Laura M. Hurley - US grants

This proposal deals with how serotonin modulates the responses of single neurons in a midbrain auditory nucleus to both simple and complex auditory stimuli. The health relatedness of this project arises from the fact that the auditory system of the experimental animal is typically mammalian in most regards, and that some of the auditory stimuli to be used frequency-modulated sweeps, are important components of human speech. In this way, the proposed experiments can be extrapolated to the human auditory system at some level, and will provide basic knowledge in an area about which little is known: serotonergic modulation of auditory processing. I will investigate three main issues. l). How serotonin modulates the excitatory and inhibitory responses of cells to pure tones of varying frequency and intensity. 2). How serotonin correspondingly modulates responses to more spectrally and temporally complex sweeps through multiple frequencies. 3). Which serotonin receptors mediate cell responses to pure tones and to frequency- modulated sweeps. What will emerge is a picture of how serotonin modulates the responses of single neurons to complex, multi-frequency sounds through modulating the simpler elements of the excitatory and inhibitory responses to single frequencies.

DESCRIPTION (provided by applicant): Neuromodulators such as serotonin (5-HT) are often considered in the context of mood or appetite disorders, but they also strongly influence the way that auditory information is processed and perceived. However, we understand very little of how the actions of 5-HT on the neural circuitry of the auditory system are involved in normal perception or in disease. The proposed experiments will address these issues by examining the influence of two types of 5-HT receptor on frequency tuning of neurons in a midbrain auditory nucleus, the inferior colliculus (IC). Frequency tuning is a fundamental characteristic of auditory neurons, but can be changed by learning or by depriving the auditory system of its normal input. In previous studies of single neurons in the IC, one of the most prominent effects of 5-HT was on frequency tuning. Two 5-HT receptors, the 5-HT1A and 5-HT1B receptors, have opposing effects on tuning, with the 5-HT1A receptor limiting frequency tuning, and the 5-HT1B receptor expanding tuning. In pursuing this finding, the objectives of this proposal are 3-fold: 1) To more fully characterize how these two receptors change frequency tuning. This will be accomplished by using 2-tone stimuli to examine the interactions between the excitatory and inhibitory inputs that establish frequency tuning in the IC, while locally manipulating the receptors. 2) To test the hypothesis that the receptors act partly by affecting inhibitory inputs to IC neurons. This will be accomplished by determining whether blockers of inhibition also block the effects of the two receptors, and by determining whether activating the receptors alters directly visualized inhibitory inputs. 3) To establish whether these changes in frequency tuning occur in groups of neurons that play particular roles in the circuitry of the IC. This will be determined by identifying neurons morphologically by filling single neurons with neurobiotin and immunohistochemically by co-labeling neurons for the inhibitory neurotransmitter, GABA. The results of these studies will provide a rich functional profile of neuronal response properties and anatomy that will clarify the role of the 5-HT1A and 5-HT1B receptors in the IC and lay the groundwork for studying their role in auditory dysfunction. PUBLIC HEALTH RELEVANCE: The potential involvement of serotonin in auditory disorders that are primary or that are associated with affective disorders has received little attention. Defining how the 5-HT1A and 5-HT1B receptors act to alter frequency filtering in the IC will lay the groundwork for addressing the role of serotonin in auditory dysfunctions such as poor speech perception, auditory hypersensitivity, or tinnitus.

In addition to its well-known roles in regulating mood and appetite, the chemical serotonin plays an important role in the response of the brain to social interaction. Despite this, very little is known about its role in a crucial type of social behavior, communication. In their past work, the researchers have shown that serotonin modifies auditory responses to communication calls in mice, and that social partners trigger these increases in serotonin in the auditory system. In other regions of the brain, the serotonergic system itself is heavily influenced by past social experience. With this rationale, the researchers hypothesize that social experience changes the role of the serotonergic system in auditory processing. They will test this idea by measuring how housing mice individually or in social groups affects the way that the serotonergic system interacts with the auditory system. This work will explore a process fundamental to communication: how sensory systems adapt to features of the social environment like social history, with implications for how animals respond to their social partners. The work will also serve as a springboard for a local K-12 outreach program in which undergraduates present interactive lessons on themes of communication and sensory systems.

The social experience hypothesis will be tested in male and female mice, which are increasingly studied models of vocal communication. Mice also demonstrate highly conserved serotonergic function in auditory regions compared with other vertebrates. The specific objectives of the proposed work are to examine the effect of group versus individual housing on three features of serotonin-auditory interactions in the inferior colliculus (IC), a mammalian auditory midbrain nucleus. 1) The first of these is the anatomy of the serotonergic system within the IC. This will be accomplished by measuring the density of immunohistochemically labeled serotonergic fibers. 2) A second feature is the transient serotonergic response to social interactions. This will be measured locally in the IC of behaving animals using carbon fiber voltammetry. 3) A final feature is the serotonergic regulation of the activation of the c-fos transcriptional pathway by social interaction, which will be explored by inducing systemic release or depletion of serotonin. These studies will provide a framework of how social experience creates plasticity in auditory-serotonin interactions at multiple levels of organization, generating testable hypotheses on the downstream consequences of such plasticity for neural encoding and perception.