Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress

Abstract

We report that 9 d of uncontrolled experimental diabetes induced by streptozotocin (STZ) in rats is an endogenous chronic stressor that produces retraction and simplification of apical dendrites of hippocampal CA3 pyramidal neurons, an effect also observed in nondiabetic rats after 21 d of repeated restraint stress or chronic corticosterone (Cort) treatment. Diabetes also induces morphological changes in the presynaptic mossy fiber terminals (MFT) that form excitatory synaptic contacts with the proximal CA3 apical dendrites. One effect, synaptic vesicle depletion, occurs in diabetes as well as after repeated stress and Cort treatment. However, diabetes produced other MFT structural changes that differ qualitatively and quantitatively from other treatments. Furthermore, whereas 7 d of repeated stress was insufficient to produce dendritic or synaptic remodeling in nondiabetic rats, it potentiated both dendritic atrophy and MFT synaptic vesicle depletion in STZ rats. These changes occurred in concert with adrenal hypertrophy and elevated basal Cort release as well as hypersensitivity and defective shutoff of Cort secretion after stress. Thus, as an endogenous stressor, STZ diabetes not only accelerates the effects of exogenous stress to alter hippocampal morphology; it also produces structural changes that overlap only partially with those produced by stress and Cort in the nondiabetic state.A drenal glucocorticoids (GCs) are major mediators of the adaptive response to stress, and they also play a crucial role in feedback mechanisms that contain or protect against defense reactions that are activated by stress, such as inflammation (1, 2). The process of adaptation to environmental demands, also called ''allostasis'' (3, 4), functions best when stress mediators such as those associated with the activation of the hypothalamo-pituitaryadrenal (HPA) axis are turned on efficiently when needed and turned off again when not needed (5). When HPA activity is elevated chronically or managed inefficiently, various forms of pathophysiology are accelerated, such as bone mineral loss, loss of muscle protein mass, insulin resistance, and dysfunction of the hippocampal region of the brain (5, 6). This cost to the body has been termed ''allostatic load' ' (4, 5). MRI studies in stress-related disorders, such as posttraumatic stress disorder, recurrent depressive illness, Cushing's syndrome, and mild cognitive impairment in aging patients, have revealed atrophy of the human hippocampus accompanied by deficits in declarative and spatial memory (7-11), in line with the recognized role of the hippocampus in cognitive processes (12). However, the exact nature of the atrophy is unclear, whether it is caused by permanent damage or by a potentially reversible form of plasticity.In experimental animals, severe and prolonged stress or GC administration has been reported to cause brain damage associated with hippocampal neuronal loss (see ref. 6 for review). We have described previously that shorter periods of repeated stress alter hippocamp...

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

“…Adult male Sprague-Dawley rats were purchased from Charles River Laboratories and housed individually for a minimum of 2 weeks before the start of experiments. Streptozocin was administered via the femoral vein at a dose of 70 mg kg -1 as described 16 . In order to be included in the study, STZ-treated rats were required to exhibit serum glucose levels ≥ 200 mg dL -1 .…”

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

“…[4][5][6][7][8][9][10][11][12][13][14]26 Corticosteroids have also been shown to increase the likelihood of neuronal death in rat embryonic hippocampal cultures. 27,28 In the present experiments, hippocampal cell cultures were prepared from postnatal rats, aged 4-5 days.…”

“…4,5 The detrimental effects of corticosteroids on the hippocampus are backed by imaging studies in humans: there is a strong negative correlation between cortisol levels and hippocampal volume in patients with major depression 6,7 and in subjects with Cushing's disease; 8 reduced hippocampal volumes were also recently found in rats treated with dexamethasone (DEX), a GR agonist. 9 While most of the hippocampal shrinkage observed may be due to neuritic atrophy, including dendritic impoverishment and synaptic loss, [10][11][12] other experiments have demonstrated that GR activation activates a molecular cascade, leading to significant levels of neuronal cell death through apoptotic mechanisms. 13 Besides apoptosis of mature hippocampal neurons, 14 there is also evidence that GRs interfere with proliferation of granule neurons of the dentate gyrus.…”

Hippocampal Neuronal Apoptosis in Rat Offspring Due to Gestational Diabetes

“…Hippocampal neurons are also sensitive to the effects of diabetes Magariños & McEwen, 2000) and often show damage to presynaptic and postsynaptic structures, dysregulation of calcium homeostasis, neuronal loss, dendriticatrophy in CA3 neurons, reduced expression of insulin growth factors and their receptors, and decreased neurogenesis (Jackson-Guilford et al; Magariños & McEwen;Li et al, 2002aLi et al, , 2002bKlein & Waxman, 2003;Saravia et al, 2002).…”