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Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression in three of the most widely used mouse strains: Balb/c, C57BL/6 and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in woman and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39,5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression.Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain.

Rewarding social behaviors including positive social interactions and sexual behaviors are shown to regulate adult neurogenesis, but the underlying biological mechanisms remain elusive. Oxytocin, a neurohypophysial hormone secreted after exposure to social interaction or sexual behaviors, has a profound role in the formation of social bonding and regulation of emotional distress. While the acute effect of oxytocin was usually studied, relatively scarce evidence showed the behavioral consequence of repeated oxytocin treatment. The purpose of the current study was to investigate the effect of repeated oxytocin treatment on hippocampal cell proliferation, dendritic maturation of new born neurons and social/emotional behaviors. Adult male Sprague–Dawley rats received treatment with either vehicle or oxytocin (1 mg/kg) daily for two weeks. Behavioral tests revealed that oxytocin increased social behaviors and reduced the anxiety- and depression-like behaviors. Cell proliferation, differentiation and the dendritic complexity of new born neurons in the hippocampus were promoted by oxytocin treatment. Depression- and anxiety-like behaviors were induced by repeated treatment of corticosterone (40 mg/kg) for two weeks while oxytocin treatment reversed the behavioral disturbances. Suppression of cell proliferation caused by corticosterone was reverted by oxytocin treatment in which cell proliferation, cell differentiation, and dendritic complexity increased. The present findings reveal that oxytocin not only enhances cell proliferation, but also promotes the development of the new neurons which is associated with the induction of positive emotional and social behaviors. The results also suggest that oxytocin may be a potential therapeutic agent for treatment of emotional and social dysfunction. [ABSTRACT FROM AUTHOR]

Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain. [ABSTRACT FROM AUTHOR]

Despite an increasing amount of evidence about the regulation of adult hippocampal neurogenesis on the local level, less attention has been paid to its systemic embedding in wider brain circuits. The aim of the present study was to obtain evidence for a potential role of the prefrontal cortex in the regulation of adult hippocampal neurogenesis. We hypothesised that activation of the prefrontal cortex by environmental enrichment or a working-memory task would decrease previously enhanced cell proliferation rates. Wheel running was applied as a common stimulator of cell proliferation in CD1 mice reared under deprivation of natural environmental stimulation. Next, the animals were assigned to four groups for different treatments in the following three days: housing under continued deprivation, environmental enrichment, a spatial-delayed alternation task in an automated T-maze that activates the prefrontal cortex by working-memory requirements or a control task in the automated T-maze differing only in the single parameter working-memory-associated delay. Both the environmental enrichment and spatial-delayed alternation tasks decreased cell proliferation rates in the dentate gyrus compared to deprived housing and the control task in the T-maze. As the control animals underwent the same procedures and stressors and differed only in the single parameter working-memory-associated delay, the working-memory requirement seems to be the crucial factor for decreasing cell proliferation rates. Taken together, these results suggest that the prefrontal cortex may play a role in the regulation of hippocampal cell proliferation. [ABSTRACT FROM AUTHOR]

Environmental factors can significantly affect disease prevalence, including neuropsychiatric disorders such as depression. The ratio of deuterium to protium in water shows substantial geographical variation, which could affect disease susceptibility. Thus the link between deuterium content of water and depression was investigated, both epidemiologically, and in a mouse model of chronic mild stress. We performed a correlation analysis between deuterium content of tap water and rates of depression in regions of the USA. Next, we used a 10-day chronic stress paradigm to test whether 2-week deuterium-depleted water treatment (91 ppm) affects depressive-like behavior and hippocampal SERT. The effect of deuterium-depletion on sleep electrophysiology was also evaluated in naïve mice. There was a geographic correlation between a content of deuterium and the prevalence of depression across the USA. In the chronic stress model, depressive-like features were reduced in mice fed with deuterium-depleted water, and SERT expression was decreased in mice treated with deuterium-treated water compared with regular water. Five days of predator stress also suppressed proliferation in the dentate gyrus; this effect was attenuated in mice fed with deuterium-depleted water. Finally, in naïve mice, deuterium-depleted water treatment increased EEG indices of wakefulness, and decreased duration of REM sleep, phenomena that have been shown to result from the administration of selective serotonin reuptake inhibitors (SSRI). Our data suggest that the deuterium content of water may influence the incidence of affective disorder-related pathophysiology and major depression, which might be mediated by the serotoninergic mechanisms. [ABSTRACT FROM AUTHOR]

Optical fractionators have dominated the field of neural cell counting for two decades. These unbiased stereological techniques are often used for the quantification of hippocampal cell proliferation in neurogenesis experiments. However the heterogeneous distribution of labeled cells, especially in the form of clusters, confounds the application of these techniques. A critical evaluation of the applicability of the optical fractionator suggests that absolute counting achieves higher efficiency in the quantification of cell proliferation than unbiased estimations.

Highlights: [•] Maternal exposure to titanium dioxide nanoparticles declines cell proliferation in the offspring hippocampus. [•] Maternal exposure to titanium dioxide nanoparticles significantly impairs memory in the offspring. [•] Maternal exposure to titanium dioxide nanoparticles significantly impairs spatial memory in the offspring. [ABSTRACT FROM AUTHOR]

Abstract: The neurobiological mechanisms underlying the pathophysiology and therapeutics of bipolar disorder are still unknown. In recent years, protein kinase C (PKC) has emerged as a potential key player in mania. To further investigate the role of this signaling system in mood regulation, we examined the effects of PKC modulators in behavioral tests modeling several facets of bipolar disorder and in adult hippocampal cell proliferation in rats. Our results showed that a single injection of the PKC inhibitors tamoxifen (80mg/kg, i.p.) and chelerythrine (3mg/kg, s.c.) attenuated amphetamine-induced hyperlocomotion and decreased risk-taking behavior, supporting the efficacy of PKC blockade in acute mania. Moreover, chronic exposure to tamoxifen (10mg/kg/day, i.p., for 14days) or chelerythrine (0.3mg/kg/day, s.c., for 14days) caused depressive-like behavior in the forced swim test, and resulted in a reduction of cell proliferation in the dentate gyrus of the hippocampus. Finally, we showed that, contrary to the PKC inhibitors, the PKC activator phorbol 12-myristate 13-acetate (PMA) enhanced risk-taking behavior and induced an antidepressant-like effect. Taken together, these findings support the involvement of PKC in regulating opposite facets of bipolar disorder, and emphasize a major role for PKC in this disease. [Copyright &y& Elsevier]

Abstract: Previous studies have shown that a 2-week treatment with 40mg/kg corticosterone (CORT) in rats suppresses hippocampal neurogenesis and decreases hippocampal brain-derived neurotrophic factor (BDNF) levels and impairs spatial learning, all of which could be counteracted by voluntary wheel running. BDNF and insulin-like growth factor (IGF-1) have been suggested to mediate physical exercise-enhanced hippocampal neurogenesis and cognition. Here we examined whether such running-elicited benefits were accompanied by corresponding changes of peripheral BDNF and IGF-1 levels in a rat model of stress. We examined the effects of acute (5days) and chronic (4weeks) treatment with CORT and/or wheel running on (1) hippocampal cell proliferation, (2) spatial learning and memory and (3) plasma levels of BDNF and IGF-1. Acute CORT treatment improved spatial learning without altered cell proliferation compared to vehicle treatment. Acute CORT-treated non-runners showed an increased trend in plasma BDNF levels together with a significant increase in hippocampal BDNF levels. Acute running showed no effect on cognition, cell proliferation and peripheral BDNF and IGF-1 levels. Conversely, chronic CORT treatment in non-runners significantly impaired spatial learning and suppressed cell proliferation in association with a decreased trend in plasma BDNF level and a significant increase in hippocampal BDNF levels. Running counteracted cognitive deficit and restored hippocampal cell proliferation following chronic CORT treatment; but without corresponding changes in plasma BDNF and IGF-1 levels. The results suggest that the beneficial effects of acute stress on cognitive improvement may be mediated by BDNF-enhanced synaptic plasticity that is hippocampal cell proliferation-independent, whereas chronic stress may impair cognition by decreasing hippocampal cell proliferation and BDNF levels. Furthermore, the results indicate a trend in changes of plasma BDNF levels associated with a significant alteration in hippocampal levels, suggesting that treatment with running/CORT for 4 weeks may induce a change in central levels of hippocampal BDNF level, which may not lead to a significant change in peripheral levels. [Copyright &y& Elsevier]

Abstract: Although controversial, estrogen replacement therapy has been implicated as a possible therapeutic agent for ameliorating age-related cognitive decline in postmenopausal women. We have shown previously that different types of estrogen promote hippocampal neurogenesis in a dose-dependent manner in young adult female rats. However, previous studies have not found a beneficial effect of 17β-estradiol in middle-aged female rats. The aim of the present study was to determine the acute effects of 17β-estradiol, 17α-estradiol, and estrone on hippocampal cell proliferation in middle-aged ovariectomized female rats and to determine whether effects are dependent on previous reproductive experience. Middle-aged multiparous female rats or age-matched virgin female rats were injected subcutaneously with vehicle or 10μg dose of 17β-estradiol, 17α-estradiol, or estrone, and then given BrdU 30min later and perfused 24h later to assess cell proliferation. All estrogens significantly upregulated cell proliferation in the hippocampus in middle-aged multiparous females but none of the estrogens upregulated cell proliferation in the middle-aged virgins. Therefore, previous reproductive experience may make the older brain more responsive to estrogens later in life. We also found that 17α-estradiol upregulated cell proliferation to a greater degree than the other estrogens in the multiparous females. Together these findings may lead to the development of new therapeutic advances in the treatment of symptoms associated with menopause in women. [Copyright &y& Elsevier]

Abstract: There is evidence that depression may have a different neural basis at different ages. Although chronic stress and elevated glucocorticoid levels have been demonstrated to lead to the emergence of mood disorders, it remains unclear how moderate elevation of glucocorticoid levels in young animals influences depression-like behaviors and brain functions. To address this issue, the present study examines how chronic corticosterone (CORT) administration during adolescence and early adulthood influences depression-like behaviors, hypothalamic–pituitary–adrenal (HPA) axis response and hippocampal cell proliferation. Male mice were chronically administrated with CORT drinking water (20mg/L) during adolescence. After two months of treatment, serum CORT levels were measured using enzyme immunoassay. Hippocampal glucocorticoid and mineralocorticoid receptors were characterized using Western blot. Tail suspension and forced swim tests were used to assess depression-related behaviors in mice. Immunohistochemistry was performed to measure bromodeoxyuridine (BrdU) incorporation in order to assess cell proliferation in the hippocampus. Our results suggest that chronic CORT administration induced a mild but not significant elevation in basal CORT levels and attenuated the physiological responses to stress. Chronic CORT administration also reduced expression of the hippocampal mineralocorticoid receptor and decreased immobility time in both the tail suspension test and the forced swim test. Moreover, chronic CORT administration increased the BrdU immunoreactivities in the hippocampus. Taken together, these findings suggest that chronic mild elevation by CORT administration during the adolescence and early adulthood attenuates depression-like behaviors. [Copyright &y& Elsevier]

Agomelatine is a novel antidepressant which acts as a melatonergic (MT1/MT2) receptor agonist and serotonergic (5-HT2C) receptor antagonist. The antidepressant properties of agomelatine have been demonstrated in animal models as well as in clinical studies. Several preclinical studies reported agomelatine-induced effects on brain plasticity, mainly under basal conditions in healthy animals. Yet, it is important to unravel agomelatine-mediated changes in the brain affected by psychopathology or exposed to conditions that might predispose to mood disorders. Since stress is implicated in the etiology of depression, it is valid to investigate antidepressant-induced effects in animals subjected to chronic stress. In this context, we sought to determine changes in the brain after agomelatine treatment in chronically stressed rats. Adult male rats were subjected to footshock stress and agomelatine treatment for 21 consecutive days. Rats exposed to footshock showed a robust increase in adrenocorticotropic hormone (ACTH) and corticosterone. Chronic agomelatine treatment did not markedly influence this HPA-axis response. Whereas chronic exposure to daily footshock stress reduced c-Fos expression in the hippocampal dentate gyrus, agomelatine treatment reversed this effect and normalized neuronal activity to basal levels. Moreover, chronic agomelatine administration was associated with enhanced hippocampal cell proliferation and survival in stressed but not in control rats. Furthermore, agomelatine reversed the stress-induced decrease in doublecortin expression in the dentate gyrus. Taken together, these data show a beneficial action of agomelatine in the stress-compromised brain, where it restores stress-affected hippocampal neuronal activity and promotes adult hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Methotrexate is a widely used cytostatic in chemotherapy cocktails for the treatment of cancer but is associated with cognitive impairment. Previous animal studies indicated that methorexate decreases hippocampal cell proliferation, which might contribute to the observed cognitive impairment. However, clinical studies have shown that cognitive impairment can also be noticed in some cancer patients before any systemic treatment is initiated. We aim in the present study to discern whether hippocampal cell proliferation is negatively affected by tumor growth and if the presence of a tumor amplifies the effects of methotrexate. Buffalo rats were subcutaneously injected with PBS or Morris Hepatoma 7777 cells to induce a tumor. Two weeks after this injection the animals received an intraperitoneal injection of methotrexate or saline. Three weeks later hippocampal cell proliferation was quantified using immunohistochemical staining. Treatment with Morris Hepatoma 7777 cells decreased the number of proliferating cells as compared to control animals. An overall tumor effect was absent mainly because methotrexate treatment significantly decreased cell proliferation with no differences between animals with or without a tumor. Neither methotrexate nor the tumor induced pica behavior. These findings indicate that although the presence of a tumor reduces hippocampal cell proliferation it does not affect the negative effect of methotrexate on this plasticity marker. Since sickness behavior is not induced by methotrexate or tumor presence it does not play a role in the development of cognitive deficits. This study further indicates that the effects of methotrexate on brain and behavior can be studied in healthy animals. [Copyright &y& Elsevier]

Abstract: Methotrexate (MTX) is a cytostatic agent used in adjuvant chemotherapy for treatment of breast cancer and is associated with cognitive impairment in a subgroup of patients. The aim of this paper is to test whether MTX can rapidly affect various brain structures resulting in decreased hippocampal cell proliferation and white matter damage. We also studied whether cell death occurs in the hippocampus following MTX. All these processes may contribute to the memory deficits reported in patients. The first study explored the effect of an intravenously injected high-dose MTX (250mg/kg) on hippocampal cell proliferation, white matter, and cell death. Proliferation was not significantly decreased 1 day after administration of MTX, although a high individual variation was seen. However, 7 days after MTX treatment hippocampal cell proliferation was significantly lower compared to control animals. White matter density was decreased in the lateral corpus callosum of animals treated with MTX, 1 day, 1 week, and 3 weeks after treatment. MTX did not induce hippocampal cell death at any of the time intervals after treatment. The second study examined the effect of MTX on memory by subjecting animals to a learning task directly followed with MTX treatment. In both learning tasks, memory was impaired in treated animals. In the Morris water maze, animals treated with MTX spent significantly less time in the correct quadrant compared to control animals during the probe trial which was performed 1 week after training and treatment. In contextual fear conditioning, animals treated with MTX showed significantly less freezing behavior compared to control animals, 4 weeks after training and treatment. These studies suggest that the negative effect of MTX on hippocampal cell proliferation and white matter density may be part of the mechanisms underlying the cognitive impairment observed as side effect after cytotoxic treatment in humans. [Copyright &y& Elsevier]

Methotrexate (MTX) is a drug widely used for chemotherapy and can reduce cancer cell production by inhibiting dihydrofolate reductase and decreasing cancer cell growth. MTX has a neurotoxic effect on neural stem and glial cells, leading to memory deficits. Chrysin is a natural flavonoid that contains essential biological activities, such as neuroprotective and cognitive-improving properties. Therefore, the aim of the present study was to investigate the protective effect of chrysin against MTX-induced memory impairments related to hippocampal neurogenesis. Seventy-two male Sprague Dawley rats were divided into six groups: control, MTX, chrysin (10 and 30 mg/kg), and MTX+ chrysin (10 and 30 mg/kg) groups. Chrysin (10 and 30 mg/kg) was administered by oral gavage for 15 days. MTX (75 mg/kg) was administered by intravenous injection on days 8 and 15. Spatial and recognition memories were evaluated using the novel object location (NOL) and novel object recognition (NOR) tests, respectively. Moreover, cell proliferation, neuronal cell survival, and immature neurons in the subgranular zone of the hippocampal dentate gyrus were quantified by Ki-67, bromodeoxyuridine/neuronal nuclear protein (BrdU/NeuN), and doublecortin (DCX) immunohistochemistry staining. The results of the MTX group demonstrated that spatial and recognition memories were both impaired. Furthermore, cell division reduction, neuronal cell survival reduction, and immature neuron decreases were detected in the MTX group and not observed in the co-administration groups. Therefore, these results revealed that chrysin could alleviate memory and neurogenesis impairments in MTX-treated rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflicts of Interest There was no competing interest to express., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania. Methods: Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control. Results: We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD. Conclusions: Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties. [ABSTRACT FROM AUTHOR]

Background: Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania., Methods: Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72 h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control., Results: We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD., Conclusions: Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)