James P. Burkett - US grants

Empathy, or the ability to detect and respond to the emotions of others, is a fundamental component of normal social communication and is necessary for the maintenance of social relationships. Many social cognitive disorders, including autism spectrum disorder, schizophrenia, and psychopathy, are characterized by empathy deficits, which impair normal social interaction and decrease quality of life. Nonetheless, the biological mechanisms that underlie empathy are poorly understood, and no medical interventions exist for the treatment of these deficits. Before such medical therapies can be developed, the significant gap in our knowledge about the biology of empathy must be addressed. A variety of recent studies have shown that many animals also have the capacity to detect and respond to the emotions of other animals. Therefore, this gap in knowledge can and should be addressed through the use of appropriate animal models that display empathy-based behaviors analogous to human behaviors. One common empathy-based response to the distress of others in humans is to provide consolation. Social response to distress in others is now known to be present in a small number of animal species, making it an ideal candidate behavior for learning more about the biology of empathy. Our laboratory has demonstrated for the first time that a laboratory rodent, the prairie vole, displays social response to distress under experimental conditions, that this behavior is empathy-based, and that the behavior is abolished through administration of an oxytocin (OT) receptor antagonist directly into the brain. Our lab is therefore uniquely positioned to discover the neurobiological basis of social response to distress in a way that is not possible in any other existing model. We propose to use social response to distress in the prairie vole as a model for learning about the neurobiology of empathy. In pursuit of this knowledge, we propose the following specific experiments. In Aim 1, we propose to locate one or more of the specific brain regions where OT receptor antagonist acts to prevent consolation. We will do so using site-specific infusions of the antagonist in combination with the social distress test developed in our pilot studies. In Aim 2, we will expand on this neural circuit by locating the source of OT release into the region of interest. We will do so using a triple-labeling technique to locate neurons that contain OT, project to the region of interest, and are active during social response to distress. In Aim 3, we propose to determine how natural variations in OT receptor density during development impact consolation. To determine this, we will experimentally manipulate the density of OT receptors in juvenile prairie voles using viral vector techniques developed in our laboratory, and measure the impact of these manipulations at adulthood on social response to distress. The results of these experiments will begin to bridge the gap in our knowledge of empathy by providing the first evidence of a behavioral circuit for social response to distress in the prairie vole. The proposed experiments will expand our knowledge of social cognition and the neurobiology of social response to distress. In addition, these findings may inform future studies into the clinical treatment of empathy deficits.

Project Summary Pesticides are biocidal, principally neurotoxic chemicals commonly used in the USA and throughout the world for agriculture, landscaping, household use, and insect-born disease control. Because many pesticides have been linked to risk for various neurological disorders, the proper determination of safe exposure levels for each pesticide is critical to public health. Recent epidemiological studies in our lab and others have linked perinatal exposure to pyrethroid pesticides with increased risk for autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) in children. Our lab has also demonstrated that mice exposed to pyrethroid concentrations below the EPA ?no observable adverse effect? level have alterations in dopamine (DA) release, storage, and trafficking, as well as an ADHD-related behavioral phenotype. Critically, no existing animal study has evaluated the impact of pyrethroid exposure on social behaviors relevant to psychiatric disorders like ASD. There is a critical knowledge gap regarding the full extent of the behavioral and neurophysiological phenotypes caused by low-dose exposure to pyrethroids and relevant to ADHD and ASD risk. To address this knowledge gap, we will take advantage of the extraordinary expertise of the Miller lab in neurotoxicology, as well as my expertise in complex social behavior and the prairie vole, an animal model with unique social behaviors considered translationally relevant to ASD. We propose to study the effects of developmental pyrethroid exposure on neurophysiology and behavior in translational animal models relevant to human psychiatric disorders. In Aim 1, we will determine the behavioral phenotype of pyrethroid-exposed mice by testing for a broad range of behavioral deficits relevant to ASD, including social interaction, communication, repetitive behaviors, and the new generation of empathy-based behavioral tests. In Aim 2, we will use a wide range of morphological, neurochemical and electrophysiological techniques to determine the neurophysiological changes in DA storage and release in pyrethroid-exposed mice. In Aim 3, I will carry these same techniques into my independent research program, where I will use them to determine the critical disruptions in DAT in pyrethroid-exposed mice. In Aim 4, I will more fully develop my independent research program by determining the behavioral and neurophysiological phenotype of pyrethroid exposed prairie voles, focusing on alterations in unique social behaviors shared between human and vole, including social bonding, spontaneous parental care, and empathy-based consoling behavior. This project is designed to develop a successful long-term research program focused on the contribution of environmental toxins to risk for psychiatric disease. This will involve a substantial training and career development program led by primary mentor Dr. Gary Miller, an expert in neurotoxicology; and involving a mentoring team consisting of Dr. Shannon Gourley, an expert on animal models of psychopathy and psychiatric disease; Dr. Donald Rainnie, an expert on neurodevelopment and electrophysiology; and Dr. Michael Caudle, a toxicologist and expert on mouse models of developmental toxic exposure. In addition to their expert guidance and mentorship, Dr. Gourley will contribute her significant expertise on spine density morphometry and analysis, and Dr. Rainnie will contribute his significant expertise on whole cell patch clamp. Completion of these Aims, along with the extensive training and career development plan outlined in this proposal, will help to build an innovative, productive, and long-term research program focused on the contribution of environmental toxicants to risk for psychiatric and neurological disorders, which may inform treatments, preventive measures and regulations.