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Principal Investigator: Arnaldo Carreira-Rosario
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $223,931
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Towards the end of nervous system development, neural circuits are extremely plastic. Small perturbations
during this time can cause lifelong circuit and behavioral changes. Not surprisingly, mounting evidence suggests
that several neurodevelopmental disorders, including autism spectrum disorder and epilepsy, have origins in
defective late neural circuit formation. During this late stage, neural circuits refinement takes place, and
components of the mature behavior gradually appear. As this occurs, stimulus-independent bursts of activity
sweep through neuronal populations. This type of activity, known as spontaneous network activity (SNA), has
been characterized in vertebrate systems where it refines neural connections to generate sensory maps and
establish local circuits. However, we know surprisingly little about the molecular mechanisms by which SNA is
initiated, how it functions, and how it ultimately underpins behavior. This proposal establishes the developing
Drosophila larval locomotor system as a genetically tractable model, with a wealth of knowledge on early stages
of neurodevelopment and circuit function, where these questions can be tackled. We combine genetic and
systems neuroscience techniques to gain new understanding into SNA function during late circuit formation. This
proposal has three goals. (1) The exact neurons that initiate SNA within locomotor circuits are not known. The
first aim of this proposal is to identify the SNA initiator neurons and the mechanism by which they act. Uncovering
the mechanism that initiates SNA at the neural and activity level is fundamental to understand how SNA is
implemented. (2) After initiation, SNA expands and begins to produce motor outputs that mature into the larval
behavior. How does this activity pattern develop? The second aim of this proposal is to reveal the structure of
SNA at the population level and the pattern of activity in individual neurons, and begin to learn the effect of SNA
on mature behavior. (3) The molecular mechanisms that produce SNA remain poorly understood in any
organism. The third aim will identify genes that are necessary for the initiation and/or expansion of SNA. We will
focus on genes that have been associated with neurodevelopmental disorders, which intriguingly are highly
expressed specifically during the SNA window. In sum, this proposal will reveal the neural mechanisms for how
SNA initiates, the structure and neural components of SNA after initiation, and genes required for SNA. These
studies will provide new insight into how neural circuits form, or fail to form properly, in neurodevelopmental
disorders.
Terms: <ASD><Address><Affect><Anatomic Sites><Anatomic structures><Anatomy><Assay><Autism><Autistic Disorder><Behavior><Behavioral><Bioassay><Biologic Models><Biological Assay><Biological Models><Calcium><Calcium Binding><Candidate Disease Gene><Candidate Gene><Cell Body><Cells><Cognition><Connector Neuron><Data><Defect><Development><Drosophila><Drosophila genus><Early Infantile Autism><Electron Microscope><Embryo><Embryonic><Emotions><Epilepsy><Epileptic Seizures><Epileptics><Foundations><Future><Genes><Genetic><Goals><Human><Image><Individual><Infantile Autism><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Kanner's Syndrome><Knowledge><Label><Learning><Link><Locomotion><Maps><Membrane><Methods><Model System><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Monitor><Motor><Motor output><Musculoskeletal System><Nerve Cells><Nerve Unit><Nervous System><Neural Cell><Neural Development><Neural Transmission><Neurocyte><Neurodevelopmental Disorder><Neurologic Body System><Neurologic Organ System><Neurological Development Disorder><Neurons><Neurosciences><Organism><Ortholog><Orthologous Gene><Pattern><Perception><Phase><Population><Process><Property><RNA interference screen><RNAi screen><RNAi-based screen><Rapid screening><Research><Seizure Disorder><Sensory><Stereotyping><Stimulus><Stochastic Processes><Structure><Synaptic Transmission><System><Techniques><Testing><Time><Training><Transmission><Work><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><calcium bound><cell type><connectome><developmental><epilepsia><epileptogenic><fruit fly><hatching><imaging><insight><intervention design><knock-down><knockdown><larva control><larval control><living system><locomotor system><membrane structure><molecular profile><molecular signature><nervous system development><neural><neural circuit><neural circuitry><neural mechanism><neurocircuitry><neurodevelopment><neurodevelopmental disease><neuromechanism><neuronal><novel><optogenetics><post-doctoral training><postdoctoral training><programs><quantitative imaging><spatiotemporal><stereotypy><stochastic method><synaptic circuit><synaptic circuitry><therapy design><tool><transmission process><treatment design>