Acute Lesioning and Rapid Repair of Hypothalamic Neurons outside the Blood-Brain Barrier

Abstract

Neurons expressing agouti-related protein (AgRP) are essential for feeding. The majority of these neurons are located outside the blood-brain barrier (BBB), allowing them to directly sense circulating metabolic factors. Here, we show that, in adult mice, AgRP neurons outside the BBB (AgRP^OBBB) were rapidly ablated by peripheral administration of monosodium glutamate (MSG), whereas AgRP neurons inside the BBB and most proopiomelanocortin (POMC) neurons were spared. MSG treatment induced proliferation of tanycytes, the putative hypothalamic neural progenitor cells, but the newly proliferated tanycytes did not become neurons. Intriguingly, AgRP^OBBB neuronal number increased within a week after MSG treatment, and newly emerging AgRP neurons were derived from post-mitotic cells, including some from the Pomc-expressing cell lineage. Our study reveals that the lack of protection by the BBB renders AgRP^OBBB vulnerable to lesioning by circulating toxins but that the rapid re-emergence of AgRP^OBBB is part of a reparative process to maintain energy balance.

Keywords: AgRP; blood-brain barrier; hypothalamus; monosodium glutamate; repair.