VIP Circuits Dynamics in Sensory Processing in Rett Syndrome

We take a multi-pronged approach spanning human, mouse, and computational models to examine neural network dynamics in response to sensory stimuli. Using paradigms designed to elicit brain oscillations specifically attributable to VIP+ interneurons (VIP+INs), we will shed new light on crucial disinhibitory sub- circuits often implicated in neurodevelopmental disorders, using Rett syndrome (RTT) as a model for VIP+IN dysfunction. Aim 1 will characterize engagement of VIP+INs in rhythmic abnormalities in vivo in RTT during sensory processing. a. In RTT and typically developing individuals, we will probe aberrant electroencephalogram (EEG) oscillations. b. In mice, we will characterize sensory responses involving VIP+INs, during threshold-level and oddball responses, using oscillatory dynamics captured by EEG, local field potential (LFP), single-unit recordings and simultaneous 2-photon (2P) imaging. Optogenetic tagging of VIP+INs in Mecp2 mutant mice (known for altered VIP+IN connectivity) will be used to directly assess VIP+IN contributions to aberrant oscillatory dynamics. c. Using optogenetics and chemogenetics, we will correct aberrant rhythms by adjusting VIP+IN function locally or diffusively during threshold or oddball detection. Aim 2 will test acute and modulatory contributions of VIP+INs to neural circuit dynamics in RTT. a. We will characterize in vitro intrinsic and synaptic properties of VIP+INs to identify subtypes that are deficient in RTT mice. b. Using optogenetic approaches, we will explore resonance crosstalk between VIP+INs, parvalbumin- expressing INs and principal cells by studying spiking properties. Aim 3 will create a biophysically detailed computational model of VIP+IN circuit function in RTT. a. We will investigate how VIP+INs engage cortical pyramidal cells to enable threshold detection. b. We will modify this model to account for changes in VIP+INs and their connectivity in primary sensory cortex in human RTT and MeCP2 mice to understand how changes in VIP+INs impair threshold detection. c. We will add inputs to our model from anterior cingulate cortex (ACC) to investigate the role of VIP+INs in oddball tasks with typically developing/ Rett phenotypes. We will also add a second subtype of VIP+IN. d. We will use our results to identify strategies for therapeutic rescue. Project Number: 1R01NS144555-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Michela Fagiolini (+3 co-PIs) | Institution: BOSTON CHILDREN'S HOSPITAL, BOSTON, MA | Award Amount: $714,060 | Activity Code: R01 | Study Section: Developmental Brain Disorders Study Section[DBD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368592