Abstract
We have developed a mouse model in which a specific population of inhibitory neurons can be selectively ablated by the action of diphtheria toxin (DT). The model involves targeting the human DT receptor to the agouti-related protein (Agrp) locus so that systemic administration of DT kills all of the AgRP-expressing neurons, resulting in starvation of the mice. Ablation of AgRP neurons results in robust (5- to 10-fold) activation of Fos gene expression in many brain regions that are innervated by AgRP neurons, including the arcuate nucleus (ARC), the paraventricular nucleus, the medial preoptic area, the lateral septum, and nucleus of the solitary tract. As expected, there is robust increase in GFAP staining (astrocytes) as well as IBA1 and CD11b staining (microglia) in the ARC in response to AgRP neuron ablation. There is also a dramatic increase of these markers in most, but not all, postsynaptic targets of AgRP axons. We used a genetic approach to reduce melanocortin signaling, which attenuated Fos activation in some brain regions after ablation of AgRP neurons. We suggest that loss of inhibitory signaling onto target neurons results in unopposed excitation that is responsible for the activation of Fos and that dysregulation of these neuronal circuits is responsible for starvation. Furthermore, glial cell activation in target areas of AgRP neurons appears to be a result of excitotoxicity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenocorticotropic Hormone / metabolism
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Agouti-Related Protein / genetics
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Agouti-Related Protein / metabolism*
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Analysis of Variance
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Animals
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Brain / cytology*
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CD11b Antigen / genetics
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CD11b Antigen / metabolism
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Death / drug effects
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Diphtheria Toxin / toxicity
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Gene Expression Regulation / drug effects
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Glial Fibrillary Acidic Protein / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Gliosis / chemically induced
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Gliosis / pathology
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Gliosis / physiopathology*
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Transgenic
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Microfilament Proteins
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Neurons / drug effects
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Neurons / pathology*
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Peptides / metabolism
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Phosphopyruvate Hydratase / metabolism
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Poisons / toxicity
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Pro-Opiomelanocortin / metabolism
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism*
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Signal Transduction / physiology
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Signal Transduction / radiation effects
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Synapses / drug effects
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Synapses / pathology*
Substances
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Agouti-Related Protein
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Agrp protein, mouse
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Aif1 protein, mouse
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CD11b Antigen
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Calcium-Binding Proteins
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Diphtheria Toxin
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Glial Fibrillary Acidic Protein
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HBEGF protein, human
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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MCR 4 peptide
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Microfilament Proteins
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Peptides
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Poisons
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Proto-Oncogene Proteins c-fos
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Pro-Opiomelanocortin
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Adrenocorticotropic Hormone
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Phosphopyruvate Hydratase