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Early life experiences shape neurodevelopmental, epigenetic, and future behavioral landscapes of individuals. While both animal models and human twin studies suggest that there is a predisposition for certain stimuli to be innately fear-inducing, molecular mechanisms remain poorly understood. Prior work in our laboratory has demonstrated that administering TMT (2,5-dihydro-2,4,5-trimethylthaizonline), a synthetic odorant from fox feces, induces robust freezing in naïve rodents without any prior learning. However, experiencing predator odor during early development alters the response later in life, suggesting a change in perception of the innate fear-inducing odor. Administering TMT to dams and pups during development (PN1-21) inside the home-cage alters the quality of maternal care, pup ultrasonic-vocalizations, and lowers freezing (PN30) upon re-exposure comparable to control animals. To extend these findings to other predator odorants and examine how maternal behavior may alter later innate fear responses, pups with or without their dam were exposed to either a noxious control (butyric acid) or a bobcat urine for 20 minutes in their home-cage for the first 21 days of life. Concurrent with odor exposures, video and USV recordings were captured to quantify maternal care and pup behavior, respectively. On PN30, rodents were exposed to bobcat urine for 10 minutes and freezing behavior was recorded. Finally, on PN35, to examine if fear behaviors were generalized to other paradigms, an open-field test was administered. Preliminary results suggest that developmental exposure to bobcat urine lowered the quality of maternal care and increased freezing upon re-exposure on PN30. There were no differences in open-field behavior or pup ultrasonic vocalizations. These results support the complex relationship of early exposure to predator stimuli, effects of maternal behavior, and the expression of innate fear later in life. Future research will examine epigenetic alterations linked to long lasting changes in fear responses from early experience with predator odors.

Delaware Neuroscience Symposium 2021

Impact of developmental exposure to predator urine on maternal behavior and the expression of innate fear

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.

The pain of Black Americans is historically underdiagnosed and undertreated (Anderson, Green, & Payne, 2009). While many structural and individual level factors associated with a history of, and ongoing medical racism contribute to these disparities (Gee & Ford, 2011; Feagin & Bennefield, 2014) recent work has demonstrated that these disparities are also evident at the level of face and emotion perception and contribute to disparities in care (Mende-Siedlecki, 2019). The present work examines whether perceiver deficits in pain recognition are reflected in divergent neural activity in regions associated with face processing, pain, and empathy. Replicating previous work, we find that participants had higher thresholds for perceiving pain on Black male vs White male faces, such that more pain needed to be expressed on Black male faces to be seen as equivalent to White male pain. In turn, we find that Black males were prescribed less pain-relieving cream than White males overall. Moreover, we find that perceptual bias continued to facilitate the effect of target race on treatment when status/strength stereotypes and explicit racial bias were included as competing within-subjects mediators. Finally, we find differential activity in posterior STS and ATL associated with increasing pain on White vs Black faces, which overlap with face selective regions identified by a face localizer as well as the broader literature.

Neural Underpinnings of Racial Bias in Pain Perception & Treatment

Several studies have shown that receiving speech or language services for expressive language delays positively impacts academic indices of success (e.g., Del Tufo, Earle, & Cutting, 2019). However, beyond expressive language delays we do not know if receiving services before the age of 5 has a positive impact on academic performance. Expressive language refers to the production of spoken language, and the milestones of expressive language, such as the onset of babbling, production of first words, and putting several words together, are early indicators of normal language development. We analyzed a national sample of data (National Survey of Children’s Health, 2011/2012) of children 0-17 years of age, through cross-sectional, telephone-based interviews to determine the (1) factors that impact whether or not a child will receive speech and/or language services before the age of 5, and (2) the impact of receiving speech and/or language services on the indices of academic success. To answer the aforementioned questions we implemented hierarchical logistic regression and linear regression, respectively. The results indicate that several factors beyond expressive language impact children’s receipt of speech and/and language services before age 5. These factors include sex of the child, socioeconomic status, period of gestation, and parent’s concerns regarding receptive language. These factors together predicted if a child would receive speech and/or language, which, in turn, had an impact on academic performance.

Which factors beyond expressive language delays lead to the receipt of speech and/or language services before age 5?

Alcohol exposure (AE) during pregnancy is known to affect fetal medial prefrontal cortex (mPFC) and hippocampus (HC) development. Previous work has demonstrated that these two structures are vulnerable to AE during the brain growth spurt, which occurs during 3rd trimester of human pregnancy and the first two postnatal weeks in rodents. Our lab has shown that thalamic nucleus reuniens (Re) is damaged in a rodent model of human 3rd trimester AE. We have also shown that Re is critical for mPFC–HC oscillatory synchrony and spatial working memory (SWM). The current study investigated the effects of early AE on SWM ability in adulthood in rats. We predicted that AE would lead to SWM impairment that worsened as working memory demand increased. We administered 5.25 g/kg/day of ethanol in milk formula via intragastric intubations in a binge manner on PD 4-9 (AE group) or performed intubations without liquid (sham intubated (SI) group). On PD90, rats were trained on a continuous alternation (CA) T-maze task. Upon reaching a choice accuracy criterion of 80% for two consecutive days on CA, we introduced a delay between trials (DA) in order to increase SWM demand. The rats underwent 6 DA sessions, consisting of 12 each of 10-second (s), 30 s, and 60 s delay trials given in a pseudorandom sequence. Our results show that animals in both AE and SI groups learned the CA task at similar rates. However, on the DA task, the SI group showed consistent improvement across sessions on the 30-s delay trials, whereas the AE group did not (postnatal - treatment x day interaction: F(5,195)=2.70, p = .02). For the 10 s delay trials, both AE and SI groups showed improvement across days (main effect of day: F(5,195)=7.93 , p < .001), whereas for the 60 s delay trials, both groups performed uniformly poorly across days. These findings support the hypothesis that binge AE during the brain growth spurt produces SWM deficits that depend on SWM demand. This study will lead to a better understanding of the impact of HC-Re-mPFC circuitry damage due to developmental AE on cognitive function later in life.

Delay-dependent spatial working memory deficits in a rat model of third trimester alcohol exposure.

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.

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

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.

Impact of developmental exposure to predator urine on maternal behavior and the expression of innate fear

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