Two Nicholas Hobbs Discovery Grants and two Director’s Strategic Priorities Grants have been awarded to Vanderbilt Kennedy Center (VKC) researchers for 2021-22. The projects address facial recognition in autism, sleep in Down syndrome, identifying a biomarker pipeline in Rett syndrome, and a better understanding of adult neurogenesis impairment in the hippocampus in neurodevelopmental disorders.
Both funding mechanisms are meant to provide seed money to pilot studies in preparation for submitting competitive grant applications to federal agencies or private foundations. The VKC IDDRC uses philanthropic funds to support Nicholas Hobbs Discovery Grants, an internal mechanism to support interdisciplinary research pilot studies consistent with the IDDRC translational research mission. Director’s Strategic Priorities Grants are open to VKC members and investigators for projects that are directed to original, empirical research addressing precision care related to intellectual and developmental disabilities.
2021-22 Hobbs Discovery Grants
Understanding early face learning in autism through ultra-high-resolution imaging
- Principal Investigators: Carissa Cascio, Ph.D. (Psychiatry & Behavioral Sciences); Rankin McGugin, Ph.D. (Psychology); Allen Newton, Ph.D. (Radiology & Radiological Sciences)
- Co-Investigators: Isabel Gauthier, Ph.D. (Psychology); Caitlin Convery, Ph.D. (Psychiatry & Behavioral Sciences); and Brianna Lewis, Ph.D. (Psychiatry & Behavioral Sciences)
People on the autism spectrum sometimes have difficulty recognizing or remembering faces, skills that depend on daily practice and learning that starts from birth and continues throughout life. In this project, researchers will measure the thickness of a part of the brain necessary for identifying faces, the fusiform face area, or FFA, in autistic adults. Previous research suggests that in non-autistic adults, those with a thinner FFA are better at recognizing faces than those with a thicker FFA.
Using advanced, ultra-high-resolution imaging shows that the effect is localized to deep layers of the cortex. The thinning of deep layers may be the result of brain remodeling, or plasticity, in response to face learning in early life. The team will test whether these patterns are the same in individuals with autism, or whether they point to divergent processes in early face learning and associated brain plasticity that may contribute to subsequent social difficulties.
Findings will then be translated more directly to early development by measuring the thickness of this region in a large, publicly available dataset. This dataset includes MRI scans acquired at 6, 12, and 24 months in infants at high vs. average familial likelihood for autism. By examining this brain region with specialized techniques in infants during this period, researchers hope to learn more about infants’ experience-dependent face learning by assessing associated changes in cortical thickness of the FFA over the first two years of life.
Finally, researchers hope to assess how these changes in the FFA relate to clinical symptoms reflecting difficulties with social interaction. The work promises to deepen an understanding of the brain mechanisms behind a skill that develops atypically in autism and will eventually inform early intervention approaches for face learning as part of a broader focus on early-developing, foundational social skills.
Circuit mechanisms of neurogenesis deficits in the 22q11 deletion mouse model
- Principal Investigators: Alan Lewis, M.D., Ph.D. (Psychiatry & Behavioral Sciences): Cody Siciliano, Ph.D. (Pharmacology)
- Co-Investigator: William Nobis, M.D., Ph.D. (Neurology)
Most of the brain’s nerve cells, called neurons, are formed very early in life during development. However, in a small number of brain regions, the brain continues to add new neurons throughout adulthood. In a part of the brain called the hippocampus, adult-born neurons are important for learning, memory, and emotion. Mice with genetic changes that model human neurodevelopmental disorders have shown in some cases that the process of adding new neurons during adulthood, adult neurogenesis, is abnormal, leading to either too few or too many adult-born neurons or altering the process by which they are wired into the existing circuitry in the hippocampus.
This project is a collaboration with the goal of better understanding why adult neurogenesis in the hippocampus is impaired in neurodevelopmental disorders. Answering this question is important because it may lead to new ways to address functional impairments. Previous research has shown that the rate at which new neurons are added to the adult hippocampus is regulated in part by the activity of a cell type called mossy cells, which innervate the stem cells that generate adult-born neurons. Early studies from the investigative team found that mossy cells are less active and reduced in number in a mouse model of 22q11.2 deletion syndrome and that this mouse shows a reduced quantity of adult-born neurons. The 22q11.2 deletion syndrome results from a chromosomal deletion in humans that can result in schizophrenia, autism, and/or learning disabilities. A genetic deletion very similar to the human deletion has been engineered in mice.
In this project, the investigators will conduct several experiments to test the hypothesis that reduced mossy cell activity causes reduced adult neurogenesis in a 22q11.2 deletion syndrome mouse model. In the first set of studies, the activity changes of mossy cells will be defined using several complementary techniques. In the second set of studies, the investigators will use a method to experimentally increase the activity of mossy cells over long periods of time to test whether this strategy normalizes the rate of adult neurogenesis. Taken together, this project will lay the foundation for identifying underlying reasons for impaired adult neurogenesis in neurodevelopmental disorders as well as for finding neurobiologically-based methods to address this process that is critically important to maximize cognitive function.
2021-22 Director’s Strategic Priorities Grants
Validation of a wearable sensor for remote sleep assessment in Down syndrome
- Principal Investigator: Sarika Peters, Ph.D. (Pediatrics and Psychiatry & Behavioral Sciences)
- Co-Investigators: Angela Maxwell-Horn, M.D. (Pediatrics); Althea Shelton, M.D. (Neurology)
Down syndrome (DS) is the most common genetic/chromosomal condition diagnosed in the United States and it is estimated to occur in 1 out of 700 babies. Obstructive sleep apnea (OSA) impacts a large percentage of individuals with DS, and the American Academy of Pediatrics recommends screening starting at age 4. Disrupted sleep has a large burden on the health and well-being of both the child and parents/caregivers affected by DS and studies show that individuals who have DS and OSA have more challenges regarding behavior, obesity, and their ability to learn.
Polysomnography (PSG) is considered the gold standard in sleep research, but requires many resources, and requires that a child sleep in an unfamiliar environment. There is a need for alternative, objective, and less costly methods of quantifying sleep, especially in younger children with DS. Wearable sensors measuring body movements are increasingly used in sleep research studies because of they are sensitive, easy to use, and can capture data for extended periods of time within the home environment. These devices are worn on the wrist and can be used to estimate sleep.
This project will determine the feasibility of use of a wearable sensor to assess sleep in younger children with DS (ages 4-10 years), how these measurements compare to gold-standard PSG, and how they relate to measures of clinical severity in DS. Data from this pilot study can help develop a new data collection format and determine whether wearable sensors are useful as a marker of meaningful clinical improvement. Also, better identification and treatment of OSA from a younger age could mitigate some of the co-occurring difficulties.
Evaluation of a novel biomarker approach for Rett syndrome therapeutics
- Principal Investigators: Colleen M. Niswender, Ph.D. (Pharmacology); Hongwei Dong, Ph.D (Pediatrics)
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations that disrupt the function of the gene CpG Binding Protein 2 (MECP2). As MECP2 is expressed from the X chromosome, most RTT patients are females who exhibit a constellation of symptoms including apneas, seizures, gait disturbances, and intellectual disability. In mouse models, symptoms of the disorder can be significantly improved by increasing levels of MeCP2, providing hope for treatment, and the team’s research has shown that disease symptoms in mice can also be impacted by small molecules that target other brain proteins downstream of MeCP2.
As RTT therapeutic strategies move to the clinic, the importance of translational biomarkers that are sensitive to treatment becomes imperative. Ideally, such a biomarker would be quantitative, non-invasive, sensitive to drug treatments, and present in both patients and animal models of RTT. To achieve the project’s goal, researchers are testing the hypothesis that electroencephalography (EEG) will serve as a biomarker in a mouse model of RTT. Our data demonstrate that mice modeling RTT have abnormal responses to auditory cues that can be measured using EEG. When animals are dosed with a small molecule drug treatment for RTT developed at the Warren Center for Neuroscience Drug Discovery (WCNDD), the EEG signatures of the RTT mice are now more similar to the signatures observed in control animals. Because individuals with RTT exhibit similar EEG changes to auditory cues when compared to these mice, these encouraging results suggest that this treatment strategy may be effective in RTT patients and, importantly, allow us to use EEG as a biomarker in a clinical trial in individuals with RTT.
In the current study, researchers will leverage a collaboration between the WCNDD and the Vanderbilt Kennedy Center to validate EEG signatures as responsive to a new treatment recently uncovered in the WCNDD as relevant for RTT. It is anticipated that these studies will form the basis of a “biomarker pipeline” that can be used to interrogate multiple therapeutic candidates under development at the WCNDD for the treatment of RTT and other neurological disorders.
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