Abstract
IntroductionAlthough 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.MethodsAs 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.ResultsFifteen 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.ConclusionsThese 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.
Highlights
The hippocampus (HIP) is thought impermeable to bloodborne proteins because of the integrity of the blood–brain barrier (BBB), it was recently suggested to be susceptible to hydrophilic hormones
Blood-borne proteins such as albumin and hydrophilic hormones are thought to be unable to leak into most brain areas including the HIP, except for the circumventricular organs (CVOs), because of the integrity of the BBB in the physiologically normal state
Our recent study showed that blood-borne angiotensin II (Ang II) stimulated the HIP, thereby enhancing neurogenesis in physiologically normal adult rats (Koyama et al, 2018; Mukuda et al, 2014)
Summary
Almost all brain regions, including the hippocampus (HIP), are thought to be isolated from the systemic circulation by the blood– brain barrier (BBB), which provides tight control over the passage of small molecules from the blood. Contrary to the established theory of BBB integrity, accumulating evidence has suggested that several blood-derived products can penetrate into the HIP in the absence of stimuli that increase BBB permeability under healthy conditions. Circulating ghrelin, a 28-residue peptide hormone, was translocated from blood to the HIP at a low level (Banks, Tschöp, Robinson, & Heiman, 2002; Rhea et al, 2018). This peptide regulates the synapse density of the HIP (Diano et al, 2006) and stimulates adult neurogenesis directly (Li et al, 2013). Immunohistochemical staining was performed on EB-accumulating neurons to identify their neurochemical features
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