Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age.

Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer's disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats.

Cellular and molecular signatures of motherhood in the adult and ageing rat brain.

Pregnancy is marked by robust changes, including brain changes to volume, structure, connectivity and neuroplasticity. Although some brain changes are restricted to pregnancy and the postpartum, others are long-lasting. Few studies have examined possible mechanisms of these changes or the effects of multiple pregnancies.

Are sex differences in cognitive impairment reflected in epigenetic age acceleration metrics?

Sex differences are well-established in Alzheimer's disease (AD) frequency and pathogenesis, but are not mechanistically understood. Accelerated epigenetic age has been associated with both cognitive aging and AD pathophysiology, but has not been studied by sex in AD or related cognitive impairment. Using the ADNI cohort, we found that none of sex, cognitive impairment diagnosis, nor load of APOEε4 alleles (strongest genetic AD risk factor) were associated with epigenetic age acceleration (DNAmAge, Intrinsic DNAmAge, PhenoAge, or GrimAge), although females exhibit more accelerated epigenetic aging using the Skin & Blood clock in the transition from normal cognition to cognitive impairment than males.

Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin.

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring.

Sex influences the effects of APOE genotype and Alzheimer's diagnosis on neuropathology and memory.

Alzheimer's disease (AD) is characterized by severe cognitive decline and pathological changes in the brain (brain atrophy, hyperphosphorylation of tau, and deposition of amyloid-beta protein). Females have greater neuropathology (AD biomarkers and brain atrophy rates) and cognitive decline than males, however these effects can depend on diagnosis (amnestic mild cognitive impairment (aMCI) or AD) and APOE genotype (presence of ε4 alleles). Using the ADNI database (N = 630 females, N = 830 males), we analyzed the effect of sex, APOE genotype (non-carriers or carriers of APOEε4 alleles), and diagnosis (cognitively normal (CN), early aMCI (EMCI), late aMCI (LMCI), probable AD) on cognition (memory and executive function), hippocampal volume, and AD biomarkers (CSF levels of amyloid beta, tau, and ptau).

Inflammation in Alzheimer's Disease: Do Sex and APOE Matter?

Background: Alzheimer's disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOEɛ4 allele. The risk of developing AD is also higher in female APOEɛ4 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.

Postpartum fluoxetine increased maternal inflammatory signalling and decreased tryptophan metabolism: 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.

Oxytocin has sex-specific effects on social behaviour and hypothalamic oxytocin immunoreactive cells but not hippocampal neurogenesis in adult rats.

Oxytocin regulates social behaviours, pair bonding and hippocampal neurogenesis but most studies have used adult males. Our study investigated the effects of oxytocin on social investigation and adult hippocampal neurogenesis in male and female rats. Oxytocin has poor penetration of the blood-brain barrier, therefore we tested a nanoparticle drug, TRIOZAN™ (Ovensa Inc.

Selective activation of estrogen receptors α and β: Implications for depressive-like phenotypes in female mice exposed to chronic unpredictable stress.

The estrogen receptor (ER) mechanisms by which 17β-estradiol influences depressive-like behaviour have primarily been investigated acutely and not within an animal model of depression. Therefore, the current study aimed to dissect the contribution of ERα and ERβ to the effects of 17β-estradiol under non-stress and chronic stress conditions. Ovariectomized (OVX) or sham-operated mice were treated chronically (47 days) with 17β-estradiol (E2), the ERβ agonist diarylpropionitrile (DPN), the ERα agonist propylpyrazole-triol (PPT), or vehicle.

Androgens Enhance Adult Hippocampal Neurogenesis in Males but Not Females in an Age-Dependent Manner.

Androgens (testosterone and DHT) increase adult hippocampal neurogenesis by increasing survival of new neurons in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in female rats and whether the effect is age-dependent. We investigated the effects of DHT, a potent androgen, on neurogenesis in young adult and middle-aged male and female rats. Rats were gonadectomized and injected with the DNA synthesis marker bromodeoxyuridine (BrdU).

The long and short term effects of motherhood on the brain.

Becoming a mother is associated with dramatic changes in physiology, endocrinology, immune function, and behaviour that begins during pregnancy and persists into the postpartum. Evidence also suggests that motherhood is accompanied by long-term changes in brain function. In this review, we summarize the short (pregnancy and postpartum) and long-term (beyond the postpartum and into middle age) effects of pregnancy and motherhood on cognition, neuroplasticity, and neuroimmune signalling.

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history.

Menopause is associated with cognitive decline, and hormone therapies (HTs) may improve cognition depending on type and timing of HTs. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT.

Neural androgen receptors affect the number of surviving new neurones in the adult dentate gyrus of male mice.

Adult hippocampal neurogenesis occurs in many mammalian species. In rats, the survival of new neurones within the hippocampus is modulated by the action of androgen via the androgen receptor (AR); however, it is not known whether this holds true in mice. Furthermore, the evidence is mixed regarding whether androgens act in neural tissue or via peripheral non-neural targets to promote new neurone survival in the hippocampus.

Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults.

This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus.

Estradiol and GPER Activation Differentially Affect Cell Proliferation but Not GPER Expression in the Hippocampus of Adult Female Rats.

Estradiol increases cell proliferation in the dentate gyrus of the female rodent but it is not known whether the G protein-coupled estrogen receptor (GPER), a membrane receptor, is involved in this process, nor whether there are regional differences in estradiol's effects on cell proliferation. Thus, we investigated whether estradiol exerts its effects on cell proliferation in the dorsal and ventral dentate gyrus through GPER, using the GPER agonist, G1, and antagonist, G15. Ovariectomized adult female rats received a single injection of either: 17β-estradiol (10 μg), G1 (0.

Mechanisms of crosstalk between endocrine systems: regulation of sex steroid hormone synthesis and action by thyroid hormones.

Thyroid hormones (THs) are well-known regulators of development and metabolism in vertebrates. There is increasing evidence that THs are also involved in gonadal differentiation and reproductive function. Changes in TH status affect sex ratios in developing fish and frogs and reproduction (e.

Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females.

Sexing frogs by real-time PCR: using aromatase (cyp19) as an early ovarian differentiation marker.

Most anurans have no identified sex-markers; therefore, alternative methods for identification of early changes in sex ratios are required. In this study, Lithobates sylvaticus and Silurana tropicalis tadpoles were sampled at different developmental stages covering the entire process of sex differentiation. Three candidate genes known to be involved in sex differentiation in other vertebrate species were selected to develop a method to identify phenotypic sex in frogs: cytochrome p450 aromatase (cyp19), forkhead box L2 (foxl2) and the cytochrome 17-alpha-hydroxylase/17,20 lyase (cyp17).

Developmental expression of sex steroid- and thyroid hormone-related genes and their regulation by triiodothyronine in the gonad-mesonephros of a Neotropical frog, Physalaemus pustulosus.

Gonadal differentiation in frogs is affected by sex steroids and thyroid hormones (THs); however, the genes controlling differentiation and the molecular effects of THs in the gonad are not clear and have only been investigated in a few anuran species. In this study, we established developmental profiles and TH regulation of sex steroid- and TH-related genes in the gonad-mesonephros complex (GMC) of the túngara frog (Physalaemus pustulosus), and compared the results to our previous research in another tropical frog, Silurana tropicalis. The developmental profiles allowed us to identify three genes as markers of ovarian development.

Developmental profiles and thyroid hormone regulation of brain transcripts in frogs: a species comparison with emphasis on Physalaemus pustulosus.

In amphibians, thyroid hormones (THs) are considered key regulators of brain remodeling during metamorphosis, while sex steroids (estrogens and androgens) control sexual differentiation and gonadal development. However, these two endocrine axes can interact during tadpole brain development. Previously, we demonstrated that THs affect sex steroid-related gene expression in the developing brain of Silurana tropicalis and Rana pipiens; however, the gene expression changes differed between species.

Expression profiles of reproduction- and thyroid hormone-related transcripts in the brains of chemically-induced intersex frogs.

Endocrine disrupting chemicals can induce intersex animals in amphibians and fish. Our previous study in frogs demonstrated that chemically-induced intersex animals can display different hepatic profiles of transcript levels than normal animals. In this study, we extend the observations to the developing frog brain.

Waterborne fluoxetine disrupts the reproductive axis in sexually mature male goldfish, Carassius auratus.

Fluoxetine (FLX) is a pharmaceutical acting as a selective serotonin reuptake inhibitor and is used to treat depression in humans. Fluoxetine and the major active metabolite norfluoxetine (NFLX) are released to aquatic systems via sewage-treatment effluents. They have been found to bioconcentrate in wild fish, raising concerns over potential endocrine disrupting effects.

Transcript profiles and triiodothyronine regulation of sex steroid- and thyroid hormone-related genes in the gonad-mesonephros complex of Silurana tropicalis.

In amphibians, the main role of thyroid hormones (THs) is to regulate metamorphosis; however, there is evidence that THs also affect gonadal sexual differentiation. In this study, Silurana (Xenopus) tropicalis tadpoles were exposed to triiodothyronine (T3; 0, 0.5, 5 and 50 nM), the bioactive form of THs for 48h.

Preexposure to ultraviolet B radiation and 4-tert-octylphenol affects the response of Rana pipiens tadpoles to 3,5,3'-triiodothyronine.

Exposure to multiple environmental stressors is negatively impacting the health of amphibians worldwide. Increased exposure to ultraviolet B radiation (UVBR) and chemical pollutants may affect amphibian populations by disrupting metamorphosis; however, the actual mechanisms by which these stressors affect development remain unknown. Because amphibian metamorphosis is controlled by thyroid hormones (TH), changes in developmental rates by environmental stress suggest a disruption of the thyroid system.