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

Abstract

Summary 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 (AgRPOBBB) 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, AgRPOBBB 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 AgRPOBBB vulnerable to lesioning by circulating toxins, but that the rapid re-emergence of AgRPOBBB is part of a reparative process to maintain energy balance.

Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus

“…The anatomical position of the vast majority of the CNTF-responsive NPY neurons closely resembles the position of the recently characterized NPY neurons that lie outside the BBB (Olofsson et al, 2013;Yulyaningsih et al, 2017). These neurons have been suggested to sense the smallest changes in plasma metabolic signals and to serve as fast first-line responders to metabolically relevant circulating hormones and peptides (Yulyaningsih et al, 2017). Collectively, these data suggest that circulating CNTF crosses the fenestrated capillaries of the ME, diffuses over the ME milieu, and targets the ARC NPY neurons located outside the BBB, where it activates JAK2-STAT3 signaling and rapidly induces a satiety effect.…”

“…In this way, β1-tanycytes are believed to form a lateral barrier preventing the diffusion of blood-borne substances extravasated from the fenestrated portal capillaries of the ME to the adjacent ARC (Krisch et al, 1983;Peruzzo et al, 2000). The anatomical position of the vast majority of the CNTF-responsive NPY neurons closely resembles the position of the recently characterized NPY neurons that lie outside the BBB (Olofsson et al, 2013;Yulyaningsih et al, 2017). These neurons have been suggested to sense the smallest changes in plasma metabolic signals and to serve as fast first-line responders to metabolically relevant circulating hormones and peptides (Yulyaningsih et al, 2017).…”

Connexin-43 Gap Junctions Are Responsible for the Hypothalamic Tanycyte-Coupled Network

“…Moreover, tanycytes may act as adult hypothalamic neuronal precursor cells (NPCs; Lee and Blackshaw, 2012 ; Haan et al, 2013 ; Robins et al, 2013 ; Jourdon et al, 2016 ) because they express radial glia markers, are capable of forming neurospheres (Robins et al, 2013 ), and can proliferate and differentiate into glia and functionally leptin-activating neurons. Neuronal degeneration (Yulyaningsih et al, 2017 ), environmental changes in the diet (Lee and Blackshaw, 2012 ; Gouazé et al, 2013 ), and intracerebroventricular administration of intrinsic factors are known to accelerate the low rate of basal hypothalamic cell division (Pencea et al, 2001 ; Kokoeva et al, 2005 ; Pérez-Martín et al, 2010 ; Yulyaningsih et al, 2017 ) in order to restore the energy balance. However, the mechanisms underlying the proliferation and synchronization of the cell cycle in tanycytes remain to be elucidated.…”

Repeated hypoglycemia remodels neural inputs and disrupts mitochondrial function to blunt glucose-inhibited GHRH neuron responsiveness

“…These neurons express Ghrh and genes critical to glucose sensing, such as Gck and glucose transporters (28). Published studies report that medial basal ARC neurons, such as GHRH neurons, lie outside the blood-brain barrier (29)(30)(31)(32) and so are probably exposed to glucose levels equivalent to those in the circulation. We therefore used glucose levels of 2.5 mM (equivalent to those in our in vivo studies) to mimic hypoglycemia.…”