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Immunotoxic lesion of hypothalamic noradrenergic/adrenergic input ameliorates the effects of peripheral LPS challenge on sickness behavior and associated brain c-Fos expression

Gaykema RP, Thacker GC, Shapiro NJ, Goehler LE (2009) Immunotoxic lesion of hypothalamic noradrenergic/adrenergic input ameliorates the effects of peripheral LPS challenge on sickness behavior and associated brain c-Fos expression. Neuroscience 2009 Abstracts 570.11/EE120. Society for Neuroscience, Chicago, IL.

Summary: Caudal medullary catecholamine neurons that innervate the hypothalamus play a major role in the activation of paraventricular neurons that drive pituitary adrenocorticotropin and adrenal corticosteroid release in response to peripheral pro-inflammatory challenges with interleukin-1 or lipopolysaccharide (LPS). Pro-inflammatory challenges also lead to marked behavioral changes, including fatigue, loss of social interest, anorexia, somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. We reasoned that the medulla-hypothalamic catecholaminergic pathway may also contribute to the behavioral manifestations in illness. To investigate such possible role, we applied a targeted lesion approach in rats to determine whether or not caudal brainstem catecholaminergic neurons that innervate the hypothalamus are also necessary for the expression of sickness behavior. Anti-dopamine beta hydroxylase antibodies conjugated to saporin (DSAP), when injected into a target region, selectively poisons and destroy noradrenergic/adrenergic neurons that innervate the target. DSAP was micro-injected bilaterally into the hypothalamic paraventricular nucleus (PVN), whereas control rats received unconjugated saporin (SAP controls). Fourteen days later the animals were injected intraperitoneally with either LPS or saline, and 2h later were submitted to the open field to record their exploratory behavior, 1h after which the rats were sacrificed for brain immunohistochemical analyses. LPS-treated SAP control rats showed drastic reduction in exploratory behavior (reduced locomotion distance and velocity). Prior DSAP microinjections largely reversed the LPS-induced reduction in locomotor behavior. The brains of these DSAP rats showed a dramatic loss of noradrenergic innervation of the PVN but also in other parts of the medial, tuberal and tuberomammilary regions of the hypothalamus. The behavioral resilience to LPS coincided with diminished LPS-related c-Fos staining in the PVN, and increased c-Fos staining in the lateral and tuberomammillary regions related to behavior and/or arousal. In summary, our findings support the hypothesis that hypothalamic catecholaminergic projections originating in the lower brainstem play a critical role in the expression of sickness behavior in the context of novelty-induced exploratory activity, but we cannot determine with precision in which part of the hypothalamus the noradrenergic/adrenergic input contributes to the expression of sickness behavior due to extensive collateralization of the ascending projections throughout the hypothalamus.

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