Hippocampal brain‐derived neurotrophic factor determines recruitment of anatomically connected networks after stress in diabetic mice

Abstract

Diabetes increases adrenal steroids in humans and animal models, but potential interactions with psychological stress remain poorly understood. Diabetic rodents exhibit anxiety and reductions in hippocampal brain-derived neurotrophic factor (BDNF) expression, and these studies investigated whether loss of BDNF-driven hippocampal activity promotes anxiety and disinhibits the HPA axis. Mice with genetic obesity and diabetes (db/db) received intrahippocampal injections of lentivirus for BDNF overexpression (db/db-BDNFOE), and Wt mice received lentiviral constructs for BDNF knockdown (Wt-BDNFKD). Behavioral anxiety and glucocorticoid responses to acute restraint were compared with mice that received a fluorescent reporter (Wt-GFP, db/db-GFP). These experiments revealed that changes in hippocampal BDNF were necessary and sufficient for behavioral anxiety and HPA axis disinhibition. To examine patterns of stress-induced regional activity, we used algorithmic detection of cFos and automated segmentation of forebrain regions to generate maps of functional covariance, which were subsequently aligned with anatomical connectivity weights from the Brain Architecture Management database. db/db-GFP mice exhibited reduced activation of the hippocampal ventral subiculum (vSub) and anterior bed nucleus of stria terminalis (aBNST), and increases in the paraventricular hypothalamus (PVH), relative to Wt-GFP. BDNFKD recapitulated this pattern in Wt mice, and BDNFOE normalized activation of the vSub> aBNST > PVH pathway in db/db mice. Analysis of forebrain activation revealed largely overlapping patterns of network disruption in db/db-GFP and Wt-BDNFKD mice, implicating BDNF-driven hippocampal activity as a determinant of stress vulnerability in both the intact and diabetic brain.

Behavioral defects and downregulation of hippocampal BDNF and nNOS expression in db/db mice did not improved by chronic TGF-β2 treatment

“…The present data suggest that BDNF and nNOS expression is low at both the mRNA and protein levels in the hippocampus of db/db mice. The low expression of BDNF in db/db mice is consistent with the results of previous studies of other mouse models of diabetes ( Wosiski-Kuhn et al, 2018 ; Hussain et al, 2019 ).…”

“…Animal studies have shown that db/db mice, which a model of T2D, show abnormal behaviors, including depression-like or anxiety-like behaviors ( Dinel et al, 2011 ; Liu et al, 2017 ; Fourrier et al, 2019 ; Zhang et al, 2019 ). Brain-derived neurotrophic factor (BDNF) in the hippocampus is important for mood regulation ( Hashimoto et al, 2004 ) and its expression is low in db/db mice ( Dinel et al, 2011 ; Shima et al, 2017 ; Wosiski-Kuhn et al, 2018 ). It has been shown that hippocampal BDNF expression is regulated by molecules including neuronal nitric oxide synthase (nNOS, encoded by Nos1 ) in the hippocampus ( Stanquini et al, 2018 ).…”

Immediate Early Gene c-fos in the Brain: Focus on Glial Cells

“…Moreover, it has been suggested that c-fos/Fos-B could be reliable markers for investigating the adaptive capabilities of the brain under stress conditions [ 61 , 62 ]. In addition, the study of endocrine responses demonstrated that suckling can modify the c-fos expression in the cerebral cortex [ 63 ], and that metabolic dysfunction produced by diabetes activates c-fos in the bed nucleus of stria terminalis (BNST) [ 64 ]. Research on circadian cycles and their alterations also evidenced c-fos changes in the suprachiasmatic nuclei (SCN), the main pacemaker in mammals [ 65 , 66 ].…”

Habenula lesions improve glucose metabolism in rats with type 2 diabetes by increasing insulin sensitivity and inhibiting gluconeogenesis

“…Studies have shown that reduced BDNF expression in the hippocampus of diabetic rodents have a disinhibited effect on the HPA axis. 22 We observed that Hb lesions can significantly increase the expression of BDNF and TrkB in the hippocampus of T2DM rats (p<0.05; figure 4A,B), indicating that Hb lesions might inhibit the HPA axis in T2DM rats by increasing the expression of BDNF in the hippocampus. Although the glucocorticoid receptor expression in the rat hippocampus of the lesion group was not significantly higher than that of the sham group, a clear upward trend was observed.…”