Vasoactive Intestinal Peptide Expressing Neurons as Regulators of Auditory Thalamocortical Signaling and Plasticity

Abstract

Sensory perception and learning rely on the dynamic interplay between external stimuli, contextual information, and internal brain states. Inhibitory neurons and neuropeptidergic signaling play critical roles in shaping this process, yet the underlying circuit and molecular mechanisms remain incompletely understood. This dissertation investigates how vasoactive intestinal peptide (VIP)-expressing interneu- rons and VIP signaling contribute to auditory thalamocortical function and plasticity. In Chapter 1, we show that superficial VIP-expressing neurons in the auditory cortex (ACtx) receive robust, monosy- naptic input from the ventral subdivision of the medial geniculate body (MGBv), indicating that these interneurons integrate direct, tonotopically organized sensory input alongside established top-down and neuromodulatory inputs. In Chapter 2, we demonstrate that the neuropeptide VIP induces a persis- tent potentiation of thalamocortical excitatory drive onto cortical pyramidal neurons, uncovering a novel mechanism by which neuromodulators control thalamocortical plasticity. Furthermore, using a newly developed genetically encoded fluorescent VIP sensor, we show that VIP is endogenously released in au- ditory cortex during sensory-reward association learning, providing evidence that VIP release is dynam- ically modulated based on behavioral relevance. In Chapter 3, we map unexpected long-range projec- tions of inhibitory neurons—including VIP-expressing subtypes—from auditory cortex to contralateral cortical and subcortical regions, revealing a potential pathway for inhibitory control of distributed sen- sory networks. Together, these findings uncover circuit and neuromodulatory mechanisms by which inhibitory neurons modulate thalamocortical signaling and plasticity, offering new insight into how ex- perience shapes sensory processing and identifying potential targets for promoting adaptive plasticity in learning and recovery contexts.