Network Dysfunction and Neuromodulation following TBI

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Summary: Although memory dysfunction is a frequent and debilitating symptom of traumatic brain injury (TBI), there are currently no effective treatments available for this often persistent deficit. In addition, the neurophysiological basis of this dysfunction remains unknown, hindering rational treatment design. There is mounting evidence that precisely coordinated communications between brain regions are necessary to encode and recall information in the neuronal ensembles that represent episodic, spatial, and working memory. The hippocampus (HC) is the most well-studied region of memory encoding and is considered to be selectively vulnerable in both human and animal TBI. We and others have demonstrated disruptions of oscillations in the HC following TBI, with the loss of theta a notable finding. Rodent studies have demonstrated that restoration of theta using stimulation (neuromodulation) can restore aspects of HC dependent memory. However, the mechanism remains unknown, as does the complex relationship of these neuronal ensembles to oscillations and their correlation with memory deficits after TBI. Without a deeper understanding of how ensemble coding underlying cognition and memory is disrupted post injury, rational design of neuromodulatory and other therapies remains challenging. Therefore, a critical need exists to determine the underlying mechanisms of the disruption of coding in networks underlying memory formation after TBI, and how a reintroduction of theta restores cognitive function. The overall objective of the current application is to determine how the coding of memory in the hippocampus and associated circuitry is disrupted following TBI, and how theta neuromodulation restores function. Our central hypothesis is that TBI disrupts communication within the larger hippocampal network which disrupts oscillatory interactions required for encoding and recall of memory in networks of synchronized neuronal ensembles. This hypothesis is based in part on our preliminary data demonstrating that neurons in the hippocampus synchronize improperly with oscillations following injury, and that prominent interactions between oscillations are lost. We therefore propose to determine whether TBI affects phase precession, theta sequences, and phase amplitude coupling in area CA1 of the hippocampus during overtrained tasks designed for these measures, as well as whether both hippocampi are affected by a unilateral injury. In addition, we will determine the mechanism of learning and memory dysfunction following TBI by examining neuronal ensemble activity across HC-PFC, quantifying ripple features and replay, and correlating these measures with behavioral memory function relying on HC-PFC networks. We will also examine the mechanism of neuromodulatory restoration of spatial/working memory in rats via simultaneous medial septal stimulation and high-density laminar hippocampal/mPFC recordings. Accomplishment of these goals will provide the first detailed analysis of disrupted neuronal coding and oscillatory interactions between brain regions underlying TBI induced memory dysfunction, identify the effects of neuromodulation on these networks, and lead to clinical treatments for this persistent sequelae of TBI.