Amygdala-Activated Inhibition of Thalamic Pathways: Influences on Cortical Activity and Seizures

PROJECT SUMMARY / ABSTRACT People with epilepsy often face both seizures and neuropsychiatric diseases including anxiety, depression, and attention deficit hyperactivity disorder. Existing medication and surgical treatments for epilepsy are not always effective in treating seizures and neuropsychiatric comorbidities, and a greater understanding of the disrupted neural circuits is necessary to develop new therapies. The nucleus reticularis thalami (nRT), an inhibitory nucleus that influences how signals in the thalamus are relayed to cortex, has been implicated in both neuropsychiatric disease and generalized seizures. The nRT receives input from cortical and thalamocortical neurons, as well as from the amygdala, the emotional sensor of the brain. Through this connection to nRT neurons, the amygdala is well positioned to alter the state of thalamic and cortical networks that are activated by seizures and emotion. Studying the amygdala-nRT pathway and downstream network effects could generate new therapeutic targets for both seizures and neuropsychiatric comorbidities in people with epilepsy. The proposed experiments will test the hypothesis that the pathway connecting the amygdala with nRT influences both thalamic and cortical network function during typical behavior and in epilepsy. Aim 1 will test the hypothesis that amygdala-nRT pathways modulate thalamocortical circuits and prefrontal cortex activity. These experiments will use advanced optogenetic techniques to selectively activate amygdala-nRT pathways with light, in brain slices and in awake behaving mice, while recording neuronal activity in the thalamus and in cortex. Aim 2 will test the hypothesis that amygdala-nRT pathway activation can disrupt seizures and improve behavioral deficits in a rodent model of genetic generalized epilepsy. Together, these experiments will characterize for the first time the function of pathways connecting the amygdala with nRT, in behavior and in epilepsy. Studying these pathways in detail is essential to understanding the pathogenic mechanisms of generalized epilepsy and psychiatric comorbidities, and to developing new therapeutic approaches for refractory generalized epilepsy, which has fewer treatment options. Further, this proposal also provides the candidate, Dr. Clare Timbie, with mentored training in optogenetics, electrophysiology, behavioral testing, and rodent models of epilepsy needed to study the function of neural pathways. Dr. Timbie’s mentoring team brings expertise in the treatment and mechanisms of epilepsy, using electrophysiology to dissect neural circuits, behavioral testing, and cortical oscillatory rhythms in cognition. This will build upon her prior research in primate limbic neuroanatomy and clinical expertise in pediatric epilepsy, to form the foundation for an independent research program aimed at studying limbic and thalamic circuits to guide new therapeutic strategies for epilepsy and neuropsychiatric disease.