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Aversive caregiving in early life is a risk factor for aberrant brain and behavioral development throughout the lifespan. This outcome is related to aberrant epigenetic regulation of the Bdnf gene. The Bdnf gene encodes for brain-derived neurotrophic factor (BDNF), a neurotrophin involved in neural plasticity, learning, and memory. Disruptions in caregiver-infant interactions lead to increased methylation and decreased expression of the Bdnf gene. One way to mitigate this effect is hypothesized to be through aerobic exercise. Exercise increases BDNF at the protein and gene expression levels, making it an exciting target for therapeutic interventions. To our knowledge, exercise has never been studied as a therapeutic intervention in preclinical rodent models of early life maltreatment. To that end, the current study is investigating the effect of an adult voluntary wheel running intervention on Bdnf aberrant methylation and expression in the prefrontal cortex of rats who experienced aversive caregiving in infancy. This study presents novel findings on the mechanisms underlying neural plasticity in the prefrontal cortex in an early life stress context.

Delaware Neuroscience Symposium 2021

Mitigating the Epigenetic Consequences of Early Life Stress with a Behavioral Intervention

technical paper

This annual event showcases and celebrates the neuroscience research in Delaware.  Posters and talks highlight neuroscience research carried out by graduate students, undergraduate students, and research staff at all of Delaware’s research and education institutions. The Lounge section of the symposium allows real-time interactions and networking among attendees.  New this year is an expo of research core facilities in Delaware.  Check them out in the Research Cores section of our poster session, or see the logos below.

In adolescents, low sleep duration is associated with psychiatric disorders, cognitive problems (Cheng et al., 2020), and diminished academic performance (Eliasson et al., 2002). This is particularly problematic for racial and ethnic minority adolescents, who are at increased risk of low sleep duration (Singh et al., 2013). While adolescent racial and ethnic low sleep duration has been linked to socioeconomic status (Gugllelmo et al., 2018), physical activity in girls (Bates et al., 2016), and school engagement (Dunbar, Mirpuri, & Yip, 2017), all four factors have not yet been explored together. The current study aims to understand the physiological impact of stress on sleep, which in turn is expected to impact behavior and development differentially by race and ethnicity. The present study will include participants from the National Institute of Health Adolescent Brain Cognitive Development (ABCD) Study. Resting-state neuroimaging data will be used to explore differences in intrinsic connectivity. The results of the current study have the potential to bring to light protective factors: factors that reduce the effects of stress on sleep.

Sleep Disparities in Adolescents

Individuals with chronic stroke affecting the corticospinal track often show severe motor impairment or paralysis of hand. Functional magnetic resonance imaging (fMRI) studies have shown that this impairment corresponds to in a reduction in bold activity in the lesioned hemisphere. It still unclear whether this reduction of brain activity also correspond to changes in the cortical representation of this body part in the motor cortex or whether this representation is preserved. To explore this issue, two individuals with subcortical stroke and paralysis of the hand were presented with an fMRI experiment in which they were asked to move (or to imagine for the paralyzed hand) each digit of hand following a random sequence. Representation similarity analysis was used to explore whether the pattern of activations across fingers in the motor cortex differed, indicating a maintained representation of the hand, or was similar, indicating damage to this representation. Both individuals showed finger differentiation in the ipsilateral M1 and one individual showed differentiation also in the contralateral hemisphere. These results suggest that the representation of the hand in M1 is maintained in individuals with corticospinal damage despite the complete paralysis of the hand, providing important clinical implications for rehabilitation.

Hand representation in individuals with subcortical stroke

Zika Virus (ZIKV) is a single-stranded RNA flavivirus whose primary vector is the Aedes aegypti mosquito and that became widely recognized during the outbreak in Brazil in 2015. In infected adults, symptoms are typically mild and short-lasting. However, in Brazil during the ZIKV outbreak, researchers reported a 20-fold increase of neonatal microcephaly. This congenital ZIKV infection leads to serious clinical outcomes, including seizures and cognitive developmental delays. Our lab has developed a unique rat model of prenatal ZIKV infection to help elucidate the mechanisms and outcomes of this virus throughout development and adulthood. In this study we assessed the long-term impact of congenital ZIKV infection on motor function, cellular proliferation and survival, and on immune response later in life. We found that these prenatally exposed animals demonstrated motor deficits in a sex specific manner and failed to mount a typical immune response to later-life infection. These results suggest that there are significant later life consequences to congenital ZIKV exposure. Continuation of ZIKV research is imperative to understanding the full spectrum of neurological and immunological consequences ZIKV and to help the children currently affected by ZIKV as well as prepare for future outbreaks.

Effect of Prenatal ZIKV Infection on Later-Life Neurogenesis in the Brain

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects movement. Previous magnetic resonance imaging (MRI) studies in PD focused primarily on identifying the neural correlates of upper extremity dysfunction. Although PD progresses to affect lower extremities, there is still a limited understanding of the brain circuitry underlying lower limb symptoms in PD in part because excessive head motion occurs during leg movements in a supine position affecting the functional MRI signal. Here, 11 PD and 14 controls underwent a functional MRI session during which they performed a visually cued isometric ankle dorsiflexion task at 15% of their maximum voluntary contraction (MVC). PD participants were tested off antiparkinsonian medication and their motor symptoms were measured with the MDS-UPDRS- III. While both groups were able to produce 15% of MVC during the ankle dorsiflexion task (p=0.182), PD had a lower rate of force increase (p=0.003) and force decrease (p=0.002) than controls. The fMRI analysis, revealed a reduction in the blood-oxygen-level-dependent (BOLD) signal during the task in PD compared to controls in the contralateral putamen, internal globus pallidus, and sensorimotor cortex. PD also had decreased motor-related signal in the cerebellum, specifically vermis I-IV and the ipsilateral dorsal dentate nucleus. Importantly, percent signal change in vermis I-IV was negatively correlated in PD with total MDS-UPDRS-III (r=-0.759, p=0.007) and the axial subcore (r=-0.615, p=0.044). A trend towards significance was detected for the correlation with the posture and gait subscore (p=0.054). Collectively, results demonstrate force control deficits during lower limb movements in PD that are related to functional abnormalities within both the basal ganglia- and cerebellar-cortical loops. The correlation analyses suggest that the cerebellum may be an important component of the pathophysiology of the disease. Further testing in a larger cohort is necessary to establish if its reduced activity underlies balance and gait symptoms in PD.

Neural Correlates of Ankle Dorsiflexion Movements in Parkinson's Disease

Novel neuroimaging biomarkers are urgently being sought to characterize early changes to the brain in mild cognitive impairment (MCI), typically a precursor to Alzheimer’s disease (AD). As the hippocampus is a critical site of AD pathogenesis that underlies principal symptoms of memory impairment, numerous studies have utilized multiple imaging modalities to characterize hippocampal integrity. The purpose of this study was to utilize a wide range of neuroimaging techniques to determine which measures were the most sensitive in detecting differences in hippocampal integrity between cognitively healthy older adults (OA) and those with amnestic MCI. We used a multimodal neuroimaging approach consisting of measures of hippocampal viscoelasticity, volume, perfusion, and diffusion – including neurite orientation and dispersion density imaging (NODDI) metrics – resulting in a total of twelve separate measures of hippocampal health. We recruited 23 OA and 7 MCI participants. A binomial logistical regression was performed to establish the effect of the 12 hippocampal measures on the likelihood of an MCI diagnosis. We also assessed the odds ratio as a measure of effect size. The full model correctly classified 92% of cases. Viscoelastic damping ratio (DR) from MRE was 27% higher in the MCI group and was the only significant predictor in differentiating between OA and MCI (p=0.024). The significant relationship between MCI status and DR (B=0.911, S.E.=0.404, after adjusting for age and sex) suggests that for every 0.01 increase in DR, the likelihood of having MCI is 2.49 times higher. No other hippocampal measures were significant predictors in the model, although hippocampal volume was close to approaching significance (p=0.056). Viscoelastic damping ratio of the hippocampus was the only significant predictor of MCI. This suggests that MRE measures of viscoelasticity may provide a unique and highly sensitive biophysical signature of hippocampal health relevant to microstructural changes that are expected to occur in MCI.

Multimodal Characterization of Hippocampal Integrity in Mild Cognitive Impairment: Combining Volumetry, Diffusion, Perfusion, and Viscoelasticity from Magnetic Resonance Imaging

The Biomolecular Core Laboratory (BCL) is located at the Nemours/Alfred I duPont Hospital for Children in Wilmington, Delaware and has been serving the clinical and scientific community for 20 years. This resource laboratory has provided essential services in molecular biology and genetics to clinicians and research scientists at Nemours Children’s Health System and affiliated partner institutions including University of Delaware, Thomas Jefferson College of Medicine, Delaware State University, Wesley College, Delaware Technical Community College, and Christiana Care Health System. Working in close collaboration with our partnering institutions throughout the CTR and IDeA networks, our global mission is to facilitate discoveries that begin at both the basic and translational research levels. The BCL is a collaborative research lab providing support for the development of new research projects as well as mentoring, training, and educational opportunities to staff and students. We offer low-cost, fast-turnaround, high-quality services that are essential to many clinical and hypothesis driven projects. The BCL enables research excellence by offering genomics technologies including sanger sequencing, fragment analysis, nucleic acid isolation, digital PCR, genotyping, copy number analysis, gene expression analysis, as well as access to shared instrumentation. The BCL staff not only provides expertise in project design and data troubleshooting but also offers support for grant applications, budget preparations and manuscripts. The ultimate goal of this laboratory is to provide biomedical investigators with state-of-the-art technical support and clinicians with tools that can help improve pediatric supportive care and/or therapeutic intervention. This poster will present an overview of the services available to the IDeA community.

The Nemours Biomolecular Core Lab: A Resource for Biomedical Research

The OSCAR Imaging Facility at Delaware State University (DSU): a multi-user core facility

The OSCAR Imaging Facility at Delaware State University

The “Delaware Nucleotide Analysis (DNA) Core Center” is a genomics core facility debuting at Delaware State University. The Core offers services for a variety of research focuses including biology, medical, environmental, and agricultural sciences. The core is equipped with instruments covering most DNA and RNA sequencing studies. Services include automated systems for sample library preparation and quality control as well as second generation Illumina sequencer and third generation PacBio sequencer. For members of the DSU community, external academic institutions, and the private sector, the core offers full service and a la carte service options dependent upon client request. The DNA Core also provides workshops and educational training for new users of Core systems in the DSU family and external community.

Launching the DNA Core Center at Delaware State University

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized in part by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although the precise cause of PD is not yet fully understood, environmental factors are known to contribute to the etiology of a vast number of cases. Rotenone, a pesticide that inhibits Complex 1 of the Mitochondrial Electron Transport Chain, is one such toxin. Importantly, there is no known cure for PD and effective treatment options are severely limited both in number and efficacy. We are interested in measuring mitochondrial oxygen consumption rate (OCR) using the Seahorse Analyzer in our in vitro and ex vivo model exposed to mitochondrial stressors (Oligomycin, FCCP, and Rotenone/Antimycin). Once mitochondrial respiration measurements have been optimized, we aim to test whether treatment with dacarbazine, a possible neuroprotective agent, can ameliorate the effects of mitochondrial stress. Here, we present preliminary data on the effect of mitochondrial stressors in fly heads and Schneider cells (S2 cells) and the effect of dacarbazine on OCR in fly heads and S2 cells. In sum, our report shows the effects of toxins in mitochondrial metabolism and the utility of a potential neuroprotective chemical against a model of PD and suggests a possible neuroprotective chemical against the disease.

Optimizing the measurement of mitochondrial respiration in Drosophila melanogaster adult brains and late-stage embryonic cells

Most animals, including humans appear symmetrical externally, but display visceral lateral asymmetry with a bias for one enantiomeric body plane over the other. We are interested in understanding functional effects of bilateral asymmetry in the nervous system. The left and right cerebral hemispheres appear symmetrical in gross anatomy but are known to be functionally asymmetrical. For example, language dominance has an asymmetrical presence on the left side of the brain in 90% of the population classified as right handed. Hemispheric laterality plays an important role in neuropsychological models of neuro-psychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder and schizophrenia. Typically developing individuals more commonly have a right dominant laterality when it comes to handedness, footedness and language laterality. These reflect a leftward asymmetry in the brain. Previous studies have found higher rates of atypical modalities such as handedness and footedness in the ASD community. However, many of these modalities have been studied separately. We propose to observe handedness, footedness, language laterality, eye dominance and hair whorl in individuals in the ASD community to observe whether or not an occurrence of atypical asymmetry is observed. Samples have been collected from the typical population as well as the ASD community. To begin with, we have tested university students and faculty to standardize the WatHand Box, The Measurement of Foot Preference, Distance in Hole Card Test and iDichotic listening app. Our preliminary data on individual modalities is in line with previous studies. We will continue this testing with children in the ASD community. In a separate line of experiments, the C. elegans model will be used to test laterality phenotypes of genes implicated in ASD, schizophrenia, bipolar disorder and left handedness. Effects of these genes on laterality are being observed in early embryonic development as well as in the neurons of the adult organism. Effects on behavior as a result of functional laterality will be observed through associative and nonassociative learning assays.

Mitigating the Epigenetic Consequences of Early Life Stress with a Behavioral Intervention

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