Self-Stimulation Rewarding Experience Restores Stress-Induced CA3 Dendritic Atrophy,Spatial Memory Deficits and Alterations in the Levels of Neurotransmitters in the Hippocampus

Chronic restraint stress causes spatial learning and memory deficits, dendritic atrophy of the hippocampal pyramidal neurons and alterations in the levels of neurotransmitters in the hippocampus. In contrast, intracranial self-stimulation (ICSS) rewarding behavioral experience is known to increase dendritic arborization, spine and synaptic density, and increase neurotransmitter levels in the hippocampus. In addition, ICSS facilitates operant and spatial learning, and ameliorates fornix-lesion induced behavioral deficits. Although the effects of stress and ICSS are documented, it is not known whether ICSS following stress would ameliorate the stress-induced deficits. Accordingly, the present study was aimed to evaluate the role of ICSS on stress-induced changes in hippocampal morphology, neurochemistry, and behavioral performance in the T-maze. Experiments were conducted on adult male Wistar rats, which were randomly divided into four groups; normal control, stress (ST), self-stimulation (SS), and stress + self-stimulation (ST + SS). Stress group of rats were subjected to restraint stress for 6 h daily over 21 days, SS group animals were subjected to SS from ventral tegmental area for 10 days and ST + SS rats were subjected to restraint stress for 21 days followed by 10 days of SS. Interestingly, our results show that stress-induced behavioral deficits, dendritic atrophy, and decreased levels of neurotransmitters were completely reversed following 10 days of SS experience. We propose that SS rewarding behavioral experience ameliorates the stress-induced cognitive deficits by inducing structural and biochemical changes in the hippocampus.     

Diffusion-weighted MRI and quantitative biophysical modeling of hippocampal neurite loss in chronic stress

Chronic stress has detrimental effects on physiology, learning and memory and is involved in the development of anxiety and depressive disorders. Besides changes in synaptic formation and neurogenesis, chronic stress also induces dendritic remodeling in the hippocampus, amygdala and the prefrontal cortex. Investigations of dendritic remodeling during development and treatment of stress are currently limited by the invasive nature of histological and stereological methods. Here we show that high field diffusion-weighted MRI combined with quantitative biophysical modeling of the hippocampal dendritic loss in 21 day restraint stressed rats highly correlates with former histological findings. Our study strongly indicates that diffusion-weighted MRI is sensitive to regional dendritic loss and thus a promising candidate for non-invasive studies of dendritic plasticity in chronic stress and stress-related disorders.     

Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress.     

Prolonged moderate elevation of corticosterone does not affect hippocampal anatomy or cell proliferation rates in mountain chickadees (Poecile gambeli)

Chronic stress and corresponding chronic elevations of glucocorticoid hormones have been widely assumed to have deleterious effects on brain anatomy and functions such as learning and memory. In particular, it has been suggested that chronic elevations of glucocorticoid hormones result in death of hippocampal neurons and in reduced rates of hippocampal neurogenesis. It is not clear, however, if any increase in glucocorticoid levels has negative effects on hippocampal anatomy as many animals regularly maintain moderately elevated levels of glucocrticoids over long periods of time under natural energetically demanding conditions. We used unbiased stereological methods to investigate whether mountain chickadees (Poecile gambeli) implanted for 49 days with continuous time-release corticosterone pellets, designed to approximately double the baseline corticosterone levels, differed from placebo-implanted chickadees in their hippocampal anatomy and cell proliferation rates. We found no significant differences between corticosterone and placebo-implanted birds in either telencephalon volume, volume of the hippocampal formation, or the total number of hippocampal neurons. Cell proliferation rates, measured as the total number of BrdU-labeled cells in the ventricular zone adjacent either to the hippocampus or to the mesopallium, were also not significantly different between corticosterone and placebo-implanted chickadees. Our results suggest that prolonged moderate elevation of corticosterone might not provide the suggested deleterious effects on hippocampal anatomy and neurogenesis in food-caching birds and, as we have shown previously, it actually enhances spatial memory.     

Estrogen-dependent modifications to hippocampal plasticity in paternal California mice (Peromyscus californicus)

In many biparental species, mothers and fathers experience similar modifications to circulating hormones. With these modifications come alterations in neural structure and function suggesting that neuroendocrine mechanisms may underlie postpartum plasticity in both males and females. In the biparental California mouse (Peromyscus californicus), adult neurogenesis is maintained and anxiety-like behavior is attenuated in fathers during the mid-postpartum period. Given a causal relationship between estrogen and regulation of both adult neurogenesis and anxiety, we aimed to elucidate the role of estrogen-dependent mechanisms in paternal experience-related modifications to hippocampal neuroplasticity in California mice. In Experiment 1, hippocampal estrogen receptor beta (ERβ) mRNA expression, along with circulating estradiol concentrations, were determined throughout the postpartum period. An upregulation in ERβ expression was observed in postnatal day 16 males compared to virgins. Additionally, a rise in circulating estradiol concentrations was detected on postnatal day 2 compared to virgins; levels began to decline toward virgin levels on postnatal day 16 and postnatal day 30. In Experiment 2, we determined the role of estrogen-dependent mechanisms in adult neurogenesis and anxiety-like behavior by treating virgin and paternal males with saline or the selective estrogen receptor modulator, tamoxifen (TMX), during the time of axon extension (i.e., one week after bromodeoxyuridine injection). While TMX failed to alter elevated plus maze performance, TMX treatment inhibited survival of adult born neurons but only in paternal mice. These findings highlight the potential for estrogen-dependent pathways to mediate hippocampal adult neurogenesis in paternal mice.     

Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats

Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats") showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.     

La dépression et le traitement antidépresseur: de la neurotoxicité à la neurogenèse

Major depressive disorder is characterized by structural and neurochemical changes in limbic structures, including the hippocampus that regulates mood and cognitive functions. Hippocampal atrophy is observed in patients with depression: structural changes in the hippocampus associated with depression include dendritic atrophy, decreased adult neurogenesis and reduced volume. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, episodic verbal memory and emotions are altered in depression. Chronic stress exposure and depression leads to hippocampal atrophy and cell loss as well as to decreased expression of neurotrophic growth factors. All types of antidepressant drugs reverse or block the effects of stress. Chronic antidepressant administration upregulates neurogenesis and neuroplasticity in the adult hippocampus and these cellular responses are required for the effects of antidepressants in animal models of depression.     

Stress and the pregnant female: Impact on hippocampal cell proliferation, but not affective-like behaviors

Fifteen percent of women worldwide develop postpartum depression; however, many women also suffer from mood disorders during pregnancy. Our knowledge of how these stress-related disorders affect the neurobiology of the mother is very limited. In animal models, depressive-like behavior is often associated with repeated stress and alterations in adult neurogenesis in the hippocampus. However, research has yet to investigate the effect of stress on affective-like behavior and hippocampal neurogenesis in the pregnant female. The aim of the present study was to determine whether stress during gestation alters affective-like behaviors, corticosterone levels, and hippocampal cell proliferation and new cell survival in the pregnant female, and whether these effects differ from virgin females. Age-matched pregnant and virgin Sprague-Dawley rats were divided into two conditions: 1) stress and 2) control. Females in the stress condition were repeatedly restrained during gestation, and at matched time points in virgin females. Affective-like behaviors were assessed at the end of gestation, and at matched time points in virgin females. Results demonstrate that regardless of repeated restraint stress, pregnant females have increased anxiety-like behavior, decreased depressive-like behavior, and lower corticosterone levels, compared to non-stressed, and at times stressed, virgin females. In addition, stressed virgin females have lower levels of depressive-like behavior compared to control virgin females. Interestingly, hippocampal cell proliferation was increased in both virgin and pregnant females after stress. Understanding how stress affects the female during different reproductive states will aid in improving the health and well being of the mother and child.     

Rapid spinogenesis of pyramidal neurons induced by activation of glucocorticoid receptors in adult male rat hippocampus

Modulation of hippocampal synaptic plasticity by glucocorticoids has been attracting much attention, due to its importance in stress responses. Dendritic spines are essential for memory storage processes. Here, we investigated the effect of dexamethasone (DEX), a specific agonist of glucocorticoid receptor (GR), on density and morphology of dendritic spines in adult male rat hippocampus by imaging of Lucifer Yellow-injected spines in slices. The application of 100 nM DEX (stressful high concentration) induced rapid modulation of the density and morphology of dendritic spines in CA1 pyramidal neurons within 1h. The total spine density increased from 0.88 spines/microm (control) to 1.36 spines/microm (DEX-treated). DEX significantly increased the density of thin and mushroom type spines, however only a slight increase was observed for stubby and filopodium type spines. Because the presence of 10 microM cycloheximide, an inhibitor of protein synthesis, did not suppress the DEX effect, these responses are probably non-genomic. Western immunoblot analysis demonstrated the localization of classical type GR in Triton-insoluble synaptosomal fractions (enriched in postsynaptic membranes) from hippocampal slices, suggesting a possible action site of DEX at spines.     

A neurogenic theory of depression gains momentum

The rate of adult neurogenesis fluctuates in response to several environmental factors. Chronic stress, which can lead to neuronal apoptosis and dendritic atrophy, certainly affects the overall rate of neurogenesis in the adult brain. Depression, which arises from several causes, including chronically stressful situations, is known to correlate with altered hippocampal morphology. But is the link between depression and neuronal regeneration merely coincidental? Recent studies indicate that ingestion of antidepressants leads to increased neurogenesis in the hippocampus. However, the hippocampus is generally thought important for learning and memory-not for "mood" state-thus, there is much more to the story that requires clarification. Also, caveats abound in the interpretation of neurogenesis in the amelioration of depression; nonetheless, these results are quite intriguing and might point to better design and prediction of new-generation antidepressants.     

Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration.

Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. For example, both stress and chronic administration of corticosterone produce dendritic atrophy in hippocampal neurons (Woolley C, Gould E, McEwen BS. 1990. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225-231; Watanabe Y, Gould E, McEwen BS, 1992b. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588:341-345). Prefrontal cortex is also a target for glucocorticoids involved in the stress response (Meaney MJ, Aitken DH. 1985. [(3)H]Dexamethasone binding in rat frontal cortex. Brain Res 328:176-180); it shows neurochemical changes in response to stress (e.g., Luine VN, Spencer RL, McEwen BS. 1993. Effect of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function. Brain Res 616:55-70; Crayton JW, Joshi I, Gulati A, Arora RC, Wolf WA. 1996. Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex. Brain Res 728:260-262; Takao K, Nagatani T, Kitamura Y, Yamawaki S. 1997. Effects of corticosterone on 5-HT(1A) and 5-HT(2) receptor binding and on the receptor-mediated behavioral responses of rats. Eur J Pharmacol 333:123-128; Sandi C, Loscertales M. 1999. Opposite effects on NCAM expression in the rat frontal cortex induced by acute vs. chronic corticosterone treatments. Brain Res 828:127-134), and mediates many of the behaviors that are altered by chronic corticosterone administration (e.g., Lyons DM, Lopez JM, Yang C, Schatzberg AF. 2000. Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys. J Neurosci 20:7816-7821). To determine if glucocorticoid-induced morphological changes also occur in medial prefrontal cortex, the effects of chronic corticosterone administration on dendritic morphology in this corticolimbic structure were assessed. Adult male rats received s.c. injections of either corticosterone (10 mg in 250 microL sesame oil; n = 8) or vehicle (250 microL; n = 8) daily for 3 weeks. A third group of rats served as intact controls (n = 4). Brains were stained using a Golgi-Cox procedure and pyramidal neurons in layer II-III of medial prefrontal cortex were drawn; dendritic morphology was quantified in three dimensions. Sholl analyses demonstrated a significant redistribution of apical dendrites in corticosterone-treated animals: the amount of dendritic material proximal to the soma was increased relative to intact rats, while distal dendritic material was decreased relative to intact animals. Thus, chronic glucocorticoid administration dramatically reorganized apical arbors in medial prefrontal cortex. This reorganization likely reflects functional changes and may contribute to stress-induced changes in cognition.     

Exposure to social defeat stress in adolescence improves the working memory and anxiety-like behavior of adult female rats with intrauterine growth restriction,independently of hippocampal neurogenesis

Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR.     

Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration

Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. For example, both stress and chronic administration of corticosterone produce dendritic atrophy in hippocampal neurons (Woolley C, Gould E, McEwen BS. 1990. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225–231; Watanabe Y, Gould E, McEwen BS, 1992b. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588:341–345). Prefrontal cortex is also a target for glucocorticoids involved in the stress response (Meaney MJ, Aitken DH. 1985. [³H]Dexamethasone binding in rat frontal cortex. Brain Res 328:176–180); it shows neurochemical changes in response to stress (e.g., Luine VN, Spencer RL, McEwen BS. 1993. Effect of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function. Brain Res 616:55–70; Crayton JW, Joshi I, Gulati A, Arora RC, Wolf WA. 1996. Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex. Brain Res 728:260–262; Takao K, Nagatani T, Kitamura Y, Yamawaki S. 1997. Effects of corticosterone on 5‐HT_1A and 5‐HT₂ receptor binding and on the receptor‐mediated behavioral responses of rats. Eur J Pharmacol 333:123–128; Sandi C, Loscertales M. 1999. Opposite effects on NCAM expression in the rat frontal cortex induced by acute vs. chronic corticosterone treatments. Brain Res 828:127–134), and mediates many of the behaviors that are altered by chronic corticosterone administration (e.g., Lyons DM, Lopez JM, Yang C, Schatzberg AF. 2000. Stress‐level cortisol treatment impairs inhibitory control of behavior in monkeys. J Neurosci 20:7816–7821). To determine if glucocorticoid‐induced morphological changes also occur in medial prefrontal cortex, the effects of chronic corticosterone administration on dendritic morphology in this corticolimbic structure were assessed. Adult male rats received s.c. injections of either corticosterone (10 mg in 250 μL sesame oil; n = 8) or vehicle (250 μL; n = 8) daily for 3 weeks. A third group of rats served as intact controls (n = 4). Brains were stained using a Golgi‐Cox procedure and pyramidal neurons in layer II‐III of medial prefrontal cortex were drawn; dendritic morphology was quantified in three dimensions. Sholl analyses demonstrated a significant redistribution of apical dendrites in corticosterone‐treated animals: the amount of dendritic material proximal to the soma was increased relative to intact rats, while distal dendritic material was decreased relative to intact animals. Thus, chronic glucocorticoid administration dramatically reorganized apical arbors in medial prefrontal cortex. This reorganization likely reflects functional changes and may contribute to stress‐induced changes in cognition. © 2001 John Wiley & Sons, Inc. J Neurobiol 49: 245–253, 2001     

Electroconvulsive seizure promotes spine maturation in newborn dentate granule cells in adult rat

Neurogenesis continues in the dentate gyrus of the hippocampus throughout life in mammals. This process is influenced by daily activities such as exercise, learning, and stress and may contribute to certain forms of hippocampus-dependent learning and memory. Adult hippocampal neurogenesis is also subject to regulation by antidepressant treatment, including chronic treatment with antidepressant drugs or electroconvulsive seizure (ECS) therapy. Here we investigated how the connectivity of newborn and mature granule cells is influenced by ECS administration in rats. Specifically, we examined the dendritic spine morphology of newborn and mature granule cells in rats and found that ECS administration promoted the maturation of dendritic spines in newborn cells and increased spine density in mature cells. These changes could potentially lead to alteration in dentate circuitry and may partially contribute to the functional effects of ECS.     

Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses

Social isolation of rodents during development is thought to be a relevant model of early-life chronic stress. We investigated the effects of early-life social isolation on later adult fear and anxiety behavior, and on corticosterone stress responses, in male rats. On postnatal day 21, male rats were either housed in isolation or in groups of 3 for a 3 week period, after which, all rats were group-reared for an additional 2 weeks. After the 5-week treatment, adult rats were examined for conditioned fear, open field anxiety-like behavior, social interaction behavior and corticosterone responses to restraint stress. Isolates exhibited increased anxiety-like behaviors in a brightly-lit open field during the first 10 min of the test period compared to group-reared rats. Isolation-reared rats also showed increased fear behavior and reduced social contact in a social interaction test, and a transient increase in fear behavior to a conditioned stimulus that predicted foot-shock. Isolation-reared rats showed similar restraint-induced increases in plasma corticosterone as group-reared controls, but plasma corticosterone levels 2 h after restraint were significantly lower than pre-stress levels in isolates. Overall, this study shows that isolation restricted to an early part of development increases anxiety-like and fear behaviors in adulthood, and also results in depressed levels of plasma corticosterone following restraint stress.     

Dietary Vitamin E Deficiency Increases Anxiety-Like Behavior in Juvenile and Adult Rats

Vitamin E deficiency from birth or infancy has recently been found to increase anxiety-like behavior in rodents. The present study was undertaken to elucidate the effect of dietary vitamin E deficiency on anxiety in adult rats in comparison with juvenile rats. Male Wistar rats, 3 or 10 weeks old, were divided into two groups and fed a control or vitamin E-deficient diet for 4 weeks. The results of behavioral analysis revealed that vitamin E-deficiency increased anxiety in both juvenile and adult rats. Plasma, liver, and brain α-tocopherol concentrations decreased significantly due to vitamin E deficiency in both age groups. Plasma corticosterone concentrations were higher in the vitamin E-deficient rats in response to the stress of a behavioral test. Based on these results, we conclude that dietary vitamin-E deficiency induces anxiety in adult rats as well as juvenile rats. This might be due to an elevated plasma corticosterone concentration.     

Dietary vitamin E deficiency increases anxiety-like behavior in juvenile and adult rats

Vitamin E deficiency from birth or infancy has recently been found to increase anxiety-like behavior in rodents. The present study was undertaken to elucidate the effect of dietary vitamin E deficiency on anxiety in adult rats in comparison with juvenile rats. Male Wistar rats, 3 or 10 weeks old, were divided into two groups and fed a control or vitamin E-deficient diet for 4 weeks. The results of behavioral analysis revealed that vitamin E-deficiency increased anxiety in both juvenile and adult rats. Plasma, liver, and brain α-tocopherol concentrations decreased significantly due to vitamin E deficiency in both age groups. Plasma corticosterone concentrations were higher in the vitamin E-deficient rats in response to the stress of a behavioral test. Based on these results, we conclude that dietary vitamin-E deficiency induces anxiety in adult rats as well as juvenile rats. This might be due to an elevated plasma corticosterone concentration.     

Polysaccharides from wolfberry prevents corticosterone-induced inhibition of sexual behavior and increases neurogenesis

Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of infertility and sexual dysfunction. However, there is still a scarcity of experimental evidence to support the pro-sexual effect of wolfberry. The aim of this study is to determine the effect of Lycium barbarum polysaccharides (LBP) on male sexual behavior of rats. Here we report that oral feeding of LBP for 21 days significantly improved the male copulatory performance including increase of copulatory efficiency, increase of ejaculation frequency and shortening of ejaculation latency. Furthermore, sexual inhibition caused by chronic corticosterone was prevented by LBP. Simultaneously, corticosterone suppressed neurogenesis in subventricular zone and hippocampus in adult rats, which could be reversed by LBP. The neurogenic effect of LBP was also shown in vitro. Significant correlation was found between neurogenesis and sexual performance, suggesting that the newborn neurons are associated with reproductive successfulness. Blocking neurogenesis in male rats abolished the pro-sexual effect of LBP. Taken together, these results demonstrate the pro-sexual effect of LBP on normal and sexually-inhibited rats, and LBP may modulate sexual behavior by regulating neurogenesis.     

Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice

Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.     

Effects of chronic mild stress on behavioral and neurobiological parameters — Role of glucocorticoid

Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus–pituitary–adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors.