It is widely appreciated that the cerebral cortex exerts a powerful influence on stomach function. However, the precise location of cortical neurons capable of influencing the stomach remains poorly identified. Thus, defining the neural substrate allowing for such "brain-gut" interactions is critical to understanding how cognitive events influence stomach function in both health and disease. Retrograde transneuronal transport of rabies virus, coupled with careful adjustment of survival times and use of nerve sections, is capable of identifying the cortical areas that most directly influence each branch of the autonomic innervation of the rat stomach. The findings demonstrate that largely separate networks of cortical areas within the rat medial prefrontal and lateral frontal cortex are linked with the descending control of parasympathetic or sympathetic function. However, there are well-known differences in the organization of these regions of the cortex of primates compared to rats, with cortical areas present in monkeys and humans that are entirely absent in rats. Other experiments in the Mentor's laboratory have confirmed substantial differences in the cortical areas that influence sympathetic control in monkeys compared to the rat. Therefore, future neuroanatomical studies of the cortical networks involved in autonomic control will need to be performed in non-human primates. The goal of this career development award is three-fold. First, the applicant will acquire specific skills in neuroanatomical techniques using non-human primates to define the cortical targets for parasympathetic and sympathetic control of the stomach (Specific Aim 1). Second, the applicant will learn techniques for the non-invasive manipulation of cerebral cortical activity in humans. Third, the applicant will apply these techniques in human subjects to non- invasively manipulate the activity of identified cortical areas to influence the autonomic regulation of the stomach (Specific Aim 2). This career development proposal will provide the applicant with critical training and expertise necessary to establish an independent research career focused on characterizing the neurobiological basis of brain-gut interactions. The proposed training also establishes a strong foundation to support future exploration of the neuroanatomical basis of cortical-autonomic interactions, to pursue translational physiologic studies in humans, and to support the development of novel brain-based therapies for patients with refractory functional gastrointestinal disorders.
The applicant will obtain training and conduct research that lays the foundation for his independent research career studying the neural basis of cerebral cortical influences on gastrointestinal function. This line of work supports the future development of novel brain-based treatments for refractory functional gastrointestinal disorders.