Yaroslav I. Molkov, PhD - US grants

DESCRIPTION (provided by applicant): Dysfunctions of the mechanisms controlling sympathetic activity play a relevant role in the development of arterial hypertension. Excessive sympathetic activity is often reported in patients with hypertension, especially those with resistant hypertension. Such scenario is also observed in a large proportion of patients with obstructive sleep apnea (OSA). Chronic exposure to intermittent hypoxia (CIH) that occurs in OSA is considered a major factor leading to sympathetic overactivity and hypertension. However, the CIH-elicited changes in the nervous system that underpin the development of augmented sympathetic activity are still under investigation. We previously demonstrated that the higher levels of baseline sympathetic activity of CIH-treated rats strongly correlate with the emergence of active expiratory pattern at normoxic/normocapnic conditions. These findings indicate that changes in the central mechanisms providing expiratory motor activity and its interaction with sympathetic nervous systems play an essential role in sympathetic overactivity in CIH conditions. The neural substrates required for generating expiratory motor outputs in response to environmental challenges and their interactions with sympathetic activity are still unidentified. Therefore, this project focuses on the investigation of two neural oscillators potentially involved in the dynamic control of breathing and sympathetic activity, in order to reveal the neural mechanisms underlying sympathetic overactivity in CIH/OSA conditions. The first oscillator is the respiratory central pattern generator (CPG) located in the brainstem. The core of this CPG is composed of pre-B¿tzinger (pre-B¿tC) and B¿tzinger complexes (B¿tC) which together generate respiratory oscillations controlling lung movements. The second oscillator, termed the parafacial respiratory group (pFRG), resides rostally to B¿tC in the retrotrapezoid nucleus (RTN). The pFRG oscillations, emerging in certain conditions, are synchronized with the B¿tC/pre-B¿tC oscillations and drive an expressed expiratory motor activity. Both oscillators require pontine tonic drive for coordinating cranial and spinal motor outflows. These respiratory circuits interact with the sympathetic nervous system to generate state-dependent respiratory related oscillations in sympathetic drive. It has been proposed that CIH exposure introduces plastic changes in these central respiratory-sympathetic mechanisms that contribute to enhance baseline sympathetic activity. However, there are still heated debates on the exact physiological role of pFRG oscillations, the specific conditions for their emergence and their coupling with sympathetic nervous system in health and disease states. In the present study we aim to build a multi-scale computational model of the neural cardiorespiratory network that will help reveal central mechanisms underlying sympathetic overactivity associated with OSA. We will do so by combining computational and mathematical modeling and electrophysiological and immunohistochemical experiments. The overall goals are to investigate: (i) the neural mechanisms involved in the interactions between B¿tC/pre-B¿tC and pFRG oscillators, (ii) the role of these interactions in shaping coordinated respiratory and sympathetic motor outputs under different metabolic conditions: resting, hypoxia and hypercapnia; and (iii) the neural mechanisms underlying the CIH-induced emergence of pFRGrelated component in the sympathetic efferent activity. Intellectual Merit: The intellectual merit lies on the fact that this will be the first comprehensie computational model of the central sympathetic-respiratory network that will provide cellular level resolution of cardio-respiratory coupling in health and disease. This study will lead to a better understanding of autonomic dysfunctions such as neurogenic hypertension, and will contribute to the design of new treatment strategies. Broader Impacts: The proposed studies will have broader impacts as it will serve as corner stone for the modeling neural oscillatory circuits. Models will be made available publicly. It will also promote integration of research and education at all three institutions involved in the projec by training graduate and MD students. By the end of the project, all developed models will be integrated into the NIH Biowulf distributed parallel computing system and made available to neuroscientists through the NIH. This project represents a unique, recently formed collaboration among three young researchers, none of which has ever served as a PI or a Co-PI in any government or extramural funding. One of Co-PIs, Dr Ana Abdala, is an extremely productive female neuroscientist.

This program of Research Experiences for Undergraduates (REU) at Indiana University-Purdue University Indianapolis (IUPUI) will provide eight undergraduate students from across the United States with the opportunity to conduct applied mathematics research in the medical sciences, biophysics, and inverse problems. The students will spend eight weeks during the summer working with faculty mentors from the IUPUI Department of Mathematical Sciences on one of four main projects: (i) modeling the redistribution of blood flow and pressure in the leg following a major arterial occlusion, (ii) investigating the influence of abused drugs on the human brain, (iii) analyzing the diffusion dynamics of biomolecules, and (iv) uncovering methods to solve inverse problems for phase retrieval, gravitational fields, and acoustic waves. Research in mathematics provides students with important skills that they can use to analyze and solve problems in all disciplines and environments. The projects in this program will also train students to answer specific questions in vascular surgery, emergency medicine, biophysics, and astronomy. As the world continues to make technological advances at an incredibly rapid pace, there is an increased need for scientists and engineers. Exposing the students to applied mathematics research will encourage many of these students to pursue careers in STEM-related fields, and will ultimately provide the United States with individuals who possess a deep knowledge of modern science and who are well-equipped to have an impact on science and technology in the public and private sectors. The award is supported by the Division of Mathematical Sciences (DMS) in the Directorate for Mathematical and Physical Sciences (MPS) and the Division of Biological Infrastructure (DBI) in the Directorate for Biological Sciences (BIO).

The REU projects address new and open problems in applied mathematics, and the progress that the students make on the summer projects will advance these research areas. Students participating in the first REU project will work closely with a mathematician and vascular physiologist to develop a model, based on experiments conducted in the mouse hind limb, to simulate the effects of increased vascular number or diameter on blood flow following a major arterial occlusion to determine whether angiogenic or arteriogenic therapies provide the maximum benefit. The second project involves the development of a mathematical model for the response of the human brain to drugs. The model will be based on electrophysiological experiments, and the inputs, intrinsic properties, and release of dopamine will be modeled. In the third project, students will explore a framework for diffusion dynamics motivated by the observations that the heat released from a catalytic reaction enhances an enzyme's diffusion coefficient by causing a sudden center of mass translation of the enzyme, and that particles and biomolecules of various types and sizes diffuse faster inside cells with an active metabolism. The students will explore a novel framework based on the regular Fokker-Planck equation (which describes diffusion driven by forces and random Brownian motion) to determine the importance of inertial effects for a protein. Students working on the fourth project will be studying a variety of inverse problems and solutions based on algebraic and analytic algorithms. The students will tackle problems of phase retrieval that arise in the experimental use of diffraction to determine internal structure, as well as inverse problems for gravitational fields and acoustical waves.