Browsing by Subject "Autism Spectrum Disorder"
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Item Cell-Type-Specific Contributions of the Transcription Factor FOXP1 to Striatal Development and Function(2019-08-07) Anderson, Ashley Grace; Kourrich, Said; Konopka, Genevieve; Takahashi, Joseph; Huber, Kimberly M.Mutations in FOXP1, a member of the forkhead box protein (FOXP) family of transcription factors, have been identified as among the most significantly recurring de novo mutations associated with autism spectrum disorder (ASD). ASD is a genetically complex disorder, however, recent studies have identified distinct neuronal cell-types particularly vulnerable in this disorder. These cell-types include deep layer cortical neurons and dopamine receptor 1 (D1) and 2 (D2) expressing striatal spiny projection neurons (SPNs) where FOXP1 is highly expressed. However, the role of Foxp1 within these cell-types was largely unknown. Using a Foxp1 heterozygous mouse model and a human in vitro model system, I reported that FoxP1 regulates conserved pathways within the striatum based on a module preservation analysis between human and rodent gene co-expression networks. I also found a cell-type-specific functional consequence of reduced Foxp1 expression in Foxp1 heterozygous mice, whereby D2 SPNs had increased intrinsic excitability with no significant changes in dSPNs. Together, these data strongly support a conserved, cell-type-specific role for Foxp1 in striatal development and function. The striatum is a critical forebrain structure for integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. Therefore, the overarching goal of my project is to investigate the cell-type specific molecular pathways regulated by Foxp1 within distinct striatal SPNs and link these molecular pathways to functional and behavioral outcomes. To do this, I generated mice with deletion of Foxp1 from D1 SPNs, D2 SPNs, or both populations, and used a combination of single-cell RNA-sequencing (scRNA-seq), serial-two-photon tomography, and behavioral assays to delineate the contribution of Foxp1 to striatal development and function. I show that Foxp1 is crucial for maintaining the cellular composition of the striatum, especially D2 SPN specification, and proper formation of the striosome-matrix compartments at early postnatal and adult timepoints. I uncover downstream targets regulated by Foxp1 within D1 and D2 SPNs and connect these molecular findings to cell-type-specific deficits in motor and limbic system-associated behaviors, including motor-learning, ultrasonic vocalizations, and fear conditioning. Moreover, I identify non-cell autonomous molecular and functional effects produced by disruption of Foxp1 within one SPN subpopulation and the molecular compensation that occurs. Using the scRNA-seq data, I also examined gene expression changes within neuronal and non-neuronal cell-types of the developing striatum. Using my above findings, I attempted to pharmacologically rescue motor-learning deficits in Foxp1 cKO mice by targeting dopaminergic and mTOR-regulated pathways. Finally, I discuss the current challenges and future strategies for therapeutic intervention in cases of FOXP1 mutations. Overall, the findings presented in this thesis provide an important molecular window into striatal development and furthers our understanding of striatal circuits underlying ASD-relevant phenotypes.Item Evaluation of Social Stories in Sleep Treatment for Children with Autism Spectrum Disorder: A Feasibility Study(2020-12-01T06:00:00.000Z) Israelsen, Lora Jane; Brown, William David; Germann, Julie; Kao, Yungfei; Bellone, Katherine; Nakonezny, PaulA majority of children with autism spectrum disorders (ASD) experience sleep disturbances which are apt to negatively impact cognition, behavioral functioning, and the general trajectory of psychosocial development. Additionally, pediatric sleep disorders may contribute to disordered sleep in parents and reduced quality of life for family members. While children with ASD often respond positively to general standard of care in pediatric sleep medicine, there are few sleep treatments that address ASD-specific factors that contribute to sleep disturbances. This limitation may be addressed through the development of a treatment that incorporates sleep behavioral strategies in a format developed for children with ASD, such as a social story. This study evaluated the feasibility and acceptability of using a social story on bedtime routine developed for children as a complementary intervention for standard of care in a pediatric sleep clinic. Results from this study indicated social stories are acceptable as a complementary tool to sleep treatment. All participants approached for the study gave consent. Of those enrolled in the treatment group, all participants randomized to the treatment group read the story for at least one week as part of the bedtime routine (100%) with a mean utilization of 19.4 days during the month. Participants reported the social story was easy to implement and well received by the children, though feedback indicated the need for personalization and flexibility in the implementation of social stories. There were no significant differences in pediatric sleep outcomes between treatment groups. There were significant challenges related to the feasibility of the study in terms of gathering follow-up data, partially due to the impact of the COVID-19 worldwide pandemic that occurred during the study. Secondary analyses found no significant differences in parental sleep outcomes or psychosocial functioning between treatment groups. These findings suggest that social stories may be a promising tool in pediatric sleep treatment for children with ASD, but additional research is warranted to clarify its efficacy.Item Experience-Dependent and Input-Specific Regulation of Neocortical Circuit Development by Genes Linked to Neurodevelopmental Disorders(2022-05) Zhang, Zhe; Volk, Lenora J.; Huber, Kimberly M.; Gibson, Jay R.; Roberts, Todd; Chahrour, MariaAbnormal structural and functional brain connectivity has been widely observed in human neuropsychiatric diseases. Specifically, patients with neurodevelopmental disorders like autism often show an imbalance in the local versus long-range connectivity for cerebral cortex. Whether and how genes implicated in neurodevelopmental disorders regulate development of cortical synaptic connectivity in a pathway-specific manner remain largely unknown. Furthermore, environmental sensory experience can determine or significantly remodel the postnatal development of synaptic connections and neural circuits in sensory cortices. Knowledge on what intracellular proteins or mechanisms can mediate experience-dependent development of specific cortical synaptic connections is also lacking. In this work, I studied the roles of two neurodevelopment disease implicated genes, namely, fragile X mental retardation 1 (Fmr1) and myocyte enhancer factor 2c (Mef2c) in the postnatal experience-dependent development of input-specific synaptic connections. I report that postnatal, cell-autonomous deletion of Fmr1 in postsynaptic L2/3 or L5 neurons results in a selective weakening of AMPA receptor-, but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. Unlike callosal inputs, synapses originating from local L4 and L2/3 circuits are normal with postsynaptic Fmr1 deletion, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. Opposite to Fmr1 KO, postnatal deletion of Mef2c in L2/3 neurons leads to a cell autonomous and selective weakening of excitatory synapses from L4, whereas ipsilateral or contralateral long-range excitatory synaptic inputs are unaffected. Postsynaptic Mef2c only promotes the development but not the maintenance of L4-to-L2/3 excitatory synaptic connections and Fmr1 is not required for this process, in contrast to predictions from work in CA1 hippocampal neurons. Weakening of L4-L2/3 synaptic strength by sensory deprivation can be rescued by postnatal postsynaptic expression of a transcriptionally active form of MEF2C (MEF2-VP16), suggesting that MEF2C transcriptional activation drives experience-dependent development of L4-L2/3 synapses. Together, my findings on Fmr1 and Mef2c demonstrate an interaction of experience and gene functions in regulation of specific synaptic connections with important implications for neurodevelopmental disorders.Item Exploratory Study of Manualized Parent Training with Parental Support for Children with Autism Spectrum Disorder(2018-07-02) Cartwright, Julia Elizabeth; Bellone, Katherine; White, Stormi P.; Travis, Rebekah; Jarrett, Robin B.; Elliott, StephenParents of children with Autism Spectrum Disorder (ASD) present for therapeutic services with two essential needs: training on behavioral strategies specific to children with ASD and support for parental stress. Training parents as agents of behavior change increases intervention exposure naturally. Parents of children with ASD experience high parental stress, which negatively impacts parenting and treatment engagement. The current study assessed outcomes of adding a parent-support component to RUBI Autism Network's Parent Training for Disruptive Behaviors (RUBI Manual). A single-subject alternating treatments design was implemented within a community-based sample of parent-child dyads (10 participants). Each dyad received two treatment packages in a rapid alternating fashion. PT-Alone sessions included a manualized parent-training module, while PT-Plus sessions included a manualized parent-training module and 15-minute pre-session parent-support component. Five dyads with a child (average age=32 months) with ASD and disruptive behavior participated in three baseline and 11 RUBI Manual sessions, six included the parent-support component. Hypotheses included that parental stress and child disruptive behavior would decrease with intervention, while parent positive praise would increase. While the intervention effectively reduced child disruptive behaviors and increased parent praise, the primary finding was that the addition of the parent-support component further increased parent treatment integrity and parent praise. Results support a model of change for parenting behavior. Specifically, meaningfully programming for parent support within child behavioral treatment improved parent engagement, reflected in increased parent treatment integrity, which resulted in increased parenting skills, reflected in increased parent praise. Increased parenting skills likely contributed to decreased child disruptive behavior and parental stress. Inclusion of a parent-support component is supported as an effective practice for parent training within this specialized population.Item Family Studies of Sensorimotor Disturbances in Autism Spectrum Disorder(2016-07-26) Schmitt, Lauren Michelle; Mosconi, Matthew W.; Sweeney, John A.; White, Stormi P.; Bellone, Katherine; Tsai, PeterSensorimotor impairments are prevalent in individuals with autism spectrum disorder (ASD) and among the earliest emerging features, yet the pathophysiological mechanisms underlying these deficits remain poorly understood. Family studies are one approach to better understand these pathophysiological mechanisms by identifying sensorimotor impairments that are present in both individuals with ASD (probands) and their unaffected biological family members. Previous studies have identified reduced saccade accuracy and increased variability of saccade in probands as well as analogous deficits in unaffected relatives. We also have recently demonstrated reduced accuracy and increased variability of precision gripping in ASD. Accuracy of ocular and manual motor behaviors is controlled by feedforward motor control processes responsible for guiding initial motor output prior to available visual feedback as well as feedback processes that use visual feedback information to compensate for any systematic error. Thus, previous findings implicated disruptions of feedforward and feedback mechanisms in ASD. Here, we characterized saccade and precision gripping abnormalities in probands and their unaffected biological parents, and determined the extent to which these abnormalities are familial by studying family trios (proband, biological mother, biological father). Our results demonstrated that probands show reduced accuracy of rapid ocular and manual motor responses as well as increased variability of sustained manual motor behaviors, suggesting that cerebellar-mediated feedforward and feedback motor control processes are disrupted in ASD. Biological parents demonstrated a similar pattern of sensorimotor abnormalities to individuals with ASD. Further, impaired saccade dynamics and variability of sustained gripping inter-correlated among probands and their parents indicating that these deficits may be familial. Oculomotor and manual motor abilities were relatively independent in controls, whereas these abilities were correlated in both probands and parents suggesting reduced differentiation of these motor control systems in ASD. Sensorimotor deficits also were related to core diagnostic features in probands as well as to sub-clinical phenotypic features in parents, suggesting that deficits in sensorimotor behaviors may share pathogenic mechanisms with core symptoms. Overall, our findings provide support that sensorimotor impairments are highly prevalent in ASD, and that they may be familial, suggesting their use as intermediate phenotypes and potential biological markers of risk in ASD.Item Identifying Autism Spectrum Disorder in a Clinical Sample of Preschool-Aged Children Using the BASC-3 Parent Rating Scales(2020-07-19) Duley, Savanna S.; Bellone, Katherine; LePage, James; Foxwell, Aleksandra; Anton, Corinne; Elliott, StephenThe Behavior Assessment System for Children, Third Edition (BASC-3) is a broadband behavioral rating scale commonly used in medical and educational settings to assess a variety of emotional and behavioral difficulties in preschool age children. The DSD content scale on the BASC is intended to measure impairments in a child's social skills, communication, interests, and activities. Use of the scale has been suggested to improve early identification efforts in the areas of developmental screening and diagnosis of autism spectrum disorders (ASD). Previous research investigating the DSD scale reported evidence for the scale's ability to aid in the identification of preschoolers with developmental delays, and discriminate between children diagnosed with ASDs, other diagnoses, and those who were typically developing; however the DSD scale has not been re-validated in clinical preschool populations using the updated BASC edition, the BASC-3. The current study examined whether T-Scores on the DSD content scale on BASC-3 Parent Rating Scales, Preschool Form could identify preschool-aged children diagnosed with an ASD and meaningfully differentiate these children from those diagnosed with other developmental delays. DSD T-Scores were generated for each participant using several different normative scoring comparison groups and compared across scoring methods to fully examine the utility of the DSD scale specific to a clinical sample. Results indicated that the DSD scale was able to effectively identify and confirm the presence of symptoms related to developmental social disorders among all participants; however, the scale was unable to distinguish between preschoolers diagnosed with ASD versus those with other developmental delays.Item Molecular Underpinnings of Human Brain Evolution and Cognition at Cellular Resolution(December 2023) Caglayan, Emre; Chahrour, Maria; Hon, Gary C.; Madabhushi, Ram; Sun, Lu O.; Konopka, GenevieveMolecular and functional characterization of the human brain is challenging due to its experimental inaccessibility. Most of our understanding about human brain function relies on the assumption that biological processes uncovered in model organisms are conserved in humans. Comparisons of the humanii brain with non-human primate brains offer to both uncover the novelties in human brain evolution and better evaluate the insights obtained from model organisms about human brain function. To achieve this, highthroughput sequencing methods on post-mortem brain tissues provide a rewarding readout to understand human brain evolution at the molecular level. In addition to their use in comparative studies, these technologies were also utilized with a hope to understand molecular underpinnings of measurable human brain activity metrics. During my dissertation, I read relevant literature extensively (Chapter 1) and sought to understand human-specific epigenomic and transcriptomic changes at cellular resolution in the cortical brain (Chapter 2). Additionally, after in-depth analysis of many human brain single-nuclei RNA-seq datasets, I found a pervasive ambient RNA contamination problem, and devised in silico solutions to tackle this problem. My efforts improved the analytical approach in the field as well as in my research (Chapter 3). I have also been involved in efforts to identify transcriptomic correlates of brain activity in human subjects (Chapters 4-5). After detailing these efforts, I discuss the implications of these findings, weigh their impact on our understanding of human brain function and offer ideas for further research (Chapter 6).Item Obstructive Sleep Apnea in Children with Autism Spectrum Disorder(2019-03-22) Tomkies, Anna Troshkina; Mitchell, Ron; Johnson, Romaine F.; Shah, GopiSTUDY OBJECTIVES: To describe the demographic and clinical characteristics of children with autism spectrum disorder (ASD) referred for polysomnography (PSG) and to look for predictors of obstructive sleep apnea (OSA) and severe OSA in these children. METHODS: This is a retrospective case series of children ages 2-18 years who underwent PSG between January 2009 and February 2015. Children were excluded if they had major comorbidities, prior tonsillectomy, or missing data. The following information was collected: age, gender, race, height, weight, tonsil size, and prior diagnosis of allergies, asthma, gastroesophageal reflux disease (GERD), seizure disorder, developmental delay, cerebral palsy (CP) or attention deficit hyperactivity disorder (ADHD). Predictors of OSA were evaluated. RESULTS: A total of 45 children were included with a mean (SD) age of 6.1 (2.8). The patients were 80% male, 49% Hispanic, 27% African American, 22% Caucasian, and 2.2% other. Of these children 26 (58%) had OSA (apnea hypopnea index, AHI >1) and 15 (33%) were obese (body mass index, BMI z-score ≥ 95th percentile). The mean (SD) AHI was 7.7 (15.0) (range 1.0-76.6). A total of 9 (20%) had severe OSA (AHI≥10). There were no demographic or clinical predictors of OSA in this group. However, increasing weight served as a predictor of severe OSA and children who were of African American or Hispanic race had the tendency to be more likely obese. CONCLUSION: The absence of demographic or clinical predictors of OSA supports using general indications for polysomnography in children with ASD.Item Regulation of Autism-Relevant Behaviors by Distinct Cerebellar-Prefrontal Cortical Circuits(2020-08-01T05:00:00.000Z) Kelly, Elyza Hope; Pfeiffer, Brad E.; Huber, Kimberly M.; Meeks, Julian P.; Tsai, PeterLong thought to have exclusive roles in motor coordination, the cerebellum is increasingly implicated in the regulation of complex behavior and cognition, while cerebellar dysfunction has been demonstrated in many neuropsychiatric disorders, including autism spectrum disorders (ASD). However, the circuit mechanisms and cerebellar regions underlying the cerebellar contribution to ASD behaviors remain unknown. Here, we demonstrate the importance of cerebellar area right crus1 (Rcrus1) in social and repetitive behaviors. We also demonstrate functional connectivity between the cerebellum and the clinically-implicated medial prefrontal cortex (mPFC), show that mPFC function mediates cerebellar-regulated, ASD-relevant behaviors, and highlight disruptions in connectivity between these disparate regions across a large cohort of mouse models of ASD-linked genes as well as in individuals with ASD. Moreover, we delineate a four-stage, multi-synaptic circuit between the cerebellum and the mPFC, and we provide evidence that modulation across this circuit is sufficient to rescue ASD-relevant behaviors. Additionally, we show that output from two distinct, clinically- implicated cerebellar regions, Rcrus1 and the posterior vermis, culminate on thalamic projections to the mPFC and demonstrate that these two regions mediate the specific rescue of social impairments and repetitive/inflexible behaviors respectively. Taken together, these data highlight neural circuit connections bridging clinically implicated cerebellar and cortical domains that regulate behaviors relevant to both core diagnostic criteria in ASD and raise the intriguing possibility that neuromodulation of these specific circuits may offer therapeutic targets for the treatment of ASD.