Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633–0.773; juvenile USVs, d = 1.103–1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36

While Alzheimer's Disease (AD) typically triggers cognitive decline, some individuals with significant AD pathology maintain normal cognition into late life. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia. To this end, we used cognitive testing to identify a subset of cognitively resilient 13-month-old TgF344-AD rats (established AD) and their non-transgenic littermates, followed by Neuropixels recording from 8500 neurons during repeated somatosensory stimulation. Cognitively resilient TgF344-AD rats recruited fewer neurons yet displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness during network activation and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid and tau levels. For the first time, our study revealed neuronal population-level hallmarks of maintained cognition that may serve as a novel neurophysiological biomarker of cognitive resilience and a target for stabilizing cognition.

BACKGROUND:Integrase strand transfer inhibitors (INSTIs) are preferred for treatment of human immunodeficiency virus (HIV). However, safety data in pregnancy are limited for newer INSTIs. METHODS:Pregnant C57BL/6 mice were randomly allocated to control (water), dolutegravir (DTG), raltegravir (RAL), bictegravir (BIC), or cabotegravir (CAB) at clinically relevant doses, administered orally with tenofovir disoproxil fumarate and emtricitabine, once daily from gestational day (GD) 0.5 to sacrifice (GD 15.5). Fetuses were assessed for gross anomalies. Descriptive statistics were used to compare proportions of gross anomalies. RESULTS:In total, 550 litters (115 in the control group, 150 for DTG, 113 for RAL, 79 for BIC, and 93 for CAB) were assessed. RAL was associated with the highest fetal weight, placental weight, and fetal-placental weight ratio (placental efficiency). Fetal weight, placental efficiency, and litter size were lowest in BIC and CAB. Neural tube defects were observed only in INSTI groups, with litter prevalence rates of 0.66% for RAL, 0.45% for DTG, 0.39% for BIC, 0.15% for CAB, and 0% for the control. Tail defects, eye defects, bleeding defects, cranial swelling, and growth restriction were significantly more common in all INSTI groups than in the control group. Overall rates of defects were lowest with DTG. Compared with the DTG group, limb and tail defects (indicative of spinal dysraphism) were significantly more prevalent in the RAL group, while bleeding defects were significantly more prevalent in the BIC and CAB groups. CONCLUSIONS:While INSTIs represent a critical advance in the management of HIV infection, the findings of the current study demonstrate a link between INSTI therapy and adverse fetal outcomes. This highlights the need for continued surveillance of pregnancy outcomes in women exposed to INSTIs.

Introduction: The timing of myelination during development varies spatially according to the evolving functional demands of the maturing brain and is likely a mechanism of plasticity that contributes to sensitive periods of brain development during which the brain has heightened susceptibility to environmental influences. Disruption to this myelination process is therefore likely to have spatially and temporally heterogeneous effects. Myelinating oligodendrocytes arise from the differentiation of oligodendrocyte precursor cells, a process that depends on the transcription factor Myrf. In this study, the inducible Myrf conditional knockout mouse model is leveraged to characterize the impact of inhibiting oligodendrogenesis during the juvenile or adolescent period on white matter tracts with different timing of maturation. Methods: Electron microscopy (EM) was used to quantify the fraction of myelinated axons, axon diameter, and myelin thickness, or T2- and diffusion-weighted MRI (dMRI) were used to compute white matter volumes and measures sensitive to microstructure. Results: Mice with inhibited oligodendrogenesis during the juvenile period had a lower fraction of myelinated axons in the corpus callosum, which was not the case when oligodendrogenesis was halted during adolescence. Halting oligodendrogenesis in either developmental period had no effect on myelinated fraction in the earlier-to-mature optic tracts. Halted oligodendrogenesis during the juvenile period was detected with MRI as decreased volume of late-myelinating structures (corpus callosum, anterior commissure, and fornix) relative to controls. No group differences were observed in dMRI measures. Additionally, thinner myelin on larger calibre axons in the optics tracts of adolescent mice with halted oligodendrogenesis was detected with EM, but no MRI measures were sensitive to this difference. Conclusion: This study demonstrates that the impact of disrupting developmental oligodendrogenesis on white matter differs depending on the timing of disruption relative to the developmental stage of the structure. The results also highlight that morphological measures from structural MRI have high sensitivity to disrupted developmental myelination of white matter tracts.

Antiretroviral therapy (ART) has dramatically reduced perinatal HIV transmission, leading to a growing population of children who are HIV-exposed but uninfected (CHEU). While the neuroanatomic developmental impacts of in utero HIV and ART exposure have been studied in young children, long-term effects on school-aged children are poorly understood, prompting this investigation. Fifty-eight CHEU and 38 children who are HIV-unexposed, uninfected (CHUU), 6–12 years old, were recruited through hospitals and community groups in Ontario, Canada. From T1-weighted magnetic resonance images, volume, cortical thickness, and gray-/white-matter tissue volume were extracted. Multiple linear regression models controlling for sex, age, household income, and total brain volume were fit to assess differences by in utero HIV exposure, with additional sex-stratified analyses to uncover sex-specific effects. Compared with CHUU, CHEU showed total brain volumes that were significantly smaller by 49.7cm3 (95

Newborns with congenital heart diseases requiring cardiopulmonary bypass (CPB) are at risk of neurodevelopmental impairment. The impact of deep hypothermia cardiopulmonary bypass (DH-CPB) on cerebrovascular autoregulation (CAR) that controls brain perfusion in the presence of blood pressure variation is not well understood. Recently, ultrafast power Doppler (UPD) showed potential to study CAR in neonates based on cerebral blood volume (CBV). However, since CAR relies mainly on arterial vasoconstriction/vasodilation, monitoring of brain perfusion variation based on CBV requires the discrimination of arterial from venous CBV. This study aims to use UPD combined with an algorithm for the discrimination of arteries and veins to monitor CAR during DH-CPB in neonates. Transfontanellar ultrafast power Doppler was performed in two groups of newborns: those undergoing deep hypothermic cardiopulmonary bypass with circulatory arrest (18–20 °C, n = 6, “DH group”) and those undergoing full-flow CPB at mild hypothermia (32–34 °C, n = 6, “non-DH group”). Blood flow directionality was used to differentiate arterial compartments of CBV from venous CBV in specific brain regions where arterial and venous flows exhibit opposite directions. To study CAR, a linear mixed effect model was used to find the association between arterial CBV and mean arterial blood pressure (MAP). In the “non-DH group”, we found a negative association between arterial CBV and MAP, indicating that an increase in MAP is associated with a decrease in arterial CBV (slope = -0.020 $$\:{mmHg}^{-1}$$ , p = 0.047). Conversely, in the “DH group” no significant association was found such that arterial CBV remained stable as MAP increased (p = 0.314). We interpret the reduction in arterial CBV with increasing MAP in the “non-DH group” as an active arterial vasoconstriction triggered by CAR, whereas the lack of variation of arterial CBV in the DH group suggests impaired CAR response. Our findings highlight the potential of ultrafast ultrasound imaging for intra-operative CAR monitoring, paving the way for a better understanding of the impact of different types of CPB on cerebral perfusion.

Purpose: Brain temperature is tightly regulated and reflects a balance between cerebral metabolic heat production and heat transfer between the brain, blood, and external environment. Blood temperature and flow are critical to the regulation of brain temperature. Current methods for measuring in vivo brain and blood temperature are invasive and impractical for use in small animals. This work presents a methodology to measure both brain and arterial blood temperature in anesthetized mice by MRI using a paramagnetic lanthanide complex: thulium tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (TmDOTMA-). Methods: A phase-based imaging approach using a multi-TE gradient echo sequence was used to measure the temperature-dependent chemical shift difference between thulium tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid methyl protons and water, and from this calculate absolute temperature using calibration data. Results: In a series of mice in which core body temperature was held stable but at different values within the range of 33 degrees to 37 degrees C, brain temperature away from the midline was independent of carotid artery blood temperature. In contrast, midline voxels correlated with carotid artery blood temperature, likely reflecting the preponderance of larger arteries and veins in this region. Conclusion: These results are consistent with brain temperature being actively regulated. A limitation of the present implementation is that the spatial resolution in the brain is coarse relative to the size of the mouse brain, and further optimization is required for this method to be applied for finer spatial scale mapping or to characterize focal pathology.

IntroductionEarly detection of neurodegeneration is essential for optimizing interventions. The highly reproducible progression of neurodegeneration in the decrepit (dcr) mouse allows investigation of early biomarkers and mechanisms of brain injury.MethodsUsing high-frequency ultrasound, the common carotid arteries of female and male dcr and control mice were imaged longitudinally at time points bracketing the disease progression (50, 75, and 125 days of age) (n = 6 mice/group/sex).ResultsOver the disease time course, the female dcr mice demonstrated increased carotid artery blood flow and pulse wave velocity while the male dcr mice had a decrease in heart rate and no change in carotid artery ultrasound parameters. Early imaging biomarkers were sex-specific, with decreased carotid artery blood flow in female dcr mice and increased carotid artery diameter and decreased pulse wave velocity in males.DiscussionCarotid artery and wave reflection ultrasound is a promising screening tool for early detection of neurodegeneration.

Sphingolipids are a class of bioactive signaling lipids that regulate an array of fundamental cellular processes, including cell survival, proliferation and differentiation. Deficiency of acid sphingomyelinase - an enzyme of the sphingolipid metabolic pathway - has been previously implicated in human placental pathologies. We demonstrate that acid sphingomyelinase (Smpd1) is required for normal placental development in the mouse, and its deficiency results in an intrauterine growth restriction phenotype. Smpd1-deficient placentas display several anatomical abnormalities, including a reduced labyrinth compartment and increased fetal-maternal interhaemal distance. Finally, we observed several hallmarks of defective autophagy and lysosomal impairment in Smpd1-/- placentas, which could explain the inability of Smpd1-/- trophoblast to respond to nutrient starvation. Fetal growth restriction could not be rescued by transfer of Smpd1-deficient embryos into a wildtype uterine environment; however, restoration of transcription factor EB phosphorylation was detected. Thus, we conclude that, due to a smaller labyrinthine area, Smpd1 deficiency leads to a decrease in exchange between maternal and fetal blood space, limiting the supply of nutrients to the fetus and resulting in growth restriction.

Objective.Cerebral arterial and venous flow (A/V) classification is a key parameter for understanding dynamic changes in neonatal brain perfusion. Currently, transfontanellar ultrasound Doppler imaging is the reference clinical technique able to discriminate between A/V using vascular indices such as resistivity index (RI) or pulsatility index (PI). However, under conditions of slow arterial and venular flow, small signal fluctuations can lead to potential misclassifications of vessels. Recently, ultrafast ultrasound imaging has paved the way for better sensitivity and spatial resolution. Here, we show that A/V classification can be performed robustly using ultrafast Doppler spectrogram.Approach.The overall classification steps are as follows: for any pixel within a vessel, a normalized Doppler spectrogram (NDS) is computed that allows for normalized correlation analysis with ground-truth signals that were established semi-automatically based on anatomical/physiological references. Furthermore, A/V classification is performed by computing Pearson correlation coefficient between NDS in ground-truth domains and the individual pixel's NDS inside vessels and finding an optimal threshold.Main Results.When applied to human newborns (n= 40), the overall accuracy, sensitivity, and specificity were found to be 88.5% ± 6.7%, 88.5% ± 6.5%, and 87.0% ± 8.8% respectively. We also examined strategies to fully automate this process, leading to a moderate decrease of 1%-3% in the same metrics. Additionally, when compared to the main clinical metrics such as RI, and PI, the receiver operating characteristic curves exhibited higher areas under the curve; on average by +36% (p< 0.0001) in the full imaging sector, +35% (p= 0.0116) in the cortical regions, +53% (p< 0.0001) in the basal ganglia, +28% (p= 0.0051) in the cingulate gyrus, and +35% (p< 0.0001) in the remaining brain structures.Significance:Our findings suggest that the proposed NDS-based approach can distinguish between A/V when studying cerebral perfusion in neonates.

Neurovascular coupling (NVC), or the adjustment of blood flow in response to local increases in neuronal activity is a hallmark of healthy brain function, and the physiological foundation for functional magnetic resonance imaging (fMRI). However, it remains only partly understood due to the high complexity of the structure and function of the cerebrovascular network. Here we set out to understand NVC at the network level, i.e. map cerebrovascular network reactivity to activation of neighbouring neurons within a 500x500x500 mu m(3) cortical volume (similar to 30 high -resolution 3-nL fMRI voxels). Using 3D two -photon fluorescence microscopy data, we quantified blood volume and flow changes in the brain vessels in response to spatially targeted optogenetic activation of cortical pyramidal neurons. We registered the vessels in a series of image stacks acquired before and after stimulations and applied a deep learning pipeline to segment the microvascular network from each time frame acquired. We then performed image analysis to extract the microvascular graphs, and graph analysis to identify the branch order of each vessel in the network, enabling the stratification of vessels by their branch order, designating branches 1-3 as precapillary arterioles and branches 4+ as capillaries. Forty-five percent of all vessels showed significant calibre changes; with 85 % of responses being dilations. The largest absolute CBV change was in the capillaries; the smallest, in the venules. Capillary CBV change was also the largest fraction of the total CBV change, but normalized to the baseline volume, arterioles and precapillary arterioles showed the biggest relative CBV change. From linescans along arteriole-venule microvascular paths, we measured red blood cell velocities and hematocrit, allowing for estimation of pressure and local resistance along these paths. While diameter changes following neuronal activation gradually declined along the paths; the pressure drops from arterioles to venules increased despite decreasing resistance: blood flow thus increased more than local resistance decreases would predict. By leveraging functional volumetric imaging and high throughput deep learning -based analysis, our study revealed distinct hemodynamic responses across the vessel types comprising the microvascular network. Our findings underscore the need for large, dense sampling of brain vessels for characterization of neurovascular coupling at the network level in health and disease.

While microplastics have been recently detected in human blood and the placenta, their impact on human health is not well understood. Using a mouse model of environmental exposure during pregnancy, our group has previously reported that exposure to polystyrene micro- and nanoplastics throughout gestation results in fetal growth restriction. While polystyrene is environmentally relevant, polyethylene is the most widely produced plastic and amongst the most commonly detected microplastic in drinking water and human blood. In this study, we investigated the effect of maternal exposure to polyethylene micro- and nanoplastics on fetal growth and placental function. Healthy, pregnant CD-1 dams were divided into three groups: 106 ng/L of 740–4990 nm polyethylene with surfactant in drinking water (n = 12), surfactant alone in drinking water (n = 12) or regular filtered drinking water (n = 11). At embryonic day 17.5, high-frequency ultrasound was used to investigate the placental and fetal hemodynamic responses following exposure. While maternal exposure to polyethylene did not impact fetal growth, there was a significant effect on placental function with a 43% increase in umbilical artery blood flow in the polyethylene group compared to controls (p < 0.01). These results suggest polyethylene has the potential to cause adverse pregnancy outcomes through abnormal placental function.