Interaction with the external environment is made possible by sensory systems, which transduce physical, chemical, or visual information into electrical signals that the brain can encode and interpret. Once transduced into electrical signals, environmental stimuli are subject to filtering to enhance or diminish specific features and to prevent overstimulation. Presynaptic inhibition is a ubiquitous feature of early sensory processing and is imperative for modulating synaptic output from sensory neurons to central neurons. The inhibitory neurotransmitter GABA is released onto sensory afferents, depolarizes the axon terminal, and suppresses neurotransmitter release. Despite the importance and prevalence of presynaptic inhibition, it is not clear how depolarization of the axon terminal results in synaptic inhibition. In addition, the GABAergic interneurons providing synaptic input to the afferent terminals remain elusive and therefore their function and regulation are unknown. In order to understand presynaptic inhibition and its role in sensory encoding, I propose to use Drosophila leg proprioceptors as a model system. Across animals from humans to insects, proprioceptors located throughout the body project to the central nervous system, where information such as limb movement or position are encoded. By investigating the mechanism and regulation of presynaptic inhibition in Drosophila, I will benefit from the relatively simplified circuitry of their nervous system and the unparalleled ability to genetically target subpopulations of neurons. I will perform experiments to address three specific questions: 1) what is the biophysical mechanism of presynaptic inhibition in proprioceptors and 2) do GABAergic interneurons have target specificity for specific proprioceptors, and 3) how are proprioceptors dynamically regulated during spontaneous and passive movement? To address the first question, I will use voltage imaging to measure membrane voltage of proprioceptors during induced inhibition by stimulating with exogenous GABA. Then, I will determine whether GABAergic interneurons are promiscuous or if they have functionally segregated targets. Lastly, I will determine which GABAergic interneurons are activated by direction-sensitive or movement-sensitive proprioceptors. By measuring membrane voltage across proprioceptors during GABA application, active movements, and passive movements, I hope to identify the biophysical mechanism of presynaptic inhibition and determine how the inhibitory neurons are dynamically recruited to provide feedback.
One in three Americans will experience chronic pain and many patients are resistant to treatment, leaving them without relief from the debilitating discomfort. The cause of chronic pain remains disputed; however, a wealth of evidence has implicated a reduction of presynaptic inhibition at the axon terminals of primary somatosensory neurons, which may result in aberrant encoding of touch and proprioceptive stimuli. Advancing our understanding of how the nervous system gates somatosensory information may lead to the development of therapies for conditions such as chronic pain.
