Cachexia is a condition marked by decreased appetite and loss of lean body mass that occurs in many states of chronic inflammation. One area of the brain that is likely to be involved in producing the appetite changes associated with cachexia is the brainstem, which receives neural afferent input from the gastro-intestinal tract and sends efferent signals producing responses such as gastroperesis. Because peripheral injection of cytokines produces an anorexic response similar to that seen in cachexia, we set out to investigate whether neurons in brainstem nuclei co-express cytokine receptors and Cocaine and Amphetamine Related Transcript (CART), a potently anorexigenic peptide which is up-regulated during inflammation in other appetite-regulating centers. We performed a double-label in situ hybridization on sections of a single rat brainstem using a digoxinen-labeled probe to CART and a 33P radioactively-labeled probe to the receptor for Leukemic Inhibitory Factor (LIF-R), a cytokine which has been shown to produce a cachexic response. We then analyzed fluorescent cells (CART-labeled) for the number of silver grains that had been exposed inside the cell compared to non-cellular background silver grain levels. We used this information to generate a signal-to background ratio (SBR) for each of the cells. A SBR of greater than 2.5 is generally considered to be good evidence of co-expression. We found that CART and LIF-R were moderately co-expressed in the Area Postrema (AP), which is an important site of afferent synapsing, with 34% of CART-expressing cells having a SBR of 2.5 or greater and 17% of cells having a SBR of 10 or greater. In the lateral reticular nucleus, cells co-expressed to a greater degree to that seen in the AP with 63% of cells having an SBR ≥2.5 and 16% ≥10 SBR. The most striking difference in expression levels were seen between rostral and caudal inferior olivary (IO) nuclei with 87% of cells ≥2.5 SBR and 48% ≥10 SBR in the rostral IO while in the caudal IO only 24% of cells showed co-expression ≥ 2.5 SBR and 0% ≥ 10 SBR. Though the role of CART and LIF-R expression in the IO is unclear, the co-expression in the AP may reflect one way that cytokines can directly stimulate the production of CART, leading to a decrease in feeding response. Experiments are currently underway to analyze the extent of CART and LIF-R co-expression between groups of rats pre-treated with peripheral injections of either saline or lipopolysaccharide to induce cytokine storm. This will help confirm the findings in this abstract and determine whether LIF-R expression increases in response to LPS-induced cytokine cascade.
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