Liisa Ann Margaret Galea


Research Interests

Aging Process
Alzheimer's disease
Drugs and Pregnancy / Breast Feeding
Hormones and Growth Factors
Learning and Memory
Neurogenesis and Gliogenesis
Postpartum Depression
Sex differences
women's health

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Research Methodology

multiplex electrochemiluminescence
radioimmunoassay, ELISA


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Great Supervisor Week Mentions

Each year graduate students are encouraged to give kudos to their supervisors through social media and our website as part of #GreatSupervisorWeek. Below are students who mentioned this supervisor since the initiative was started in 2017.


S/o to my #GreatSupervisor at #UBC @LiisaGalea. Thank you for your brilliance, guidance, kindness, patience, and perhaps most of all, your sass. Thank you for always keeping it real❤️


Installment #3 for #GreatSupervisor wk: @LiisaGalea: I first met Liisa in a #lecture she gave in class. I asked her a question about #females in #research. I don’t remember the question now, but I do remember her. #Badass. THAT’s what I remember and appreciate. Fast forward ~3 months & she was now #Neuroscience #chair. I went up to introduce myself a few wks later. “Hi, I’m Daphne…” “Ling,” she finished. Def badass. ~3.5 wks into her chairship & she knew my name. (I'm staunchly refusing to believe I might be a trouble-maker).

Liisa is now also my committee chair. I remember a #professor once gave me a hard time about my #research, & Liisa said: “That’s #science. We all make predictions & propose future directions. They don't always work. You cannot ask her to precisely predict the future.” She also ALWAYS HAS #CHOCOLATE. Her chocolate has chocolate. And she loves #purple. Liisa reminds me that it’s ok to let my #personality show in #science (hello, sparkly purple #tiara) & that “progress” in #GradSchool is very individual. (I'm due for a reminder soon). She is fantastic at commiserating. I am cognizant of the unrewarded #emotional burden placed on #women & other #URMs in #academia. And I can understand why. When the emotional toil of the #PhD feels unbearable, #women like Liisa can give u a hug. A male person-in-power? "Thank you," "I appreciate you," and "Nice work" need to be incorporated into our academic vocabulary more! #DontBeReviewer3 #BeTheMentorYouWishYouHad #BeKind


It is Supervisor Appreciation Week at #UBC, so I want to express my endless gratitude to my #greatsupervisor, the amazing @LiisaGalea, for her unwavering support and guidance. Her investment in our success as scientists and wellbeing as individuals is truly inspiring.


Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Perinatal depression and treatment implications for mother and offspring: lessons from an animal model (2022)

Perinatal depression (PND) is a heterogenous disease where risk factors, symptoms, severity, treatment efficacy, and effects on children can differ depending on timing of onset. The majority of new cases occur with depression onset in the postpartum (postpartum depression; PPD). Very few people with PPD are adequately treated and even in these individuals only ~50% will reach remission with current front-line treatments of selective serotonin reuptake inhibitors (SSRIs). Inflammatory signalling has been related to antidepressant efficacy outside of the postpartum, and I investigated inflammatory mechanisms that may modulate the efficacy of fluoxetine (FLX) in the postpartum. In children, maternal SSRI treatment alters neurodevelopment, including an increased risk for autism spectrum disorder. In Chapter 4, I investigate oxytocin (OT) as a therapeutic in preadolescent offspring to ameliorate maternal treatment effects of CORT and FLX. In Chapter 2, postpartum FLX did not reduce passive coping behaviour in the dams and was commensurate with FLX induced elevations in hippocampal IL-1β levels, peripheral CXCL1 levels, and reduced plasma tryptophan concentrations. In Chapter 3, postpartum CORT treatment increased putative neurotoxic and neuroprotective metabolites within the tryptophan-metabolic pathway in dams. Maternal postpartum FLX did not reverse any postpartum CORT effects, and together with CORT, shifted the tryptophan metabolism towards neurotoxicity. In Chapter 4, maternal FLX reduced neurogenesis and IL-10, IL-13, IFN-γ expression in the hippocampus of offspring. Maternal CORT increased hippocampal neurogenesis and hippocampal IL-6:IL-10 ratio in both sexes, while periadolescent OT treatment reversed these and increased social behaviour in offspring of maternal CORT-treated dams. OT increased neurogenesis in the hippocampus of adult male offspring but not adult female offspring. Collectively, these data suggest the inefficacy of FLX long-term during the postpartum may be due to increased proinflammatory signalling in the hippocampus and reduced tryptophan, and future studies should investigate these pathways to improve long-term efficacy of SSRIs. Moreover, PPD and postpartum antidepressant treatments can have long-term consequences in offspring, which may be ameliorated with OT treatment prior to adolescence. Together, these data can facilitate a better understanding of the consequences of untreated and treated maternal PPD for better outcomes in mothers and children. 

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Ovarian hormones as determinants of risk and resilience to stress: behavioural, neuroplastic, and neuroimmune outcomes (2020)

Major Depressive Disorder (MDD) affects twice more women than men, yet little attention is paid to female-specific factors that may contribute to this disparity. Ovarian hormones regulate mood and influence MDD, but their roles are complex and sometimes contradictory. Importantly, ovarian hormones regulate processes and systems that are compromised in MDD, including neural plasticity, stress response, and immune systems. To clarify the complex roles of ovarian hormones in MDD models, this thesis examined ovarian hormones at the intersection of stress, neuroplasticity, and neuroinflammation. Chapter 2 investigated the effects of long-term ovariectomy on the expression of depressive-like phenotypes and antidepressant efficacy in middle-aged female rats exposed to chronic unpredictable stress (CUS). Under CUS conditions, long-term ovariectomy increased depressive- and anxiety-like behaviour and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback function. The selective serotonin reuptake inhibitor fluoxetine had limited behavioural efficacy, but significant efficacy on neural and endocrine measures, as seen by increased adult hippocampal neurogenesis, reduced microglial number, and enhanced HPA axis negative feedback function. Chapter 3 investigated the effects of long-term ovariectomy on the neuroinflammatory and behavioural consequences of sub-chronic stress exposure in middle-aged mice. Under non-stress conditions, long-term ovariectomy modestly increased depressive-like behaviour, but robustly modified the central cytokine milieu, as evidence by reduced concentrations in the frontal cortex and increased concentrations in the hippocampus. Interestingly, intact mice showed a greater behavioural susceptibility to the depressive-like effects of sub-chronic stress exposure, and this was coupled with an exaggerated neuroinflammatory response in the frontal cortex and hippocampus. Chapter 4 dissected the role of estrogen receptor (ER) α and β in regulating depressive-like phenotypes under CUS conditions in young-adult female mice. CUS exposure increased depressive-like behaviour, increased cytokine concentrations and reduced postsynaptic density protein-95 expression in the hippocampus and frontal cortex, effects that were largely driven by groups treated with ERα and ERβ agonists. Further, in a CUS-independent manner, 17β-estradiol increased neurogenesis in the dorsal hippocampus, blunted the corticosterone response to an acute stressor, and increased anxiety-like behaviour. Collectively, these findings shed light on the complex roles of ovarian hormones in regulating depressive-like behaviour, and in modulating neuroplastic and neuroimmune signatures.

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Comparison of pharmacological and non-pharmacological antidepressants in postpartum depression: outcomes of mother and male and female offspring (2017)

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.

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Androgens and neuroplasticity: contributions to the pathogenesis and treatment of depression (2016)

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.

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Effects of prenatal alcohol exposure on interactions between stress and dopamine systems : a potential pathway to increased vulnerability to substance use disorders (2013)

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.

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The Effects of Estrogens and Hormone Replacement Therapy on Adult Hippocampal Neurogenesis and Cognition in Young and Middle-Aged Female Rats (2012)

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.

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Sex Differences in the Neurogenic and Behavioural Effects of Repeated Estradiol Administration in the Adult Rat (2010)

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.

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The effects of spatial learning on adult neurogenesis in the dentate gyrus (2010)

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.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Examining impact of interleukin-1 receptor antagonist on fluoxetine efficacy in a preclinical rodent model of postpartum depression (2021)

Depression is the leading cause of disability worldwide, where women are twice as likely to be diagnosed than men. Pregnancy and early postpartum is an especially vulnerable period, where approximately 15% of birthing individuals are diagnosed with perinatal depression (PND). Approximately 40% of PND cases occur in the postpartum period. Overwhelmingly, most of these cases are the first depressive episode in the birthing individual’s life. Concerningly, selective serotonin reuptake inhibitors (SSRIs), the first line antidepressant treatment for PND, show decreased efficacy in treating postpartum depression symptoms compared to antepartum depression symptoms. Previous research using an animal model of de novo postpartum depression indicates that SSRI inefficacy may be related to increased levels of the proinflammatory cytokine interleukin-1β (IL-1β). This thesis aims to further investigate the relationship between inflammation and the postpartum onset of depression, by targeting the IL-1 receptor using an animal model of postpartum depression. In this model, high corticosterone (primary rat glucocorticoid) is given to the rat dam postpartum. Rat dams received either daily injections of corticosterone, fluoxetine and/or the IL-1 receptor antagonist, anakinra, or their vehicles. Anakinra competitively binds to the IL-1 receptor to block IL-1β activity. Our results indicate anakinra treatment has mixed effects on PND endophenotypes, depending on co-treatment with fluoxetine. With and without fluoxetine co-treatment, anakinra decreases microglia in the hippocampus, indicating an overall dampening of neuroinflammation through IL-1 receptors. Without fluoxetine co-treatment, anakinra decreases maternal care behaviour, whereas anakinra with fluoxetine treatment returned to control levels. Co-treatment of anakinra and fluoxetine resulted in increased active coping behaviours during the Forced Swim Test and increased hippocampal neurogenesis in the ventral dentate gyrus. Notably, fluoxetine with anakinra co-treatment increased ventral hippocampal neurogenesis, while fluoxetine treatment alone was ineffective in these outcome variables. These results suggest a possible therapeutic benefit of anakinra when used as an adjuvant with fluoxetine. Further research is critical to build upon this foundation and continue to explore the connection between neuroinflammation and antidepressant efficacy.

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The role of mirroring and mentalizing brain systems in action understanding (2020)

Mirror neurons, which are critical for social learning, respond to both the observation and execution of an action. They do so by forming a complex brain network known as the Mirror Neuron System (MNS) in which visual neural representations of actions trigger a corresponding motor representation. Another essential feature of social learning is the ability to reason about the minds of others by inferring not just how they do something but why they are doing it. The mentalizing brain system (MZN) is implicated in the process of inferring others’ mental states5. This study utilizes high-density EEG to quantify dynamics in functional brain networks supporting mirroring and mentalizing processes in neurotypical adults. We used the photo judgement task6 which has been shown to differentiate the MNS and MZN using fMRI. Participants were shown pictures of faces or hands and asked about how (mirroring) or why (mentalizing) the actions were being performed. We see clear differences between mirroring and mentalizing tasks that can be detected by EEG. Brain activity appears to diverge around 300 ms after stimulus onset, and several EEG ERP components uniquely identify mirroring and mentalizing activity. Using mu and beta suppression as markers for mirroring and mentalizing activity respectively, the data suggests that the MNS is more active in processing action means associated with facial expressions, whereas the MZN is more active in processing intent associated with hand movements. Using microstate analysis, we show that ~300 ms after stimulus presentation, the brain undergoes several state transitions while processing intent, whereas while processing action means (mirroring), the brain appears to stay in one stable state. The neural sources of these microstates demonstrate that the how and why conditions more strongly activate regions associated with the MNS (occipital and left superior temporal gyrus) and MZN (medial prefrontal cortex) respectively. Altogether, the results show that the photo-judgement task can be used with EEG to detect differential engagement of the MNS and the MZN. The MNS appears to be more active in immediately after stimulus presentation, whereas the MZN appears to be engaged following primary context comprehension.

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Evaluation of oxytocin as a possible treatment for the effects of prenatal alcohol exposure on neurogenesis, stress reactivity, and anxiety-like behaviour in male and female rats (2018)

The hippocampus provides inhibitory regulation on the hypothalamic-pituitary-adrenal (HPA) axis. Hippocampal neurogenesis (birth of new neurons) has been implicated in the HPA axis ability to mount an appropriate response to stress. Both the hippocampus and HPA axis are highly susceptible to early environmental modulation. Prenatal alcohol exposure (PAE) has been shown to alter HPA axis activity, reduce hippocampal neurogenesis, and increase anxiety-like behaviour. Dysregulated HPA axis activity and altered hippocampal neurogenesis following PAE likely underlie the behavioural expression of anxiety. The neuropeptide, oxytocin (OT), has been shown to dampen HPA axis response to stress, stimulate hippocampal neurogenesis, and act as an anxiolytic. OT is a prime therapeutic candidate to treat the altered stress responsivity and increased anxiety following PAE because it may act on underlying neurogenic and endocrine mechanisms. The objective of this study was to examine whether OT can modulate the effects of PAE on neurogenic, stress-response, and behavioural outcomes. In adulthood, male and female offspring from alcohol-fed, pair-fed, and control dams were treated daily with OT or vehicle for 10 days. OT-treated animals exhibited sedative-like effects and reduced locomotor activity. PAE animals showed fewer sedative-like effects, which may suggest altered OT sensitivity, as well as exhibited hyperactivity. Decreased locomotor activity following OT may preferentially impact hyperactive PAE animals. Interestingly, PAE animals also showed decreased anxiety-like behaviour; however, this effect may be confounded by hyperactivity and reflect impulsivity or inappropriate risk-assessment. PAE males showed attenuated CORT recovery following acute restraint stress, which OT did not modulate. PAE animals exhibited increased density of immature neurons in the dorsal dentate gyrus, whereas OT had no effect on neurogenesis. Utilizing the methods in this study OT was not able to mitigate the effects of PAE on endocrine or neurogenic domains. However, OT may act to reduce hyperactivity following PAE, which may support attenuation of learning and memory deficits, attention problems, and impulsivity. Our findings are an important extension of previous work on altered neurogenic, endocrine, and behavioural responses following PAE. Our results support and extend literature on the use of OT as a therapeutic intervention, with novel utilization following PAE.

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Sex differences in the effects of aerobic exercise on neurogenesis and cognitive function in adult C57BL/6 mice (2018)

Aerobic exercise has positive effects on the brain and is associated with improved cognition. One mechanism through which exercise can promote brain health is by increasing adult hippocampal neurogenesis, a phenomenon that produces new function brain cells after the developmental period and throughout life. Meta-analyses of exercise interventions have shown a sex-difference in the efficacy of exercise on cognition in older adults. This current study sought to determine whether there are sex-differences in the efficacy of exercise for promoting neurogenesis and improving cognition in healthy, adult mice. Adult male and female mice were given access to a running wheel (or a disassembled wheel) for 28 days and on day 22 were given 6 days in the Morris water maze, for spatial learning, memory and reversal training. Mice were then sacrificed and examined for neurogenesis in the dentate gyrus using the endogenous protein doublecortin (DCX), a marker for immature neurons. Mice that ran for 28 days showed increased hippocampal neurogenesis, regardless of sex. All mice, irrespective of exercise intervention or sex, showed learned the reference memory version of the Morris water maze. There was a positive correlation between time spent in the platform zone and doublecortin-expressing neurons in the dorsal dentate gyrus in males, but not females. Future studies should continue to address sex-differences in the effects of exercise on neurogenesis and cognition by using more specific and challenging cognitive tests for young, healthy rodents, or using animals with impaired or naturally decreased levels of neurogenesis.

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Sex and strategy use matters for pattern separation, adult neurogenesis and immediate early gene expression in the hippocampus (2015)

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.

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Motherhood and ovarian hormones influence hippocampus-dependent cognition and neurogenesis later in life (2013)

Age-related cognitive decline in women may be influenced by hormonal experiences over the lifespan including parity (pregnancy and motherhood) and menopause. Previous research implicates hippocampal neurogenesis in spatial learning and age-related cognitive decline and indicates that different regions of the hippocampus (dorsal and ventral) may contribute differentially to spatial working and reference memory. Therefore, the current study investigates influences of parity and ovarian hormones on hippocampus-dependent spatial working and reference memory and neurogenesis during middle age. Multiparous and nulliparous middle-aged rats were either ovariectomized or received sham surgery and were injected with the DNA synthesis marker bromodeoxyuridine (BrdU). Rats were trained on working/reference (hidden platform moved every two days) and reference (hidden platform was stationary) memory versions of the Morris water maze on days 12-21 after BrdU injection. On day 22 rats were given a probe trial to assess memory retention. Multiparous rats had enhanced early working/reference memory acquisition compared to nulliparous rats and this was more prominent in ovariectomized rats. In contrast, nulliparous females had better reference memory acquisition compared to multiparous rats and had enhanced spatial reference memory during the probe trial. Multiparous females had a larger ventral dentate gyrus and greater density of immature neurons compared to nulliparous females, whereas nulliparous females had greater density of older BrdU-labelled cells in the dentate gyrus compared to multiparous females. Depending on ovarian hormone status and parity, neurogenesis in the dorsal dentate gyrus correlated with measures of spatial reference learning, whereas neurogenesis in the ventral dentate gyrus correlated with spatial working/reference performance. Overall, results indicate multiparous rats have better spatial working memory performance whereas nulliparous rats have enhanced reference performance. These results may reflect differences in neuroplasticity (with multiparous rats having more immature neurons and nulliparous rats having greater survival of new neurons) and/or stress resilience differences between the parous groups. Importantly, the influence of parity on spatial working and reference memory and acquisition was modified by ovarian hormone status. These results also suggest that the role of new neurons in cognition may be moderated by parity and ovarian status in middle age.

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Ovarian hormones modulate antidepressant-induced hippocampal cell proliferation in the dentate gyrus of adult female rats (2013)

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.

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17B-Estradiol, but not estrone, increases hippocampal neurogenesis and activation of new granule neurons in response to spatial memory in adult female rats (2012)

Estrogens fluctuate across the lifespan in women, with circulating 17β-estradiol levels higher pre-menopause than estrone and circulating estrone levels higher postmenopause than 17β- estradiol. Estrone is a common component of hormone replacement therapies, but research shows that 17β-estradiol may have a greater positive impact on cognition. Previous studies show that acute estrone and 17β-estradiol impact hippocampus-dependent learning and cell proliferation in the dentate gyrus in a dose-dependent manner in adult female rats. The current study explores how chronic treatment with estrone and 17β-estradiol differentially influences spatial learning, hippocampal neurogenesis and activation of new neurons in response to spatial memory. Adult female rats received daily injections of vehicle (sesame oil), or a 10μg dose of either 17β-estradiol or estrone for 20 days. One day following the first hormone injection all rats were injected with the DNA synthesis marker, bromodeoxyuridine. On days 11-15 after BrdU injection rats were trained on a spatial reference version of the Morris water maze, and five days later (day 20 of estrogens treatment) were given a probe trial to assess memory retention. There were no significant differences between groups in acquisition or retention of Morris water maze. However, the 17β-estradiol group had significantly higher, while the estrone group had significantly lower, levels of neurogenesis in the dentate gyrus compared to controls. Furthermore, rats injected with 17β-estradiol showed significantly higher levels of activation of new neurons in response to spatial memory compared to controls. These results provide insight into how estrogens differentially influence the brain and behaviour, and may provide insight into the development of hormone replacement therapies for women.

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Adult hippocampal neurogenesis and cell activation are regulated by sex differences in spatial learning (2012)

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.

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The effects of reproductive experience on prefrontal cortex dependent learning and memory and pyramidal cell morphology in the rat dam (2010)

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.

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