In order to properly transmit and store information, neural networks must be able to compensate for short and long-term changes in internal environment (e.g. sleep/wake cycles, development, aging, and disease) as well rapid changes in external, stimulus-driven inputs. Homeostatic plasticity mechanisms that stabilize neuronal activity in the face of such perturbations have been described in vitro (1), but little is known about their role in stabilizing circuit function in the freely behaving animal. Dysregulation of homeostatic plasticity is widely hypothesized to contribute to debilitating pathologies including Alzheimer's disease (2), Rett syndrome (3), and epilepsy (4), thus an understanding of its role in vivo is critical. It is currently unknown whether neurons and neural networks exhibit homeostatic regulation of spike activity (firing rate homeostasis) and/or complex network properties in the awake and freely behaving animal, a prediction I aim to test in this study by following the activit of individual neocortical neurons over time in the freely behaving rat. First, neuronal activity an the response to activity deprivation will be assessed in the visual cortex of freely behaving and freely viewing juvenile rats. Through the use of genetic manipulations and activity deprivation, the mechanistic role of a well- studied form of homeostatic synaptic plasticity, synaptic scaling, in firing rate homeostasis in vivo will be investigated. Finally, I will exploit a unique feature o this experimental technique to examine the interaction between plasticity mechanisms and behavioral state. Chronic recordings in normally behaving animals enable me to ask whether the expression of homeostatic plasticity is governed by behavior, arousal state, network state (via local field potentials), and circadian factors (5). Characterization of firing rate homeostasi in the normally behaving animal is essential for understanding how neural networks operate. Investigating the contributions of homeostatic plasticity mechanisms such as synaptic scaling to normal brain function is critical for understanding their physiological role. Further, an examination of the role of activity and arousal-state in the expression of homeostatic plasticity will clarify the role of sleep in brain function and plasticity. This knowledge will advance our understanding of basic cellular, systems, and computational neuroscience, as well as provide insight for future investigations of diseases that disrupt neuronal homeostasis.
It is widely hypothesized that dysregulation of homeostatic plasticity is important in the pathogenesis of many neurological disorders, including Alzheimer's disease, epilepsy, and Rett syndrome. In order to begin addressing the role of homeostatic plasticity in disease, it is essential first to understand how homeostatic plasticity of neuronal activity operates in the intact, freely behaving animal. This work will provide the first characterization of homeostatic plasticity in the normally behaving animal, will explore molecular mechanisms of this plasticity, and will determine the expression patterns of homeostatic plasticity as they relate to behavior and activity state.
|Hengen, Keith B; Lambo, Mary E; Van Hooser, Stephen D et al. (2013) Firing rate homeostasis in visual cortex of freely behaving rodents. Neuron 80:335-42|
|Hengen, Keith B; Behan, Mary; Carey, Hannah V et al. (2009) Hibernation induces pentobarbital insensitivity in medulla but not cortex. Am J Physiol Regul Integr Comp Physiol 297:R1028-36|