How do embryonic events pattern adult neural circuits?
Early gene expression during development serves to pattern the neuroprogenitors in the hindbrain that will give rise to the adult brainstem. Disruption of these early genetic events is thought to play a role in a number of physiological and behavioral disorders. However, the structure and function of many circuits are often influenced by or determined after development through the local environment, activity dependent cues, and remodeling. To better understand how early embryonic patterning plays a role in neural circuit organization, we use a range of optogenetic and pharmacogenetic tools in combination dual recombinase fatemapping to functionally and molecularly map embryonically defined neurons in adult behavior and physiology.
How are brainstem circuits disrupted in Sudden Infant Death Syndrome?
Several respiratory pathophysiologies including SIDS, Rett syndrome, and CCHS feature both disordered breathing and are associated with brainstem noradrenergic system abnormalities. In multiple model systems, the central NA system has been shown to be involved in respiratory control. However, prior experimental techniques, including lesions, gene knockouts, and pharmacological manipulations have been hampered by the imprecision inherent in these techniques. To determine the requirement of the central NA system in neonate respiratory control, we use a variety of genetic tools for precise and non-invasive circuit mapping and pair these models with our custom designed equipment to measure respiratory function in neonate mice.
What is the impact of sleep disordered breathing on Alzheimer’s disease?
Alzheimer’s disease (AD) is a chronic neurodegenerative disease. Early presentation starts with short-term memory loss that progresses to disorientation, dementia, and the need for assistance with basic activity of daily living. As neurodegeneration worsens, key bodily functions fail, leading to death. There are currently no effective treatments to reverse AD, although work is now focused on delaying AD onset or halting disease progression. Intriguingly, it has become clear that a strong association exists between the onset and progression of AD and sleep disordered breathing (SDB) such as sleep apnea. However, the mechanisms and extent of this relationship remains unclear. The goal of this project is to determine the role of chronic intermittent hypoxia in the physiological and behavioral progression of Alzheimer’s disease, a necessary step toward defining the impact of sleep disordered breathing in the onset and progression of Alzheimer’s disease.
What circuits in the brainstem are vulnerable during seizures leading to Sudden Unexpected Death in Epilepsy (SUDEP)?
Sudden Unexpected Death in Epilepsy results in the passing of over 7000 individuals each year in Europe and the United States. Perplexingly, most if not all SUDEP cases are in individuals with a history of seizures. However, from one day to the next, a threshold is crossed that results in death. It remains unknown what that threshold is and what circuits, whether in the brainstem or elsewhere, may play a role in death. Our preliminary work has identified several brainstem regions, that when stimulated, each result in a unique pattern of cardio-respiratory arrest. This work offers a path forward toward our goal of identifying autonomic neural circuits that may play a role in SUDEP.
How do cortical circuits influence breathing during vocalization and exercise?
As Mike the headless chicken has shown, you don’t need much of your brain to breath, but it helps. While breathing is a highly regulated process that is critical for maintaining Oxygen and Carbon Dioxide homeostasis, breathing is also highly responsive to input from other circuits with the nervous system. When we exercise, we increase our breathing well before there is any metabolic need through sensory motor integration. Breathing is also dynamically regulated during speech and other vocalizations. It is our goal to map the key regions in the brainstem that are part of the circuitry for exercise and vocalization mediated breathing regulation.