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      Age-dependent alterations to paraventricular nucleus insulin-like growth factor 1 receptor (IGF-1R) as a possible link between sympathoexcitation and inflammation

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          Abstract

          Modifications to neural circuits of the paraventricular hypothalamic nucleus (PVN) have been implicated in sympathoexcitation and systemic cardiovascular dysfunction. However, to date, the role of insulin-like growth factor 1 receptor (IGF-1R) expression on PVN pathophysiology is unknown. Using confocal immunofluorescence quantification and electrophysiological recordings from acute PVN slices, we investigated the mechanism through which age-dependent IGF-1R depletion contributes to the progression of inflammation and sympathoexcitation in the PVN of spontaneously hypertensive rats (SHR). Four and twenty weeks old SHR and Wistar Kyoto (WKY) rats were used for this study. Our data showed that Angiotensin I/II and pro-inflammatory high mobility box group protein 1 (HMGB1) exhibited increased expression in the PVN of SHR versus WKY at 4 weeks (p<0.01), and were even more highly expressed with age in SHR (p<0.001). This correlated with a significant decrease in IGF-1R expression, with age, in the PVN of SHR when compared with WKY (p<0.001) and were accompanied by related changes in astrocytes and microglia. In subsequent analyses, we found an age-dependent change in the expression of proteins associated with IGF-1R signaling pathways involved in inflammatory responses and synaptic function in the PVN. MAPK/ErK was more highly expressed in the PVN of SHR by the 4 th week (p<0.001; vs WKY), while expression of neuronal nitric oxide synthase (nNOS; p<0.001) and calcium-calmodulin dependent kinase II alpha (CamKIIα; p<0.001) were significantly decreased by the 4 th and 20 th week respectively.

          Age-dependent changes in MAPK/ErK expression in the PVN correlated with an increase in the expression of vesicular glutamate transporter (VGLUT2) (p<0.001 vs WKY), while decreased levels of CamKIIα was associated with a decreased expression of tyrosine hydroxylase (p<0.001) by the 20 th week. In addition, reduced labeling for GABA in the PVN of SHR (p<0.001) correlated with a decrease in nNOS labeling (p<0.001) when compared with the WKY by the 20 th week. Electrophysiological recordings from neurons in acute slice preparations of the PVN of 4 weeks old SHR revealed spontaneous post-synaptic currents of higher frequency when compared with neurons from WKY PNV slices of the same age (p<0.001; n=14 cells). This also correlated with an increase in post-synaptic densities (PSD-95) in the PVN of SHR when compared with the WKY (p<0.001). Overall, we found an age-dependent reduction of IGF-1R, and related altered expression of associated downstream signaling molecules that may represent a link between the concurrent progression of synaptic dysfunction and inflammation in the PVN of SHR.

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          Author and article information

          Journal
          2985190R
          5004
          J Neurochem
          J. Neurochem.
          Journal of neurochemistry
          0022-3042
          1471-4159
          19 August 2017
          19 October 2016
          December 2016
          01 December 2017
          : 139
          : 5
          : 706-721
          Affiliations
          [1 ]Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana
          Author notes
          Corresponding Author: Joseph Francis [ jfrancis@ 123456lsu.edu Tel: 225-578-9414]
          Article
          PMC5590639 PMC5590639 5590639 nihpa900444
          10.1111/jnc.13842
          5590639
          27626839
          4122a1ce-a942-44f5-a7e5-1385fe529f66
          History
          Categories
          Article

          PVN,SHR,Angiotensin II,IGF-1/IGF-1R,EPSCs,Sympathoexcitation
          PVN, SHR, Angiotensin II, IGF-1/IGF-1R, EPSCs, Sympathoexcitation

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