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Biology subjects

Stevens, H. E.

Publications and source records attributed to Stevens, H. E..

9 recordsLinked to original sources

Coordinated Brain-Network Dynamics of Maternal Adaptation

The maternal brain exhibits impressive plasticity, undergoing many anatomical and functional alterations over the transition to parenting. Such alterations can reflect maternal adaptation to offspring needs, aligning with the onset and maintenance of maternal care behaviors. These brain-wide neural changes occur across stages, starting during pregnancy and continuing through the peripartal transition. We therefore wanted to understand brain changes with pregnancy, parenting, and care behaviors over time. Many brain regions have been implicated in the coordination of maternal adaptation and corresponding care behaviors. We used computational modeling of multi-region neural oscillation data to identify distinct electrical networks during naturally-occurring care behaviors and across multiple maternal stages in outbred, highly maternal mice. This work demonstrates that multi-region oscillatory electrical dynamics at high spatiotemporal resolution reflect these functions. Distinct, discriminative networks predict maternal behavior and stage, showcasing network adaptation with parental transition. Maternal behavior and stage also had substantial effects on other distinct, multi-region oscillatory electrical networks relevant to stress susceptibility, further linking maternal adaptation to the neurophysiology of stress. While these stress networks were perturbed by maternal experience of early life stress, networks trained on maternal behavior and stage remained robust against such perturbation. This suggests a uniquely persistent strength of maternal electrical dynamics. Together, this work supports the role of oscillatory electrical dynamics as networks underlying fundamentally conserved behaviors and transitions, demonstrating wide relevance and significance to brain-behavior discovery.

neuroscience↗

Prenatal stress interacts with embryonic loss of Fgfr2 to increase locomotor hyperactivity in mice

Attention-deficit/hyperactivity disorder (ADHD) is a developmental psychiatric disorder associated with a complex interplay of genetic and environmental risk factors. We have shown embryonic dorsal forebrain loss in mice of fibroblast growth factor receptor 2 (Fgfr2), which has a critical role in normal brain development, results in ADHD-relevant phenotypes: increased locomotion and sociability, and impaired working memory postnatally. How such genetic vulnerabilities interact with environmental exposures to translationally model human ADHD risk remains unclear. Here, we pair the embryonic hGFAP-cre Fgfr2 conditional knockout (Fgfr2 cKO) mouse model with prenatal repetitive restraint stress, modeling an environmental factor associated with ADHD risk, to assess adult offspring behaviors and dopamine transporter (DAT) levels. Offspring of prenatally stressed, Fgfr2 cKO mice show increased locomotion (80% compared to non-stressed, Fgfr2 cKO animals). Prenatal stress led to a trend increase in impulsivity and trend decrease in working memory but did not affect sociability. There were no interactions with Fgfr2 cKO observed in these behaviors. Neurobiologically, prenatal stress led to a trend decrease in medial frontal cortex DAT, but these changes did not correlate with behavior. Taken together, our findings implicate prenatal stress as a potential contributor to gene-environment interactions for ADHD risk, supporting its use in translational animal models of childhood psychiatric disorders.

neuroscience↗

Placental Insulin-like Growth Factor 1 Deficiency Drives Autism-Relevant Behavioral Changes with Sex-Specific Vulnerabilities

Preterm birth, placental insufficiency, and other perinatal adversities lead to the loss of placental support including critical hormones, such as Insulin-like growth factor 1 (IGF1), required for neurodevelopment. Decreased IGF1 and preterm birth are associated with neurodevelopmental disorder risk, including autism spectrum disorder. Whether placental Igf1 insufficiency drives neurodevelopmental risks is not understood. To understand these mechanisms, placental-targeted CRISPR manipulation in mice was employed to induce placental Igf1 insufficiency. Subsequently, embryonic forebrain development was assessed sex-specifically to identify structural, cellular, and transcriptomic changes. Postnatal offspring were used to determine neurobehavioral trajectories relevant to neurodevelopmental disorders as assessed through learning, motor, and affective behavioral tasks and neurostereology. Placental Igf1 insufficiency reduced embryonic forebrain growth, including decreased cell population across males and females. Embryonic forebrain transcriptomics revealed sex-specific alterations. Developmental pathways including insulin-like growth factor receptor signaling, laminin processes, and hormone synthesis were downregulated in male forebrain, driven by autism risk genes, Reln and Lama1. Altered genes in female forebrain were enriched for autism-risk genes including Grin2b and Dync1h1. Following these transcriptomic differences, postnatal neurobehavioral trajectories were sex-specific. Male offspring uniquely showed reduced motor learning, increased stereotyped behaviors, altered reversal learning, and reduced forebrain neuronal number. Female offspring displayed opposite behavioral changes as males and few changes in forebrain structure. Assessment of both adult male and female offspring forebrain white matter revealed an increased astrocyte population, a phenotype that appears similar to reactive astrogliosis seen in other models of preterm birth and placental insufficiency. The provision of Igf1 specifically from placenta is critical for offspring forebrain development. This temporary early deficit has persistent sex-specific neurobehavioral effects. These outcomes have relevance for neurodevelopmental disorder risk and highlight mechanisms that could facilitate intervention development for adverse outcomes after early loss of placental hormone support in perinatal adversity.

neuroscience↗

Psychiatric risk implications of adolescent exposure to environmental insecticides: a systematic review of rodent studies

Adolescence is a sensitive period of neurodevelopment marked by remodeling of brain circuits that support cognitive development and emotion and behavior regulation. These maturation processes heighten psychiatric vulnerability to environmental exposures, including to toxicants such as insecticides. Epidemiological studies show widespread adolescent insecticide exposure and increasingly link this with psychiatric outcomes, yet underlying neural mechanisms remain poorly understood. Preclinical studies can clarify these associations and identify insecticide-induced mechanisms that may disrupt neurodevelopment and produce consequent long-term behavioral outcomes. Here, we performed a systematic review of rodent studies following PRISMA guidelines. 50 original articles met inclusion criteria, examining neurotoxic outcomes following insecticide exposure during adolescence (postnatal days 21-60). Outcomes were categorized into four domains: neurocognitive, neuropsychiatric, neurobiological, and general neurotoxicity. Risk of bias was assessed using the SYRCLE Risk of Bias tool. Across studies, insecticide exposure during adolescence led to learning and memory impairments and tended to increase depression relevant behaviors, alter locomotor activity, and produce general neurotoxic effects. Mechanistic findings highlighted disruptions in cholinergic and monoaminergic signaling, oxidative stress, neuroimmune changes, and cell death and other neurodegenerative processes. Together, these findings indicate adolescent insecticide exposure disrupts multiple neural systems with behavioral consequences relevant to adolescent development and psychiatric risk. Future research should model real-world exposures (e.g. dose, timing) to better inform translational understanding of adolescent psychiatric vulnerability. Because many life-long neuropsychiatric disorders emerge in adolescence, identifying how modifiable environmental exposures shape risk offers an opportunity for prevention and intervention strategies to alter the course of disease across the lifespan.

neuroscience↗

A dataset of adult heart and liver mass after placental Insulin-like growth factor 1 overexpression and partial knockout in mice

The placenta is an important producer of hormones essential for fetal development. Insulin-like growth factor 1 (IGF1) is a hormone primarily produced in the placenta in utero and is an important regulator of various developmental pathways including those in heart and liver. Embryonic disruptions in these developmental pathways can lead to lifelong changes and are often associated with chronic disease. Further, the placenta has sex-specific impacts on offspring development in response to hormonal changes. Previous work has shown that altered expression of Igf1 in the placenta results in sexually dimorphic changes to placental and fetal developmental outcomes. Here, mice underwent placental-targeted CRISPR manipulation for overexpression or insufficiency of Igf1. At the time of euthanasia, heart and liver tissues were collected and weighed. This dataset presents the heart and liver mass of these postnatal mice. There was a significant increase in proportional heart mass in placental Igf1 overexpression adult female mice and a trending increase in proportional liver mass in placental Igf1 overexpression adult male mice. No significant changes in heart or liver mass were seen in placental Igf1 insufficiency mice. These data provide insight into the impact of placental IGF1 on long-term heart and liver development. VALUE OF THE DATAO_LIThere is significant evidence for the role of early genetic changes in influencing long-term health outcomes, as laid out by the Developmental Origins of Health and Disease (DOHaD) hypothesis [1]. According to this hypothesis, genetic factors may be critical in determining the timing and severity of chronic disease, with varying effects based on sex. Genetics of the placenta, which makes up the maternal-fetal interface, plays an important role in modulating exposures associated with the DOHaD hypothesis [2]. C_LIO_LIThe placenta provides essential hormones to the fetus during pregnancy [3]. Placental changes are associated with the development of chronic disease and metabolic changes [4,5]. Disruptions in placental functions have been linked to defects including congenital heart disease which affects approximately 40,000 babies each year in the United States [6,7]. The placenta is also linked to metabolic diseases later in life such as nonalcoholic fatty liver disease, a chronic liver disease which has increased in prevalence by over 50% from 1990 to 2019 [5,8,9]. C_LIO_LIInsulin-like growth factor 1 (IGF1) is a placentally produced factor that regulates pathways involved in fetal growth and development and has been shown to be critical in growth of the heart and liver [10-13]. Despite the importance of the placenta and IGF1 in heart and liver growth, specific links between placental Igf1 expression and developmental outcomes remain understudied. C_LIO_LIPlacental function is known to have sex-specific impacts on fetal growth [14]. Further, Igf1 expression in the placenta is linked to differences in offspring developmental outcomes by sex [15]. Placental Igf1 overexpression and insufficiency affect offspring in a sexually dimorphic manner. IGF1 is a hormone and interacts with sex hormones, likely contributing to sex differences in response to changes in Igf1 expression [16]. Further research, including the work done to produce this dataset, may help clarify the role of placenta Igf1 expression in fetal outcomes, specifically regarding sex differences. C_LIO_LIThe data presented in this paper provide insight into the effects of placental Insulin-like growth factor 1 overexpression and insufficiency on adult heart and liver mass. More research is needed to understand specific functional impacts on these organs. Further, understanding the effects of placental genetic changes may support the development of future treatments and therapies for placental insufficiencies. C_LI

physiology↗

Placental Igf1 Overexpression Sex-Specifically Impacts Mouse Placenta Structure, Altering Offspring Striatal Development and Behavior

Insulin-like growth factor 1 (IGF1) is produced primarily in the placenta in utero and is an essential hormone for neurodevelopment. Specifically, how placental IGF1 production persistently influences the brain is unclear. This study evaluated the effects of placental Igf1 overexpression on embryonic and postnatal brain development, particularly for striatum, a region highly linked to neurodevelopmental disorders. Placental Igf1 was overexpressed via placental-targeted CRISPR manipulation. This overexpression altered placenta structure and function distinctly in females and males. Early differences in placental function altered the trajectory of striatal development, as adult females showed persistent changes in striatal cell composition and striatal dependent behavior while males were less affected in brain and behavior outcomes. Overall, these results demonstrate that placental Igf1 expression alters striatal development and behavior in ways relevant to neurodevelopmental disorders. These findings expand our understanding of placental influence on neurodevelopment and will aid in identifying placental-targeted preventive interventions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/644829v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@22f53borg.highwire.dtl.DTLVardef@1120913org.highwire.dtl.DTLVardef@111c61forg.highwire.dtl.DTLVardef@1e6531d_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

Maternal α-cypermethrin and permethrin exert differential effects on fetal growth, placental morphology, and fetal neurodevelopment in mice

Pyrethroid insecticides represent a broad class of chemicals used widely in agriculture and household applications. Human studies show mixed effects of maternal pyrethroid exposure on fetal growth and neurodevelopment. Assessment of shared pyrethroid metabolites as a biomarker for exposure obscures effects of specific chemicals within this broader class. To better characterize pyrethroid effects on fetal development, we investigated maternal exposure to permethrin, a type I pyrethroid, and -cypermethrin, a type II pyrethroid, on fetal development in mice. Pregnant CD1 mice were exposed to permethrin (1.5, 15, or 50 mg/kg), -cypermethrin (0.3, 3, or 10 mg/kg), or corn oil vehicle via oral gavage on gestational days (GD) 6-16. Effects on fetal growth, placental toxicity, and neurodevelopment were evaluated at GD 16. Cypermethrin, but not permethrin, significantly reduced fetal growth and altered placental layer morphology. Placental RNAseq analysis revealed downregulation of genes involved in extracellular matrix remodeling in response to -cypermethrin. Both pyrethroids induced shifts in fetal dorsal forebrain microglia morphology from ramified to ameboid states; however, effects of -cypermethrin were more pronounced. The -cypermethrin transcriptome of fetal dorsal forebrain implicated altered glutamate receptor signaling, synaptogenesis, and c-AMP signaling. Coregulated gene modules in individual placenta and fetal dorsal forebrain pairs were correlated and overlapped in biological processes characterizing synapses, mitotic cell cycle, and chromatin organization, suggesting placenta-fetal brain shared mechanisms with -cypermethrin exposure. In summary, maternal type II pyrethroid -cypermethrin exposure but not type I pyrethroid permethrin significantly affected placental development, fetal growth, and neurodevelopment, and these effects were linked.

pharmacology and toxicology↗

Threshold effects of prenatal stress on striatal microglia and relevant behaviors

AbstractPrenatal stress, a risk factor for neurodevelopmental disorders (NDDs), leads to immune alterations, including offspring neuroimmune cells. Differences in offspring outcomes may arise from whether the extent of prenatal stress crosses "thresholds" for effects on specific outcomes. Therefore, we sought to determine offspring outcomes using models with different extents of prenatal stress. We focused on striatal outcomes, because of their relevance for NDDs. Pregnant CD1 mice were assigned to four groups (each: N=6): no stress ("NoS") or one of the following stressors administered three times daily: i.p. saline injections (low prenatal stress, LoS), Interleukin-6 injections as a component of prenatal stress (immune prenatal stress; ImS), or restraint stress + saline injections (high prenatal stress, HiS), embryonic day 12-18. In adult offspring, HiS altered striatal-dependent behavior across males and females, while ImS induced fewer behavioral changes, and LoS did not affect behavior. Adult striatal microglia morphologies were mostly unchanged across groups, with only HiS leading to altered striatal density of minimally ramified cells. However, embryonic striatal microglia were affected by all models of stress, albeit in distinct ways. The HiS model, and to a lesser extent LoS, also influenced immune components of the maternal-fetal interface: placental macrophages. In conclusion, high and immune stress affected adult striatal-dependent behavior, exceeding the threshold necessary for persistent impacts, but all stress models affected embryonic microglia, suggesting that early neuroimmune outcomes had a lower threshold for impacts. Distinct severities and aspects of prenatal stress may therefore underlie different outcomes relevant to NDDs.

neuroscience↗

Long-term, cell type-specific effects of prenatal stress on dorsal striatum and relevant behaviors in mice

Maternal stress during pregnancy, or prenatal stress, is a risk factor for neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD). In ASD, dorsal striatum displays abnormalities correlating with symptom severity, but there is a gap in knowledge about dorsal striatal cellular and molecular mechanisms that may contribute. Using a mouse model, we investigated how prenatal stress impacted striatal-dependent behavior in adult offspring. We observed enhanced motor learning and earlier response times on an interval timing task, with accompanying changes in time-related medium spiny neuron (MSN) activity. We performed adult dorsal striatal single-cell RNA sequencing following prenatal stress which revealed differentially expressed genes (DEGs) in multiple cell types; downregulated DEGs were enriched for ribosome and translational pathways consistently in MSN subtypes, microglia, and somatostatin neurons. DEGs in MSN subtypes over-represented ASD risk genes and were enriched for synapse-related processes. These results provide insights into striatal alterations relevant to neurodevelopmental disorders.

neuroscience↗