A homeostatic mechanism functions to stabilize a key parameter of a system, much like a thermostat functions to stabilize the temperature in a building. In neurons, homeostatic synaptic plasticity is believed to counteract the destabilizing influence of Hebbian-plasticity mechanisms that underlie the activity-dependent refinement of synaptic connectivity. It is postulated that severe human pathologies arise from impaired mechanisms of neuronal homeostasis, including Alzheimer's disease, epilepsy, and Rett syndrome. A significant barrier to progress in this field is our nearly complete lack of insight ino homeostatic plasticity in the intact brain. I propose to study how homeostatic synaptic plasticity supports brain function and behavior in the freely behaving animal. Research in this proposal will focus on synaptic scaling, one of the best-understood mechanisms of neuronal activity homeostasis in vitro. First, work performed during the mentored (K99) component will define a functional role for synaptic scaling in firing rate homeostasis in vivo. To do this, I will utilizeviral-mediated gene transfer to block synaptic scaling in a subset of cortical neurons and test the homeostatic response to long-term sensory deprivation. Next, work performed during the mentored and independent phases will test the hypothesis that sleep is necessary for the expression of homeostatic plasticity in vivo. This will be achieved in two steps: (i) neuromodulatory state-specific and/or circadian patterns will be examined in the normal expression of homeostatic plasticity, and (ii) modulatory states will be disrupted at key times during the emergence of firing rate homeostasis in the freely behaving animal. Finally, during the independent stage (R00), I will assess the core prediction about homeostatic plasticity: those homeostatic mechanisms serve to offset the inherently destabilizing effects of Hebbian plasticity during experience dependent refinement of networks (i.e. learning and development). In this work, I will determine the role of synaptic scaling in a) the development of information transmission in cortical networks, and b) the development of cortex-dependent behavior. The proposed research will be instrumental for the understanding and treatment of disorders that are theorized to involve dysregulated homeostatic plasticity mechanisms. Further, these data will provide novel insight into the effects of sleep deprivation. Finally, this work will identify parameters necessary for homeostatic plasticity in the healthy brain and provide insight into the role of homeostatic plasticity in higher-level brain functions. Candidate's immediate and long-term career goals my graduate training and postdoctoral experience thus far have provided me with a solid background in the methods and concepts related to the research proposed here. My long-term research goal is to understand the role of dysregulated homeostatic mechanisms in neurological disorders and disease, and to unravel the contributions of homeostatic plasticity to normal brain function. In order to complete this work, I will need additional training in a variet of techniques as well as intellectual, professional, and academic guidance. The environment at Brandeis University combined with the dedication and expertise of my mentor, the members of my scientific and career subcommittee, and collaborators provides a perfect base from which to pursue an academic tenure-track position at a research university. The combined training in in vivo molecular biology, computational neuroscience, behavior, and technology development will provide the final elements necessary for me to begin an independent career investigating the role of homeostatic plasticity in normal brain function and disease. Key elements of the research career development plan. The research described in the mentored phase of this application will be performed at Brandeis University under the supervision of Dr. Gina Turrigiano. The Turrigiano laboratory pioneered the study of synaptic scaling and is a recognized leader in the field of homeostatic plasticity. I have assembled a scientific and career advisory subcommittee that is scientifically diverse and dedicated to my development as an independent scientist. Dr. Stephen Van Hooser will provide expertise in animal vision, computational techniques, and in vivo optogenetic manipulations. Dr. Avital Rodal will provide expertise in molecular biology techniques and oversee the interpretation of AMPAR trafficking manipulations. Dr. Eve Marder will provide expertise in computational neuroscience, experimental design, and theory. In addition to this training, I will spend two months in the laboratory of my collaborator, Dr. Timoth Gardner (Boston University) learning cutting-edge technology fabrication necessary for the advancement of in vivo neuroscience. Finally, I will support these activities with regular attendance of international meetings and research seminars to develop an international presence for myself and continue my education in relevant topics. As I begin my career, my committee will provide ongoing support in early career issues, further supporting my transition to independence.
In order to transmit information effectively, neurons must maintain some stability despite continuous fluctuations in the environment. The failure of stabilizing, or 'homeostatic', mechanisms is believed to underlie a number of common neurological diseases. I will be studying the molecular mechanisms that stabilize the brain, the role of sleep in stabilizing the brain, and how these homeostatic mechanisms support cognition and behavior.
| Hengen, Keith B; Torrado Pacheco, Alejandro; McGregor, James N et al. (2016) Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake. Cell 165:180-191 |
