Branco Weiss Fellow Since
2023
Research Category
Neuroscience, Control Engineering, Integrative Physiology
Research Location
Molecular and Cellular Biology Department, Harvard University, Cambridge, USA
Background
How do the brain and heart modulate each other? Heart-brain neural communication is implemented by the autonomic nervous system: autonomic motor circuits send signals from the brain to the heart and autonomic sensory circuits send signals from the heart to the brain. While some of the brain regions involved in organ feedback control have been identified, we know very little about the computations carried out by neural circuits within and between these brain regions. Furthermore, the physiological role of most intra-organ neurons and autonomic circuits remains largely unexplored. The quantitative and analytical methods that have enabled the mechanistic and systems-level understanding of several sensory processing and decision-making circuits in the brain have not yet been applied to circuits for brain-body interactions. To conduct systems-level studies of organ-brain feedback loops, we need to (1) trigger and measure temporal organ physiology changes, and (2) make single-cell resolution functional measurements and perturbations of neural dynamics in the central, autonomic, and intra-organ nervous systems. Quantitative application of these experiments will lead to constrained mathematical models of organ modulation of brain function and brain modulation of organ function.
The field of neuroscience has made tremendous progress in developing microscopes and neural activity indicators that enable cellular-resolution functional imaging of entire brains in small model organisms, such as Caenorhabditis elegans, Drosophila, and zebrafish. These advances, combined with progress in optogenetic methods and genome editing technologies, make this an ideal time to study the central and autonomic circuits that mediate organ control. Zebrafish heart-brain communication is an excellent starting point for this endeavor because zebrafish has a closed circulatory system and is likely the only vertebrate model organism in which simultaneous functional imaging with single-cell resolution of the entire central and autonomic nervous systems is possible. Furthermore, zebrafish and mammals have homologous organ systems and use parasympathetic and sympathetic pathways to control viscera, including the heart.
Details of Research
Dr. Luis Hernandez-Nunez will be using a multidisciplinary approach combining systems neuroscience, genetics, and control theory to study the cardiac role of central (CNS), autonomic (ANS), and intracardiac neural circuits in larval zebrafish. While larval zebrafish optic and genetic accessibility have made it a widely used model organism for studying modulation of neural circuits and behavior, larval zebrafish has not yet been used to study neural control of organs from a quantitative perspective. In the past two years, he has developed new experimental tools and assays to study the development and function of the motor and sensory components of the ANS. He has determined the ages at which it is relevant to study cardiac autonomic feedback control. In the 2023-2024 academic year, Dr. Hernandez-Nunez will (1) combine functional whole-brain imaging with our previous findings in the autonomic sensory and motor circuits to constrain mathematical models of cardiac control, (2) use multiplexed fluorescent in situ hybridization to maps the molecular profile of autonomic sensory ganglia, and (3) reconstruct the connectivity map of intracardiac neurons with synaptic resolution. In the future, he will leverage the neurophysiology, transcriptomic, and connectomic technologies he is developing to continue studying how central, autonomic, and intracardiac circuits control heart function and he will progressively expand his focus to include neural control of the gills and cardiorespiratory coordination.
