Biology subjects

Duarte-Guterman, P.

Publications and source records attributed to Duarte-Guterman, P..

10 recordsLinked to original sources

bioRxiv2026

Can you run from your worries? The effects of exercise on anxiety-like behaviour and immune signaling in female and male mice

Exercise is a positive health behaviour associated with improved mood. However, the mechanisms underlying the benefits of exercise on affective health are unclear, particularly with respect to type of exercise and sex. Chronic exercise decreases neuroinflammation, which is linked to improvements in mood and anxiety. However, exercise is also a physiological stressor that can transiently upregulate systemic inflammation, and its effects on neuroinflammation are not well understood. This study examined how acute and chronic exercise affect circulating and brain cytokine levels and anxiety-related behaviour in young healthy male and female mice. In Experiment 1, mice were placed on a treadmill for a two-hour bout of moderate exercise. Two hours after exercise, animals were either tested in the open field or euthanized for measurement of cytokines (IL-1{beta}, TNF, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IFN-{gamma}, KC/GRO). In Experiment 2, mice underwent an 8-week moderate treadmill exercise paradigm followed by open field testing and tissue collection. Acute exercise decreased time spent in the centre of the open field in males only, suggesting increased anxiety-like behaviour in males. Acute exercise increased IL-6 and decreased TNF in serum, and increased amygdala principal component 1 (loading IL-12p70, IL-10, IFN-{gamma}, and TNF) in both sexes. Chronic exercise increased open field centre entries, increased IL-6 in the prefrontal cortex, decreased TNF in the dorsal hippocampus, and had minimal effects on circulating cytokines in both sexes. These results demonstrate that the effects of exercise on anxiety-related behaviour and cytokine levels depend on recurrence, tissue, and brain region. NEW & NOTEWORTHYOur work highlights the contrast between anxiogenic and anxiolytic effects of acute versus chronic exercise, respectively, in healthy mice. Acute and chronic exercise differentially affected circulating and brain cytokines, providing insight into physiological adaptations to exercise. Both sexes demonstrated similar cytokine responses to exercise. These similarities are novel with respect to exercise research and noteworthy given sex differences in anxiety with respect to acute exercise.

neuroscience↗

bioRxiv2025

Cell Type-Specific Remodelling of the Female Hippocampus by Reproductive Experience and Age

BackgroundThe hippocampus undergoes extensive cellular remodelling throughout life. Parity, the experience of pregnancy and motherhood, triggers profound hormonal changes which modulate brain plasticity in the short and long term. Signatures of past parity are seen in the middle-aged hippocampus in humans and rodents, but how parity shapes cellular composition long-term after pregnancy have not been systematically examined using quantitative, cell-type-specific approaches. MethodsWe performed cell type deconvolution on bulk RNA-sequencing data from female rat hippocampus, comparing nulliparous and parous females across age (7 or 13 months either 30 days or 7 months after parturition). We harmonized 349 cell type annotations from three single-cell reference datasets into 27 biologically coherent categories using female-only data. Three-way ANOVA identified independent and interactive effects, while complementary analyses (random forest, PCA, DESeq2) identified parity-associated transcriptional signatures. Cell-specific functional enrichment employed weighted gene set meta-analysis across multiple pathway databases. ResultsAge emerged as the dominant factor, significantly altering six cell types, particularly somatostatin (SST) and parvalbumin/Vip interneurons. Regional effects (dorsal and ventral hippocampus) affected nine cell types, while age x region interactions identified two cell types. Parity independently affected three populations: dorsal CA3 pyramidal neurons, SST interneurons, and astrocytes. Cell-type-specific pathway analysis revealed distinct mechanisms including protein degradation in CA3 neurons, stress-response regulation in astrocytes, and disrupted GPCR/signalling-receptor programs in SST interneurons. ConclusionsOur study shows that parity selectively remodels hippocampal cellular architecture through distinct, cell-type-specific molecular programs operating independently of age and region, establishing parity as a critical biological variable in aging research.

neuroscience↗

bioRxiv2025

Cross-fostering affects microglia and cell death in the hippocampus of female and male degu pups

Parental care is essential for social, behavioural, and neural development of offspring. Disruption of parental care, for example through parental separation, can negatively affect offspring development in rodents. While previous work has focused on maternal and paternal deprivation, the effects of cross-fostering, another form of parental-offspring instability, on brain development remain poorly understood. Such disruptions are thought to induce stress, which in turn can suppress neurogenesis and increases inflammation and apoptosis in the hippocampus, with effects that often differ between sexes. Given that degus (Octodon degus) are born precocial and form strong attachments with their parents early in life, this study aimed to investigate the effect of cross-fostering on hippocampal development in female and male degu pups. At postnatal day 8, degus were assigned to either control (pups remained with parents and littermates), partial cross-foster (one pup per litter was cross-fostered), or full cross-foster (the entire litter was cross-fostered) conditions. At weaning (5-weeks-old), offspring brains were collected for immunohistochemistry to examine dentate gyrus volume, density of pyknotic cells, density of immature neurons, and number and morphology of microglia. Both types of cross-fostering reduced hippocampal cell death in both sexes relative to controls, while no significant effects were observed in the dentate gyrus volume or density of immature neurons. Cross-fostering did not affect total microglia density in either sex however full cross-fostered females had fewer amoeboid microglia compared to female controls. Together, these findings indicate that cross-fostering affects hippocampal microglia and cell death in pups, potentially disrupting circuit refinement and plasticity during development, with effects that vary by cross-fostering type, sex, and hippocampal region.

neuroscience↗

bioRxiv2023

Running to remember: The effects of exercise on perineuronal nets, microglia, and hippocampal angiogenesis in female and male mice

Exercise is accepted as a positive health behaviour; however, the mechanisms of exercise on neuroprotection and cognitive health are not completely understood. The purpose of this study was to explore the neurobiological benefits of chronic treadmill exercise in female and male mice through its role in microglial content and morphology, cerebral vascularization, and perineuronal net (PNN) expression. We further examined how these neurobiological changes relate to spatial memory outcomes. Adult mice were assigned to a sedentary or treadmill exercise group for eight weeks. During the final week, all mice were trained on a spatial memory task (Barnes maze) and brains were collected for immunohistochemistry. Exercised mice made fewer errors than sedentary mice during the first two days of training and probe trial. Females, regardless of exercise training, made fewer errors during Barnes maze training and demonstrated a greater frequency of spatial strategy use compared to males. Exercised mice, regardless of sex, had fewer PNNs in the dentate gyrus of the hippocampus compared to sedentary controls. The number of PNNs in the dorsal dentate gyrus was positively correlated with total errors during training. During the probe, greater errors correlated with more PNNs among the exercised group only. Microglia count and cerebral vascularization were not affected by exercise, although proportions of microglia type (ameboid, stout/thick, and thick/thin) were regulated by exercise in the ventral dentate gyrus. We conclude that exercise decreases PNNs in the dentate gyrus in both sexes and this may be related to better spatial learning and memory.

neuroscience↗

bioRxiv2023

Brain aromatase dynamics reflect parental experience and behaviour in male mice

In most mammals, paternal care is not mandatory for raising offspring. In house mice, experience with pups governs the extent and quality of paternal care. First-time fathers undergo a dramatic transition from ignoring or killing pups to caring for pups. The behavioral shift occurs together with changes in brain estrogen signaling as indicated by changes in estrogen receptor presence and distribution in multiple areas regulating olfaction, emotion, and motivation. Here, we report changes in the expression of aromatase, the enzyme converting testosterone into estrogen, as an indirect measure of estrogen synthesis. The amount of paternal experience (5 or 27 days) was associated with increased numbers of immunocytochemically-identified aromatase expressing cells in the medial and cortical amygdala, posterior piriform cortex, and ventromedial hypothalamus. Functionally, these changes can be related to the disappearance of aggression or neglect towards pups when first-time fathers or, even more, well-experienced fathers are handling their own pups. In the lateral septum, the anterior piriform cortex and to some extent in the medial preoptic area, parental experience increased the number of aromatase-positive cells only in fathers with 27 days of experience, and only in the right hemisphere. This is a new case of brain-functional lateralization due to experience that has activated certain instinctive behavior. Nuclei/areas associated with maternal care (medial preoptic area, bed nucleus of stria terminalis, nucleus accumbens) exhibited a left-hemisphere advantage in aromatase expressing cells, both in pup-naive and pup-experienced males. This newly found lateralization may contribute to the left-hemisphere dominant processing and perception of pup calls to release parental behavior. In general, the experience-dependent changes in aromatase expression we observed in most brain areas did not mirror the previously reported changes in estrogen receptors (ER) when pup-naive males became pup-caring fathers. Hence, paternal behavior may depend in a brain area-specific way on the differential action of estrogen through its receptors and/or direct local modulation of neural processing.

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

neuroscience↗

bioRxiv2019

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, TRIOZANTM (Ovensa Inc.), which permits greater blood-brain-barrier penetration. Adult male and female rats were injected daily (i.p.) for 10 days with either: oxytocin in PBS (0.5 or 1.0 mg/kg), oxytocin in TRIOZANTM (0.5 or 1.0 mg/kg), or vehicle (PBS) and tested for social investigation. Oxytocin decreased body mass and increased social investigation and number of oxytocin-immunoreactive cells in the supraoptic nucleus (SON) of the hypothalamus in male rats only. In both sexes, oxytocin decreased the number of immature neurons (doublecortin+ cells) in the ventral hippocampus and reduced plasma 17{beta}-estradiol levels in a dose- and delivery-dependent way. Oxytocin in TRIOZANTM reduced sedation observed post-injection and increased some central effects (oxytocin levels in the hypothalamus and ventral hippocampus neurogenesis) relative to oxytocin in PBS indicating that the nanoparticle may be used as an alternative brain delivery system. We showed that oxytocin has sex-specific effects on social investigation, body mass, sedation, and the oxytocin system. In contrast, similar effects were observed in both sexes in neurogenesis and plasma 17{beta}-estradiol. Our work suggests that sex differences in oxytocin regulation of brain endpoints is region-specific (hypothalamus versus hippocampus) and that oxytocin does not promote social investigation in females.

neuroscience↗

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.

neuroscience↗

bioRxiv2019

Androgens enhance adult hippocampal neurogenesis in males but not females in an age-dependent manner

Androgens (testosterone and dihydrotestosterone) increase adult hippocampal neurogenesis by increasing new neuron survival in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in females and whether the effect is age-dependent. We investigated the effects of dihydrotestosterone, a potent androgen, on neurogenesis in adult and middle-aged males and females. Rats were gonadectomized and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU). The following day rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell proliferation (Ki67) and new neuron survival (BrdU and BrdU/NeuN) in the hippocampus of male and female rats using immunohistochemistry. As expected, DHT increased new neuron survival in young males but surprisingly not in middle-aged male rats. In females, DHT did not significantly affect adult neurogenesis in young or middle age. Our results indicate that DHT regulates adult hippocampal neurogenesis in a sex- and age-dependent manner.

neuroscience↗

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.

neuroscience↗