Sex differences in adult neurogenesis and learning&memory
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Postpartum depression (PPD) is a psychiatric illness that affects approximately 15% of mothers, negatively impacting mental health during the postpartum as well as increasing risk for future depression. For the developing child, untreated PPD is associated with several adverse outcomes including increased risk for depression, anxiety, and poor cognition particularly in boys. However, treating PPD is complicated because pharmacological antidepressants like fluoxetine (FLX) may function differently within the physiological conditions of the postpartum period. Additionally, these drugs are active in breast milk, directly reaching the infant and potentially influencing neurodevelopment. The long-term effects of neonatal antidepressant exposure are unclear. Alternatively, non-pharmacological antidepressants such as exercise are generally beneficial for maternal and fetal health; however, its potential as an antidepressant in the postpartum and its long-term effects on offspring are unclear. To investigate this, this thesis used a rat model of PPD in which dams are treated with high levels of corticosterone (CORT; primary rat glucocorticoid) and compared how different types of antidepressants affected dams and adult male and female offspring. In chapter 2, maternal postpartum FLX prevented CORT-induced disruptions in maternal care but was unable to prevent CORT-induced depressive-like behaviour or reductions in hippocampal neurogenesis. In chapter 3, maternal postpartum FLX increased anxiety-like behaviour, impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback, and increased hippocampal neurogenesis in adult male but not female offspring. In chapter 4, maternal exercise did not prevent CORT-induced disruptions in maternal care but it prevented CORT-induced depressive-like behaviour and increased hippocampal neurogenesis. While neither antidepressant alone increased maternal neurogenesis, the combination of both treatments increased neurogenesis. In chapter 5, maternal exercise increased hippocampal neurogenesis in dorsal hippocampus but maternal postpartum FLX reduced it. However, exposure to maternal postpartum FLX prevented the neurogenic effect of maternal exercise. Maternal exercise facilitated HPA axis negative feedback in males but impaired in females. Collectively, these data indicate that antidepressants can have dynamic effects on endophenotypes of PPD, emphasizing the need for further research in PPD. Furthermore, male and female offspring development is differentially sensitive to these maternal antidepressant interventions, highlighting the importance of studying sex differences in neurodevelopment.
Depression is a devastating neuropsychiatric disease that has profound effects on neural structure and function, however the pathogenesis and modes of effective treatment remain poorly understood. Stress is the primary preceding factor in depression, leading to profound deficits in neurophysiology, particularly in the hippocampus. Depressed patients show reduced hippocampal neuroplasticity, while antidepressant treatment enhances both neurogenesis and the expression of proteins that mediate plasticity such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). Interestingly, men are half as likely as women to develop depression, where androgens appear to confer resiliency in males, as hypogonadal men are more likely to develop depression and supplementation of testosterone shows antidepressant efficacy. Little is known about the neurological underpinnings of this profound sex difference, however androgens influence the stress response and enhance hippocampal neurogenesis. The experiments in this thesis aimed to examine the role of androgens in the pathogenesis and treatment of depression using an animal model, with a specific eye toward the impact on hippocampal neurogenesis and neuroplasticity, and whether neuroplasticity mediated through PSA-NCAM is essential to antidepressant efficacy. In Chapter 2, surgically-induced hypogonadism potentiates the expression of depressive-like endophenotypes in male rodents within a chronic unpredictable stress (CUS) model of depression. Hypogonadal males showed potentiated behavioural, endocrine, and neurophysiological depressive-like phenotypes, including reductions in hippocampal neurogenesis and the expression of PSA-NCAM, compared to intact males. In Chapter 3, the hypogonadism-induced susceptibility to depressive-like phenotypes following CUS is largely inhibited by supplementation with testosterone. Testosterone treatment ameliorated physiological and endocrine phenotypes while showing independent antidepressant-like effects and facilitating the efficacy of an antidepressant drug in some measures. In Chapter 4, the enzymatic cleavage of the polysialic acid moiety from NCAM completely inhibits the behavioural efficacy of antidepressant treatment, while also serving to attenuate the survival of newly generated hippocampal neurons. Collectively, this body of research demonstrates the protective effects of androgens against the development of depression in males, coinciding with enhanced hippocampal neuroplasticity, and delineates an essential role for neuroplasticity mediated through PSA-NCAM in antidepressant action.
Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of substance use disorders (SUDs). Dopaminergic systems provide a key neurobiological substrate for SUDs. The hypothalamic-pituitary-adrenal (HPA) axis and dopamine systems have overlapping neurocircuitries, with stress altering dopamine pathways implicated in drug-related reinforcement and motivation, and conversely drug exposure activating stress systems, enhancing sensitivity to subsequent stressors. PAE alters both HPA and dopaminergic regulation, resulting in increased HPA tone and an overall reduction in tonic dopamine activity. Thus, alterations in HPA-dopamine interactions in PAE subjects may provide a neurobiological mechanism underlying enhanced vulnerability to SUDs. Adult Sprague- Dawley offspring from PAE, pair-fed, and ad libitum-fed control groups were examined. In Chapter 2, the effects of PAE and stress on basal regulation of stress and dopamine systems are discussed. Subjects were subjected to either chronic variable stress (CVS) or no stress conditions, and corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and dopamine receptor expression, were measured under basal conditions. In the hippocampus, glucocorticoid receptor (MR) mRNA levels were lower in PAE than control females under non- CVS conditions, while CVS resulted in broader upregulation of MR in PAE compared to control males. A decrease in dopamine receptors was observed following CVS exposure in control but not in PAE subjects. Overall, PAE enhanced sensitivity to CVS and attenuated the effects of chronic stress on basal dopamine receptor expression, and did so in a sexually-dimorphic manner. In Chapter 3, repeated exposure to d-amphetamine (AMPH) induced behavioral sensitization in PAE but not control subjects, and this behavioral measure is positively correlated with vulnerability to SUDs. The current study also assessed cross-sensitization between AMPH and stress, and indeed PAE facilitated cross-sensitization between AMPH and stress, and did so in a sexually dimorphic manner. PAE altered AMPH-stress interactions, and did so in a manner consistent with increased neurobiological vulnerability to SUDs. Together, the present results enhance our understanding of PAE effects on the cross-talk between dopamine and stress systems, and provide insight into underlying mechanisms influencing the increased prevalence of SUDs among individuals with an FASD.
In women, age-associated decline in cognitive functioning is associated with the onset of menopause, which is the cessation of ovarian functioning and leads to dramatic reduction in circulating levels of ovarian hormones including estradiol. Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer’s disease. However, the utility of replacement with estrogens has recently been questioned in the literature. The experiments in this thesis aimed to determine the effects of replacement with different estrogens on hippocampus-dependent learning and memory and hippocampal neurogenesis in female rats, and whether these effects were dependent on different factors, including length of exposure, type of estrogens, dose of estrogens, type of memory system examined, age of subjects, and previous reproductive experience. The main findings of the experiments presented in this thesis are that hormone replacement therapy and estrone negatively impact hippocampus-dependent learning and memory (Chapters 2 and 4; Barha and Galea, in press; Barha et al., 2010), whereas other estrogens can improve hippocampus-dependent learning and memory (Chapter 4; Barha et al., 2010). Additionally, hormone replacement therapy alters hippocampal neurogenesis and decreases new neuronal activation in the dentate gyrus, which may account for impairments seen in memory functioning (Chapter 2; Barha and Galea, in press). Naturally occurring estrogens also differentially increase cell proliferation in the dentate gyrus in adult and middle-aged female rats (Chapters 3, 5; Barha et al., 2009; Barha and Galea, 2011), and this effect is dependent on previous reproductive experience in middle-aged females (Chapter 5; Barha and Galea, 2011). Thus, taken together the results from these experiments suggest that some estrogens increase while other estrogens decrease hippocampal neurogenesis and hippocampus-dependent learning and memory. These findings have important implications for determining which alternative forms of estrogens to incorporate into hormone therapy treatments in the future. Furthermore, the findings from this thesis provide new insights into our understanding of the mechanisms and function of adult neurogenesis in the female rat.
Estradiol affects neurogenesis in the hippocampus of adult female mammals, but relatively little is known about how estradiol affects cells in the male brain, or how repeated estradiol administration affects either sex. I show in this thesis that repeated estradiol affects cell production and neuron survival in the dentate gyrus of female, but not male rats. Specifically, estradiol administered to female rats increased cell proliferation, decreased the number of young neurons, and decreased the number of dying cells. This difference was not due to differential uptake of estradiol, as the administration of estradiol resulted in concentrations of estradiol in the serum, hippocampus, amygdala, and prefrontal cortex that were similar between males and females. The function served by the new neurons in the hippocampus remains controversial, but evidence suggests they may play a particularly important role in modulating performance in hippocampus-dependent tasks. I used a hippocampus-dependent task, contextual fear conditioning, to determine whether the effects of estradiol on different aspects of neurogenesis - or lack thereof - could be related to its effects on learning and memory. I found a consistent sex difference, with males spending more time freezing than females regardless of treatment. Furthermore, I found that repeated estradiol reduces the amount of time spent freezing in response to a novel context after training in females but not in males. Collectively my results suggest that repeated estradiol influences hippocampal structure and function in female but not male rats. Furthermore the production and survival of adult-generated neurons are regulated differently in males and females which has strong implications for any potentially therapeutic manipulations of these cells.
In the hippocampus, unlike most areas of the mammalian brain, new neurons are continuously produced throughout life. Studies have demonstrated that spatial learning, a process dependent on the hippocampus, regulates neurogenesis (i.e. the survival of new neurons) in the hippocampus. Studies have found that spatial learning either causes an increase, no change, or a decrease in neurogenesis. It was the goal of this thesis to determine under what conditions neurogenesis is increased, decreased or unaffected by spatial learning using the Morris water task. Experiment 1 demonstrated that there was a critical period in the developmental of new neurons in adult rats, at 6-10 days old, during which spatial learning can increase neurogenesis. Experiment 2 showed that spatial learning at a later time point (days 11-15) decreased cell survival but this decrease occurred gradually and as a result may only be seen if several days are waited after training prior to examining levels of neurogenesis. Experiment 3 demonstrated that although neurogenesis may be increased if spatial training occurs when the new neurons are 6-10 days old in adult rats, this effect can be eliminated or reversed by increasing the difficulty of the spatial task. Finally, in Experiment 4 I showed that the effect of spatial learning is affected by the strain of rats used, possibly due to differences in the rate of maturation of new neurons. Sixteen day old bromodeoxyuridine-labeled cells were increased in both Sprague-Dawley and Long-Evans rats following spatial learning but doublecortin-labeling (which labels a broader age of new neurons) is increased only in Sprague-Dawley rats after spatial learning. Thus, numerous methodological factors must be considered when examining the effects of spatial learning on neurogenesis. There are likely more factors (i.e., stress, age, sex, etc.) that interact with spatial learning and neurogenesis than described here however these studies have clarified many prior conflicting studies.
Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU) and were tested for spatial pattern separation in a delayed nonmatching to place task using the 8-arm radial arm maze. Twenty eight days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity.
Major depression is twice as common in women and symptoms are more severe in women than in men. These sex differences are linked to ovarian hormone levels in women. Interestingly, ovarian hormones may modulate antidepressant efficacy, with low ovarian hormone levels in women associated with a poorer antidepressant response. The mechanisms behind antidepressant efficacy have not yet been established, but chronic, and not acute, antidepressant treatment increases hippocampal neurogenesis in rodents and humans and normalizes hypothalamic-pituitary-adrenal axis negative feedback in rodents and humans. The antidepressant-induced increase in neurogenesis is, therefore, one mechanism by which antidepressants may work to alleviate some depressive symptoms. In this experiment we examined the effect of ovarian hormone status on the ability of chronic antidepressant treatment to increase cell proliferation in the dentate gyrus of female rats. Adult female rats were ovariectomized (OVX) or sham ovariectomized (Sham) prior to receiving 21 daily injections with either vehicle, the tricyclic antidepressant imipramine, or the selective serotonin reuptake inhibitor fluoxetine. Animals were then perfused, and brains were immunohistochemically processed for two endogenous markers: Ki67, which labels proliferating cells in the previous 24 hours, and doublecortin, which labels immature neurons aged 1-21 days. Ki67- and doublecortin-labeled cells were counted in two regions of the dentate gyrus: the dorsal region, important for memory, and the ventral region, important for regulating stress/emotion. Chronic imipramine treatment increased cell proliferation (Ki67-labeled cells) in the ventral dentate gyrus of Sham animals only, while chronic fluoxetine treatment increased cell proliferation in the dorsal dentate gyrus of OVX animals only. Furthermore, OVX animals receiving imipramine had an increased number of immature neurons (doublecortin-labeled cells) in the ventral dentate gyrus. OVX/water compared to Sham/water controls had significantly decreased adrenal to body weight ratios that were restored following chronic treatment with imipramine and fluoxetine. Both antidepressants also lengthened the estrous cycle. This study is the first to demonstrate that ovarian hormones modulate antidepressant-induced increases in cell proliferation in females in a drug-specific and region-specific manner, and highlights the importance of considering ovarian hormone status when examining the neurogenic effects of antidepressants.
No abstract available.
Adult hippocampal neurogenesis is associated with hippocampus-dependent learning and memory. Throughout the course of a new neuron’s development, it is differentially sensitive to factors that can influence its survival and subsequent functionality. Previous research shows that in male rats, spatial training that occurred 6 to 10 days after an injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), increased cell survival, but no change was observed in animals trained on days 1 to 5 or 11 to 15 and perfused 16 days after BrdU injection (Epp et al., 2007). Because sex differences favouring males in spatial cognition and in hippocampal neurogenesis have been reported, it is unclear whether spatial learning would influence hippocampal neurogenesis in the same way in males and females. Therefore, this study aimed to compare sex differences in hippocampal neurogenesis relative to training in a spatial task. Male and female rats were exposed to training in the spatial or cued version of the Morris Water Maze 6 to 10 days after one injection of BrdU (200mg/kg). Twenty days following BrdU injection, all animals were given a 30-second probe trial and perfused. Males showed better performance in the spatial task, but not cue task, than females. Spatial learning increased the density of BrdU-labeled cells relative to cue training only in males, but both males and females showed greater cell activation (BrdU co-labeled with immediate early gene product zif268) after spatial training compared to cue training. Furthermore, performance during spatial training and testing were positively correlated with cell activation in females but not males. This study shows that while spatial learning differentially regulates hippocampal neurogenesis in males and females, the activity of new neurons in response to spatial memory is similar. These findings highlight the importance of sex on neural plasticity and cognition.
Pregnancy, parturition, and motherhood, collectively known as reproductive experience, bring about profound and enduring changes in the hormonal, neural, and behavioral profile of the female rat. Much of the research to date investigating the effects of reproductive experience on learning and memory and cellular morphology in the rat dam has focused on the hippocampus. These studies revealed enhancements in spatial working and reference memory as well as alterations in pyramidal cell morphology following reproductive experience. Interestingly, it has long been established that other brain regions undergo persistent changes in response to reproductive experience including the prefrontal cortex, yet there remains a paucity of research investigating this area. Thus, the objective of the following experiments was to determine the effects of reproductive experience on prefrontal cortex-dependent learning and memory as well as pyramidal cell morphology in the prelimbic region in nulliparous, primiparous, and multiparous rats. For Experiment 1, age-matched nulli-, primi- and multiparous rats were tested for seventeen consecutive days using the delayed spatial win-shift task. This experiment revealed that multiparous rats committed fewer within-phase and omission errors than nulli- or primiparous rats on Blocks 2, 3, and 4 as well as committing fewer across-phase errors in Blocks 2 and 4 than either the nulli- or primiparous groups. Furthermore, the total number of within-phase errors significantly and negatively correlated with an increase in the total time engaged in nursing behaviors. Using Golgi impregnation, pyramidal cell morphology in Laminae 2/3 and 5 of the prelimbic region of the prefrontal cortex was examined in Experiment 2. The results of Experiment 2 revealed that multiparous rats have more total branch points in the apical region of Lamina 2/3. In addition, arched-back nursing was found to significantly positively correlate with the number of branch points in apical and basal regions of Lamina 5. Passive nursing significantly correlated with the number of basal branch points in Lamina 5 and apical length in Lamina 2/3. The findings from these studies suggest that multiparity may be necessary in realizing the effects of enhanced learning and memory and morphological changes associated with the prefrontal cortex in female rats.
Crozier, T.M. and Pawluski, J.L. and Brummelte, S. and Galea, L.A.M.
Dendritic Spines: Biochemistry, Modeling and Properties 1-24
Gould, E. and McEwen, B.S. and Tanapat, P. and Galea, L.A.M. and Fuchs, E.
Journal of Neuroscience 17 (7) 2492-2498
Galea, L.A.M. and Kavaliers, M. and Ossenkopp, K.-P.
Journal of Experimental Biology 199 (1) 195-200
Kavaliers, M. and Ossenkopp, K.-P. and Prato, F.S. and Innes, D.G.L. and Galea, L.A.M. and Kinsella, D.M. and Perrot-Sinal, T.S.
Journal of Comparative Physiology - A Sensory, Neural, and Behavioral Physiology 179 (5) 715-724