Yale E. Cohen - US grants

The long-term objective of this research is to examine the neural mechanisms underlying spatial attention and, in particular, different forms of spatial attention. Attention modulates the brain's representations of sensory stimuli and helps extract those aspects of the stimuli that are immediately relevant. For example, when searching for someone in a crowd, attention can be used to key in on a selected visual feature, such as color. Similarly, when listening to a symphony orchestra, attention allows us to focus on the music being played by particular sections (e.g., the violin section) of the orchestra. Besides working on individual senses, attention can cross stimulus-modality boundaries and link evens that involve different senses. For example, in the ventriloquism effect, if a person's lips are moving, their lips are perceived to be the source of the speech, regardless of the fact that the speech source originates elsewhere. While attention can be conceptualized as being uni-modal or cross-modal, it is unclear whether these forms of attention are mediated by common or distinct neural mechanisms. One hypothesis is that attention is controlled by a single "supra-modal" attentional system. An alternative hypothesis is that spatial attention results from the cooperation of different auditory and visual attentional system. Human studies, using psychophysical and electrophysiological techniques that were designed to test these alternative hypotheses have provided evidence in support of both hypotheses. This important issue can be probed further by comparing the responses of single neurons that are recorded while a monkey is engaged in tasks that probe uni-modal or cross-modal spatial attention. The advantage of this technique is that couples the high spatial and temporal resolution of single-unit recordings with the power of the awake, behaving monkey preparation. This proposal uses this technique to examine whether, in the lateral intraparietal area, attention is mediated through a supra-modal mechanism or through modality-dependent mechanisms. Since the macaque is a good model of human cortical function, this study has ramifications for the treatment of human disease. For example, underlying attention may increase our understanding of neuropathologies that have an attentional element such as neglect and schizophrenia.

[unreadable] DESCRIPTION (provided by applicant): Communication is 1 of the fundamental components of both human and non-human animal behavior. While the benefits and importance of language in human evolution are obvious, other non-human communication systems are also important. These communication systems are important, because for most, if not all, species, they are critical to the species' survival. For example, auditory communication signals (i.e., species-specific vocalizations, SSVs) play a fundamental role in the socioecology of several species of non-human primates, such as rhesus monkeys (Macaca mulatta). While neurophysiological experiments examining the representation of SSVs in the non-human primate cortex have a long and rich history, there have not been any studies, to date, that have tested how neurons code the abstract qualities of SSVs. This grant proposal examines this important issue by testing how neurons in the ventrolateral prefrontal cortex (vPFC) code the information conveyed by SSVs. The experiments in this grant proposal test the following general hypothesis: vPFC neurons are preferentially modulated by the information conveyed by SSVs and not by their spectrotemporal properties. In EXPERIMENT #1A, we test whether vPFC neurons code the information conveyed by SSVs in superordinate (e.g., food versus nonfood) or subordinate (high-quality food or low-quality food) categories. In EXPERIMENT #1B, we test the hypothesis that vPFC neurons respond to transitions between SSVs based on presentation context and the information conveyed by the SSVs. Together, these studies will provide a more comprehensive understanding of the role that the vPFC has in representing the information conveyed by the SSVs and the role of the PFC, in general, in the representing information in category-dependent formats. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Communication is one of the fundamental components of human and non-human animal behavior. The lateral belt of the auditory cortex (LB) in rhesus monkeys has recently been identified as a cortical area that plays an important role in vocalization processing. This grant application, which uses auditory-object analysis as a theoretical framework, tests the role of LB neurons in processing communication signals, both species-specific vocalizations and human spoken words. In Aim 1, we test the capacity of neural activity in the lateral belt (LB) to differentiate between different vocalizations (auditory objects). We hypothesize that (1) LB neurons preferentially code different vocalizations as opposed to their spectrotemporal acoustic features and that (2) the capacity of LB neurons to code different vocalizations increases as the number of simultaneously tested neurons increases. In Aim 2, we test the hypothesis that LB neurons respond in a categorical manner. Moreover, we hypothesize that the neural sensitivity of individual LB neurons mirrors the monkeys'perceptual sensitivity. This Aim is accomplished by obtained extracellular recordings of LB neurons while monkeys participate in a delayed category-to-match task. During this task, the monkeys categorize two human phonemes and morphed versions of these phonemes. In Aim 3, we test the hypothesis that LB activity is less sensitive to the variance that occurs naturally in vocalizations than to types of variance that are not found naturally. We also hypothesize that this sensitivity mirrors the monkeys'behavioral sensitivity. This aim is accomplished by correlating recordings of LB neurons with the monkeys'performance on a delayed category-to-match task. During this task, the monkeys categorize vocalizations and these sets of artificial stimuli.

DESCRIPTION (provided by applicant): Objects are the core building blocks of our auditory-perceptual world. However, when our current understanding of auditory-object processing is compared to the putative steps needed to process auditory objects, it is clear that there are key gaps in our knowledge. The most fundamental and important gap is our lack of understanding of the relationship between the acoustic features of an auditory stimulus, neural activity, and perception. Indeed, what we know of this relationship is lacking at the most fundamental level: the manner in which stimuli are integrated and segregated into one or more perceptual auditory objects. Two key innovations of this proposal are designed to fill this gap in our understanding. First, the PI directly tests the relationship between the acoustic features of auditory stimuli, single-neuron activity, and subjects' behavioral reports of auditory-object integration and segregation. Second, the PI records and contrasts neural correlate of auditory-object processing in both the primary auditory cortex and the secondary auditory cortex (i.e., the anterolateral belt). Aim #1 tests whether neurons in the auditory cortex code for (1) the acoustic features of an auditory stimulus, or (2) the monkeys' behavioral reports of auditory-object integration and segregation. This Aim is achieved by evaluating the hypothesis that neural activity in the primary auditory cortex is reliably modulated by the acoustic features of an auditory stimulus but is not modulated by the subjects' behavioral reports. In contrast, it is also hypothesized that neural activity in the secondary auditory cortex (the anterolateral belt) is reliably modulated by the subjects' behavioral reports but is not modulated by the acoustic features of an auditory stimulus. Both hypotheses are tested by recording extracellular from neurons in the auditory cortex while monkeys participate in a one-interval, two-alternative-forced-choice task that requires them to listen to an auditory stimulus and report whether they hear one or two auditory objects.

DESCRIPTION (provided by applicant): Selective auditory attention allows individuals to selectively attend to a dining companion's voice in a loud, noisy restaurant or toward the location of different musicians in a band. Attentional dysfunction is one of the hallmarks of human aging. Indeed, whereas aging's effect on hearing can often be characterized by changes in the audiogram, nearly half of all humans over 75 years of age suffer from dysfunction in perceptual and cognitive components of audition, such as selective auditory attention, even in cases where the audiogram is normal. These deficits lead to social isolation, depression, and other types of cognitive dysfunction. The neural mechanisms underlying auditory attention, the causal role that different brain areas play in attention, and the effect that aging has on attentio are not known. In the auditory system, stimuli are hypothesized to be processed by two cortical pathways: (1) a dorsal pathway from the auditory cortex to the prefrontal cortex (dPFC) that mediates spatial components of audition and (2) an analogous ventral pathway that mediates non-spatial components of audition in adjacent regions of the prefrontal cortex (vPFC). This anatomical segregation leads us to our hypothesis that the PFC is a major participant in the top-down control of selectively attending to different auditory features (spatial and non-spatial. Further, we also hypothesize that natural aging reduces the effectiveness of this top-down control, giving rise to age-related auditory attention deficits. Aim #1 tests the causal role of th PFC in auditory attention. Young adult animals participate in a spatial or non-spatial auditory attention task while either the vPFC or the dPFC is selectively inactivated by cortical cooling. We hypothesize that inactivation of the dorsal pathway will cause selective behavioral deficits on the spatial task, whereas inactivation of the ventral pathway will cause selective behavioral deficits on the non-spatial task. Aim #2 tests the effect of aging on auditory attention by comparing the results of cortical cooling in young vs. aged animals. We hypothesize that, in the geriatric monkeys, the ability of directed attention to improve behavioral performance will be impaired relative to young adult monkeys. Second, we hypothesize that the PFC activity in geriatric monkeys is diminished and, as a consequence, inactivation of either pathway will impair performance less in geriatric monkeys relative to younger adult monkeys. These results will provide the foundation of knowledge necessary to develop remedial therapies to limit or reverse attention deficits in the aged.

PROJECT SUMMARY A fundamental goal of hearing research and auditory neuroscience is to understand the neurophysiological mechanisms that underlie sound perception and auditory cognition and to use this knowledge to mitigate hearing disorders. One of the premier venues for promoting scientific progress toward this goal is the International Conference on Auditory Cortex (ICAC; http://auditorycortex.org/). In 2017, ICAC will take place on September 10-15 in Banff, Alberta, Canada; this will be the first time that ICAC will be held in North America. ICAC is the only multi-day meeting that focuses exclusively on the neurophysiological underpinnings of auditory perception. Further, because ICAC takes place in a cloistered setting and without any parallel sessions, it maximizes formal and informal scientific discourse in a collegial atmosphere. Aim #1 is to bring together auditory scientists to exchange ideas, methods, and concepts on auditory perception. The goal of the 2017 meeting is to promote our understanding of the neurophysiological mechanisms that underlie sound perception and auditory cognition and to use this knowledge to mitigate hearing disorders. In particular, the organizers of ICAC are interested in attracting scientists that (1) employ methodologies and conceptual/theoretical paradigms that are often novel to studies of auditory cortex; and (2) whose research focuses on studying the structure and function of the auditory cortex through a synthesis of both human and animal research. Aim #2. To facilitate meaningful and educational interactions between junior and senior auditory neuroscientists during the program and to broaden the pipeline for women and minority scientists in auditory research. ?Trainee talks? give a cadre of students and post-doctoral fellows opportunities to advertise their posters as a short oral presentation. Select speaker slots will be reserved for junior faculty members and post-doctoral fellows. Further, we will award a number of travel grants for graduate students and post-doctoral fellows that offset the cost of attending ICAC to significantly increase the footprint of trainees at the 2017 ICAC. This judging also provides an opportunity for the senior scientists on the Program Committee to provide valuable oral feedback to these trainees. ICAC is extremely relevant to the scientific mission of the NIDCD. This conference supports the NIDCD mission in three ways. First, the program brings together successful junior and established investigators who represent a substantial component of NIDCD-sponsored programs to foster new ideas in hearing research. Second, the conference provides a superb environment in which to educate and engage students and junior faculty in our field. Third, the program features numerous presentations on clinically relevant research into temporary and permanent hearing loss, vulnerability to acoustic noise, tinnitus, cognitive and psychological factors influencing hearing (attention, tinnitus), and language acquisition.

PROJECT SUMMMARY The annual meeting of Advances and Perspectives in Auditory Neuroscience (APAN; http://www.med.upenn.edu/APAN/) is a one-day satellite meeting of the annual meeting of the Society for Neuroscience; the first APAN symposium was in 2003. The typical attendance of APAN is ~225 people; mostly, graduate students, post-doctoral fellows, and other trainees. The primary Aim of APAN is to bring together the cohort of neuroscientists who are engaged in identifying the neural correlates (both cortical and sub-cortical) of auditory behavior ?including the perceptual, cognitive, and sensorimotor factors? that underlie communication, multisensory processing, and neural plasticity. Bringing together this group of scientists in this forum is critical because many of the theoretical approaches, techniques, and methodologies of this research field are relatively unique. Consequently, a focused symposium spurs the scientific enterprise in this important research area. Our second Aim is to facilitate meaningful and educational interactions between junior and senior neuroscientists throughout the program and to promote women and those in underrepresented groups in communicative and auditory neuroscience. In our selection criteria for oral presentations, we have consistently, since our inception, highlighted the contributions of junior scientists as well as women and those from underrepresented groups. In 2013, we established ?poster teasers? that give a cadre of junior scientists? opportunities to draw attention to their posters as a short oral presentation. In the previous grant cycle, we established a ?Young Investigator Spotlight? talk that features an outstanding junior scientist. In the current proposal, we are offering a second Spotlight talk and will increase the number of travel awards trainees to offset the cost of travel to APAN. Both of these changes facilitate a more inclusive APAN community. Finally, APAN is extremely relevant to the scientific mission of the NIDCD for a variety of reasons. For example, the majority of scientists at APAN are funded through an NIDCD mechanism and conduct basic research on communication, auditory processing, plasticity, and hearing prosthetics. Further, APAN provides an outstanding training opportunity for junior neuroscientists. Finally, the translational and clinical impact of many of the presentations is high due to their focus on fundamental mechanisms underlying auditory perception, whose dysfunction can lead to various hearing-related problems. We seek funding to continue this flagship conference.

NEURONAL CIRCUITS FOR CONTEXT-DRIVEN BIAS IN AUDITORY CATEGORIZATION In everyday life, because both sensory signals and neuronal responses are noisy, important cognitive tasks, such as auditory categorization, are based on uncertain information. To overcome this limitation, listeners incorporate other types of signals, such as the statistics of sounds over short and long time scales and signals from other sensory modalities into their categorization decision processes. At the behavioral level, such contextual signals bias categorization by shifting the listener's psychometric curve. At the neuronal level, categorization requires a transformation of sensory representation into a representation of category membership that is modulated by these contextual signals. While categorical representations have been found in the cortex, the cell types and neuronal mechanisms supporting the emergence of these representations remains unknown. Furthermore, the mechanisms by which neuronal categorical representations are modulated by contextual signals, giving rise to a behavioral bias, have not been explored. Our goal is to identify the contribution of specific cell types to categorization and to understand the neuronal mechanisms for how contextual signals bias auditory categorization. Multiple studies have demonstrated that neurons in auditory cortex (AC) and the posterior parietal cortex (PPC) are involved in auditory categorization. Based on the well-described circuit architecture of the AC, recent studies, and our preliminary data, we propose a series of hypotheses that delineate the role of excitatory-inhibitory circuits within AC in creating and biasing categorical stimulus representations and for the role of PPC-AC projections in driving the source for the bias signal. To test these hypotheses, we train mice in a two-alternative-forced choice task in which mice categorize the task, associations). frequency of a ?target? sound into one of two overlapping categories (?low? or ?high?). While mice participate in this we systematically manipulate three bias signals (short-term and long-term stimulus statistics, and cross-modal Thisdesign allows us to frame the cognitive task within a Bayesian framework, which generates formal computational models for the function of specific neuronal cell types that are tested experimentally. behavioral activity. category. in auditory We will combine this and computational framework with electrophysiological recordings and optogenetic manipulations of neuronal First, we will test whether distinct neuronal cell types in AC differentially encode information about stimulus Second, we will test whether and how specific inhibitory neuronal cell types in AC mediate context dependence auditory categorization. Third, we will test whether and how cortico-cortical feedback mediates context dependence in categorization. Aligned with the goals of the BRAIN initiative, our project will deliver a mechanistic framework for a cortical circuit supporting a complex behavior. These results will quantitatively address an important open question to what extent the same or distinct neuronal populations integrate information across multiple temporal scales and across sensory modalities, generalizing or specializing the representation of the bias in categorization.