Glucocorticoid receptor activation impairs hippocampal plasticity by suppressing BDNF expression in obese mice

Abstract

Diabetes and obesity are associated with perturbation of adrenal steroid hormones and impairment of hippocampal plasticity, but the question of whether these conditions recruit glucocorticoid-mediated molecular cascades that are comparable to other stressors has yet to be fully addressed. We have used a genetic mouse model of obesity and diabetes with chronically elevated glucocorticoids to determine the mechanism for glucocorticoid-induced deficits in hippocampal synaptic function. Pharmacological inhibition of adrenal steroidogenesis attenuates structural and functional impairments by regulating plasticity among dendritic spines in the hippocampus of leptin receptor deficient (db/db) mice. Synaptic deficits evoked by exposure to elevated corticosterone levels in db/db mice are attributable to glucocorticoid receptor-mediated transrepression of AP-1 actions at BDNF promoters I and IV. db/db mice exhibit corticosterone-mediated reductions in brain-derived neurotrophic factor (BDNF), and a change in the ratio of TrkB to P75NTR that silences the functional response to BDNF stimulation. Lentiviral suppression of glucocorticoid receptor expression rescues behavioral and synaptic function in db/db mice, and also reinstates BDNF expression, underscoring the relevance of molecular mechanisms previously demonstrated after psychological stress to the functional alterations observed in obesity and diabetes.

Blood–brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice

“…Recordings were made at medial perforant path (mPP) inputs to the hippocampal dentate gyrus, which were identified anatomically by their location in the middle molecular layer, and functionally by the presence of presynaptic paired-pulse depression (PPD). 33 Consistent with previous reports, 4,5,30,41 slices from vehicle-treated db/db mice exhibit impaired LTP relative to slices from Wt mice ( Figure 3 Analysis of the input-output ratio revealed no differences between groups (F 2,22 ¼ 0.24, ns; Figure 3(d)), and PPD magnitude was unchanged (F 2,22 ¼ 0.68, ns; Figure 3(e)), implying that there may be a postsynaptic mechanism for synaptic deficits following obesityinduced BBB leakiness.…”

“…Testing in both paradigms was carried out between 18:00 and 22:00 h (lights-off at 1800) under red light illumination, as described. 4,5,30 Testing in the Y-maze involved (6) left/right choices, with correct choices expressed relative to the total number of potential alternations. Novel object recognition testing involved 10-min exposure to two identical objects, followed by 30 min in the home cage, after which the mouse was returned to the arena in the presence of one novel and one familiar object.…”

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…These results support the notion that inflammatory factors and HPA axis, which are tightly interrelated and highly activated in obesity (Dinel et al, 2011(Dinel et al, , 2014, may act together in that context to promote mood alterations Hryhorczuk et al, 2013;Stranahan et al, 2008). Both cytokines and glucocorticoids have been shown to impair hippocampal neurogenesis and neuronal function in obese mice (Dinel et al, 2011;Erion et al, 2014;Stranahan et al, 2008;Wosiski-Kuhn et al, 2014). Moreover, behavioral alterations reported in obese animals are linked to increased inflammation and reduced levels of the neurotrophic factor BDNF in the cortex and hippocampus (Dinel et al, 2011;Pistell et al, 2010), whereas normalization of hippocampal BDNF levels prevents hippocampus-mediated cognitive impairments (Kariharan et al, 2015;Moy and McNay, 2013).…”

New hypothesis and treatment targets of depression: an integrated view of key findings

“…The increased secretion of CRH, ACTH, and glucocorticoids has been reported in the cerebrospinal fluid of patients with depression [69] . High concentrations of glucocorticoids can have long-term adverse effects, which include: (1) imbalance of negative feedback in the HPA axis, including downregulation of negative feedback and dysfunction of GRs, disinhibition in the dexamethasone suppression test, and high concentrations of glucocorticoids in the blood; (2) excessive activation of GRs in its target cells in the CNS leads to neuronal apoptosis and degeneration [48] which is explained by the attenuation of BDNF expression and proliferation [70,71] . In addition, the increased glucocorticoid levels enhance the expression of 5-HT transporters in the hippocampus, the frontal cortex, the amygdala, the dorsal raphe nucleus, and other brain regions in a GR-dependent manner, resulting in reduced 5-HT in the synaptic cleft and aggravation of depressive symptoms [72] .…”