The thalamus is a subcortical structure that is widely interconnected with cortical circuits and plays a critical role in such vital and diverse brain functions as processing of sensory information, sleep and memory. Disruptions in thalamic structure and function are implicated in both generalized and focal epilepsies, yet certain aspects of thalamic function may serve to constrain epileptiform activity. Our preliminary results suggest mechanisms through which thalamic circuits provide activity-dependent adaptive and maladaptive changes that suppress or enhance epileptogenesis, respectively. In particular, cortical infarction or generation of focal cortical epileptiform activity leads to maladaptive increases in thalamic network connectivity and function that would enhance epileptogenesis. By contrast, multiple lines of evidence suggest that endogenous ligands for the benzodiazepine site of inhibitory GABA receptors, endozepines, are constitutively expressed in the thalamus to augment synaptic inhibition specifically in the thalamic reticular nucleus, a site proposed to underlie a key seizure regulatory pathway. In addition, the endozepine effects appear to be increased by experimental absence seizures, and act to blunt seizure intensity and duration. The proposed experiments will employ anatomical and electrophysiological approaches to analyze each mechanism individually in addition to their interactions, with the long term goal of providing an integrated view of adaptive and maladaptive processes important in the roles of this key brain structure in normal brain function and epilepsy.

Public Health Relevance

Injury to the cortex can result in reorganization of circuits in both thalamus and cortex and in many cases this leads to abnormal neural circuit activity, including seizures. The thalamus in turn has internal mechanisms built in that serve to regulate thalamocortical activity and may serve as an internal brake on seizures. Proposed studies will determine whether reorganization of thalamic circuits in cortical injury models leads to overexcitation, and whether thalamic compensatory mechanisms have the ability to counter the excessive excitation arising from circuit reorganization following injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS006477-47
Application #
8308510
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
1978-01-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
47
Fiscal Year
2012
Total Cost
$344,337
Indirect Cost
$129,962
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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