Committee:
Astrid A. Prinz, Ph.D. (Emory University), Advisor
Deborah J. Baro.Ph.D. (Georgia State University)
Ravi V. Bellamkonda, Ph.D. (Georgia Institute of Technology)
Robert J. Butera, Ph.D. (Georgia Institute of Technology)
Ronald L. Calabrese, Ph.D. (Emory University)
 
Homeostatic regulation of neuronal activity is integral to neural function. Without successful mechanisms to constrain the process of plasticity and counter the entropic effects of high molecular turnover, every neuron would drift toward silence or death via excitotoxicity. When these mechanisms falter there is the risk of loss of function, such as after neuronal injury, or the development of neural disorders, such as the runaway excitation involved in epilepsy. The study of mechanisms involved in homeostatic regulation is not only central to understanding brain function, it may also provide therapeutic targets for treatment of brain injury and disease.
 
The pyloric central pattern generator of the stomatogastric ganglion (STG) is a premier model of homeostatic regulation. This small neural circuit controls the filtering action of the pylorus in the crustacean stomach, and its activity is maintained within strict and well-characterized bounds throughout the life of the animal. This circuit has the advantage of relatively simple connectivity between identified cells which allows the same cell to be compared between animals. Recent experimental evidence has shown that identified cells of the STG conform to type-specific fixed ratios between conductances, and these conductance ratios have been suggested to stabilize neuronal activity. We hypothesize that implementation of fixed conductance ratios will constrain single or multiple features of electrical activity in a population of healthy, uninjured neurons. However, these ratios are lost when the pyloric circuit is isolated from top-down control via neuromodulatory input, a process termed decentralization. After decentralization, the pyloric central pattern generator briefly loses its characteristic rhythmic activity, but the same activity profile returns 3-5 days later via poorly understood homeostatic changes. This re-emergence of the pyloric rhythm somehow occurs without fixed conductance ratios. In some systems, the extracellular matrix has been shown to stabilize neuronal structure and function. We hypothesize that the extracellular environment guides the conductance changes that accompany successful recovery of pyloric network function after injury. Specifically, our preliminary data suggest that a well-studied component of mammalian perineuronal extracellular matrix, a family of molecules called chondroitin sulfate proteoglycans (CSPGs), participate in the homeostatic recovery process after decentralization.  
 
The proposed experiments are threefold. First, we will use a mathematical model to quantitatively assess how conductance correlations influence neuronal electrical activity on a population scale. Next, we will characterize the contribution of CSPGs to the homeostatic maintenance of the pyloric rhythm by removing them with the enzyme chondroitinase ABC (chABC) before decentralization. Finally, we will measure the conductance values of identified cells before and after decentralization, with or without pretreatment with chABC, to evaluate the involvement of CSPGs in the conductance changes needed for successful recovery. This work will contribute to theoretical and molecular knowledge of the processes of homeostatic regulation in the STG.