Projections from the dorsomedial division of the bed nucleus of the stria terminalis to hypothalamic nuclei in the mouse

Barbier, Marie; González, Joaquín; Houdayer, Christophe; Burdakov, Denis; Risold, Pierre‐Yves; Croizier, Sophie

doi:10.1002/cne.24988

Cited by 22 publications

(23 citation statements)

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“…363123S; VWR, Radnor, PA). Computerized cartography of Fgf15-expressing neurons in the DMH was performed with use of the camera lucida method (29).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis

et al. 2021

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The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose-responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this glucoregulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus (DMH), as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15 CretdTomato mice and their use to further characterize these neurons. We show that they were glutamatergic and comprised glucose-inhibited and glucose-excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the DMH participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia.The central nervous system controls multiple aspects of glucose homeostasis including pancreatic islet hormone secretion and hepatic glucose production as well as glucose utilization by muscle and fat. The connection between the brain and these peripheral tissues is ensured, in large part, by the autonomic nervous system. This is activated in response to changes in the concentration of circulating hormones such as insulin, leptin, or ghrelin and of nutrients such as glucose and lipids. Glucose-responsive neurons, which increase their firing activity in response to hyperglycemia (glucose-excited [GE] neurons) or to hypoglycemia (glucose-inhibited [GI] neurons) (1-3), are thought to couple fluctuations in blood glucose concentrations to the regulation of sympathetic or parasympathetic nerve activity.A major glucoregulatory role of the central nervous system is to maintain glycemic levels at a minimum value of $5 mmol/L to preserve sufficient glucose provision to the brain. Hypoglycemia does not usually occur in healthy subjects because of the rapid secretion of the counterregulatory hormones glucagon, epinephrine, norepinephrine, cortisol, and growth hormones when blood glucose concentrations fall below the euglycemic level (4,5). However, in insulin-treated patients with type 1 or type 2 diabetes, this counterregulatory response becomes blunted, leading to hypoglycemic episodes of progressively increased severity; this condition represents a major limitation in the insulin treatment of diabetes (6-8). The cellular and molecular basis ...

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“…363123S; VWR, Radnor, PA). Computerized cartography of Fgf15-expressing neurons in the DMH was performed with use of the camera lucida method (29).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis

et al. 2021

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“…To study whether EphrinB1 and EphrinB2 can directly modulate the number of glutamatergic terminals on POMC neurites, we had to identify the glutamatergic areas innervating POMC neurons. Previous monosynaptic retrograde mapping showed that POMC prog receive inputs from several sites, such as the preoptic area, the bed nucleus of the stria terminalis [19], the Confocal images and high magnification of vGLUT2-positive terminals (turquoise)/DAPI (white) into Pomc-Cre;tdTomato neurons (red) in the ARH of P6 and P22 male mice. (B) Example of 3D reconstruction (P6 and P22, IMARIS) and quantification (C) of vGLUT2-positive inputs in direct apposition with Pomc-Cre;tdTomato neurons of P6, P14, and P22 male pups (n = 2-3/group, 2 sections/animal).…”

Section: Ephrinb Members Are Expressed During Development Of Hypothalmentioning

confidence: 99%

“…lateral septum [19], and, in particular, the paraventricular nucleus of the hypothalamus (PVH) [18]. The PVH is known to contain glutamatergic neurons [17]; however, whether glutamatergic PVH neurons innervate ARH POMC neurons remain elusive.…”

Section: Plos Biologymentioning

confidence: 99%

“…POMC and AgRP/NPY neurons are major integrators of peripheral hormones (insulin, leptin, and ghrelin) and nutrients (glucose) to control energy and glucose homeostasis through neuroendocrine and autonomic responses [13][14][15][16][17]. Besides, POMC and AgRP/NPY neurons also receive abundant central information through GABAergic (inhibitory) and glutamatergic (excitatory) inputs [18,19]. Notably, POMC neurons primarily receive glutamatergic inputs, whereas AgRP/NPY neurons receive primarily GABAergic inputs [20].…”

Section: Introductionmentioning

confidence: 99%

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EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis

et al. 2020

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Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

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“…Mechanistic insights into ALS hypermetabolism remain limited. Hypothalamic nuclei receive and integrate inputs coming from a large fraction of the brain [16][17][18][19] in order to establish the proper balance of feeding, energy storage and energy expenditure [20]. Thus, disruption of these inputs may be sufficient to drive metabolic imbalances.…”

Section: Introductionmentioning

confidence: 99%

Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

Bayer

Antonucci

Müller

et al. 2020

Preprint

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Increased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.

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Projections from the dorsomedial division of the bed nucleus of the stria terminalis to hypothalamic nuclei in the mouse

Cited by 22 publications

References 100 publications

Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis

Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis

EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis

Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

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