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The Journal of Neuroscience, September 10, 2008, 28(37):9218-9226; doi:10.1523/JNEUROSCI.2449-08.2008

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Neurobiology of Disease
Ablation of Neurons Expressing Agouti-Related Protein Activates Fos and Gliosis in Postsynaptic Target Regions

Qi Wu,^1,2 Maureen P. Howell,³ and Richard D. Palmiter^1,2

¹Howard Hughes Medical Institute, ²Department of Biochemistry, University of Washington, Seattle, Washington 98195, and ³Allen Institute for Brain Science, Seattle, Washington 98103

Correspondence should be addressed to Richard D. Palmiter at the above address. Email: palmiter{at}u.washington.edu

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.

Key words: neuronal death; feeding; glia; hypothalamus; appetite; network; hindbrain

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Received May 30, 2008; revised July 22, 2008; accepted July 31, 2008.

Correspondence should be addressed to Richard D. Palmiter at the above address. Email: palmiter{at}u.washington.edu

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