Anne Takesian - US grants

[unreadable] DESCRIPTION (provided by applicant): Humans who have suffered from periods of hearing loss during development can experience permanent debilitating impairments in sound and language perception! These impairments include deficits in spectrotemporal processing. Inhibitory circuits in the auditory cortex are vulnerable to hearing loss and may be critical for spectrotemporal processing. Specifically, inhibitory transmission displays short-term plasticity which may contribute to the encoding of temporal patterns of acoustic stimuli. My preliminary data suggests that inhibitory short-term plasticity is altered by deafness. The objective of this application is to study how deafness may impact normal development of inhibitory short-term plasticity and how these changes may alter efficacy and timing of auditory cortex discharge patterns. A series of whole-cell experiments in neurons of the'auditory cortex are specifically designed to characterize (1) the normal development of inhibitory short-term plasticity (2) the impact of deafness on inhibitory short- term plasticity (3) the effects of inhibitory short-term plasticity on discharge properties. To characterize development of inhibitory short-term plasticity in normal and deaf animals, paired and multiple-pulse stimuli will be used to evoke trains of inhibitory synaptic events. Pharmacological manipulations, particularly targeting pre and postsynaptic GABAB receptors, will be used to uncover the mechanisms underlying normal developmental short-term plasticity and the changes following deafness. Finally, to understand the functional consequences of these changes, the effects of inhibitory short-term plasticity on spike efficacy and timing will be evaluated by integrating synaptic inhibition with neuronal spiking. Relevance: These experiments will assess whether changes in temporal responses of inhibitory synapses may partially explain auditory processing deficits following hearing loss, including impairments in speech production and perception. Particularly due to pur extensive knowledge of GABAB receptor pharmacology, revealing the involvement of these receptors in temporal responses will broaden our strategies to prevent and alleviate behavioral deficits associated with hearing loss. [unreadable] [unreadable] [unreadable]

Project Summary The circuitry and function of sensory cortices, including auditory cortex, are sensitive to changes in experience and sensory environment. Neurons in layer 1 (L1) of cortex have a privileged position in controlling the activity and plasticity of cortex induced by salient experiences. L1 contains a small number but diverse class of inhibitory neurons that nearly all express the ionotropic serotonin 5-HT3A receptor. These neurons are known to increase cortical activity by inhibiting other inhibitory GABAergic interneurons. Nevertheless, the mechanisms by which L1 neurons are activated and control cortical state are not fully understood. We unexpectedly found that, in primary auditory cortex (A1), L1 neurons receive a direct and tonotopically-organized input from auditory thalamus. Furthermore, we made the surprising discovery that L1 neurons send inhibitory projections back to thalamus. Here we propose to use anatomical, electrophysiological, and viral approaches to elucidate the pre and post-synaptic partners of 5-HT3A-expressing neurons in L1 of A1, focusing on the possibility of a closed loop from thalamic relay neurons to L1 neurons and back. Our findings suggest that classical models of cortico-thalamic interactions are incomplete and indicate that L1 receives tuned sensory input and contains projection neurons. These studies will lay the foundation of a future RO1 examining the functional effects of this novel inhibitory cortico-thalamic projection on the activity and plasticity of A1 circuits.

Project Summary. The primary auditory cortex (A1) is a central site of convergence for ascending sensory projections and projections from diverse neuromodulatory regions. These inputs interact in A1 to both influence moment-to-moment cortical activity and drive long-lasting changes in synaptic connections that may underlie auditory behavioral learning. Our recent work has revealed that a diverse group of inhibitory interneurons in cortical layer 1 (L1) has a privileged capacity to integrate tuned sensory input from the auditory thalamus and neuromodulatory inputs from cholinergic and serotonergic brain regions. These L1 interneurons send spatially- precise axonal projections to their postsynaptic targets that powerfully control cortical network activity and plasticity. Our recent results suggest that two distinct classes of L1 interneurons defined by the expression of either neuron-derived neurotrophic factor (NDNF) or vasoactive intestinal peptide (VIP) may receive differential inputs and send distinct outputs to their cortical targets. We propose that each L1 interneuron class has a specialized function in controlling cortical activity and plasticity. However, the mechanisms by which NDNF and VIP L1 interneuron subtypes are activated and control cortical state and plasticity are not fully understood. To address this unknown, we will use anatomical, trans-synaptic viral tracing, and electrophysiological approaches to elucidate the pre and post-synaptic partners of NDNF and VIP L1 interneurons in mouse A1. We will also use two-photon imaging in behaving mice to determine the in vivo activity and plasticity of NDNF and VIP L1 interneurons during auditory perceptual learning. The results of this research will identify L1 circuit mechanisms that promote auditory plasticity in adulthood and can be exploited to advance treatments following hearing loss.