Nonconventional role of ADCY in Gq-mediated neuronal signaling and neuroplasticity

This research examines a critical, understudied dimension of cortical function: how internal cortical pathways shape sensory processing and the cellular mechanisms that enable experience-dependent change. This project, focused on the nonconventional role of adenylyl cyclase (ADCY) in Gq-mediated neuronal signaling and neuroplasticity, situates molecular signaling within the broader context of neocortical feedback that links higher-order cortical centers with primary sensory areas. The neocortex, the most elaborated structure of the mammalian brain, integrates raw sensory inputs with prior experience to guide perception and behavior. Top-down connections from associative and higher-order cortices back to sensory regions are thought to mediate attention, expectation, and predictive coding, yet their complexity has historically prevented mechanistic dissection. Crandall’s lab aims to bridge scales—from molecular signaling pathways to synapses, cells, and circuits—to reveal how ADCY and Gq-coupled signaling pathways contribute to the modulation of sensory responsiveness and enduring changes in circuit function.

Supported by a five-year NIH award, the project leverages recent advances in genetic, optical, and physiological tools to gain access to these elusive feedback pathways. Modern optogenetic approaches will allow precise, cell-type-specific control of activity within intact neocortical circuits and in reduced preparations, enabling experiments that link defined manipulations to downstream cellular and synaptic outcomes. Within this framework, the research will probe how ADCY, traditionally associated with canonical Gs signaling and cyclic AMP production, may operate in unconventional roles downstream of Gq-coupled receptors to influence intracellular signaling cascades, synaptic strength, and plasticity rules. By interrogating ADCY’s participation in Gq-driven processes, the work seeks to clarify molecular determinants that enable or gate the influence of top-down cortical input on sensory circuits.

A primary aim is to determine how neocortical feedback alters sensory responsiveness at cellular and circuit levels and to identify the signaling steps that translate such modulatory inputs into persistent changes in synaptic efficacy. This involves mapping the effects of targeted manipulations on neuronal excitability, synaptic transmission, and plasticity induction, and linking these physiological outcomes to the presence or absence of ADCY activity in Gq contexts. The multi-level approach promises to reveal whether ADCY serves as a critical nodal point in converting neuromodulatory and receptor-driven signals into lasting alterations in circuit dynamics, thereby shaping perception and behavior.

Beyond fundamental science, Crandall emphasizes the translational relevance: aberrant neocortical communication and maladaptive plasticity underlie many neurological and psychiatric disorders. By elucidating ADCY’s nonconventional role in Gq-mediated signaling within neocortical feedback circuits, the project may identify new targets or strategies for interventions that restore proper cortical communication and adaptive plasticity. With robust NIH backing and contemporary experimental approaches, this work is positioned to advance a comprehensive, mechanistic understanding of how molecular signaling pathways enable cortex-to-cortex interactions to sculpt sensory processing and behavior.