Biology subjects

Galea, L.

Publications and source records attributed to Galea, L..

29 records · Page 2Linked to original sources

bioRxiv2021

Harnessing the Power of Sex Differences: What a Difference Ten Years Did Not Make

Sex differences exist in many neurological and psychiatric diseases. Mandates have been initiated across funding agencies for research to include males and females. What has been lacking in the literature is a detailed assessment of how sex is incorporated into the design (e.g. balanced design) and into the analyses (e.g. covariate). We surveyed papers in 2009 and 2019 across six journals in Neuroscience and Psychiatry. There was a 30% increase in the percentage of papers that included both sexes to 68% in 2019. Despite this increase, in 2019 only 19% of studies used an optimal design for discovery of possible sex differences and only 5% analyzed sex as a discovery variable. Here we show that little progress has been made in harnessing the power that sex differences can afford in research for discovery and therapeutic potential for neurological and psychiatric disease to improve the health of men, women and gender diverse individuals. Highlights68% of Neuroscience and Psychiatry papers reported the use of both sexes in 2019 Only 19% of studies in 2019 used sex consistently throughout the study analyses Of the studies that used males and females, 59% did not include sex in the analyses Only 5% of studies in 2019 used sex as a discovery variable in their analyses Male only papers were 8.4 times more prevalent than female-only papers

neuroscience↗

bioRxiv2021

Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1b levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target. HighlightsO_LITryptophan-kynurenine pathway (TKP) is altered by postpartum corticosterone (CORT) C_LIO_LIPostpartum CORT upregulated neurotoxic more metabolites (3HK, 3HAA) C_LIO_LIPostpartum fluoxetine (FLX) increased xanthurenic acid concentrations C_LIO_LIPostpartum CORT and FLX together shifted the TKP balance towards neurotoxicity C_LI

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bioRxiv2020

Sex Differences in Risk-based Decision Making

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17{beta}-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17{beta}-estradiol benzoate (0.3 g) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17{beta}-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias towards larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

neuroscience↗

bioRxiv2020

Postpartum fluoxetine increased maternal hippocampal IL-1β and decreased plasma tryptophan: clues for efficacy

Perinatal depression (PND) affects approximately 15% of women, and de novo postpartum depression affects approximately 40% of PND cases. Selective serotonin reuptake inhibitors (SSRIs) are a common class of antidepressants prescribed to treat PND. However, the safety and efficacy of SSRIs have been questioned in both clinical and preclinical research. Here, using a preclinical rodent model of postpartum depression, we aim to better understand neuroinflammatory cytokines and tryptophan mechanisms that may be related to SSRIs efficacy. Rodent dams were treated with high corticosterone (CORT; 40mg/kg, s.c.) for 21 days in the postpartum period to simulate depressive-like behaviors in the late postpartum period. Concurrently, a subset of dams was treated with the SSRI, fluoxetine (FLX; 10mg/kg, s.c.), in the postpartum period. We showed, consistent with previous studies, that although maternal FLX treatment prevented CORT-induced disturbances in maternal care behavior during the early postpartum, it failed to prevent the expression of CORT-induced depressive-like behavior in the late postpartum. Furthermore, FLX treatment, regardless of CORT treatment, increased maternal hippocampal IL-1{beta} and decreased maternal plasma tryptophan levels, plasma tryptophan, 4-pyridoxic acid, and pyridoxal concentrations. Maternal CORT treatment reduced maternal hippocampal TNF- and IFN-{gamma} levels. Our work suggests that the limited efficacy of FLX in the late postpartum may be associated with elevated levels of the proinflammatory cytokine IL-1{beta} in the maternal hippocampus, decreased plasma tryptophan concentration, and changes in vitamin B6 dependent tryptophan-kynurenine pathway. These findings suggest novel pathways for improving SSRI efficacy in alleviating perinatal depression. HIGHLIGHTSO_LIPostpartum fluoxetine (FLX) increased interleukin-1{beta} levels in hippocampus C_LIO_LIPostpartum corticosterone (CORT) decreased TNF- and IFN-{gamma} in the hippocampus C_LIO_LIPostpartum FLX did not prevent CORT-induced depressive-like behavior C_LIO_LIPostpartum FLX prevented CORT-induced changes in maternal behavior C_LIO_LIPostpartum FLX decreased plasma tryptophan, 4-pyridoxic acid, and pyridoxal levels C_LI

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bioRxiv2019

Sex and APOE genotype influence AD neuropathology but not epigenetic age across diagnosis

Alzheimers disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOE{varepsilon}4 allele. The risk of developing AD is also higher in female APOE{varepsilon}4 carriers in earlier age groups (aged 65-75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation. The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOE{varepsilon}4 carriers. We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOE{varepsilon}4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N= 279) and plasma (N= 527) markers of stress and inflammation. We found CSF IL-16 and IL-8 levels were significantly lower in female non-carriers of APOE{varepsilon}4 alleles compared to males, whereas levels were similar between the sexes among carriers of APOE{varepsilon}4 alleles. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOE{varepsilon}4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. Sex differences in inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.

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bioRxiv2019

Sex differences in maturation and attrition rate of adult born neurons in the hippocampus of rats

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis. Significance StatementPreviously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimers disease and depression.

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bioRxiv2019

Ovarian hormone status dictates the neuroinflammatory and behavioural consequences of sub-chronic stress exposure in middle-aged female mice

Ovarian hormones influence the outcomes of stress exposure and are implicated in stress-related disorders including depression, yet their roles are often complex and seemingly contradictory. Importantly, depression and stress exposure are associated with immune dysregulation, and ovarian hormones have immunomodulatory properties. However, how ovarian hormones can influence the inflammatory outcomes of stress exposure is poorly understood. Here, we examined the effects of long-term ovariectomy on the behavioral and neuroinflammatory outcomes of sub-chronic stress exposure in middle-aged mice. Briefly, sham-operated and ovariectomized mice were assigned to non-stress groups or exposed to 6 days of variable stress. Mice were assessed on a battery of behavioral tests, and cytokine concentrations were quantified in the frontal cortex and hippocampus. In the frontal cortex, postsynaptic density protein-95 expression was examined as an index of excitatory synapse number and/or stability, and phosphorylated mitogen-activated protein kinases (MAPKs) were measured to explore potential cell signaling pathways elicited by stress exposure and/or ovarian hormones. Long-term ovariectomy modified the central cytokine profile by robustly reducing cytokine concentrations in the frontal cortex and modestly increasing concentrations in the hippocampus. Under non-stress conditions, long-term ovariectomy also reduced extracellular signal-regulated kinase (ERK) phosphoprotein expression in the frontal cortex and increased some measures of depressive-like behavior. The effects of sub-chronic stress exposure were however more pronounced in sham-operated mice. Notably, in sham-operated mice only, sub-chronic stress exposure increased IL-1{beta} and IL-6:IL-10 ratio in the frontal cortex and hippocampus and reduced pERK1/2 expression in the frontal cortex. Further, although sub-chronic stress exposure increased anhedonia-like behavior regardless of ovarian status, it increased passive-coping behavior in sham-operated mice only. These data indicate that long-term ovariectomy has potent effects on the central cytokine milieu and dictates the neuroinflammatory and behavioral effects of sub-chronic stress exposure in middle-aged mice. These findings therefore suggest that the immunomodulatory properties of ovarian hormones are of relevance in the context of stress and possibly depression.

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bioRxiv2018

Dietary folic acid increases neurogenesis in the ventral hippocampus of adult female rats

Folate is an important regulator of hippocampal neurogenesis, and in utero spinal cord development. Both high levels of folic acid and low levels of folate can be harmful to health, as low levels of folate have been linked to several diseases while high folic acid supplements can mask a vitamin B12 deficiency. Depressed patients exhibit folate deficiencies, lower levels of hippocampal neurogenesis, elevated levels of homocysteine, and elevated levels of the stress hormone, cortisol, which may be inter-related. Here, we are interested in whether different doses of natural folate or synthetic folic acid diets can influence neurogenesis in the hippocampus, levels of plasma homocysteine, and serum corticosterone in adult female rats. Adult female Sprague-Dawley rats underwent dietary interventions for 29 days. Animals were randomly assigned to six different dietary groups: folate deficient + succinylsulfathiazole (SST), low 5-methyltetrahydrofolate (5-MTHF), low 5-MTHF + (SST), high 5-MTHF + SST, low folic acid, and high folic acid. SST was added to a subset of the 5-MTHF diets to eliminate folic acid production in the gut. Before and after dietary treatment, blood samples were collected for corticosterone and homocysteine analysis, and brain tissue was collected for neurogenesis analysis. High folic acid and low 5-MTHF without SST increased the number of immature neurons (doublecortin-expressing cells) within the ventral hippocampus compared to folate deficient controls. Low 5-MTHF without SST significantly increased the number of immature neurons compared to low and high 5-MTHF + SST, indicating that SST interfered with elevations in neurogenesis. Low folic acid and high 5-MTHF+SST reduced plasma homocysteine levels compared to controls, but there was no significant effect of diet on serum corticosterone levels. Low folic acid and high 5-MTHF+SST reduced the number of mature new neurons in the ventral hippocampus (BrdU/NeuN-positive cells) compared to folate deficient controls. Overall, folic acid dose-dependently influenced neurogenesis, with low levels decreasing but high levels increasing, neurogenesis in the ventral hippocampus, suggesting this region, which is important for regulating stress, is particularly sensitive to folic acid in diets. Furthermore, the addition of SST negated the effects of 5-MTHF to increase neurogenesis in the ventral hippocampus.

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bioRxiv2018

Letrozole increases hippocampal neurogenesis in middle-aged female mice

Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast cancer in middle-aged women. Though patient response to letrozole has generally been positive, there is conflicting evidence surrounding its impact on the development of depression. It is possible that letrozoles potential adverse effects on mood are a result of the impact of hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of letrozole on the hippocampus and behavior, we examined how chronic administration affects hippocampal neurogenesis and depressive-like behaviour in middle-aged, intact female mice. Mice were given either letrozole (1mg/kg) or vehicle by injection (ip) daily for 3 weeks. Depressive-like behaviour was assessed during the last 3 days of treatment using the forced swim test, tail suspension test, and sucrose preference test, and the production of new neurons was quantified using the immature neuronal marker, doublecortin (DCX). We found that letrozole increased DCX expression and maturation in the dentate gyrus, but had no significant effect on depressive-like behaviour. Our findings suggest that a reduction in circulating estrogens in middle-aged females increases hippocampal neurogenesis without any adverse impact on behavior; as such, this furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the utilization of letrozole in the clinical management of breast cancer.

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bioRxiv2018

Early and Late Effects of Maternal Experience on Hippocampal Neurogenesis, Microglia, and the Circulating Cytokine Milieu

The maternal brain displays considerable plasticity, and motherhood is associated with changes in affective and cognitive function. Motherhood can alter the trajectory of brain ageing, including modifications to neuroplasticity and cognition. Here, we investigated the short- and long-term effects of motherhood on hippocampal neurogenesis, microglial density and morphology, and circulating cytokines, domains known to be altered with age and implicated in cognition and mood. Female rats were bred then euthanized during gestation or at various postpartum timepoints, culminating in middle age, and nulliparous rats served as age-matched controls. Hippocampal neurogenesis was significantly suppressed during gestation and the postpartum period. Interestingly, neurogenesis declined significantly in middle-aged nulliparous rats, but increased in primiparous rats across the same period. Transient postpartum adaptations to the neuroimmune environment of the hippocampus were evidenced, as Iba-1-immunoreactive microglia assumed a de-ramified morphology followed by increased density. Intriguingly, ageing-related changes in circulating cytokines were dependent on parity. These adaptations in neurogenic and immune processes may have ramifications for maternal mood and cognition across the peripartum period and beyond.

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bioRxiv2017

Premarin has opposing effects on spatial learning, neural activation and serum cytokine levels in middle age dependent on reproductive history

Menopause is associated with cognitive decline, and hormone therapies (HT) can improve cognition dependent on time since menopause. Previous parity also influences cognition in later life. The present study investigated how primiparity and long-term ovariectomy influence cognition, hippocampal neurogenesis, and neuronal activation in middle-aged rats in response to the HT, Premarin. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin six months later, and trained in the Morris water maze. Premarin improved spatial learning and memory in nulliparous rats, but impaired spatial and reversal learning in primiparous rats. Primiparity increased hippocampal neurogenesis, whereas Premarin treatment decreased immature neurons in both primiparous and nulliparous middle-aged rats in a region-specific manner. Moreover, Premarin increased serum TNF and KC/GRO in nulliparous, but not primiparous, rats, whereas Premarin increased zif268 expression in the CA3 region of the hippocampus in primiparous rats. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, serum cytokines, and adrenal mass. These findings have implications for the tailored treatment of age-associated cognitive decline in women.

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