Christopher J. Machado - US grants

Neuroanatomical, electrophysiological, functional imaging and lesion data indicate that the amygdala, hippocampus and orbital frontal cortex contribute to primate social and emotional behaviors. However, due primarily to past methodological deficiencies, the involvement and specific contributions of these brain regions in a circuit responsible for adaptive social behavior and emotional expression are still a matter for debate. The research program described in this proposal will rectify some of these deficiencies by combining ethologically-valid behavioral observations, semi-naturalistic testing environments and precise lesioning techniques to investigate two specific aims. First, the specific contributions of the amygdala, hippocampus and orbital frontal cortex to emotional reactivity in rhesus monkeys (Macaca mulatta) will be studied using three paradigms, each displaying a different visual stimulus in distinct environments. Second, the contributions of these neural regions to group social interactions will be studied in the same subjects. Social skills will be examined while four individuals interact in a large enclosure and social variables, such as group membership and size, will be systematically manipulated and controlled. The results generated from these two investigations will provide a new and sophisticated understanding of how the primate brain uses emotion to modulate social behavior adaptively.

[unreadable] DESCRIPTION (provided by applicant): Deficits in social cognition characterize many human psychiatric disorders, but the neural substrates of such deficits remain largely unknown. In fact, there is little certainty about the neural systems that normally subserve social cognition. This deficiency is largely due to the use of invasive methods and a lack of standardized behavioral testing paradigms that probe components of social cognition, such as social perception and social motivation. During the proposed funding period, I will obtain additional training and expertise by addressing these deficits. During the K99 phase, I will measure cerebral glucose metabolism, a correlate of neural activity, using high-resolution positron emission tomography (microPET). Two video presentations will be created; one depicting a variety of social interactions and the other with no social content. MicroPET data will be acquired after subjects view each video to identify neural regions preferentially engaged during the perception of visual social signals. A second study will investigate the neural correlates of social motivation. Some adult animals typically forego juice rewards to view pictures of salient social signals (i.e., female sexual swellings), but not to view pictures of lower-ranked animals or objects. Comparison of microPET data acquired after each of these three conditions will identify brain regions involved in directing behavior towards socially relevant information. Both studies will use noninvasive eye tracking techniques to measure visual attention to videos or choices of social pictures versus juice rewards. In the subsequent ROO phase, I will implement the skills and behavioral tasks developed during the K99 phase to investigate how cerebral metabolism differs in subjects raised under atypical conditions (i.e., nursery-reared) or for animals that exhibit maladaptive social behavior. Relevance to Public Health: Social behavior deficits are prevalent in many human psychiatric disorders, such as autism, social anxiety disorder and depression. However, effective treatments remain elusive because little is known about how the normal brain processes social information and selects appropriate social behaviors. The goal of these studies is to develop new, noninvasive methods for identifying: brain areas subserving these abilities.

DESCRIPTION (provided by applicant): Deficits in social cognition characterize many human psychiatric disorders, but the neural substrates of such deficits remain largely unknown. In fact, there is little certainty about the neural systems that normally subserve social cognition. This deficiency is largely due to the use of invasive methods and a lack of standardized behavioral testing paradigms that probe components of social cognition, such as social perception and social motivation. During the proposed funding period, I will obtain additional training and expertise by addressing these deficits. During the K99 phase, I will measure cerebral glucose metabolism, a correlate of neural activity, using high-resolution positron emission tomography (microPET). Two video presentations will be created;one depicting a variety of social interactions and the other with no social content. MicroPET data will be acquired after subjects view each video to identify neural regions preferentially engaged during the perception of visual social signals. A second study will investigate the neural correlates of social motivation. Some adult animals typically forego juice rewards to view pictures of salient social signals (i.e., female sexual swellings), but not to view pictures of lower-ranked animals or objects. Comparison of microPET data acquired after each of these three conditions will identify brain regions involved in directing behavior towards socially relevant information. Both studies will use noninvasive eye tracking techniques to measure visual attention to videos or choices of social pictures versus juice rewards. In the subsequent ROO phase, I will implement the skills and behavioral tasks developed during the K99 phase to investigate how cerebral metabolism differs in subjects raised under atypical conditions (i.e., nursery-reared) or for animals that exhibit maladaptive social behavior. Relevance to Public Health: Social behavior deficits are prevalent in many human psychiatric disorders, such as autism, social anxiety disorder and depression. However, effective treatments remain elusive because little is known about how the normal brain processes social information and selects appropriate social behaviors. The goal of these studies is to develop new, noninvasive methods for identifying: brain areas subserving these abilities.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Controlled methods for "activation" neuroimaging comparable to human PET studies have not yet been developed for awake, behaving macaques. These studies will address this issue. With simple sensory and motor protocols, we will develop methods for 1) the systematic habituation of animals to handling procedures, 2) administering the microPET radiotracer without the animal being aware, thereby mitigating the effects of injection-related stress, and 3) standardizing head placement inside the microPET scanner across multiple scan dates.

DESCRIPTION (provided by applicant): In this application, we propose a series of experiments that, if successful, will change forever our approaches to evaluating the nonhuman primate social brain, and could have a profound influence on behavioral neuroscience more broadly. Electrophysiological recordings, brain lesions and functional neuroimaging have been the most common methods used to identify and dissociate the function of brain structures in humans and animals. However, invasive neural recordings or lesions can result in unintended damage and compensatory functional reorganization, both of which complicate the interpretation of behavioral results. Functional neuro- imaging, while having the advantage of being noninvasive and amenable to repeated studies, can indicate that a brain region is active during a particular behavior, but cannot determine that it is essential for the behavior. Complementary studies that temporarily manipulate brain function in animal models are also needed. All options currently available for transient brain activation or inactivation in nonhuman primates, however, require repeated injections into the brain and/or permanent cranial implants, both of which cause physical trauma and preclude long-term study of awake, behaving animals. A new technique, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), offers a minimally-invasive means to control brain function during long-term studies. Viral vectors transfect neurons in specific areas with a DREADD gene. These novel receptors are triggered by intravenous or oral administration of a nontoxic molecule called clozapine-N-oxide (CNO). Activation or inactivation of neural activity occurs within 15 minutes after CNO administration and lasts for up to 9 hours. This technique has been successfully used to study complex behavioral patterns in rodents. Our overall objective is to implement DREADD-based transient inactivation in nonhuman primates, which is the animal model of choice for studying the social brain. In Specific Aim 1, we will compare DREADD-based inactivation of one social brain component, the amygdala, with behavioral and metabolic deficits already characterized with permanent amygdala lesions. In Specific Aim 1A, we will use high-resolution positron emission tomography to measure how CNO infusion affects metabolism in the amygdala and other brain areas that are heavily interconnected with it. We will also examine how DREADD- based amygdala inactivation affects fear learning (Specific Aim 1B) and social interactions (Specific Aim 1C). Once we have verified that the DREADD method can reliably inhibit amygdala function, Specific Aim 2 will measure how amygdala inactivation modulates eye gaze patterns as animals view pictures or videos of species-typical social signals. Beyond providing a powerful new tool for minimally-invasive transient inactivation studies with nonhuman primates, the proposed research will also advance our understanding of how the amygdala contributes to social information processing, and how amygdala dysfunction may contribute to the profound social deficits that characterize many human psychiatric disorders. PUBLIC HEALTH RELEVANCE: Many human psychiatric disorders, including autism spectrum disorder and select anxiety disorders, exhibit social behavior impairments. One way of studying the brain regions involved in social behavior is by turning them off in animal models. The goal of these studies is to demonstrate the feasibility of a new method of temporary neural inactivation to study the function of one social brain component, the amygdala, in a nonhuman primate animal model.

DESCRIPTION (provided by applicant): While intensive behavioral intervention delivered early in life improves social functioning for some children with autism spectrum disorder (ASD), current pharmacological treatments are limited to targeting only peripheral symptoms such as aggression, anxiety, and depression. Novel pharmacological interventions specifically targeting social behavior delivered in parallel with behavioral intervention holds the promise of improving quality of life for many individuals with ASD. Development of pro-social pharmacological treatments will depend upon the successful translation of basic neuroscience research into safe and effective medicines and will require the use of sophisticated animal models. While current ASD drug discovery efforts have relied primarily upon mouse models to evaluate compound efficacy, pharmacological interventions targeting the complex social and communication deficits of ASD may ultimately require the use of an animal model more closely related to humans. Rhesus monkeys are considered the biomedical model species of choice due to their resemblance in human physiology, neuroanatomy and behavior. Although there are currently no validated nonhuman primate models of ASD, we believe that natural variation in sociability of rhesus monkeys provides a novel model to evaluate the efficacy of pro-social pharmacological treatments. We have established behavioral phenotyping protocols to identify low-social and high-social juvenile monkeys in their natal field cages and to reliably quantify changes in social functioning in a laboratory setting. Our battery of behavioral assays can be used to directly compare social outcome measures with both mouse models (i.e., high-throughput assays of sociability) and clinical populations (i.e., non-invasive eye tracking). With these developments, the nonhuman primate model is poised to provide a valuable test bed for evaluating innovative treatments targeting the core social deficits of ASD. We propose to first utilize this model to evaluate one of the most promising avenues of ASD treatment research - the oxytocin system. Although nasal oxytocin therapy is being promoted as a safe and promising therapy for ASD, we know very little about the efficacy or mechanism of oxytocin treatment in humans. Here we propose to utilize a well-characterized population of juvenile macaque monkeys to systematically evaluate the effects of intranasal oxytocin administration on primate sociability. We anticipate that the methods developed in the proposed research will result in a standard nonhuman primate testing platform that can be used to evaluate numerous future pharmacological interventions targeting the social deficits of ASD.