Document text
Principal Investigator: Kurt C. Marsden
Organization: NORTH CAROLINA STATE UNIVERSITY RALEIGH
Fiscal Year: 2024
Award: $361,883
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary. A fundamental function of the nervous system is to distinguish between threatening and non-
threatening stimuli. For example, a sudden intense sound that indicates danger should trigger an acoustic startle
response, but an innocuous sound should not. This type of behavioral threshold is a basic mechanism for
sensorimotor filtering, and the importance of setting this threshold appropriately is highlighted by the startle
hypersensitivity observed in neuropsychiatric diseases such as autism, anxiety, and schizophrenia. Despite its
importance, and in contrast to our knowledge of experience-dependent startle modulation, the molecular and
cellular pathways that establish and maintain the innate startle threshold are not well characterized. By
developing a more complete understanding of the biological mechanisms that govern the startle threshold, we
can generate new hypotheses about the neural bases for these diseases. This project will leverage the powerful
larval zebrafish model system to investigate the molecular-genetic and neural circuit bases of the startle
threshold. Here a simple, conserved, and genetically accessible circuit drives a stereotyped startle response,
with auditory afferents triggering reticulospinal neurons to activate motor neurons and initiate movement. In a
recent genome-wide screen, we identified a novel regulator of the innate startle threshold: cytoplasmic Fragile X
mental retardation protein (FMRP) interacting protein 2 (cyfip2). cyfip2 mutants are hypersensitive and startle to
low intensity sounds that rarely startle wild-types. Cyfip2 acts through FMRP and eIF4E to regulate RNA
translation, but it can also control actin polymerization through interactions with Rac1 and the WAVE regulatory
complex (WRC). In Aim 1 we will systematically test which of these molecular pathways cyfip2 uses to establish
the startle threshold and to maintain it through development. In Aim 2 we will define the cellular basis for cyfip2-
mediated threshold control by first locating the site of the primary circuit defect with optogenetic and calcium
imaging approaches and then identifying the cell types in which cyfip2 is needed for normal startle sensitivity.
Finally, our data show that acute manipulation of the actin cytoskeleton substantially alters the startle threshold
while also decreasing the number and size of excitatory synapses in inhibitory glycinergic neurons but not
excitatory glutamatergic neurons. In Aim 3 we will test the hypothesis that cyfip2 acts cell-autonomously to
maintain excitatory/inhibitory synaptic balance, combining behavioral recording with live imaging of neuronal
activity and synaptic scaffolds to define direct links between cyfip2, circuit structure and function, and behavior.
Overall, the results of this work will generate a detailed model of molecular and cellular pathways that control
the startle behavior threshold and lay a foundation for understanding how these may be affected in human
disease.
Terms: <ASD><Acoustics><Actins><Acute><Affect><Allergy><Anxiety><Architecture><Auditory><Autism><Autistic Disorder><Behavior><Behavior Disorders><Behavioral><Binding><Biologic Models><Biological><Biological Models><Brachydanio rerio><Brain><Brain Nervous System><Bypass><Calcium><Cell Body><Cells><Cellular Matrix><Cellular Morphology><Clinical><Complex><Connector Neuron><Corti Cell><Critical Paths><Critical Pathways><Cytoplasm><Cytoskeletal System><Cytoskeleton><DLG4><DLG4 gene><Danio rerio><Data><Defect><Detection><Development><Disease><Disorder><Early Infantile Autism><Electrophysiology><Electrophysiology (science)><Enabling Factors><Encephalon><Engineering / Architecture><Epilepsy><Epileptic Seizures><Epileptics><Equilibrium><Esthesia><Excitatory Synapse><FMR-1 Protein><FMR1 Protein><FMR1 gene><FMRP><FMRP protein><FRAXA><Fiber><Foundations><Fragile X Mental Retardation 1 Gene><Fragile X Mental Retardation Protein><Genetic><Genetics-Mutagenesis><Glutamates><Goals><Hair Cells><Hind Brain><Hypersensitivity><Image><Infantile Autism><Inhibitory Synapse><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Kanner's Syndrome><L-Glutamate><Label><Laboratories><Link><Measures><Mediating><Model System><Molecular><Molecular Genetics><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Motor Cell><Motor Neurons><Movement><Mutagenesis><Mutagenesis Molecular Biology><Nerve Cells><Nerve Unit><Nervous System><Nervous System Physiology><Neural Cell><Neurocyte><Neurologic Body System><Neurologic Dysfunctions><Neurologic Organ System><Neurologic function><Neurological function><Neurons><Neurophysiology - biologic function><Neurophysiology / Electrophysiology><Non-Polyadenylated RNA><Optics><PSD95><Pathway interactions><Peripheral><Phenotype><Polymers><Population><RNA><RNA Gene Products><Regulation><Reproducibility><Research><Rhombencephalon><Ribonucleic Acid><Role><SAP90><Schizophrenia><Schizophrenic Disorders><Seizure Disorder><Sensation><Sensory><Site><Startle Reaction><Stereotyping><Stimulus><Structure><Synapses><Synaptic><Testing><Therapeutic Intervention><Transgenic Organisms><Translational Inhibition><Translational Repression><Translations><Variant><Variation><Work><Zebra Danio><Zebra Fish><Zebrafish><addiction><addictive disorder><auditory stimulus><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><balance><balance function><base><bases><behavior phenotype><behavior response><behavioral disorder><behavioral phenotyping><behavioral response><biologic><body movement><cell morphology><cell type><dementia praecox><density><developmental><ear hair cell><electrophysiological><epilepsia><epileptogenic><experience><fragile X FMR1 protein><fragile X mental retardation 1><fragile X mental retardation-1 protein><genome wide screen><gephyrin><glutamatergic><hindbrain><human disease><imaging><imaging approach><imaging based approach><imaging in vivo><in vivo imaging><intervention therapy><intracellular skeleton><molecular modeling><motoneuron><mutant><nervous system function><neural><neural circuit><neural circuitry><neural function><neurocircuitry><neurological dysfunction><neuronal><neuronal circuit><neuronal circuitry><neuropsychiatric disease><neuropsychiatric disorder><novel><optical><optogenetics><pathway><perceptual stimulus><physicochemical phenomena related to the senses><polymer><polymeric><polymerization><programs><promoter><promotor><protein protein interaction><response><scaffold><scaffolding><schizophrenic><sensory processing disorder><sensory stimulus><social role><sound><startle response><synapse><synaptic circuit><synaptic circuitry><tool><transgenic><translation>