Biology subjects

Lamers, Y.

Publications and source records attributed to Lamers, Y..

4 recordsLinked to original sources

bioRxiv2023

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

Female sex and Apolipoprotein E (APOE) {varepsilon}4 genotype are top non-modifiable risk factors for Alzheimers 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 APOE{varepsilon}4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOE{varepsilon}4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOE{varepsilon}4 genotype synergistically modulate neuroinflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOE{varepsilon}4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscores the importance of considering female-specific factors and genotype in health research. O_LSTHighlightsC_LSTO_LIhAPOE{varepsilon}4 rats made more errors and used a non-spatial cognitive strategy C_LIO_LIPrimiparous hAPOE{varepsilon}4 rats increased use of a non-spatial cognitive strategy C_LIO_LIParity increased neurogenesis in wildtype rats, but decreased it in hAPOE{varepsilon}4 rats C_LIO_LIPrimiparous hAPOE{varepsilon}4 rats had less active new neurons in response to memory retrieval C_LIO_LIParity and hAPOE{varepsilon}4 affect the neuroimmune milieu in a region-specific manner C_LI

neuroscience↗

bioRxiv2023

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

Pregnancy is marked by brain changes to volume, structure, connectivity, some of which are long-lasting. Few studies have examined possible mechanisms of these changes or the effects of multiple pregnancies. Here, we characterized various cellular and molecular signatures of parity (nulliparous, primiparous, biparous) in the hippocampus, an important area for cognitive and emotional regulation, and in plasma. We investigated density of neural stems cells (Sox2) and microglia (Iba-1), and levels of the postsynaptic density protein (PSD-95), cell signalling pathways, hippocampal and peripheral inflammation and the tryptophan-kynurenine (TRP-KYN) pathway, at 1 week after weaning (7 months) and in middle-age (13 months). Parity increased PSD-95 levels in both age groups and prevented the age-related decrease in neural stem cell density observed in nulliparous rats. Biparity increased cell signalling phosphoproteins (pp706sk, S6RP) and number of microglia in the dentate gyrus, regardless of age. Parity resulted in transient changes to the TRP-KYN system and peripheral inflammation. Thus, parity has lasting effects on synaptic plasticity and alters the trajectory of hippocampal aging. Highlights- Parity increased the postsynaptic protein PSD-95 in the hippocampus, regardless of age. - Biparity increased microglial density and cell signalling in the hippocampus, regardless of age. - Parity prevented the age-related decline in hippocampal neural stem cells. - Parity transiently increased tryptophan-kynurenine pathway metabolites. - Aging reduced plasma cytokine levels, an effect more prominent with nulliparity.

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

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↗