TY - JOUR
T1 - Hippocampal brain-derived neurotrophic factor determines recruitment of anatomically connected networks after stress in diabetic mice
AU - Wosiski-Kuhn, Marlena
AU - Bota, Mihail
AU - Snider, Christina A.
AU - Wilson, Steven P.
AU - Venkataraju, Kannan U.
AU - Osten, Pavel
AU - Stranahan, Alexis M.
N1 - Funding Information:
information NIH/NIDDK, Grant/Award Number: R03DK101817; Medical College of GeorgiaWe are grateful to Christopher Bunting for assistance with stereological cell counts, and to Dr. Xin-Yun Lu and Anilkumar Pillai for critical reading of the article. This work was supported by a grant from the NIDDK to AMS (R03DK101817), and by intramural funding from the Medical College of Georgia.
Funding Information:
We are grateful to Christopher Bunting for assistance with stereological cell counts, and to Dr. Xin-Yun Lu and Anilkumar Pillai for critical reading of the article. This work was supported by a grant from the NIDDK to AMS (R03DK101817), and by intramural funding from the Medical College of Georgia.
Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - BDNF
KW - BNST
KW - HPA axis
KW - anxiety
KW - iDISCO
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U2 - 10.1002/hipo.23018
DO - 10.1002/hipo.23018
M3 - Article
C2 - 30098276
AN - SCOPUS:85056124151
SN - 1050-9631
VL - 28
SP - 900
EP - 912
JO - Hippocampus
JF - Hippocampus
IS - 12
ER -