Mechanisms of Inflammation-Mediated Neural Circuit Disruption and Dysregulation

The goal of the Translational Neuroimmunology Lab's research on the mechanisms of inflammation-mediated neural circuit disruption and dysregulation is to protect neural circuitry in patients with acute neuroinflammatory disorders.

The acute infection model has shown that inflammatory mediators drive calcium-dependent injury processes within neurons. The molecules responsible for inducing such calcium-dependent injury also are implicated in acute disruption of neural circuit function and the induction of seizures.

By longitudinally measuring EEG in animals with ongoing neuroinflammation or monitoring real-time changes in the activity of cultured neurons in response to inflammatory factors, Dr. Howe's lab is able to model and study immune-mediated neural circuit disruption. Understanding the mechanisms of such disruption will allow researchers to design therapeutic interventions that can renormalize synaptic activity. This has considerable relevance to the pathophysiological processes that occur in neonates and children during acute systemic infection, trauma and hypoxic injury.

Focus areas include:

  • Developing and refining a high-throughput, cell-based assay for directly measuring inflammation-induced disruption of network level neuronal activity
  • Using this cell-based assay to screen patient-derived biospecimens (blood and cerebrospinal fluid) to identify the molecular pathways altered in individual patients
  • Testing biospecimens from patients with undefined autoimmune neurological diseases to identify autoantigenic targets
  • Developing novel mathematical modeling tools for the rapid analysis of large network activity data sets
  • Establishing methods for longitudinally measuring and analyzing EEGs in very young mice in order to identify biomarkers of neural circuit disruption that may be relevant to acutely ill neonates and children
  • Identifying novel metabolic cascades underlying synaptic dysfunction and testing new drugs that modulate such cascades

Sean J. Pittock, M.D., collaborates on this research.