS has been postulated and documented in several in vivo experiments (64,65), drawing a conclusion that additional mechanisms exist (possibly on the molecular level) which contribute to the production, mixing, and flow of the fluid on the level of cerebral extracellular spaces. One of the most important factors is the temporal change in permeability for water and electrolytes or even larger particles of the blood-brain barrier (BBB) (66)(67)(68)(69). The BBB, with its key component-tight junctions between endothelial cells lining the interior wall of cerebral microcirculation, used to be perceived as a seal, which prevented larger molecules from passing between the intravascular lumen and extracellular space.…”