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 1 A, 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.
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.
| Grayson, David S; Bliss-Moreau, Eliza; Machado, Christopher J et al. (2016) The Rhesus Monkey Connectome Predicts Disrupted Functional Networks Resulting from Pharmacogenetic Inactivation of the Amygdala. Neuron 91:453-66 |
