The receptive fields of auditory cortical pyramidal neurons are produced by integrating multiple classes of excitatory inputs. These inputs carry different sorts of sound information and synapse onto different portions of pyramidal neuron dendrites. For example, excitatory intracortical inputs synapse more frequently onto the apical dendritic branch and tuft of pyramidal neurons and tend to carry more sound information about the edges of the spectral receptive fields. In contrast, thalamocortical inputs synapse more frequently near the soma of pyramidal neurons and tend to carry more sound information about the center of the spectral receptive fields. In addition to excitatory inputs, pyramidal neurons integrate inhibitory inputs from local cortical interneurons. These interneurons also display multiple classes that synapse onto different portions of pyramidal neuron dendrites. As one particular example, somatostatin-positive interneurons synapse predominantly onto the apical dendrites of pyramidal neurons. Because of the anatomical proximity between somatostatin-positive inhibitory synapses and excitatory intracortical synapses, I hypothesize that somatostatin-positive interneurons more strongly suppress or influence responses to intracortical inputs than thalamocortical inputs. The function of somatostatin-positive interneurons is important to understand because significant proportions of these interneurons tend to die in neurological conditions including aging, neuropsychiatric disorders, and hearing loss. To understand the changes in human neurological conditions, it is necessary to understand the functional consequences of such a loss of interneurons. In my previous work with mice that lose somatostatin-positive and other interneurons in early adulthood, I observed a compensatory weakening of intracortical inputs. I hypothesize that the loss of somatostatin-positive interneurons alone is sufficient to induce the compensatory weakening of excitatory intracortical inputs. To test these hypotheses about the interactions of somatostatin-positive interneurons and intracortical inputs in health and disease, I will conduct acute and chronic manipulations in vivo and in vitro. I will acutely activate somatostatin-positive interneurons usin optogenetics to observe their effect on intracortically-driven responses in vivo and in vitro. I wil also chronically ablate ~20% of somatostatin-positive interneurons using conditional Dlx1 mutants to examine the mice for compensatory weakening of intracortical inputs in vivo and in vitro. This work will connect the normal functional interaction of somatostatin-positive interneurons with intracortical inputs and the functional consequences for intracortical inputs from the loss of somatostatin- positive interneurons commonly observed in neurological conditions, including aging, hearing loss, and brain trauma.

Public Health Relevance

To understand the conscious perception of hearing in normal and disease states, we must understand the interactions of the individual circuit elements in auditory cortex. The aim of this proposal is to characterize the functional role of somatostatin containing interneurons that are specifically lost in aging and other neurological conditions. This knowledge is necessary to understand cortical processing and therefore necessary to treat neurological diseases.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDC1)
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Sklare, Dan
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Teschner, Magnus J; Seybold, Bryan A; Malone, Brian J et al. (2016) Effects of Signal-to-Noise Ratio on Auditory Cortical Frequency Processing. J Neurosci 36:2743-56
Seybold, Bryan A; Phillips, Elizabeth A K; Schreiner, Christoph E et al. (2015) Inhibitory Actions Unified by Network Integration. Neuron 87:1181-1192