Katalin M. Gothard - US grants

This application is to support a period of advanced training in multidisciplinary approaches to the study of the neural substrate of social cognition in monkeys. The candidate will acquire new theoretical knowledge in animal behavior, computational methods and practical skills in primate neurophysiology. The combination of behavioral, neurophysiological and computational techniques has great potential for the study of social cognition in monkeys. Additional training is needed by the candidate to achieve this potential since the species studied, the questions addressed, and the analytical methods that will be used are new to her. This training will complement her earlier experience in electrophysiological recordings in freely behaving rats. The candidate will work with a small group of talented co-mentors/consultants who will provide a sound background in primate social behavior, electrophysiology and computational methods. The candidate will also attend advanced classes and national workshops on statistical and computational methods suitable for analyzing neuronal ensemble data obtained with multielectrode arrays. UC Davis and the California Regional Primate Research Center (CRPRC) are uniquely suited for the training and research goals of the candidate. The CRPRC houses social troops of 60-120 rhesus monkeys in large outdoor enclosures where the animals develop in a socially naturalistic environment. The departments of Computer Science, Center for Animal Behavior, Center for Neuroscience and the Medical and Veterinary Schools offer advanced courses in the areas of neuroscience, animal behavior and computational science. The candidate's immediate goal is to use modern neurophysiological techniques to determine the responses of neural ensembles in different nuclei of the monkey amygdala to images of monkey faces and facial expressions. This project will complement and benefit from an ongoing research program at the CRPRC directed by the sponsor, Dr. David Amaral. The specific aims of the research proposed in this application are to determine 1) whether neuronal ensembles recorded from different nuclei of the monkey amygdala differentiate between monkey faces and facial expressions, and 2) whether ensemble responses to facial expressions are modulated by social context. The candidate's long-term career goal is to use the experience afforded by this award to develop an independent research program that combines behavioral, neurophysiological and computational methods to study the role of structures such as the amygdala and orbitofrontal cortex in emotional and social behavior in primates.

behavioral /social science research tag

DESCRIPTION (provided by applicant): The neural substrate of emotion encompasses a large brain circuit in which the amygdala plays a key role. The long-term goal of the proposed research is to determine how specific functions attributed to the amygdala are carried out at the neural level. One of the functions of the amygdala is to select from the environment stimuli with inherent emotional value and respond to them adequately, e.g., withdraw or fight when threatened. This process might rely on innately programmed and relatively inflexible pathways to ensure enduring and reliable reactions in response to objects and events of survival value. In parallel, the amygdala is required to update the reinforcing value of many stimuli that gain or lose emotional significance through learning and experience. Both functions are used for social behavior. The intricacy of primate societies requires that humans and monkeys respond reliably to facial expressions and other signals with emotional significance but also to adjust responses to social context or to the history of interactions between individuals. The neural basis of these complex and diverse functions are largely unknown. The central hypothesis of this proposal is that the lateral, basal, and central amygdaloid nuclei carry out a sequence of dissociable but complementary functions. The objective of the proposed studies is to identify in the amygdala the neural signature of stimulus differentiation, evaluation, and the initiation of emotional responses. This will be achieved by relating autonomic, behavioral, and neural ensemble responses to manipulations of the reinforcing value of face and non-face stimuli. This approach will determine (1) whether negative or positive stimuli are processed preferentially or differentially in the amygdala, (2) whether facial expressions that carry inherent positive or negative valence engage the same neuronal processes as neutral objects paired with reward or punishment, (3) whether neural activity in the amygdale predicts the autonomic and somatic expressions of emotion. These studies will determine the neural mechanism by which the amygdala evaluates stimuli of significance and relays the results of this process to a complex brain circuits that control emotional and social behavior. Understanding the neural processes carried out at each level of this circuit holds promise for more effective interventions in emotional disorders.

DESCRIPTION (provided by applicant): Humans and monkeys use eye movements to explore their world and identify, in their visual environment, the emotionally and socially important elements. The success of non-verbal social communication with facial expressions, gestures, and postures depends critically on the fast and correct evaluation of the signals displayed by others. The sequence of saccades and fixations executed by the eyes of monkeys and humans during the visual exploration of facial expressions (scanpaths) are influenced by two processes: bottom-up visual processes which allocate visual attention to salient elements of the image (e.g., the eyes), and top-down processes that reflect goals, expertise, and momentary emotional states. The majority of psychiatric disorders are accompanied by aberrant scanpaths, yet the source of the deficit is poorly understood. The observation that patients with amygdala damage fail to explore the eyes and show scanpath abnormalities similar to patients with autism, schizophrenia, social phobia, and affective disorders, suggests that the amygdala is involved in guiding visual attention during face exploration. The precise contribution of the amygdala to this process is unknown. The amygdala is a complex of two main nuclear groups with dissociable functions and we propose that different nuclear groups are involved in the bottom-up and top-down components of scanpath elaboration. The resources afforded by this application will be used to selectively inactivate the centromedial and basolateral nuclear groups of the monkey amygdala and determine the contribution of the each nuclear group to bottom-up and top-down processes of face exploration. The results are expected to clarify the contribution of the amygdala to the acquisition of socially and emotionally relevant information-a critical prerequisite in designing a more effective intervention in socio-emotional disorders. PUBLIC HEALTH RELEVANCE: The goal of this application is to determine the role of the primate amygdala in allocating visual attention to visual targets of enhanced emotional and social significance. The proposal is centered on the hypothesis that the pattern of eye movements during the visual exploration of faces depends on both top-down and bottom-up processes and that these processes can be localized to different groups of amygdaloid nuclei. The centromedial group of nuclei, reciprocally connected to reflexive and autonomic centers in the brain-stem, are hypothesized for form a circuit that contributes to bottom-up control of eye movements. In contrast, the basolateral nuclear complex, functionally connected to high-level cortical visual areas, is expected to provide top-down control of eye movements. To test these hypotheses, we will use reversible inactivation to separately manipulate the two components of the amygdalar complex, and measure the alterations in visually-guided saccades and in the exploration of images of facial expressions. This project reflects a novel integrative approach using a combination of reversible inactivation with electrophysiology under electrophysiological control, which affords causal inference between neural activity and behavior, and scanpath monitoring, which reveals untrained behavioral responses to naturalistic stimuli. The outcome will dissociate the role of two amygdaloid components within the circuit that guides eye movements, clarifying two potentially clinically relevant functions of the amygdala.

DESCRIPTION (provided by applicant): Gaze following and facial mimicry are fundamental elements of social behavior in both humans and non-human primates. Gaze following is critical for the development of shared attention and for a mental phenomenon called theory of mind. Facial mimicry is a form of shared emotion and constitutes the basis of empathy. These behaviors are profoundly affected in neurodevelopmental disorders and in severe mental illness, including schizophrenia, depression, and social phobia. When the amygdala is damaged or is functioning abnormally gaze following and facial mimicry are also impaired, suggesting that the amygdala may play an important role in these behaviors. To determine the role of the amygdala in these basic social behaviors, we propose to inactivate the amygdala of monkeys while they interact with naturalistic videos that elicit gaze following and facial mimicry. The amygala, however, comprises several nuclei, each with a different connectivity and different functions. We propose to inactivate selectively each main nucleus of the amygdala to test the following hypotheses: (1) the basolateral nuclei of the primate amygdala are necessary for gaze following, and (2) the central nuclei are necessary for facial mimicry. These hypotheses are based on the known anatomical connectivity of each nuclear group with cortical and subcortical structures involved in social behavior. The basolateral nuclei are connected to cortical areas involved the control of eye movements and in higher cognitive functions that might be necessary to determine where individuals are looking. The central nuclei are connected to subcortical circuits that serve low- level perceptual and motor functions that might be necessary to make eye contact and to imitate involuntarily facial expression. The proposed research will determine the role (s) of different amygdala nuclei in the elaboration of basic social behaviors. This will complement our current understanding of the role of the amygdala in social perception. A more detailed understanding of the role that individual nuclei of the amygdala play in the production of gaze following and facial mimicry will take us one step closer toward identifying the causes of shared social deficits in neurodevelopmental and other psychiatric disorders.

PROJECT SUMMARY (Project 4, Gothard) Despite the great diversity of species-specific social behaviors, many of the fundamental building blocks of social behavior are shared across species. For example, correct identification of individuals allows animals to learn the unique rewards or adverse outcomes expected from interacting with different individuals. The sensory modalities involved in discriminating between individuals may be different across species, but the neural mechanisms of social discrimination may be shared. Oxytocin (OT) emerged recently as a universal factor that governs social behaviors in multiple mammalian species. In this project, we explore the role of OT in shaping basic neural processes during social learning in non-human primates, such as the discrimination of individuals and the associations of individuals with different levels of reward. The experiments converge on the central hypothesis that during social learning, OT enhances the functional coupling between the basolateral amygdala (BLA) and nucleus accumbens (NAc). Consequently, neurons in the BLA are expected to show greater selectivity for unique combinations of individuals and rewards, while the neural activity across populations of neurons in the amygdalo-striatal networks are expected to show higher oscillatory coherence. To test these hypotheses we designed a conditioned social discrimination task that takes advantage of the visual abilities of macaques to discriminate between individuals presented in videos. This approximates the ability of humans to become highly familiar and accurately predict the behaviors of individuals even without real-life interactions, a process that is impaired in many psychiatric disorders, including autism. As this reward-driven task has both perceptual and operant components, it is expected to involve activation of and communication between the BLA and NAc. The task, therefore, will generate brain states that are conducive to capture the neural signature of interactions in the amygdalo-striatal networks. We will measure and compare both single unit activity and local field potential in the BLA and NAc while monkeys perform the task after local BLA infusion of OT or vehicle. In the primates, OT receptors (OXTR) are synthesized in the nucleus basalis of Meynert (NBM), not in the BLA. This inspired our secondary hypothesis that the neurophysiological effects of OT in the BLA are mediated by cholinergic (Ach) mechanisms. The mechanisms are driven by OXTR signaling on NBM neurons that project to the BLA. The ACh system enhances learning and memory across species and we hypothesize that during social learning, OT amplifies ACh release in the BLA, thereby increasing salience of social stimuli. The precise contribution and the synergy between the OT and Ach systems in the BLA will be tested by neurophysiological recordings coupled with direct injections of OT and cholinergic agonist/antagonists into the BLA or NBM. This project is highly integrated with the rodent studies in Project 3, which investigates OT/ACh interactions in social discrimination conditioned by extrinsic reward by simultaneous recordings of local field potentials and units in the BLA and NAc of rats.

The primate amygdala plays an important role in evaluating the emotional and social significance of stimuli. Our understanding of neural processes that support this role comes primarily from studies focused on vision and hearing. Using visual and auditory stimuli we learned that neurons in the amygdala respond selectively to friendly or aggressive facial expressions, to eye contact, and to social calls. Although touch can convey both positive and negative affect and can be used to build social bonds, the cellular bases of touch processing in amygdala have rarely been addressed. Recently we have identified neurons in the primate amygdala that respond to touch. The studies proposed in this application will expand on this initial finding and provide the first detailed characterization of the role of touch-sensitive neurons in the amygdala of primates. Our first aim is to determine the organization of tactile inputs in the amygdala. The second aim is to determine how subjective preference for different types of touch shapes the activity of touch-responsive neurons. The third aim will determine the role of social partners in the subjective evaluation of touch. These studies will take advantage of species-specific value of grooming and explore the role of the primate amygdala in processing the intrinsic valence of natural social stimuli. The three specific aims are bound by a conceptual framework of the amygdala that is informed by anatomical and functional differences between the component nuclei. The simultaneous monitoring of large populations of neurons will allow testing specific hypotheses regarding the transformations that take place in each nucleus. The expected findings will allow us to place touch perception and its cellular implementation in the amygdala into the framework of social neuroscience.

Touch is our first emotional language ? the language that allows us to receive and understand affective signals and help lay the foundation for future social bonds. Despite the widely recognized importance of touch in brain development and in affective and social communication throughout life, remarkably little is known about its cellular neural substrate. Relatively recent discoveries showed that the skin contains specializations for detecting and evaluating the pleasantness of touch. It is unclear how these signals might be processed in the brain. It is clear, however, that the amygdala is required for processing the social and emotional significance of sensory stimuli, regardless of modality. Studies that showed this role of the primate amygdala focused almost exclusively on vision. Recently we have reported the presence of touch-responsive neurons in the primate amygdala. We will expand on this initial finding and determine how these touch-responsive cells respond to the basic sensory features of tactile stimuli: location and intensity (Aim 1). Next, we will determine whether tactile cells in the amygdala encode the subjective value of touch (Aim 2). Given the important role of the amygdala in processing social stimuli, we will then determine how the social dimension of touch factors into the activity of tactile cells (Aim 3). Specifically, we will simultaneously monitor neural responses to touch in the amygdala and somatosensory cortex and compare neural responses to the same type of social touch, delivered to the same skin area, by two individuals with whom the recipient has a different social experience. We expect tactile cells in the amygdala, but not in the somatosensory cortex, to discriminate between social partners, supporting the idea that the amygdala extracts the social-affective dimension (value) of stimuli. Collectively, these three aims provide a conceptually new and technically advanced physiological framework for understanding how the primate amygdala responds to and evaluates tactile stimuli that vary in subjective value and social significance. Understanding the cellular machinery of affective touch in the primate brain is expected to provide important insights into why touch processing is so profoundly altered in functional pain syndromes, autism, and numerous other mental disorders.

PROJECT SUMMARY/ABSTRACT This project combines the expertise of Dr. Katalin Gothard at The University of Arizona [US] and Dr. Anna W. Roe at Zhejiang University [China]. The aim of this project is to understand changes in the brain underlying the emergence of social and emotional regulation during adolescence. Adolescence is a period of accelerated social and cognitive development, and also a time of enhanced vulnerability for anxiety and impulse-control disorders, which elevate the lifelong risk for secondary psychiatric disorders. During this period, the prefrontal cortex undergoes maturation, but little is known about the maturation of its relationship with the amygdala, considered a hub of emotional processing in the brain. In humans and nonhuman primates, the amygdala matures long before puberty; in early adolescence, emotional processes and arousal governed by the amygdala dominate emotional and social behavior. As the prefrontal cortex matures and increases its influence on amygdalar function, emotional behavior becomes more regulated. We hypothesize that the development of emotional regulation during adolescence is due to changes in amygdala-prefrontal networks. The goal of this proposal is to monitor longitudinally, in the same individuals, the reorganization of functional connections between the amygdala and the PFC. This will be accomplished by a multimodal approach of laser-fMRI functional tract tracing, and neurophysiological recordings in the amygdala and the prefrontal cortex. In parallel, punctate administration of behavioral tasks will provide a measure of longitudinal changes in impulsivity and sociability. The fMRI, neurophysiological, and behavioral measures will be correlated at matched timepoints, thereby achieving a multiscale (cellular to circuit level to behavior) understanding of adolescent development. The findings from this study will have significant bearing on our understanding of normal adolescent brain development and also of the possible risk factors for the emergence of social misadjustment and mental disease.