The overall goal of this project is to establish the time course for developing abnormalities in hippocampal neural circuit action potential firing dynamics after pilocarpine induced hippocampal injury, determine whether maintenance of normal neuronal firing dynamics prevents epileptogenesis and establish the genetic mechanisms of those effects. Temporal lobe epilepsy (TLE) associated with mesial temporal sclerosis (MTS) is a common form of focal epilepsy in which seizures are difficult to treat and memory impairments are common. These factors enormously diminish the quality of life of people with TLE. MTS/TLE develops after brain injury via pathophysiological processes that take at least weeks to reach the endpoint of seizures and memory impairments. This suggests that there is a window of therapeutic opportunity to minimize adverse outcomes. Epileptogenesis is associated with an enormous number of pathological changes at the levels of gene expression, inflammation, synaptic plasticity, neuronal loss and neuronal reorganization amongst many others. Targeting individual pathogenic mechanisms has had limited success in preventing adverse outcomes in animal models of TLE. Thus, new approaches to preventing epileptogenesis are required. We suggest that the above pathophysiological processes converge to disrupt neural dynamics (the patterns of action potential firing over time). The consequent abnormal activity dependent sculpting of synaptic weights and gene expression iteratively alters the self-organization rules governing the formation of dynamic hippocampal circuits, with the emergence of a maladapted circuit. Brain stimulation to maintain normal dynamics from forming thus represents a novel approach to modifying epileptogenesis. The observation that brain stimulation can minimize seizures and improve cognition outside of stimulation periods in animal models with structural brain abnormalities, including MTS, supports the view that patterns of neural activity can be modified to improve network function. It remains unknown whether stimulation during the process of epileptogenesis reduces the development of maladaptive circuits. We will use optimized stimulation paradigms to perturb hippocampal firing patterns during the post-injury period to maintain normal interictal dynamics and establish whether this improves outcomes and whether gene expression changes provide mechanistic insight that could also be harnessed for therapeutic gain.
Hippocampal injury is associated with multiple epileptogenic pathophysiological processes that modify neural networks with resultant seizures and memory impairments. We hypothesize that these pathophysiological processes converge onto abnormal neural dynamics that sculpt synaptic weights and gene expression that iteratively lead to formation of maladapted circuits. Medial septum / diagonal band of Broca stimulation in pilocarpine-exposed rats will alter neural dynamic and gene trajectories toward normal, and the nature of those effects will allow us to generate novel therapeutic hypotheses for future testing.
