Biology subjects

Kentner, A. C.

Publications and source records attributed to Kentner, A. C..

11 recordsLinked to original sources

bioRxiv2026

Milk-derived extracellular vesicles are functional mediators of postnatal neuroimmune rescue

Early parental experiences can be translated into biological signals that are transmitted to offspring. These signals influence developmental trajectories to both increase offspring vulnerability following adverse experiences or promote resilience when environments are supported and enriched. Among the potential routes of parental-offspring communication, milk-derived extracellular vesicles (EVs) transferred through nursing are particularly interesting because they carry bioactive molecular cargos capable of influencing recipient cells. Previously, we found that milk-derived EV cargo is remodeled by both adverse and positive experiences and that environmental enrichment (EE) can rescue adversity-associated effects, including EV-miRNA cargo changes. Environmental programming of EVs during lactation may therefore have functional consequences on offspring development and adaptability. Here, we tested whether milk-derived EVs from our rat EE model are sufficient to rescue offspring outcomes following maternal immune activation (MIA). Milk-derived EVs isolated from donor EE dams were administered directly to MIA-exposed pups, mitigating MIA-associated reductions in social behavior. EE-EV administration also promoted social behavior in non-MIA exposed male offspring. To investigate microglia as a cellular target, EE-EVs were administered to LPS-activated BV2 microglial cells. EE-EV exposure attenuated LPS-associated transcriptional alterations across inflammatory pathways, including cytokine, chemokine, and NF-B signaling, while modulating genes associated with cellular homeostasis and metabolic responses. Together, these results 1) support milk-derived EVs as a biologically active interface through which environmental experience may be communicated to offspring, and 2) identify microglial transcriptional responses as a potential cellular pathway underlying these effects.

neuroscience↗

bioRxiv2025

Investigating milk derived extracellular vesicles as mediators of maternal stress and environmental intervention

Parental communication signals are transmitted through nursing and critically shape neurodevelopmental trajectories. Mirroring some well characterized effects of gestational challenges in rodents, maternal immune activation (MIA) during the lactational period disrupts maternal physiology, decreases lipid content, and is associated with adverse neurobehavioral outcomes in offspring. This occurs without MIA significantly affecting maternal care. While gestational MIA models are responsive to environmental interventions, which beneficially alter maternal milk composition and associated offspring outcomes, the bioactive mediators in milk underlying resilience remain poorly understood. Milk-derived extracellular vesicles (MEVs) transport and deposit biologically active cargo, including microRNAs (miRNAs) that induce post-translational regulation of candidate mRNA in the nursing offsprings tissues and cells. Using a rat model, we show that lactational MIA alters MEV-miRNA cargo and the expression of hippocampal miRNAs in offspring. Several miRNAs in MEVs were also found in the hippocampus of matching offspring. Remarkably, the miRNA changes in MEVs and the neonatal hippocampus were rescued when dams were raised in an enriched environment, suggesting environmental enrichment protected from the effects of MIA. This was supported by the behavioral phenotype. RNA-seq of adult offspring hippocampus showed long-term transcriptional changes associated with the gene targets of early-life regulated miRNAs. Our results position MEV-miRNA as dynamic programming signals by which maternal experience is communicated to offspring, encoding both stress-induced and protective cues that influence development. This suggests that breastfeeding interventions can regulate the genetic cargo of the milk, programming the life of developing infants.

neuroscience↗

bioRxiv2025

Maternal immune activation during the lactational period alters offspring behavior, reproductive development, and immune function in mice

Exposure to infection during early life can lead to lasting neurodevelopmental changes. Animal models of maternal immune activation (MIA) typically assess neurobehavioral alterations in offspring following a prenatal inflammatory challenge. However, MIA effects on offspring can extend to challenges that occur during the lactational period. In the present study, we adapted previous methods focused on rats and challenged nursing C57BL/6J mouse mothers on postnatal day (P)8 with either the bacterial mimetic lipopolysaccharide (LPS; 250 g/kg, i.p.) or saline (control, i.p.). By exposing only the mother to LPS, this modeled a postpartum infection in the dam. Similar to the rat model, lactational MIA did not detrimentally alter maternal care but induced displays of maternal sickness, as expected. While neonatal offspring behaviors (e.g., huddling, ultrasonic vocalizations, negative geotaxis) were unaffected, significant effects of lactational MIA emerged in juvenile (e.g., social preference, accelerated reproductive milestones) and adult (e.g., mechanical allodynia, prepulse inhibition) offspring. In a separate set of animals, the developmental programming potential of lactational MIA on immune function was evident following a "second hit" LPS challenge in adulthood (e.g., altered plasma concentrations of interleukin-6 and leukocytes, including neutrophils, and lymphocytes). These findings confirm the generalizability of the lactational MIA model across species and highlight the importance of supporting caregiver health and wellness across the critical nursing period.

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bioRxiv2024

Peripubertal antagonism of corticotropin-releasing factor receptor 1 results in sustained, sex-specific changes in behavioral plasticity and the transcriptomic profile of the amygdala

Peripuberty is a significant period of neurodevelopment with long-lasting effects on the brain and behavior. Blocking type 1 corticotropin-releasing factor receptors (CRFR1) in neonatal and peripubertal rats attenuates detrimental effects of early-life stress on neural plasticity, behavior, and stress hormone action, long after exposure to the drug has ended. CRFR1 antagonism can also impact neural and behavioral development in the absence of stressful stimuli, suggesting sustained alterations under baseline conditions. To investigate this further, we administered the CRFR1 antagonist (CRFR1a) R121919 to young adolescent male and female rats across 4 days. Following each treatment, rats were tested for locomotion, social behavior, mechanical allodynia, or prepulse inhibition (PPI). Acute CRFR1 blockade immediately reduced PPI in peripubertal males, but not females. In adulthood, each assay was repeated without CRFR1a exposure to test for persistent effects of the adolescent treatment. Males continued to experience deficits in PPI while females displayed altered locomotion, PPI, and social behavior. The amygdala was collected to measure long-term effects on gene expression. In the adult amygdala, peripubertal CRFR1a induced alterations in pathways related to neural plasticity and stress in males. In females, pathways related to central nervous system myelination, cell junction organization, and glutamatergic regulation of synaptic transmission were affected. Understanding how acute exposure to neuropharmacological agents can have sustained impacts on brain and behavior, in the absence of further exposures, has important clinical implications for developing adolescents.

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bioRxiv2023

Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11{beta}-hydroxylase inhibitor used to treat hypercortisolism in pregnant and neonatal populations. Maternal, placental, and fetal CNS levels of corticosterone and placental 11{beta}HSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11{beta}HSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in the ventral hippocampus of adult males, but not females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

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bioRxiv2022

Maternal immune activation accelerates puberty initiation and alters mechanical allodynia in male and female C57BL6/J mice.

The mechanisms that link maternal immune activation (MIA) with the onset of neurodevelopmental disorders remain largely unclear. Accelerated puberty is also associated with a heightened risk for psychopathology in later life but there is a dearth of evidence on the impacts of maternal infection on pubertal timing. We examined the effects of MIA on reproductive development, mechanical allodynia, and sensorimotor gating in juvenile, adolescent, and adult male and female mice. Moreover, we investigated hypothalamic neural markers associated with the reproductive and stress axes. Finally, we tested the mitigating effects of environmental enrichment (EE), which has clinical relevancy in human rehabilitation settings. Our results show that administration of polyinosinic-polycytidylic acid (poly(I:C)) on gestational day 12.5 led to early preputial separation, vaginal openings, and age of first estrus in offspring. MIA exposure altered pain sensitivity across development and modestly altered prepulse inhibition. The downregulation of Nr3c1 and Oprk mRNA in the hypothalamus of juvenile mice suggests that MIAs effects may be mediated through disruption of hypothalamic-pituitary-adrenal axis activity. In contrast, life-long housing with EE rescued many of these MIA-induced consequences. Overall, our findings suggest that accelerated puberty may be associated with the deleterious effects of infection during pregnancy and the onset of psychopathology.

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bioRxiv2022

Got Milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats

Previous studies have underscored the importance of breastfeeding and parental care on offspring development and behavior. However, their contribution as dynamic variables in animal models of early life stress are often overlooked. In the present study, we investigated how lipopolysaccharide (LPS)-induced maternal immune activation (MIA) on postnatal day (P)10 affects maternal care, milk, and offspring development. MIA was associated with elevated milk corticosterone concentrations on P10, which recovered by P11. In contrast, both milk triglyceride and percent creamatocrit values demonstrated a prolonged decrease following inflammatory challenge. Adolescent MIA offspring were heavier, which is often suggestive of poor early life nutrition. While MIA did not decrease maternal care quality, there was a significant compensatory increase in maternal licking and grooming the day following inflammatory challenge. However, this did not protect against disrupted neonatal huddling or later-life alterations in sensorimotor gating, conditioned fear, mechanical allodynia, or reductions in hippocampal parvalbumin expression in MIA offspring. MIA-associated changes in brain and behavior were likely driven by differences in milk nutritional values and not by direct exposure to LPS or inflammatory molecules as neither LPS binding protein nor interleukin-6 milk levels differed between groups. These findings reflected comparable microbiome and transcriptomic patterns at the genome-wide level. Animal models of early life stress can impact both parents and their offspring. One mechanism that can mediate the effects of such stressors is changes to maternal lactation quality which our data show can confer multifaceted and compounding effects on offspring physiology and behavior.

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bioRxiv2021

Milking it for all it's worth: The effects of environmental enrichment on maternal nurturance, lactation quality, and offspring social behavior

Breastfeeding confers robust benefits to offspring development in terms of growth, immunity, and neurophysiology. Similarly, improving environmental complexity (i.e., environmental enrichment; EE) contributes developmental advantages to both humans and laboratory animal models. However, the impact of environmental context on maternal care and milk quality has not been thoroughly evaluated, nor are the biological underpinnings of EE on offspring development understood. Here, Sprague-Dawley rats were housed and bred in either EE or standard-housed (SD) conditions. EE dams gave birth to a larger number of pups, and litters were standardized and cross-fostered across groups on postnatal day (P)1. Maternal milk samples were then collected on P1 (transitional milk phase) and P10 (mature milk phase) for analysis. While EE dams spent less time nursing, postnatal enrichment exposure was associated with heavier offspring bodyweights. Milk from EE mothers had increased triglyceride levels, a greater microbiome diversity, and a significantly higher abundance of bacterial families related to bodyweight and energy metabolism. These differences reflected comparable transcriptomic changes at the genome-wide level. In addition to changes in lactational quality, we observed elevated levels of cannabinoid receptor 1 in the hypothalamus of EE dams, and sex- and time-dependent effects of EE on offspring social behavior. Together, these results underscore the multidimensional impact of the combined neonatal and maternal environments on offspring development and maternal health. Moreover, they highlight potential deficiencies in the use of "gold standard" laboratory housing in the attempt to design translationally relevant animal models in biomedical research. Significance StatementMaternal care quality is different between environmentally enriched (EE) and standard laboratory housed (SD) dams. SD rat dams spend more time nursing their young. This may result in overfeeding which can program offspring neural stress responses. Alternatively, metabolic differences in milk may affect neurodevelopmental outcomes, which are different between EE and SD animals. To test this, we evaluated milk and offspring behavior. Milk from EE dams had elevated triglyceride levels and microbiome diversity. EE offspring had heavier body weights and increased social behavior which was lost with crossfostering into SD housing. These data identify potential deficiencies in the quality of "gold standard" laboratory housing and its impact on the welfare and design of translationally relevant animal models in biomedical research.

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bioRxiv2021

Poly (I:C)-induced maternal immune activation affects mouse visual discrimination performance and reversal learning in a sex-dependent manner.

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual discrimination (VD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the VD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a two-hit stress model (MIA + loss of the social component of environmental enrichment (EE)), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right dose, early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

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bioRxiv2021

Poly (I:C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment

Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built poorer quality nests, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers. Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA axis dysregulation. Our findings provide further evidence for the viability of EE interventions in maternal and pediatric settings. Highlights- Environmental enrichment (EE) protocols are used clinically to promote rehabilitation - Use of EE in animal models may identify mechanisms underlying clinical successes - Maternal immune activation (MIA) decreased social engagement; this effect was blocked by EE - MIA reduced c-Fos activation in the dentate gyrus, while EE reduced activation in the hypothalamus, in response to social stimuli - EE inhibited MIA-induced HPA dysregulation in ventral hippocampus

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bioRxiv2019

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of positive maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1{beta} were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.

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