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

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 NMDA receptor, and BDNF I and IV promoter. Strain and CORT exposure interacted to alter tropomyosine-receptor-kinase B (TrkB) expression and this may be 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.

A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests

“…However, using these and related HDAC inhibitor tool compounds in basic research, future studies hold promise to resolve how HDAC subtype affinity, brain penetrance and clearance relate to both beneficial and deleterious effects of HDAC inhibition. To this end, it is interesting to consider the impact of selective HDAC1/2 inhibition on CNS disease models including chronic corticosteroid exposure [50], as well as chemical and genetic models of neurodegenerative disease [51]–[53]. Likewise, emerging compounds such as a highly selective HDAC3 inhibitor recently used in a study of addiction-related memory [54] will be important in further describing the role of HDAC enzymes in mood-related behaviors and how these enzymes may be best targeted in clinical drug development.…”

Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress

“…This microgliasecreted cytokine may thus contribute to the effects of chronic stress on brain function and behavioral responses (Sierra et al, 2014a), including anhedonia (Goshen et al, 2009;Koo and Duman, 2008). Other mechanisms underlying stress resilience/resistance in the CX 3 CR1 knockout mice should be considered, including modulation by other cytokines, trophic factors, inflammasome targets, and matrix metalloproteinases (MMPs) that have been recently associated whit strain resistance to stress (Franklin et al, 2012;Hodes et al, 2012;Pfau and Russo, 2015).…”

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

“…Progressively impairing BDNF-TrkB signaling in patients with mood disturbances may directly impact the biology of somatostatin-expressing neurons, resulting in somatostatin deficits. In addition, Bdnf-TrkB signaling itself is vulnerable to increased inflammation (Goshen et al, 2008; Koo and Duman, 2008; Song and Wang, 2011) and high glucocorticoids insults (Hodes et al, 2012). Mild oxidative stress inhibits tyrosine phosphatases activity (Barrett et al, 2005), potentially leading to impaired TrkB downstream signaling.…”