Repeated exposure to corticosterone, but not restraint, decreases the number of reelin-positive cells in the adult rat hippocampus

doi:10.1016/j.neulet.2009.05.050

Neuroscience Letters

Volume 460, Issue 2, 28 August 2009, Pages 170-174

https://doi.org/10.1016/j.neulet.2009.05.050 Get rights and content

Abstract

Stress is an important risk factor for the emergence of depression, but little is known about the neurobiological mechanisms by which stress might promote depressive symptomatology. Much of the research on this topic has focused on stress-induced changes in hippocampal plasticity, specifically the idea that decreased hippocampal plasticity could be a precipitating factor for depression. Interestingly, recent evidence has described a regulatory role for the extracellular matrix protein reelin in important aspects of neural plasticity within the hippocampus and dentate gyrus. Given this association between reelin and hippocampal plasticity, we investigated whether repeated exposure to corticosterone or physical restraint might decrease reelin expression in specific hippocampal regions. Rats were subjected to either 21 days of corticosterone injections or physical restraint and then sacrificed so that the number of reelin-positive cells throughout the hippocampus and dentate gyrus could be quantified using immunohistochemistry. Our results revealed a significant decrease in the number of reelin-positive cells in the CA1 stratum lacunosum and the subgranular zone of the dentate gyrus in rats that received corticosterone, but not in rats that received restraint. Interestingly, these results parallel our previous observation that corticosterone increases depression-like behavior but physical restraint does not. These novel findings suggest that altered reelin signaling could play a role in the expression of depressive symptomatology after exposure to high levels of glucocorticoids.

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Acknowledgements

This work was supported by grants from the Saskatchewan Health Research Foundation and the Natural Sciences and Engineering Council of Canada (NSERC) to L.E. Kalynchuk and from the Xunta de Galicia and Ministerio de Ciencia y Tecnologia to H.J. Caruncho. The authors wish to thank Neil Fournier for helpful suggestions throughout the conduct of this experiment.

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There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3μg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.
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Repeated exposure to the stress hormone corticosterone results in depressive-like behaviours paralleled by the downregulation of hippocampal reelin expression. Reelin is expressed in key neural populations involved in the stress response, but whether its hypothalamic expression is sex-specific or involved in sex-specific vulnerability to stress is unknown. Female and male rats were treated with either daily vehicle or corticosterone injections (40 mg/kg) for 21 days. Thereafter, they were subjected to several behavioural tasks before being sacrificed to allow the analysis of reelin expression in hypothalamic nuclei. The basal density of reelin-positive cells in males was significantly higher in the paraventricular nucleus (19 %) and in the medial preoptic area (51 %) compared to females. Chronic corticosterone injections increased the immobility time in the forced swim test in males (107 %) and females (108 %) and decreased the exploration of the elevated plus maze in males (34 %). Corticosterone also caused a significant decrease in the density of reelin-positive cells in males, in both ventrodorsal (37 %) and ventrolateral (32 %) subdivisions of the paraventricular nucleus, while not affecting females. Moreover, in the paraventricular nucleus of males, 30 % of the basal reelin-positive cells co-expressed oxytocin while only 17.5 % did in females, showing a positive correlation between reelin and oxytocin levels. Chronic corticosterone did not significantly affect co-localization levels. For the first time, this study shows that there is a sexually dimorphic subpopulation of reelin-positive neurons in the paraventricular nucleus that can be differentially affected by chronic stress.
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On the other hand, cerebrospinal fluid reelin rather than plasma reelin may better reflect central reelin levels (Ignatova et al., 2004). In rodent studies, CORT reduced the number of reelin-IR cells in the dentate gyrus subgranular region (Lussier et al., 2009, 2013), whereas a single peripheral injection of reelin reversed this change (Allen et al., 2022). Furthermore, this study showed the effectiveness of repeated intravenous administration of reelin in rescuing repetitive CORT-induced behavior and neurochemical phenotypes (Allen et al., 2022).
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Chronic stress is a significant risk factor for depression onset. The effects of chronic stress can be studied preclinically using a corticosterone (CORT)-administration paradigm that results in a phenotype of depressive-like behavior associated with neurochemical abnormalities in brain regions like the hippocampus. We have recently shown that intrahippocampal infusions of Reelin have a fast effect in normalizing CORT-induced behavioral and neurochemical alterations. Reelin is also expressed in multiple peripheral systems and is found in blood plasma which prompted us to investigate whether peripheral intravenous (i.v.) Reelin injections could also result in antidepressant (ATD)-like actions. Repeated i.v. injections of Reelin were effective in rescuing the CORT-induced increases in forced-swim-test immobility in male and female rats, decreases in Reelin-immunopositive cells in the dentate gyrus subgranular zone, the expression of hippocampal GABA_A $β$ 2/3, GluA1, and GluN2B receptors, and serotonin transporter (SERT) membrane protein clustering (MPC) in blood lymphocytes. However, Reelin had only a partial effect on the number and maturation rate of dentate gyrus newborn cells. CORT and Reelin did not affect open field test behavior. After evaluating the effects of multiple Reelin injections, we demonstrated that a single Reelin injection administered at the end of CORT treatment could rescue in 24 h the behavioral (forced-swim-test and object-in-place test), as well as SERT MPC and neurochemical effects of CORT. These findings show that i.v. injections of Reelin have fast ATD-like effects associated with the restoration of hippocampal neurochemical deficits. Although additional mechanistic and pharmacokinetic studies are necessary, our data open the possibility to develop Reelin-based therapeutics with putative fast-ATD activity.
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It has been suggested that fetal programming of brain connectivity in utero occurs primarily through endocrine and inflammatory mediators that pass through the placenta and fetal blood-brain barrier and precipitate developmental cascades via direct signaling or by modifying the availability and activity of critical neural growth factors and hormones (Buss et al., 2012b). For example, there is evidence that unusually high concentrations of glucocorticoids modify the trajectories of brain development both by binding directly to regions dense in glucocorticoid receptors (including the amygdala and PFC) and initiating local changes (Welberg et al., 2001), as well as by modulating the activity of proteins that facilitate neuronal differentiation and determine cell fates (Kumamaru et al., 2008; Lussier et al., 2009; Shimizu et al., 2010). However, it is unclear whether the influences of these potential mechanisms are “by design” (i.e., adaptive processes that will benefit the developing fetus postnatally) or are byproducts of other biological tradeoffs that negatively affect fetal development.
Stressful experiences are linked to neurodevelopment. There is growing interest in the role of stress in the connectivity between the amygdala and medial prefrontal cortex (mPFC), a circuit that subserves automatic emotion regulation. However, the specific timing and mechanisms that underlie the association between stress and amygdala–mPFC connectivity are unclear. Many factors, including variations in fetal exposure to maternal stress, appear to affect early developing brain circuitry. However, few studies have examined the associations of stress and amygdala–mPFC connectivity in early life, when the brain is most plastic and sensitive to environmental influence. In this longitudinal pilot study, we characterized the association between prenatal stress and amygdala–mPFC connectivity in young infants (approximately age 5 weeks). A final sample of 33 women who provided data on preconception and prenatal stress during their pregnancy returned with their offspring for a magnetic resonance imaging scan session, which enabled us to characterize amygdala–mPFC structural and functional connectivity as a function of prenatal stress. Increased prenatal stress was associated with decreased functional connectivity and increased structural connectivity between the amygdala and mPFC. These results provide insight into the influence of prenatal maternal stress on the early development of this critical regulatory circuitry.
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In the present experiment, we have also looked at the extracellular matrix glycoprotein reelin that is closely associated with neurogenesis and synaptic plasticity. In our laboratory, the loss of hippocampal reelin levels has been consistently observed after chronic CORT administration and rescued with antidepressant treatment [25,27,26,9]. Similarly, in the current experiment, CORT reduced the number of SGZ-reelin+ cells in all time points in cycle 1 and this decrease was exacerbated after 3 cycles of CORT exposure.
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Repeated exposure to corticosterone, but not restraint, decreases the number of reelin-positive cells in the adult rat hippocampus

Abstract

Section snippets

Acknowledgements

Neuroscience

Behav. Brain Res.

Horm. Behav.

Behav. Brain Res.

Neurosci. Biobehav. Rev.

J. Affective Dis.

Behav. Brain Res.

Eur. J. Pharmacol.

Neurobiol. Learn. Mem.

J. Biol. Chem.

Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse

J. Neurosci.

The stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/spine formation

Proc. Natl. Acad. Sci. U.S.A.

Long-lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment

Eur. J. Neurosci.

Major depressive disorder

New England J. Med.

The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling

Mol. Psychiatry

Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression

Mol. Psychiatry