Rate Of Hippocampal Cell Proliferation Research Articles

Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus.

The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O) is an N-methyl-D-aspartic acid (NMDA) antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD) patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2). Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG) using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates.

Impact of the Neural Cell Adhesion Molecule-Derived Peptide FGL on Seizure Progression and Cellular Alterations in the Mouse Kindling Model

The neural cell adhesion molecule peptide mimetic fibroblast growth loop (FGL) proved to exert neuroprotective, neurotrophic, and anti-inflammatory effects in different in vitro and in vivo experiments. Based on this beneficial efficacy profile, it is currently in clinical development for neurodegenerative diseases and brain insults. Here, we addressed the hypothesis that the peptide might affect development of seizures in a kindling paradigm, as well as associated behavioral and cellular alterations. Both doses tested, 2 and 10 mg/kg FGL, significantly reduced the number of stimulations necessary to induce a generalized seizure. FGL did not exert relevant effects on the behavioral patterns of kindled animals. As expected, kindling increased the hippocampal cell proliferation rate. Whereas the low dose of FGL did not affect this kindling-associated alteration, 10 mg/kg FGL proved to attenuate the expansion of the doublecortin-positive cell population. These data suggest that FGL administration might have an impact on disease-associated alterations in the hippocampal neuronal progenitor cell population. In conclusion, the effects of the peptide mimetic FGL in the kindling model do not confirm a disease-modifying effect with a beneficial impact on the development or course of epilepsy. The results obtained with FGL rather raise some concern regarding a putative effect, which might promote the formation of a hyperexcitable network. Future studies are required to further assess the risks in models with development of spontaneous seizures.

P.2.d.023 Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress

The antidepressant agomelatine is a MT1/MT2 receptor agonist and 5-HT2C antagonist. Its antidepressant activity is proposed to result from the synergy between these sets of receptors. Agomelatine-induced changes in the brain have been reported under basal conditions. Yet, little is known about its effects in the brain exposed to chronic stress as a risk factor for major depressive disorder. Recently, we described agomelatine-induced changes on neuronal activity and adult neurogenesis in the hippocampus of rats subjected to chronic footshock stress. In order to better characterize the actions of agomelatine in the stress-compromised brain, here we investigated its effects on hippocampal neurogenesis in the chronic mild stress (CMS)model. Adultmale ratswere subjected to variousmild stressors for 5weeks, and treated with agomelatine during the last 3weeks of the stress period. The sucrose preference test was performed weekly to measure anhedonia, and the marble burying test was carried out at the end of the experiment to assess anxiety-like behavior. In ourmodel, the CMS paradigmdid not change sucrose preference; however, it increased marble burying behavior, indicating enhanced anxiety. Interestingly, this stress model differentially affected distinct stages of the neurogenesis process.Whereas CMSdid not influence the rate of hippocampal cell proliferation, it significantly decreased the newborn cell survival and doublecortin expression in the dentate gyrus. Importantly, treatmentwith agomelatine completely normalized stressaffected cell survival and partly reversed reduced doublecortin expression. Taken together, these data show that agomelatine has beneficial effects on hippocampal neurogenesis in the CMS paradigm. © 2010 Elsevier B.V. All rights reserved.

Modulation of neurogenesis by targeted hippocampal irradiation fails to affect kindling progression

Changes in the rate of dentate granule cell neurogenesis and in the fate of newborn granule cells have been implicated in the development and progression of epilepsies. Strategies to normalize neurogenesis in chronic epilepsy models are thought to increase our understanding of the functional consequences of aberrant neurogenesis in the epileptic brain. Therefore, we modulated neurogenesis in an amygdala kindling paradigm in rats by targeted irradiation of the hippocampus using a medical linear accelerator device. Selective irradiation normalized the hippocampal cell proliferation rate in kindled animals. Both, in kindled and nonkindled rats the number of BrdU/NeuN-labeled newborn neurons was reduced in response to irradiation. Whereas kindling resulted in a pronounced increase in the number of neuroblasts identified based on doublecortin-labeling, irradiation prevented the expansion of the neuroblast population. Moreover, irradiation counteracted the kindling-associated increase in hilar basal dendrites, and kept the fraction of cells with basal dendrites at control levels. Despite the efficacious modulation of neurogenesis, irradiation did not affect the rate of kindling progression. Both, the number of stimulations as well as the cumulative afterdischarge duration to reach respective seizure stages were comparable in animals with and without irradiation. In addition, pre- and postkindling thresholds as well as seizure parameters recorded at threshold stimulation remained unaffected by irradiation. In conclusion, the fact that the efficacious modulation of neurogenesis by irradiation did not exert any effects on kindling acquisition and kindled seizures suggests that newborn neurons do not critically contribute to the hyperexcitable state in the chronic epilepsy model used.

Modulation of neuroplasticity pathways and antidepressant-like behavioural responses following the short-term (3 and 7 days) administration of the 5-HT4 receptor agonist RS67333

It has been recently suggested that activation of 5-HT₄ receptors might exert antidepressant-like effects in rats after 3 d treatment, suggesting a new strategy for developing faster-acting antidepressants. We studied the effects of 3 d and 7 d treatment with the 5-HT₄ receptor partial agonist RS67333 (1.5 mg/kg.d) in behavioural tests of chronic efficacy and on neuroplastic-associated changes, such as adult hippocampal neurogenesis, expression of CREB, BDNF, β-catenin, AKT and 5-HT₄ receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, β-catenin expression and pCREB/CREB ratio after 3 d treatment. This short-term treatment also reduced immobility time in the forced swim test (FST), together with a partial reversion of the anhedonic-like state (sucrose consumption after chronic corticosterone). Administration of RS67333 for 7 d resulted in a higher increase in the rate of hippocampal cell proliferation, a significant desensitization of 5-HT₄ receptor-coupled adenylate cyclase activity and a more marked increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT): these changes reached the same magnitude as those observed after 3 wk administration of classical antidepressants. Consistently, a positive behavioural response in the novelty suppressed feeding (NSF) test and a complete reversion of the anhedonic-like state (sucrose consumption) were also observed after 7 d treatment. These results support the antidepressant-like profile of RS67333 with a shorter onset of action and suggest that this time period of administration (3-7 d) could be a good approximation to experimentally predict the onset of action of this promising strategy.

Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress

The antidepressant agomelatine is a MT1/MT2 receptor agonist and 5-HT2C antagonist. Its antidepressant activity is proposed to result from the synergy between these sets of receptors. Agomelatine-induced changes in the brain have been reported under basal conditions. Yet, little is known about its effects in the brain exposed to chronic stress as a risk factor for major depressive disorder. Recently, we described agomelatine-induced changes on neuronal activity and adult neurogenesis in the hippocampus of rats subjected to chronic footshock stress. In order to better characterize the actions of agomelatine in the stress-compromised brain, here we investigated its effects on hippocampal neurogenesis in the chronic mild stress (CMS) model. Adult male rats were subjected to various mild stressors for 5 weeks, and treated with agomelatine during the last 3 weeks of the stress period. The sucrose preference test was performed weekly to measure anhedonia, and the marble burying test was carried out at the end of the experiment to assess anxiety-like behavior. In our model, the CMS paradigm did not change sucrose preference; however, it increased marble burying behavior, indicating enhanced anxiety. Interestingly, this stress model differentially affected distinct stages of the neurogenesis process. Whereas CMS did not influence the rate of hippocampal cell proliferation, it significantly decreased the newborn cell survival and doublecortin expression in the dentate gyrus. Importantly, treatment with agomelatine completely normalized stress-affected cell survival and partly reversed reduced doublecortin expression. Taken together, these data show that agomelatine has beneficial effects on hippocampal neurogenesis in the CMS paradigm.

Chronic but not acute foot-shock stress leads to temporary suppression of cell proliferation in rat hippocampus

Stressful experiences, especially when prolonged and severe are associated with psychopathology and impaired neuronal plasticity. Among other effects on the brain, stress has been shown to negatively regulate hippocampal neurogenesis, and this effect is considered to be exerted via glucocorticoids. Here, we sought to determine the temporal dynamics of changes in hippocampal neurogenesis after acute and chronic exposure to foot-shock stress. Rats subjected to a foot-shock procedure showed strong activation of the hypothalamic–pituitary–adrenal (HPA) axis, even after exposure to daily stress for 3 weeks. Despite a robust release of corticosterone, acute foot-shock stress did not affect the rate of hippocampal cell proliferation. In contrast, exposure to foot-shock stress daily for 3 weeks led to reduced cell proliferation 2 hours after the stress procedure. Interestingly, this stress-induced effect did not persist and was no longer detected 24 hours later. Also, while chronic foot-shock stress had no impact on survival of hippocampal cells that were born before the stress procedure, it led to a decreased number of doublecortin-positive granule neurons that were born during the chronic stress period. Thus, whereas a strong activation of the HPA axis during acute foot-shock stress is not sufficient to reduce hippocampal cell proliferation, repeated exposure to stressful stimuli for prolonged period of time ultimately results in dysregulated neurogenesis. In sum, this study supports the notion that chronic stress may lead to cumulative changes in the brain that are not seen after acute stress. Such changes may indicate compromised brain plasticity and increased vulnerability to neuropathology.

Impact of the PSA-NCAM system on pathophysiology in a chronic rodent model of temporal lobe epilepsy

Polysialylation is a posttranslational modification of the neural cell adhesion molecule (NCAM). In the adult brain, polysialylated NCAM (PSA-NCAM) is restricted to regions of neurogenesis and neuroplasticity, where PSA promotes plastic changes. Because a variety of plastic changes including neurogenesis have been suggested to be functionally involved in the pathophysiology of epilepsies, it is of specific interest to define the impact of the PSA-NCAM system on development and progression of this disease and associated comorbidities. Here, we studied the impact of transient enzymatic depolysialylation of NCAM on the pathophysiology in the amygdala kindling model, a chronic rodent model of temporal lobe epilepsy. The investigations focused on seizure-induced neurogenesis, seizure progression, and on the development of kindling-associated changes in behavior and cognition. Loss of PSA decreased the number of hippocampal newborn cells that incorporated BrdU during the kindling process and the number of new neurons that were ectopically located in the hilus. The persistence of basal dendrites has been suggested to be a hallmark of newborn granule cells in the epileptic brain. Loss of PSA increased the number of cells with persistent basal dendrites. The modification of the hippocampal cell proliferation rate and the fate of newborn neurons which occurred as a consequence of PSA removal did not affect the generation of a hyperexcitable kindled network or associated behavioral changes. Kindling progression was comparable in rats with and without removal of PSA. In contrast, loss of PSA increased acute seizure susceptibility as indicated by reduced seizure thresholds before kindling. The data indicate that hippocampal proliferation rates and ectoptic hilar newborn neurons are less critical for epileptic network generation. The PSA-NCAM system was not substantiated as a target for antiepileptogenic strategies. However, its impact on ectopic newborn neurons gives evidence that modulation of PSA-NCAM function may be a strategy to promote neuroregeneration in different central nervous system insults.

Exposure to environmental enrichment elicits differential hippocampal cell proliferation: Role of individual responsiveness to anxiety

Environmental enrichment (EE) is a largely employed behavioral procedure in which animals are exposed to high stimulation compared with conventional housing conditions. Animal exposure to an EE exerts beneficial effects on the performance of different learning tasks and induces a number of behavioral, neurochemical, and neuroanatomical changes including hippocampal cell proliferation. However, the importance of voluntary interaction with the environment in these changes has not been clearly resolved yet. Moreover, the effects of a complex environment on animal emotionality still remains questionable and has not been explored in detail under conditions that allow unmasking individual responses among subjects in a group. The present study was aimed at exposing groups of rats to an EE, and analyzing individual differences in activity levels during EE sessions. We observed differences with respect to the activity level displayed by rats during the enriched sessions, which correlated with differences in the rate of hippocampal cell proliferation. It is suggested that exposure to EE may reduce anxiety-like behaviors and may elicit individual differences on emotional reactions positively linked with hippocampal neurogenesis and testosterone levels.

P.1.128 Depressive symptoms and suicidal ideationamong college students: A study of 752 students in the Boston area

The antidepressant agomelatine is a MT1/MT2 receptor agonist and 5-HT2C antagonist. Its antidepressant activity is proposed to result from the synergy between these sets of receptors. Agomelatine-induced changes in the brain have been reported under basal conditions. Yet, little is known about its effects in the brain exposed to chronic stress as a risk factor for major depressive disorder. Recently, we described agomelatine-induced changes on neuronal activity and adult neurogenesis in the hippocampus of rats subjected to chronic footshock stress. In order to better characterize the actions of agomelatine in the stress-compromised brain, here we investigated its effects on hippocampal neurogenesis in the chronic mild stress (CMS) model. Adult male rats were subjected to various mild stressors for 5 weeks, and treated with agomelatine during the last 3 weeks of the stress period. The sucrose preference test was performed weekly to measure anhedonia, and the marble burying test was carried out at the end of the experiment to assess anxiety-like behavior. In our model, the CMS paradigm did not change sucrose preference; however, it increased marble burying behavior, indicating enhanced anxiety. Interestingly, this stress model differentially affected distinct stages of the neurogenesis process. Whereas CMS did not influence the rate of hippocampal cell proliferation, it significantly decreased the newborn cell survival and doublecortin expression in the dentate gyrus. Importantly, treatment with agomelatine completely normalized stress-affected cell survival and partly reversed reduced doublecortin expression. Taken together, these data show that agomelatine has beneficial effects on hippocampal neurogenesis in the CMS paradigm.

Basal and stress-induced differences in HPA axis, 5-HT responsiveness, and hippocampal cell proliferation in two mouse lines.

To characterize individual differences in neuroendocrine and neurochemical correlates of stress coping, two lines of wild house mice were studied. These mice are genetically selected for high and low aggression and show distinctly different behavioral strategies toward environmental stimuli. Long attack latency (LAL), low aggressive mice display a passive coping style, whereas short attack latency (SAL), high aggressive mice show an active coping style. It was hypothesized that this difference in behavioral coping style is associated with differences in stress system reactivity. This was tested by investigating the regulation of the hypothalamus-pituitary-adrenal (HPA) axis and the serotonin (5-HT) system and hippocampal cell proliferation rate in these mice under baseline and stress conditions. Baseline corticosterone output in LAL mice was found to be more sensitive to adrenocorticotropic hormone, but showed less day/night variation than in SAL mice. Furthermore, LAL mice showed lower hippocampal 5-HT(1A) receptor gene expression and function. Basal hippocampal cell proliferation rate was slightly lower in LAL than in SAL mice. Exposure to acute stress (forced swimming for 5 min) resulted in a hyper-reactive HPA response, a reduced increase in brain 5-HT metabolism, and an almost 50% reduction in hippocampal cell proliferation rate in LAL compared with SAL mice. Chronic psychosocial stress (sensory contact stress) induced long-lasting changes in the HPA axis in LAL, but not in SAL mice. In conclusion, these studies show that a genetic trait in behavioral coping style in wild house mice is associated with differences in HPA regulation, 5-HT neurotransmission, and hippocampal cell proliferation rate. The results further indicate that LAL mice have a higher stress responsivity than SAL mice. These results may have implications for a differential susceptibility for stress-related mood disorders.