scholarly journals Neuropeptide Y Cells Represent a Distinct Glucose-Sensing Population in the Lateral Hypothalamus

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4046-4052 ◽  
Author(s):  
Oliver J. Marston ◽  
Paul Hurst ◽  
Mark L. Evans ◽  
Denis I. Burdakov ◽  
Lora K. Heisler
Keyword(s):  
Electrical Activity ◽  
Neuropeptide Y ◽  
Fluorescent Protein ◽  
Regulatory Elements ◽  
Glucose Sensing ◽  
Hypothalamic Area ◽  
Extracellular Glucose ◽  
The Brain

The maintenance of appropriate glucose levels is necessary for survival. Within the brain, specialized neurons detect glucose fluctuations and alter their electrical activity. These glucose-sensing cells include hypothalamic arcuate nucleus neurons expressing neuropeptide Y (NPY) and lateral hypothalamic area (LHA) neurons expressing orexin/hypocretins (ORX) or melanin-concentrating hormone (MCH). Within the LHA, a population of NPY-expressing cells exists; however, their ability to monitor energy status is unknown. We investigated whether NPY neurons located in the LHA, a classic hunger center, detect and respond to fluctuations in glucose availability and compared these responses with those of known LHA glucose sensors expressing ORX or MCH. Using mice expressing green fluorescent protein under the control of NPY regulatory elements, we identified LHA NPY cells and explored their anatomical distribution, neurochemical and electrical properties, in vivo responses to fasting and insulin-induced hypoglycemia, and in situ electrical responses to extracellular glucose. We report that NPY, ORX, and MCH are expressed in nonoverlapping populations within the LHA. Subpopulations of LHA NPY neurons were activated in vivo by both a 6-h fast and insulin-induced hypoglycemia. Likewise, increased extracellular glucose suppressed the electrical activity of approximately 70% of LHA NPY neurons in situ, eliciting hyperpolarization and activating background K+ currents. Furthermore, we report that the glucose sensitivity of LHA NPY neurons is significantly different from neighboring ORX and MCH neurons. These data suggest that NPY-expressing cells in the LHA are a novel population of glucose-sensing neurons that represent a new player in the brain circuitry integrating information about glucose homeostasis.

Effects of hypercapnia on ECoG and oxidative metabolism in neonatal dog brain

1995 ◽  
Vol 78 (6) ◽  
pp. 2272-2278 ◽  
Author(s):  
H. Yoshioka ◽  
H. Miyake ◽  
D. S. Smith ◽  
B. Chance ◽  
T. Sawada ◽  
...  
Keyword(s):  
Electrical Activity ◽  
Resonance Spectroscopy ◽  
Respiratory Enzymes ◽  
Arterial Pco2 ◽  
A Value ◽  
Electrocorticogram Ecog ◽  
The Brain ◽  
Mitochondrial Respiratory

The effects of hypercapnia on cerebral electrical activity and mitochondrial oxidative phosphorylation were studied in the anesthetized neonatal dog by using the electrocorticogram (ECoG) and 31P-magnetic resonance spectroscopy. Three levels of hypercapnia with arterial PCO2 values of approximately 70, 100, and 140 Torr reduced the intracellular pH of the brain from 7.11 to 6.99, 6.87, and 6.76, respectively. These levels of hypercapnia also reduced ADP concentration ([ADP]) from 21.5 to 18.1, 14.8, and 12.9 microM as well as the average ECoG power output by 20, 30, and 40%. A Michaelis-Menten relationship for the mitochondrial respiratory enzymes was fitted with [ADP] and the change in the average ECoG. The result suggests that mitochondrial respiration is regulated by [ADP] and that the in vivo Michaelis-Menten constant for ADP was 21 microM, a value close to the in vitro value. The mitochondrial maximal reaction velocity was reduced by only 10% during hypercapnia and showed no relationship with the degree of acidosis, suggesting that mitochondrial respiratory enzymes are not responsible for the inhibition of the brain electrical activity.

Antibodies to β-Amyloid Decrease the Blood-to-Brain Transfer of β-Amyloid Peptide1

2002 ◽  
Vol 227 (8) ◽  
pp. 609-615 ◽  
Author(s):  
Weihong Pan ◽  
Beka Solomon ◽  
Lawrence M. Maness ◽  
Abba J. Kastin
Keyword(s):  
Ex Vivo ◽  
Amyloid Β ◽  
Brain Perfusion ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Β Amyloid ◽  
Blocking Antibodies ◽  
The Brain

Amyloid-β peptides (Aβ) play an important role in the pathophysiology of dementia of the Alzheimer's type and in amyloid angiopathy. Aβ outside the CNS could contribute to plaque formation in the brain where its entry would involve interactions with the blood-brain barrier (BBB). Effective antibodies to Aβ have been developed in an effort to vaccinate against Alzheimer's disease. These antibodies could interact with Aβ in the peripheral blood, block the passage of Aβ across the BBB, or prevent Aβ deposition within the CNS. To determine whether the blocking antibodies act at the BBB level, we examined the influx of radiolabeled Aβ (125I-Aβ1-40) into the brain after ex-vivo incubation with the antibodies. Antibody mAb3D6 (élan Company) reduced the blood-to-brain influx of Aβ after iv bolus injection. It also significantly decreased the accumulation of Aβ in brain parenchyma. To confirm the in-vivo study and examine the specificity of mAb3D6, in-situ brain perfusion in serum-free buffer was performed after incubation of 125I-Aβ1-40 with another antibody mAbmc1 (DAKO Company). The presence of mAbmc1 also caused significant reduction of the influx of Aβ into the brain after perfusion. Therefore, effective antibodies to Aβ can reduce the influx of Aβ1-40 into the brain.

scholarly journals Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

2006 ◽  
Vol 361 (1471) ◽  
pp. 1159-1185 ◽  
Author(s):  
B Beck
Keyword(s):  
Neuropeptide Y ◽  
Diet Composition ◽  
High Energy ◽  
Glucose Sensing ◽  
Feeding Regulation ◽  
Treatment Of Obesity ◽  
The Brain ◽  
Diet Type

Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db / db mouse, or at the peptide level, as in ob / ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka–Long–Evans–Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an overactive NPY system (increased mRNA expression in the ARC associated with an upregulation of the receptors) is characteristic of rats or rodent strains sensitive to dietary-induced obesity. Finally, NPY appears to play an important role in body weight and feeding regulation, and while it does not constitute the only target for drug treatment of obesity, it may nevertheless provide a useful target in conjunction with others.

scholarly journals LGR4 and Its Ligands, R-Spondin 1 and R-Spondin 3, Regulate Food Intake in the Hypothalamus of Male Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 429-440 ◽  
Author(s):  
Ji-Yao Li ◽  
Biaoxin Chai ◽  
Weizhen Zhang ◽  
Danielle M. Fritze ◽  
Chao Zhang ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Median Eminence ◽  
Energy Homeostasis ◽  
Male Rats ◽  
The Third ◽  
The Brain

The hypothalamus plays a key role in the regulation of feeding behavior. Several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus, and ventromedial nucleus of the hypothalamus (VMH), are involved in energy homeostasis. Analysis of microarray data derived from ARC revealed that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is highly expressed. LGR4, LGR5, and LGR6 form a subfamily of closely related receptors. Recently, R-spondin (Rspo) family proteins were identified as ligands of the LGR4 subfamily. In the present study, we investigated the distribution and function of LGR4–LGR6 and Rspos (1–4) in the brain of male rat. In situ hybridization showed that LGR4 is expressed in the ARC, VMH, and median eminence of the hypothalamus. LGR4 colocalizes with neuropeptide Y, proopiomelanocortin, and brain-derived neurotrophic factor neurons. LGR5 is not detectable with in situ hybridization; LGR6 is only expressed in the epithelial lining of the lower portion of the third ventricle and median eminence. Rspo1 is expressed in the VMH and down-regulated with fasting. Rspo3 is expressed in the paraventricular nucleus and also down-regulated with fasting. Rspos 1 and 3 colocalize with the neuronal marker HuD, indicating that they are expressed by neurons. Injection of Rspo1 or Rspo3 into the third brain ventricle inhibited food intake. Rspo1 decreased neuropeptide Y and increased proopiomelanocortin expression in the ARC. Rspo1 and Rspo3 mRNA is up-regulated by insulin. These data indicate that Rspo1 and Rspo3 and their receptor LGR4 form novel circuits in the brain to regulate energy homeostasis.

scholarly journals Longitudinal evaluation of expression of virally delivered transgenes in gerbil cone photoreceptors

2008 ◽  
Vol 25 (3) ◽  
pp. 273-282 ◽  
Author(s):  
MATTHEW C. MAUCK ◽  
KATHERINE MANCUSO ◽  
JAMES A. KUCHENBECKER ◽  
THOMAS B. CONNOR ◽  
WILLIAM W. HAUSWIRTH ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Imaging System ◽  
Regulatory Elements ◽  
Meriones Unguiculatus ◽  
Opsin Gene ◽  
Post Injection ◽  
Cone Photoreceptors ◽  
Long Wavelength ◽  
Green Fluorescent

Delivery of foreign opsin genes to cone photoreceptors using recombinant adeno-associated virus (rAAV) is a potential tool for studying the basic mechanisms underlying cone based vision and for treating vision disorders. We used an in vivo retinal imaging system to monitor, over time, expression of virally-delivered genes targeted to cone photoreceptors in the Mongolian gerbil (Meriones unguiculatus). Gerbils have a well-developed photopic visual system, with 11–14% of their photoreceptors being cones. We used replication deficient serotype 5 rAAV to deliver a gene for green fluorescent protein (GFP). In an effort to direct expression of the gene specifically to either S or M cones, the transgene was under the control of either the human X-chromosome opsin gene regulatory elements, i.e., an enhancer termed the locus control region (LCR) and L promoter, or the human S-opsin promoter. Longitudinal fluorescence images reveal that gene expression is first detectable about 14 days post-injection, reaches a peak after about 3 months, and is observed more than a year post-injection if the initial viral concentration is sufficiently high. The regulatory elements are able to direct expression to a subpopulation of cones while excluding expression in rods and non-photoreceptor retinal cells. When the same viral constructs are used to deliver a human long-wavelength opsin gene to gerbil cones, stimulation of the introduced human photopigment with long-wavelength light produces robust cone responses.

scholarly journals Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding

Science ◽  
2019 ◽  
Vol 364 (6447) ◽  
pp. 1271-1274 ◽  
Author(s):  
Mark A. Rossi ◽  
Marcus L. Basiri ◽  
Jenna A. McHenry ◽  
Oksana Kosyk ◽  
James M. Otis ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Health Concern ◽  
Hypothalamic Area ◽  
Obesity Epidemic ◽  
Glutamatergic Neurons ◽  
Two Photon ◽  
Lateral Hypothalamic ◽  
The Brain ◽  
Transcriptional State

The current obesity epidemic is a major worldwide health concern. Despite the consensus that the brain regulates energy homeostasis, the neural adaptations governing obesity are unknown. Using a combination of high-throughput single-cell RNA sequencing and longitudinal in vivo two-photon calcium imaging, we surveyed functional alterations of the lateral hypothalamic area (LHA)—a highly conserved brain region that orchestrates feeding—in a mouse model of obesity. The transcriptional profile of LHA glutamatergic neurons was affected by obesity, exhibiting changes indicative of altered neuronal activity. Encoding properties of individual LHA glutamatergic neurons were then tracked throughout obesity, revealing greatly attenuated reward responses. These data demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.

A potential artifact in use of a new technique for rapid brain removal.

1978 ◽  
Vol 234 (4) ◽  
pp. E365
Author(s):  
K L Wong ◽  
G M Tyce
Keyword(s):  
Blood Glucose ◽  
Brain Tissue ◽  
Plasma Levels ◽  
Postmortem Changes ◽  
New Techniques ◽  
Animal Brain ◽  
A New Technique ◽  
The Brain

New techniques are are continuously being developed to obtain animal brain tissue that is as close as possible to its in vivo status. The brain-blowing technique provides a swift freezing of brain tissue (within 1 s) in which postmortem changes have been said to be minimal. Higher concentrations of glucose were present in brain samples removed by this method than have previously been found when the brain was frozen in situ, but at the same time the plasma levels of glucose were higher. It is suggested that, although the procedure did not appear to involve any stress, the hyperglycemia was stress related. Modifications of the procedure are described, by which these changes in blood glucose have been minimized.

Sustained expression of human factor VIII in mice using a parvovirus-based vector

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1594-1599 ◽  
Author(s):  
Hengjun Chao ◽  
Lan Mao ◽  
Andrew T. Bruce ◽  
Christopher E. Walsh
Keyword(s):  
Factor Viii ◽  
Human Factor ◽  
Hemophilia A ◽  
Fluorescent Protein ◽  
Regulatory Elements ◽  
Scid Mice ◽  
Major Advance ◽  
Target Tissue ◽  
Human Factor Viii

Persistent therapeutic levels of human factor VIII (hFVIII) would signify a major advance in the treatment of hemophilia A. Here we report sustained expression of hFVIII in immunocompetent mice using recombinant adeno-associated virus (rAAV) vectors. AAV can stably transduce liver cells, the target tissue for efficient hFVIII production. Because of rAAV packaging constraints, we tested 2 constructs using small regulatory elements designed for liver-specific transgene expression linked to B-domain–deleted hFVIII (BDD-hFVIII) cDNA. More than 1012/mL rAAV/BDD-hFVIII virion particles were generated using a transfection scheme that eliminates adenovirus. Coatest and APTT assays confirmed the production of functional BDD-hFVIII protein after transduction of 293 and HepG2 cells. In vivo experiments were performed in C57BL/6 and NOD/scid mice receiving 1010–11 rAAV/hFVIII particles via portal vein injection. All C57BL/6 mice tested developed anti-hFVIII antibody. In contrast, NOD/scid mice expressed hFVIII reaching 27% of normal human plasma levels. As expected, we could not detect hFVIII antigen from plasma samples isolated from control animals receiving equivalent doses of rAAV expressing enhanced green fluorescent protein (EGFP). Transgene mRNA expression was detected primarily in the liver and histologic analysis of the liver revealed no pathologic abnormalities. These results demonstrate a promising approach for treatment of hemophilia A.

Chordin and noggin promote organizing centers of forebrain development in the mouse

Development ◽  
2002 ◽  
Vol 129 (21) ◽  
pp. 4975-4987 ◽  
Author(s):  
Ryan M. Anderson ◽  
Alison R. Lawrence ◽  
Rolf W. Stottmann ◽  
Daniel Bachiller ◽  
John Klingensmith
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Craniofacial Skeleton ◽  
Neonatal Lethality ◽  
Prechordal Plate ◽  
Organizing Center ◽  
Increased Sensitivity ◽  
Bmp Antagonists ◽  
The Brain

In this study we investigate the roles of the organizer factors chordin and noggin, which are dedicated antagonists of the bone morphogenetic proteins(BMPs), in formation of the mammalian head. The mouse chordin and noggin genes(Chrd and Nog) are expressed in the organizer (the node) and its mesendodermal derivatives, including the prechordal plate, an organizing center for rostral development. They are also expressed at lower levels in and around the anterior neural ridge, another rostral organizing center. To elucidate roles of Chrd and Nog that are masked by the severe phenotype and early lethality of the double null, we have characterized embryos of the genotype Chrd-/-;Nog+/-. These animals display partially penetrant neonatal lethality, with defects restricted to the head. The variable phenotypes include cyclopia,holoprosencephaly, and rostral truncations of the brain and craniofacial skeleton. In situ hybridization reveals a loss of SHH expression and signaling by the prechordal plate, and a decrease in FGF8 expression and signaling by the anterior neural ridge at the five-somite stage. DefectiveChrd-/-;Nog+/- embryos exhibit reduced cell proliferation in the rostral neuroepithelium at 10 somites, followed by increased cell death 1 day later. Because these phenotypes result from reduced levels of BMP antagonists, we hypothesized that they are due to increased BMP activity. Ectopic application of BMP2 to wild-type cephalic explants results in decreased FGF8 and SHH expression in rostral tissue, suggesting that the decreased expression of FGF8 and SHH observed in vivo is due to ectopic BMP activity. Cephalic explants isolated from Chrd;Nog double mutant embryos show an increased sensitivity to ectopic BMP protein, further supporting the hypothesis that these mutants are deficient in BMP antagonism. These results indicate that the BMP antagonists chordin and noggin promote the inductive and trophic activities of rostral organizing centers in early development of the mammalian head.

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