Nelly Maritza Vega-Rivera

Melatonin supplementation delays the decline of adult hippocampal neurogenesis during normal aging of mice

Melatonin modulates adult hippocampal neurogenesis in adult mice. Also, plasma melatonin levels and new neuron formation decline during aging probably causing cognitive alterations. In this study, we analyzed the impact of exogenous supplementation with melatonin in three key events of hippocampal neurogenesis during normal aging of mice. The analysis was performed in rodents treated with melatonin during 3, 6, 9 or 12 months. We found an increase in cell proliferation in the dentate gyrus of the hippocampus after 3, 6 and 9 months of treatment (>90%). Additionally, exogenous melatonin promoted survival of new cells in the dentate gyrus (>50%). Moreover, melatonin increased the number of doublecortin-labeled cells after 6 and 9 months of treatment (>150%). In contrast, melatonin administered during 12 months did not induce changes in hippocampal neurogenesis. Our results indicate that melatonin also modulates the neurogenic process in the hippocampus during normal aging of mice. Together, the data support melatonin as one of the positive endogenous regulators of neurogenesis during aging.

Antidepressant effects of estrogens: a basic approximation

The use of estrogenic compounds as antidepressants or as coadjuvants to facilitate the effect of antidepressants has reported controversial results, suggesting that many factors could influence their actions. This review analyzes, from a basic research perspective, the possible factors that may underlie the antidepressant action of estrogens alone or in combination. The possible mechanisms of action of estrogens alone and in combination with the selective serotonin reuptake inhibitor, fluoxetine, the selective noradrenaline reuptake inhibitor, desipramine, and the mixed serotonin/noradrenaline reuptake inhibitor, venlafaxine are reviewed, focusing on monoaminergic systems and estrogen receptors as main targets. The antidepressant effect of estrogens depends on the type of estrogen, treatment duration, doses, sex, time after ovariectomy, and age. Estrogens potentiate the antidepressant-like action of fluoxetine, venlafaxine, and desipramine and drastically shorten their latency of action. The antidepressant-like effect of estrogens alone or in combination with antidepressants seems to be mediated by monoaminergic and classic estrogen receptors, as WAY100635, an antagonist to the serotonin 1A receptor, idaxozan, an antagonist to α2 adrenergic receptors, and RU 58668, an estrogen receptor antagonist, blocked their antidepressant-like effect. In conclusion, estrogens produce antidepressant-like actions by themselves and importantly facilitate the action of clinically used antidepressants.

Environmental enrichment induces neuroplastic changes in middle age female BalbC mice and increases the hippocampal levels of BDNF, p-Akt and p-MAPK1/2

Hippocampus is one of the brain regions in which neuroplastic changes occur. Paradigms such as environmental enrichment (ENR) have been used to prevent or delay the neuroplastic changes of the hippocampus during aging. Here, we investigated the beneficial effects of ENR on dendritic spines and hippocampal neurogenesis in middle age Balb/c mice. ENR increased the number of dendritic spines, cell survival, and intermediate stages of the hippocampal neurodevelopment process. Also, ENR alters the distribution of cells involved in the neurogenic process along the dorsal-ventral dentate gyrus. In addition, ENR increased the proportion of cells with more mature dendritic morphology and net hippocampal neurogenesis. Whole-hippocampus protein extracts revealed that ENR increases the levels of BDNF, phospho-Akt and phospho-MAPK1/2, suggesting that the positive effects of ENR on neuroplasticity in middle age Balb/c mice involve the participation of these key-signaling proteins. Our results suggest that ENR is a relevant strategy to prevent neuroplastic decline by increasing the formation of both dendritic spines and new neurons in the hippocampus during middle age.

Melatonin synergizes with citalopram to induce antidepressant‐like behavior and to promote hippocampal neurogenesis in adult mice

Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive‐like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14–33%) and citalopram (<17–30%). Additionally, the MLTCITAL combination also decreased immobility (<22–35%) in comparison with control mice, reflecting an antidepressant‐like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of ‐associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant‐like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

Acute stress further decreases the effect of ovariectomy on immobility behavior and hippocampal cell survival in rats

Most studies relating experimental depression and neurogenesis use mainly male rodents subjected to models of chronic stress. The forced swimming test (FST) is a widely utilized model of acute stress, but its effects on the neurogenic process in the hippocampus using females in different endocrine conditions has not been explored. The aim of this study was to evaluate the cell proliferation and early-, short- and long-lasting effects of forced swimming (FS) on adult hippocampal neurogenesis in rats in two endocrine conditions: proestrous and ovariectomized. To determine cell proliferation we used the endogenous marker Ki67. Cell survival was established with the thymidine analog, BrdU (75mg/kg, 2/12, i.p.), which was administered before FS to proestrous and ovariectomized rats. FS increased immobility and corticosterone levels in OVX but not in rats in proestrus. In addition, FS did not affect cell proliferation but significantly decreased the number of BrdU-labeled cells at 2h only in OVX-rats, an effect that remained for 3 and 14 days after FS. Data are discussed taking into consideration the relationship between gonadal and adrenal hormones in adult hippocampal neurogenesis in adult females. Our data also support the use of FS as a model for studying neurogenesis.

Resveratrol Enhances Neuroplastic Changes, Including Hippocampal Neurogenesis, and Memory in Balb/C Mice at Six Months of Age.

Resveratrol (RVTL) is a flavonoid found in red wine and has been publicized heavily as an anti-aging compound. Indeed, basic research confirms that although there is much hype in the promotion of RVTL, flavonoids such as RVTL have a wide range of biological effects. We here investigated the effects of RVTL treatment on hippocampal plasticity and memory performance in female Balb/C mice, a strain with low baseline levels of adult neurogenesis. Two weeks of treatment with RVTL (40 mg/kg) induced the production of new neurons in vivo by increasing cell survival and possibly precursor cell proliferation. In addition, RVTL decreased the number of apoptotic cells. The number of doublecortin (DCX)-expressing intermediate cells was increased. RVTL stimulated neuronal differentiation in vitro without effects on proliferation. In the dentate gyrus, RVTL promoted the formation and maturation of spines on granule cell dendrites. RVTL also improved performance in the step down passive avoidance test. The RVTL-treated mice showed increase in the levels of two key signaling proteins, phospho-Akt and phospho-PKC, suggesting the involvement of these signaling pathways. Our results support the vision that flavonoids such as resveratrol deserve further examination as plasticity-inducing compounds in the context of successful cognitive aging.

The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test.

17α-Ethynyl-estradiol (EE2, a synthetic steroidal estrogen) induces antidepressant-like effects in the forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors (dual antidepressants). However, the precise mechanism of action of EE2 has not been studied. In the present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic presynaptic sites in the antidepressant-like action of EE2 was evaluated in the FST. The effects of the ER antagonist ICI 182,780 (10 μg/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction with 5,7-dihydroxytryptamine (5,7-DHT; 200 μg/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine (DSP4; 10mg/kg, i.p.) were studied in ovariectomized rats treated with EE2 and subjected to the FST. In addition, the participation of α2-adrenergic receptors in the antidepressant-like action of EE2 was explored using the selective α2-receptor antagonist idazoxan (0.25, 0.5 and 1.0mg/kg, i.p.). EE2 induced an antidepressant-like action characterized by a decrease in immobility behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-DHT, DSP4, and idazoxan blocked the effects of EE2 on the immobility behavior, whereas ICI 182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP4 altered climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced by EE2. Our results suggest that the antidepressant-like action of EE2 implies a complex mechanism of action on monoaminergic systems and estrogen receptors.

The neurogenic effects of an enriched environment and its protection against the behavioral consequences of chronic mild stress persistent after enrichment cessation in six-month-old female Balb/C mice.

Because stress may underlie the presence of depressive episodes, strategies to produce protection against or to reverse the effects of stress on neuroplasticity and behavior are relevant. Preclinical studies showed that exposure to stimuli, such as physical activity and environmental enrichment (ENR), produce beneficial effects against stress causing antidepressant-like effects in rodents. Additionally, ENR induces positive effects on neuroplasticity, neurochemistry and behavior at any age of rodents tested. Here, we analyzed whether ENR exposure prevents the development of depressive-like behavior produced by unpredictable, chronic mild stress (CMS) exposure as well as changes in hippocampal neurogenesis in a six-month-old female Balb/C mice, strain that shows low baseline levels of hippocampal neurogenesis. Mice were assigned to one of four groups: (1) normal housing-normal housing (NH-NH), (2) NH-CMS, (3) ENR-NH, or (4) ENR-CMS. The animals were exposed over 46 days to ENR or NH and subsequently to NH or CMS for 4 weeks. ENR induces long-term effects protecting against CMS induction of anhedonia and hopelessness behaviors. Independent of housing conditions, ENR increased the number of proliferative cells (Ki67), and CMS decreased the number of proliferative cells. ENR increased the newborn cells (BrdU) and mature phenotypes of neurons; these effects were not changed by CMS exposure. Similarly, the number of doublecortin-positive cells was not affected by CMS in ENR mice, which showed more cells with complex dendrite arborizations. Our study suggests that ENR induces protection against the effects of CMS on behavior and neuroplasticity in six-month-old Balb/C mice.

Forced swim and chronic variable stress reduced hippocampal cell survival in OVX female rats.

Stress and glucocorticoids induce effects on neuronal and behavioral function. These effects may depend on the study design and importantly on the nature and duration of the stressor. We have previously observed that a single exposure to the forced swim test (FST) caused long-lasting effects on the HPA axis response and hippocampal cell survival. In despite that the FST and the chronic variable stress (CVS) paradigm are not strictly comparable; the aim of this study was to compare their effects on the respective depressive-like behavior, the serum corticosterone levels and cell proliferation and survival in ovariectomized female rats. Cell proliferation was determined by Ki67-labeling, while cell survival was analyzed with BrdU, a thymidine analog. The results showed that FST increased immobility and corticosterone levels at the same time that it decreased cell survival without modifying cell proliferation. In contrast, after 5 weeks of CVS there was a sharp reduction in sucrose intake, cell proliferation and survival, but a lack of effect on corticosterone levels. The FST produced a reduction on newborn cell survival analogous to that exerted by CVS. These data suggest that the FST could be considered as an attractive model to study some kind of stress-related disorders.

Effect of sub-optimal doses of fluoxetine plus estradiol on antidepressant-like behavior and hippocampal neurogenesis in ovariectomized rats.

Estrogens and antidepressants synergize to reduce depressive symptoms and stimulate neurogenesis and neuroplastic events. The aim of this study was to explore whether the antidepressant-like effect induced by the combination of low doses of estradiol (E2) and fluoxetine (FLX) involves changes in cell proliferation, early survival, morphology and dendrite complexity of hippocampal new-immature neurons. The antidepressant-like effects of E2 and/or FLX were evaluated by the forced swimming test (FST), cell proliferation was determined with the endogenous marker Ki67, survival of newborn cells was established with bromo-deoxiuridine (BrdU) and immature neurons were ascertained by doublecortin (DCX) labeling while their dendrite complexity was evaluated with Sholl analysis. Ovariectomized Wistar rats were randomly assigned to one of the following groups: Vehicle (saline/14 days+Oil/-8h before FST); E2 (saline/14 days + E2 2.5 or 10 μg/rat; -8 h before FST); FLX (1.25 or 10 mg/kg for 14 days + oil -8h before FST), and FLX plus E2 (FLX 1.25 mg/kg for 14 days + E2 2.5 μg/rat -8 h before FST). The combination of sub-threshold doses of FLX plus E2 produced antidepressant-like actions similar to those induced by FLX or E2 given independently at optimal doses. Only FLX at an optimal dose and the combination of FLX plus E2 increased cell proliferation, the number of DCX-labeled immature neurons and the complexity of their dendritic tree, suggesting that these events may be responsible for their antidepressant-like effect.