Article

Strain differences in the effects of chronic corticosterone exposure in the hippocampus.

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, United States.
Neuroscience (Impact Factor: 3.33). 06/2012; 222:269-80. DOI: 10.1016/j.neuroscience.2012.06.017
Source: PubMed

ABSTRACT Stress hormones are thought to be involved in the etiology of depression, in part, because animal models show they cause morphological damage to the brain, an effect that can be reversed by chronic antidepressant treatment. The current study examined two mouse strains selected for naturalistic variation of tissue regeneration after injury for resistance to the effects of chronic corticosterone (CORT) exposure on cell proliferation and neurotrophin mobilization. The wound healer MRL/MpJ and control C57BL/6J mice were implanted subcutaneously with pellets that released CORT for 7 days. MRL/MpJ mice were resistant to reductions of hippocampal cell proliferation by chronic exposure to CORT when compared to vulnerable C57BL/6J mice. Chronic CORT exposure also reduced protein levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of C57BL/6J but not MRL/MpJ mice. CORT pellet exposure increased circulating levels of CORT in the plasma of both strains in a dose-dependent manner although MRL/MpJ mice may have larger changes from baseline. The strains did not differ in circulating levels of corticosterone binding globulin (CBG). There were also no strain differences in CORT levels in the hippocampus, nor did CORT exposure alter glucocorticoid receptor or mineralocorticoid receptor expression in a strain-dependent manner. Strain differences were found in the N-methyl-D-aspartate (NMDA) receptor, and BDNF I and IV promoters. Strain and CORT exposure interacted to alter tropomyosine-receptor-kinase B (TrkB) expression and this may be a potential mechanism protecting MRL/MpJ mice. In addition, differences in the inflammatory response of matrix metalloproteinases (MMPs) may also contribute to these strain differences in resistance to the deleterious effects of CORT to the brain.

Download full-text

Full-text

Available from: Olivier Berton, Jun 23, 2015
0 Followers
 · 
190 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Olfactory bulbectomy (OBX), the surgical removal of the olfactory bulbs, lead, both in mice and rats, to a specific set of behavioral changes in social behavior, cognitive function and activity. The latter is often used as a readout measure to predict antidepressant effects of new compounds. More recently, the model is used to study neurodegeneration and the associated cognitive decline. Although most of the OBX-induced behavioral and neurochemical changes seen in mice and rats are very similar, there are also some remarkable differences. For instance, OBX has different effects on BDNF and the 5-HT2c receptor of these two species. These species differ also in how they respond to certain treatments after OBX. In this review we describe these species-specific differences and discuss what they may mean in terms of translational value. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmacology 11/2014; 753. DOI:10.1016/j.ejphar.2014.10.033 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation in the huntingtin gene. Lifestyle factors, such as lack of activity may contribute to the variability in the age of disease onset. Therefore, better understanding of environmental modifiers may uncover potential therapeutic approaches to delay disease onset and progression. Recent data suggest that HD patients and transgenic mouse models show a dysregulated stress response. In this present study, we elevated stress hormone levels through oral corticosterone (CORT) treatment and assessed its impact on the development of motor impairment and cognitive deficits using the R6/1 transgenic mouse model of HD. We found that CORT consumption did not alter rotarod performance of R6/1 HD or wild-type (WT) littermates. However, the onset of hippocampal-dependent Y-maze deficits was accelerated in male R6/1 mice by 5 days of CORT treatment, whereas short term memory of WT and female R6/1 mice was unaffected. We then further investigated the male HD susceptibility to CORT by measuring TrkB activation, BDNF and glucocorticoid receptor expression as well as the level of cell proliferation in the hippocampus. CORT treatment increased the levels of phosphorylated TrkB in male R6/1 mice only. There were no effects of CORT on hippocampal BDNF protein or mRNA levels; nor on expression of the glucocorticoid receptors in any group. Hippocampal cell proliferation was decreased in male R6/1 mice and this was further reduced in CORT-drinking male R6/1 mice. Female mice (WT and R6/1) appeared to be protected from the impacts of CORT treatment in all our hippocampal measures. Overall, our data demonstrate that treatment with corticosterone is able to modulate the onset of HD symptomatology. We present the first evidence of a male-specific vulnerability to stress impacting on the development of short-term memory deficits in HD. More generally, we found that female mice were protected from the detrimental effects of CORT treatment on a variety of hippocampus-based measures. Hippocampal plasticity and memory in HD may be more susceptible to the impacts of stress in a sex-dependent manner. We propose clinical investigations of stress as a key environmental modifier of HD symptom onset.
    Neurobiology of Disease 09/2014; 69. DOI:10.1016/j.nbd.2014.05.004 · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer's, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies.
    Frontiers in Psychiatry 03/2015; 6:32. DOI:10.3389/fpsyt.2015.00032