VIP Signaling Mechanisms in Thalamocortical Circuit Plasticity and Learning

Summary. Cortical plasticity — the dynamic remodeling of synaptic connections in response to experience — is essential for learning, perception, and recovery from neurological injury. While prior work has focused on classical neurotransmitters, the role of neuropeptides in regulating cortical plasticity remains poorly understood. Vasoactive intestinal peptide (VIP), expressed by a subset of cortical inhibitory interneurons, is a key candidate for modulating circuit excitability and plasticity, yet its signaling dynamics and downstream effects on plasticity in cortex have not been directly measured in vivo or examined mechanistically. This proposal, based on strong preliminary data, will investigate the central hypothesis that VIP is released in the sensory cortex during learning to trigger plasticity at thalamocortical synapses. To test this, we will combine whole-cell patch-clamp electrophysiology, fiber photometry using a genetically encoded GRAB-VIP sensor, and in vivo two-photon photoactivation and calcium imaging in the mouse auditory cortex. In Aim 1, we will define the cellular and circuit- level mechanisms of VIP signaling that drive thalamocortical plasticity by combining whole-cell electrophysiology with pharmacological and genetic approaches. In Aim 2, we will quantify the temporal dynamics of endogenous VIP release during sensory stimulation and auditory learning. In Aim 3, we will manipulate VIP signaling in vivo to determine how it shapes population-level cortical responses, plasticity and behavioral learning. This research will provide the first direct measurement of VIP release in vivo and establish a mechanistic framework for understanding its function in adaptive cortical remodeling. By revealing how peptide-based signaling contributes to sensory processing and plasticity, these findings may inform therapeutic strategies to enhance circuit reorganization in neurological conditions such as stroke, epilepsy, and neurodevelopmental disorders. Project Number: 1R01NS148386-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: ANNE TAKESIAN | Institution: MASSACHUSETTS EYE AND EAR INFIRMARY, BOSTON, MA | Award Amount: $452,713 | Activity Code: R01 | Study Section: Learning, Memory and Decision Neuroscience Study Section[LMDN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11343861