Depressed basal hypothalamic neuronal activity in type-1 diabetic mice is correlated with proinflammatory secretion of HMBG1

Abstract

We recently found indicators of hypothalamic inflammation and neurodegeneration linked to the loss of neuroprotective factors including insulin-like growth factor (IGF-1) and IGF binding protein-2 (IGFBP-3) in mice made diabetic using streptozotocin (STZ). In the current work, a genetic model of type-1 diabetes (Ins2Akita mouse) was used to evaluate changes in neuronal activity and concomitant changes in the proinflammatory mediator high-mobility group box-1 (HMBG1). We found basal hypothalamic neuronal activity as indicated by manganese-enhanced magnetic resonance imaging (MEMRI) was significantly decreased in 8 month old, but not 2 month old Ins2Akita diabetic mice compared to controls. In tissue from the same animals we evaluated the expression of HMBG1 using immunohistochemistry and confocal microscopy. We found decreased HMBG1 nuclear localization in the paraventricular nucleus of the hypothalamus (PVN) in 8 month old, but not 2 month old diabetic animals indicating nuclear release of the protein consistent with an inflammatory state. Adjacent thalamic regions showed little change in HMBG1 nuclear localization and neuronal activity as a result of diabetes. This work extends our previous findings demonstrating changes consistent with hypothalamic neuroinflammation in STZ treated animals, and shows active inflammatory processes are correlated with changes in basal hypothalamic neuronal activity in Ins2Akita mice.

A Single Angiotensin II Hypertensive Stimulus Is Associated with Prolonged Neuronal and Immune System Activation in Wistar-Kyoto Rats

“…Manganese-enhanced magnetic resonance (MEMRI) is a very powerful experimental technique that provides a novel approach for examining in vivo neuronal activity in chronic disease models (Yu et al, 2005 ; Kimura et al, 2007 ; Perez et al, 2013 ; Zubcevic et al, 2014 ; Thinschmidt et al, 2016 ). The experimental design was performed as previously described (Zubcevic et al, 2014 ).…”

“…Scans were aligned with a segmented atlas of the rat brain using an automated affine linear registration tool from FMRIB software library ( flirt program in FSL, Oxford University). We used a voxel-wise signal normalization procedure as previously published (Perez et al, 2013 ; Zubcevic et al, 2014 ; Thinschmidt et al, 2016 ). Image processing was carried out using itk SNAP ( http://www.itksnap.org ) and Matlab custom code.…”

Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: Implications for bone marrow rejuvenation

“…An imbalance in the sympathetic nervous system, with the loss of parasympathetic drive and increased sympathetic activation, occurs in diabetes. Ultimately these neuronal changes transition to neuronal loss and in the bone marrow can directly impact diabetic retinopathy [16, 17, 27, 28, 30, 37, 38, 47-50]. In chronic diabetes bone marrow denervation occurs and precedes the onset of diabetic retinopathy in rodent models of diabetes [28, 30, 37, 49].…”

Manganese-Enhanced Magnetic Resonance Imaging: Application in Central Nervous System Diseases

“…In addition, MEMRI is also used to detect changes in neuronal activity caused by neuroinflammation in metabolic diseases. Thinschmidt et al found a significant reduction in basal hypothalamic neuronal activity in 8-month-old Ins2 Akita diabetic mice using MEMRI (175).…”