STAART Network Centers: Kennedy Krieger Institute

A Mouse Model for Autism: Postnatal Effects
Principal Investigaror: Blue; site: Kennedy Krieger Institute

This project will address the role of 5-HT afferents in the initiation progression of synaptogenesis in the cortex during postnatal development. Proposed experiments will determine in a mouse model that involves neonatal serotonergic depletions whether selected structural and pharmacological changes in the neocortex resemble those observed in autistic patients. In this model, young adult mice that received neonatal injections of the serotonin neurotoxin, 5, 7, dihydroxytryptamine (5, 7-DHT) into forebrain, showed behavioral changes, indicative of altered attentional processes. Consistent with recent findings of increases in cortical volume in autistic brains, cortical width expanded in the 5,7-DHT treated group. Similar to autistic patients, specific changes varied by sex, cortical region and hemisphere. These results have led to the hypotheses that the cerebral cortical alterations observed in autism are the result of altered development of the 5-HT innervation cortex and the cognitive changes and disturbances in sensory processing are the consequence of altered cortical development. Dr. Blue will use this model to determine the time course of altered 5-HT innvervation and function and to characterize the effect of neonatal 5-HT depletion on development of thalamocortical connectivity and glutemate and serotonergic receptor ontogeny. Dr. Hohnmann will characterize sensorimotor functions, attentional, cognitive and affective behaviors in 5,7 DHT and GAP-43 mouse models and attempt to alleviate deficits with serotonergic reconstitution therapy (the selective serotonin reupate inhibitor, fluoxetine). Other experiments will compare cortical volume changes in both mouse models.

Specific Aims:

1. To determine the time course of altered 5-HT innervation (5-HT immunocytochemistry and HPLC of 5-HT and 5-HIAA) and function (5-HT receptor autoradiography) after neonatal 5,7-DHT injections into the medial forebrain bundle.
2. To determine the effect of neonatal 5-HT depletion on development of thalamocortical connectivity and receptor ontogeny using the whisker-to-barrel pathway as a model
3. To characterize behavioral differences and/or similarities between mice with prenatal (genetic model) and neonatal (5,7-DHT lesions) decreases in the 5-HT innervation to the cortex and hippocampus and to determine if fluoxetine (Prozac) treatment will lead to behavioral improvements.
4. To determine whether the volume of the cortical mantle is altered after neonatal 5-HT depletion and whether any alterations are due to changes in white or gray matter.

Early Detection, Intervention and Neurobiology of Autism
Principal Investigator: Landa; site: Kennedy Kreiger Institute

This project will address four treatment-related issues. 1) Need for early detection, identifying what developmental features differentiate autism from language impairment at 18 months of age, so that intervention may be started earlier, hopefully during sensitive periods of social and language development; 2) Need for understanding neural mechanisms underlying the symptom expression in autism; 3) Need for empirically-based guidelines for developing early intervention programs for toddlers with autism; and specifically, need to find ways to enhance early language acquisition; and 4) Need to understand predictors of language development. This is a longitudinal study involving toddlers at high risk for autism (having a sibling with autism), toddlers with autism spectrum disorders but no family history of autism, toddlers with late onset of language, and typically developing toddlers. Testing will be conducted at 18, 24, and 36 months. The early detection component of the study will assist us in understanding critical features of autism that distinguish it from language impairment, and will have implications for what to treat in early intervention programs. The study of neural mechanisms will involve longitudinal analysis of neurotrophins and neuropeptides in all groups of participating toddlers. Concentrations of these neurochemicals will be examined as they relate to symptom expression. The treatment study will involve toddlers with non-familial autism spectrum disorder. It will examine the effect of teaching social cognitive skills (specifically those related to interpersonal synchrony) on language acquisition. Furthermore, it will examine predictive value of imitation, joint attention, and interpersonal relatedness in toddlers with autism on response to treatment as well as 36-month outcome.

Specific Aims:

1. develop diagnostic criteria for autism by 18 months of age through the study of late talkers, some of whom are at high risk for autism (i.e., siblings of children with autism).
2. investigate the impact of early intervention targeting interpersonal synchrony on the process of communication development in toddlers with non-familial autism.
3. identify and characterize neurochemical differences between groups and examine whether biochemical patterns: a) differ in children with autism compared to those with non-autism language delay; b) suggest testable hypotheses concerning mechanisms of neurobiology in autism; and c) change over time in affected and nonaffected children, especially in response to treatment.

fMRI Studies of Sensorimotor Integration in Children with Autism Spectrum Disorders
Principal Investigator: Zeffiro; site: Georgetown University

Autism is a neurodevelopmental disorder that is characterized by pervasive and persistent deficits in spanning multiple domains, with a highly heterogeneous cognitive profile that is remarkable for spared or supranormal abilities coexisting with dramatic impairments in cognitive domains such as attention and language. It is characterized by large inter-individual differences in IQ, linguistic abilities, and attentional abilities and the neural basis of autism is currently poorly understood. While the deficits in social cognition have received vigorous attention, less is known about the mechanisms responsible for the disorder of motor planning and execution seen in most individuals with autism. Behavioral and neuroanatomical evidence indicates that motor development and cognitive development are intrinsically related. Motor deficits are observed in a variety of developmental and disorders of cognition such as attention deficit hyperactivity disorder. Damage to brain structures that subserve motor function such as cerebellum and striatum, also leads to disruptions in higher cognitive functions. These structures of motor control are not only closely linked anatomically to prefrontal cortex, the seat of higher cognition, but also develop in parallel to prefontral cortex. Therefore, examination of motor control may elucidate cognitive dysfunction in autism. The primary goal of this project is to use structural and functional MRI procedures to elucidate the neurobiological basis of attention, motor planning, and executive function in individuals with autism, specifically, HFA.

Specific Aims:

1. To characterize the neural mechanisms responsible for visuomotor coordination in HFA and TD populations.
2. To determine whether the neural mechanisms subserving response inhibition differ functionally between HFA and TD groups.
3. To examine the hypothesis that resolution of response competition is deficient in an HFA.

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