Jeffrey J. Wenstrup, Ph.D. - US grants

Acoustic behavior relies on information conveyed by multiple pathways projecting from the inferior colliculus to the medial geniculate body, and then to the auditory cortex. The long term goal of this research is to evaluate information processing within these auditory pathways. The proposed research will specifically examine the organization of projections from the inferior colliculus to the medial geniculate body, and the physiological properties of neurons in the medial geniculate. Special attention will be placed on connections and mechanisms involved in sound localization and in the integration of acoustic information from different frequency bands. Binaural responses and sound localization cues are organized within isofrequency representations of the mustached bat's inferior colliculus. The ascending projections of the inferior colliculus will be studied by placing deposits of anterograde tracer in regions defined physiologically by their responses to binaural input and sound frequency. Two anterograde tracers, placed in dfferent binaural subdivisions, will be used to evaluate the degree of convergent input from binaural subdivisions in the inferior colliculus. Then, physiological studies of single and multi-unit responses in the medial geniculate will evaluate the physiology and functional organization of binaural responses. These studies will establish what information regarding binaural cues is conveyed from the inferior colliculus to the medial geniculate body, and how this information is processed by neurons within the medial geniculate. It will furthermore provide the basis for a deeper understanding of how the auditory cortex processes and represents binaural cues related to sound localization, and thus underlies this important acoustic behavior. Neuml mechanisms analyzing sound location and other acoustic features may depend upon the integration of information across different isofrequency representations. The convergence of frequency-specific input from the inferior colliculus onto subdivisions of the medial geniculate will be studied by placing deposits of two anterograde tracers in different frequency represenations of the inferior colliculus. Physiological studies of single units in the medial geniculate will then confirm the organization of convergent input, and identify the physiological responses of such neurons. These studies will provide information regarding integrative mechanisms by which sound location and other acoustic features are analyzed within the auditory system.

Acoustic behavior relies on information conveyed by multiple pathways projecting from the inferior colliculus to the medial geniculate body, and then to the auditory cortex. The long term goal of this research is to evaluate information processing within these auditory pathways. The proposed research will specifically examine the organization of projections from the inferior colliculus to the medial geniculate body, and the physiological properties of neurons in the medial geniculate. Special attention will be placed on connections and mechanisms involved in sound localization and in the integration of acoustic information from different frequency bands. Binaural responses and sound localization cues are organized within isofrequency representations of the mustached bat's inferior colliculus. The ascending projections of the inferior colliculus will be studied by placing deposits of anterograde tracer in regions defined physiologically by their responses to binaural input and sound frequency. Two anterograde tracers, placed in dfferent binaural subdivisions, will be used to evaluate the degree of convergent input from binaural subdivisions in the inferior colliculus. Then, physiological studies of single and multi-unit responses in the medial geniculate will evaluate the physiology and functional organization of binaural responses. These studies will establish what information regarding binaural cues is conveyed from the inferior colliculus to the medial geniculate body, and how this information is processed by neurons within the medial geniculate. It will furthermore provide the basis for a deeper understanding of how the auditory cortex processes and represents binaural cues related to sound localization, and thus underlies this important acoustic behavior. Neuml mechanisms analyzing sound location and other acoustic features may depend upon the integration of information across different isofrequency representations. The convergence of frequency-specific input from the inferior colliculus onto subdivisions of the medial geniculate will be studied by placing deposits of two anterograde tracers in different frequency represenations of the inferior colliculus. Physiological studies of single units in the medial geniculate will then confirm the organization of convergent input, and identify the physiological responses of such neurons. These studies will provide information regarding integrative mechanisms by which sound location and other acoustic features are analyzed within the auditory system.

Acoustic behavior relies on information conveyed by multiple pathways projecting from the inferior colliculus to the medial geniculate body, and then to the auditory cortex. The long term goal of this research is to evaluate information processing within these auditory pathways. The proposed research will specifically examine the organization of projections from the inferior colliculus to the medial geniculate body, and the physiological properties of neurons in the medial geniculate. Special attention will be placed on connections and mechanisms involved in sound localization and in the integration of acoustic information from different frequency bands. Binaural responses and sound localization cues are organized within isofrequency representations of the mustached bat's inferior colliculus. The ascending projections of the inferior colliculus will be studied by placing deposits of anterograde tracer in regions defined physiologically by their responses to binaural input and sound frequency. Two anterograde tracers, placed in dfferent binaural subdivisions, will be used to evaluate the degree of convergent input from binaural subdivisions in the inferior colliculus. Then, physiological studies of single and multi-unit responses in the medial geniculate will evaluate the physiology and functional organization of binaural responses. These studies will establish what information regarding binaural cues is conveyed from the inferior colliculus to the medial geniculate body, and how this information is processed by neurons within the medial geniculate. It will furthermore provide the basis for a deeper understanding of how the auditory cortex processes and represents binaural cues related to sound localization, and thus underlies this important acoustic behavior. Neuml mechanisms analyzing sound location and other acoustic features may depend upon the integration of information across different isofrequency representations. The convergence of frequency-specific input from the inferior colliculus onto subdivisions of the medial geniculate will be studied by placing deposits of two anterograde tracers in different frequency represenations of the inferior colliculus. Physiological studies of single units in the medial geniculate will then confirm the organization of convergent input, and identify the physiological responses of such neurons. These studies will provide information regarding integrative mechanisms by which sound location and other acoustic features are analyzed within the auditory system.

biomedical equipment purchase;

Acoustic behavior relies on information conveyed by projection systems from the inferior colliculus to the medal geniculate body and then to the auditory cortex. The long term goal of this research is to evaluate auditory information processing in these projection systems. The proposed research will examine mechanisms by which neurons analyze spectrally and temporally complex sounds. Special attention is placed on anatomical connections and physiological properties which give rise to combination - sensitive neurons. These neurons, which combine inputs responding to different frequencies in the appropriate temporal relationships, perform computational analyses of complex sounds. The proposed studies examine these in the mustached bat auditory system, where they are best understood. The initial experiments describe, using physiological recording, functional properties and organization of combination-sensitive neurons in the inferior colliculus. These experiments will guide retrograde tracing studies that identify auditory brain stem nuclei which may contribute to the combination-sensitive response of collicular neurons. Physiological recordings will be obtained from auditory brain stem regions identified in the preceeding anatomical experiments. These will provide examine whether combination sensitivity originates in inferior colliculus neurons, or at lower levels. An anterograde tracer will be placed in an auditory brain stem region that appears to contribute to combination sensitivity in the inferior colliculus; this can confirm a potential contribution to inferior collicular combination sensitivity. Finally, chemical inactivation experiments will test the presumed role of brain stem nuclei in creating these response features in the colliculus. Because the thalamic reticular nucleus appears to contribute to combination-sensitive responses in the medial geniculate body, its functional properties and anatomical connections will also be examined. Acoustically-guided behavior, including speech and other forms of acoustic communication and sound localization, often relies on neural mechanisms which combine information across different frequency bands. Combination-sensitive neurons in the mustached bat form a major pathway from the inferior colliculus to the medial geniculate body, and then to the auditory cortex, in which temporal information is encoded. In humans, structural irregularities in the medial geniculate body have been implicated in language disorders characterized by temporal processing deficits. Studies of mechanisms creating combination-sensitive neurons in mustached bats may provide a deeper understanding of how analagous speech processing systems operate in humans.

DESCRIPTION: (Adapted from applicant's abstract): The long term goal of this research is to identify mechanisms and pathways that give rise to the encoding and representation of information conveyed by vocal cornmuniction signals. Communication by sound employs spectrally and temporally complex signals, and their analyses in the central nervous system require integration across spectral and temporal elements in the signals. Such integration, once considered an exclusive role of auditory cortex, now appears to occur in sub-cortical auditory regions. This proposal focuses on the neuronal mechanisms and structural features of temporal and spectral integration in the auditory midbrain. Understanding where and what types of specialized processing of speech-like sounds occurs in particular pathways to auditory cortex will provide a fuller understanding of the bases of language perception disorders and potential intervention strategies.One form of time- and frequency-sensitive integration, common in the forebrains of a wide range of vertebrates, is performed by combinatorial neurons that respond best when distinct spectral elements in vocalizations are combined in specific temporal relationships. The proposed research examines how and where combinatorial responses originate in the mustached bat. In the auditory cortex of this species, combinatorial responses are abundant and well-characterized, and there is a good understanding of their potential significance in sonar and social communication behaviors. These neurons are also abundant in the inferior colliculus (IC), and may be formed there. The first two specific aims examine how brainstem auditory neurons contribute to the combinatorial responses in the inferior colliculus that analyze the bat's sonar echoes. The first aim will examine the neurophysiological properties of neurons in the cochlear nucleus that may contribute to the construction of these combinatorial responses. The second aim is to use anterograde tracing methods to determine what projections from the auditory brainstem provide the basis for frequency integration by combinatorial neurons in the inferior colliculus. The third specific aim uses physiological recording and local application of drugs to examine the mechanisms operating in the inferior colliculus that create the temporally sensitive facilitation that characterizes combinatorial responses. The fourth specific aim uses the same physiological/pharmacological techniques to study a class of combinatorial neurons that may respond to social vocalizations. This aim will test whether there is a fundamental mechanistic link between the well-studied combinatorial neurons that analyze sonar echoes and those that analyze other complex sounds, such as social vocalizations. These mechanisms may be similar to those operating at early stages in the analysis of speech sounds.

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand how analyses of complex sounds are modified by brain centers that establish the emotional significance of auditory and other sensory input. The proposed research will examine a newly described direct pathway from the amygdala, a forebrain center mediating emotional expression, to the inferior colliculus (IC), the midbrain integration center of the ascending auditory system. The direct amygdalo-collicular projection may impose emotional content onto auditory processing at a relatively low level of the ascending auditory pathway. Moreover, this projection could mediate effects of auditory cortical activation that have been attributed to the direct cortico-collicular pathway. We hypothesize that the amygdalo-collicular projection modulates the integrative features of acoustic information processing in the IC based on emotional state and/or the emotional significance of recent sensory input. The project will examine how the amygdala modifies integrative auditory responses in the mustached bat's IC, where integrative auditory responses (termed combination-sensitive) analyze social and sonar vocalizations. The functional organization and origin of these responses in the IC and auditory brainstem are well understood. Connectional evidence suggests that amygdalo-collicular projection neurons contact combination-sensitive IC neurons. In Aim #1 of the proposed research, we will examine responses of single neurons or small clusters of neurons in the basolateral amygdala in response to simple acoustic signals and social and sonar vocalizations. The results will identify acoustic conditions under which the amygdalo-collicular pathway is active, and also develop a physiological "signature" to identify amygdalo-collicular neurons. Aim #2 will use anterograde and retrograde tract tracing to examine the organization of the amygdalo-collicular projection and circuits relating the amygdala, auditory cortex, and IC. Aim #3 will examine how chemical and electrical stimulation of the amygdala affects acoustic information processing for simple acoustic signals and complex vocalizations across the IC, using multi-channel recording methods. Aim #4 will test, using non-invasive cortical cooling, whether the amygdala affects IC neurons primarily through its direct pathway, or through its connections to auditory cortico-collicular neurons. Relevance: These studies will provide a better understanding of how our processing of acoustic signals including speech is modified by emotion-laden sounds or by our emotional state. They may further our understanding of the role of the amygdala in auditory learning. This work may also improve our understanding of the role of emotional centers in abnormal auditory perceptions such as tinnitus.

Project Summary The long-term goal of this work is to improve the understanding of neural mechanisms that underlie acoustic communication. Our premise is that the amygdala, a brain region associated with emotional expression, plays a critical role in this process. The amygdala ?decides? whether a vocal signal is significant, or salient, and whether its valence is positive or negative based on contextual information from the vocal sequence, other senses, and the listener's internal state. The amygdala orchestrates emotional responses that are appropriate for the received vocal communication signals and their context. Further, the amygdala modulates responsiveness to vocal signals through its direct and indirect projections to auditory cortex and other auditory structures. In other words, the amygdala is likely to influence how we hear and respond to social vocalizations. Our central hypothesis is that the basolateral amygdala (BLA) receives information about all types of social vocalizations, and that mechanisms within the BLA provide moment-by-moment assessment of the meaning of these social signals based on the surrounding context. This assessment is expressed by highly selective responses of most BLA neurons for contextually aversive vocal stimuli and by context-dependent temporal patterns of response. We hypothesize that this assessment depends on integration of excitatory auditory inputs with GABAergic inhibition and neuromodulatory inputs. We will examine bases for selectivity, temporal response patterns, and contextual modulation in four Specific Aims. First, we will use intracellular recording to examine subthreshold and suprathreshold responses to vocal stimuli in BLA. Second, we will examine the contributions of auditory cortical and thalamic inputs to the responses of amygdalar neurons, using optogenetic methods to separately inactivate each of these inputs. In the final two Aims, we will combine local application of drugs with single neuron recordings to examine the contributions of receptors mediating glutamatergic excitation and GABAergic inhibition, as well as receptors for cholinergic modulation that are likely to convey contextual information associated with the received social vocalizations. We will use a normal hearing mouse strain, CBA/CaJ, that has a well understood acoustic communication system. These Specific Aims provide an interconnected approach to understand the mechanisms acting within the basolateral amygdala that contribute to the analysis of meaning in social vocalizations. These mechanisms are important in acoustic communication because the amygdala is involved in disorders that result in an altered emotional response to speech, such as schizophrenia, autism, and some forms of post-traumatic stress disorder. Furthermore, these studies will assess mechanisms related to therapeutic drugs affecting glutamatergic, GABAergic, and cholinergic transmission in the amygdala.