Khaleel A. Razak - US grants

DESCRIPTION (provided by applicant): The long-term objective of the proposed research is to determine how populations of cortical neurons code for sound locations. The auditory cortex is involved in sound localization behavior. There is no evidence for a systematic map of auditory space in the cortex. Moreover, cortical neurons exhibit a wide range of spatial tuning leading to suggestions that sound location is represented by population codes. The nature of these codes remains elusive. This issue is clinically relevant as humans with auditory cortex lesions show severe sound localization deficits. Relating lesions and behavioral deficits has been difficult because how cortex represents space is not clear. The proposed research will determine the distribution of cortical activity for different sound locations. The studies will be carried out in the pallid bat. The main advantage of this model system is that its auditory cortex contains at least two systematic maps of sensitivity to interaural intensity difference (IID). These maps allow specific and testable predictions to be made about how activity spreads across cortex for different sound locations. Another advantage is that the pallid bat listens passively to localize prey-generated noise (as opposed to echolocate prey), and that the IID maps are found in cortical regions involved in passive hearing. Thus the pallid bat is a passive hearing model likely to provide fundamental insight into how mammalian, including human, cortex represents space. There are two specific aims in this study. The first aim is to characterize the organization of IID sensitivity in a cluster of neurons that appear to be selective for the frontal sound field. These neurons respond strongly to binaural (but not monaural) stimulation with a preferred response to IIDs generated from the frontal sound field. Preliminary data show systematic changes in the preferred IID within this cluster. Using dichotic stimulation and single-unit electrophysiology, the map of IID sensitivity within this cluster will be determined. A previous study on the pallid bat cortex showed that a second cluster with binaurally inhibited neurons also exhibits a systematic map of IID sensitivity. The second specific aim will address how the two clusters with known IID sensitivity maps represent space. For this purpose, a multi-electrode array system will be used in conjunction with sequential dichotic and free-field acoustic stimulation. Dichotic stimulation will be used to measure IID selectivity of multiple cortical sites. These measurements will be used to predict how activity spreads across the cortex for azimuth locations that result in known IID values. The free-field study will measure the actual spread of activity for different azimuth locations. A comparison of the predicted and actual distribution of activity will be used to develop hypotheses about population codes for sound localization. PUBLIC HEALTH RELEVANCE: Lesions in the auditory cortex of humans and other mammals cause deficits in sound localization behavior, but how cortex represents auditory space is not clear. The proposed studies will determine how the cortex codes for sound location using a relatively recent technological advance that allows simultaneous recording from multiple cortical sites. These studies will provide valuable information for clinical studies relevant to restoration of hearing following brain damage.

The cerebral cortex contains maps that represent various features of the sensory world. For example, the visual cortex contains a map of an animal's visual space and the auditory cortex contains a map of the animal's frequency hearing range. In addition to these basic brain maps, there are also maps of features that are behaviorally important to the animal. Typically these brain maps arise through complex integrations performed by neurons, but the mechanisms of these computations are not understood. Through the experiments described here, the investigator will provide fundamental insights into the construction and modulation of such computational maps and will determine how neural connections in the brain shape computational maps. The specific focus of this project is to determine how maps that underlie an animal's ability to localize a sound are formed in the auditory cortex. The investigator and his students will use electrophysiological methods to record from neurons to determine 2-D spatial sensitivity. The input/output connections of these neurons will be identified using neuro-anatomical tracing. The neurotransmitters involved in shaping responses will be determined using pharmacology. Finally, the behavioral role of these computations will be examined with behavioral testing. This research will provide insights on how cortical maps are shaped in normal brains and how brain computations may be disrupted in mental disorders.

The broader impacts of this project will include training of undergraduate and graduate students, including underrepresented minorities. The research training will be integrated with undergraduate education at the University of California, Riverside and community outreach will occur through collaborations with the California Science Center (serving inner city schools in Los Angeles) and a desert research station (educating federal and state park employees). In addition, novel neural computations discovered here will guide construction of new electronic devices with potentially wide applications.

In order for their infants to survive, mammalian parents, including humans, must engage in specific types of behavior toward infants, such as feeding, transporting, and protecting them. To do so, parents must respond appropriately to sensory cues from infants, such as odors and cries. Behavioral responses to these cues often differ between mothers and females without offspring, with mothers being more attracted to these cues and more likely to engage in caregiving behaviors. Mothers in some species also show changes in how the brain responds to infant-related sensory cues, so that mothers are better able to detect and identify these stimuli. However, almost nothing is known about how fathers’ brains respond to specific types of sensory information from infants. This research will evaluate whether fathers show different behavioral and brain responses to odors and cries from infants, compared to males without infants, and whether this difference is influenced by the hormone oxytocin, which plays a role in infant care and social bonding. The results will provide new information about how being a father affects males’ brains and changes how males respond to infants, which might ultimately improve understanding of interactions between human fathers and their children. These studies will provide training for graduate and undergraduate students, including students from underrepresented populations, and will be used as the basis for outreach activities in the local community and in schools for special-needs students.

Mammalian parents must alter their behavior to meet the needs of their offspring. This behavioral plasticity is mediated by plasticity in neural processes influencing parents’ motivational, cognitive, and affective responses to offspring-related stimuli. Sensory processing, too, can undergo plastic changes in parents, enhancing their ability to detect and discriminate infant-related sensory cues. In mothers, changes in sensory function may be mediated by the pronounced hormonal shifts that occur during pregnancy and lactation; however, the mechanisms of parenthood-related sensory plasticity are only beginning to be understood. Coordinated plasticity in multiple parts of individual sensory pathways has received scant attention, for example, and little is known about how stimuli in different sensory modalities interact to determine neural and behavioral responses. Moreover, almost nothing is known about sensory plasticity in fathers. This research will use biparental California mice (Peromyscus californicus) to test the hypotheses that 1) fatherhood alters males’ behavioral and neural responses to stimuli from infants, 2) these effects are enhanced by simultaneous exposure to stimuli in multiple modalities, and 3) oxytocin plays a key role in mediating sensory plasticity in fathers.¬¬ Pup odors and vocalizations will be presented, both separately and simultaneously, to fathers and non-breeding males, and neural responses will be quantified using immunohistochemistry for the immediate-early gene product Fos in numerous brain regions as well as electrophysiological recordings in the auditory cortex. Oxytocin signaling will be manipulated pharmacologically to determine its role in fatherhood-induced sensory plasticity. Results will provide unique insights into plasticity of the paternal brain.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Age-related decline in central auditory function significantly affects quality of life in the elderly, with impaired speech perception leading to increased risk for depression, social isolation and cognitive decline. A 2017 Lancet Commission report cites hearing loss as the largest modifiable risk factor for developing cognitive decline, exceeding smoking, high blood pressure, lack of exercise and social isolation. Remarkably, a 2019 large-scale study found that even mild hearing loss, i.e., still within the normal range, produced an even closer association with cognitive decline. Currently, there is no effective therapy for age-related central auditory decline?hearing aids only address audibility?and no drug treatment. Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing. The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits. Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking. We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline. We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics). Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms. Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG. This project features a multifaceted, parallel approach in mouse and human. Each Aim will: 1) examine auditory processing at multiple adult ages; 2) use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms; 3) test the effects of nicotine. A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.