Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

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 4th 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 4th and 20th 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 20th 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 20th 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.

Aging changes the expression of adenosine receptors, insulin-like growth factor 1 (IGF1), and hypoxia-inducible factor 1α (HIF1α) in hypothalamic astrocyte cultures

“…Furthermore, defective IGF1 gliosignaling can induce mitochondrial dysfunction and production of reactive oxygen species [21] , which actively participates in the pathomechanisms of neurodegenerative diseases. Our findings are also in accordance with a recent publication that indicated an age-dependent reduction in IGFR1 that may represent a link between the progression of synaptic dysfunction and inflammation in paraventricular hypothalamic nucleus in an experimental model of hypertension, a common condition observed during aging [29] . The IGF signaling can also modulate the activity of HIF1α [3] , [10] .…”

Antihypertensive effects of exercise involve reshaping of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rat

“…Coronal hypothalamic slices, including the paraventricular nucleus (PVN) were obtained using standard procedures as previously described. 23,24 Briefly, rats were decapitated after 1-2% isoflurane anesthesia. The whole brain was removed and submerged in ice-cold oxygenated (95% O 2 and 5% CO 2 ) artificial cerebrospinal fluid (ACSF) containing 252 mM sucrose, 2.5 mM KCl, 6 mM MgSO 4 , 0.5 mM CaCl 2 , 25 mM NaHCO 3 , 1.2 mM NaH 2 PO 4 , 10 mM glucose, and pH 7.4.…”

Systemic Sympathoexcitation Was Associated with Paraventricular Hypothalamic Phosphorylation of Synaptic CaMKIIα and MAPK/ErK

“…The PVN has initially been described as a mere relay station for neurons of the descending hypothalamic-hypophysial systems (Babović et al, 2009 ). However, morphological and electrophysiological characterization of PVN neurons shows that it is made up of several integrated excitatory and inhibitory neural circuits concerned with the regulation of autonomic cardiovascular functions (Pyner, 2009 ; Glass et al, 2015 ; Pandit et al, 2015 ; Ogundele et al, 2016a ). An important component of the pre-autonomic sympathetic control is the activity of adrenergic neurotransmitters in parts of the brain connected to the PVN (Jung et al, 2004 ).…”