Epilepsy is the second most prevalent neurological disorder, affecting approximately 2 million people in the United States. While many patients achieve satisfactory seizure control with pharmacotherapy, there is a significant proportion (20-40%) who have medically intractable seizures. For these patients identification of novel methods for seizure control is a high priority. One such method may be to harness endogenous seizure suppressive circuits in the brain. Because seizures may have multiple or unknown sites of initiation, focal stimulation approaches (e.g., deep brain stimulation [DBS]) that can control seizures originating in diverse brain networks are highly desirable. The circuitry of the basal ganglia has received particular attention in this regard. Here, we propose to employ optogenetic methodologies to analyze the contribution of the nigrotectal pathway and its descending projections to the pedunculopontine nucleus to seizure control. The SNpr is major source of inhibitory input to DLSC. Moreover, both DLSC and SNpr both provide synaptic input to PPN.
In Aim 1, we will test the hypothesis that optogenetic silencing of the SNpr, activation of DLSC, or silencing of SNpr to DLSC projections will control spontaneous recurrent seizures in a post-status epilepticus model.
In Aim 2, we will determine if projections from SNpr/DLSC to the PPN are necessary and sufficient to account for basal-ganglia mediated seizure control. We will dissect the contribution of multiple cell types within the PPN, separately analyzing glutamatergic and cholinergic cell groups. In the service of these aims, we will examine the effects of optogenetic manipulations on complementary spontaneous and evoked seizure models to map the contributions of this network to seizure suppression within divergent seizure circuits. Together the proposed studies will provide proof of principle for optogenetic modulation of seizures in diverse networks from a single circuit. Moreover, this approach allows us to examine previously untestable hypotheses about the connections that mediate basal ganglia seizure control. Finally, the proposed experiments aim to uncover the circuit and neurotransmitter mechanism by which focal manipulations in motor control regions (i.e., SNpr/DLSC) translate into brain-wide changes in excitability.

Public Health Relevance

Epilepsy is the second most common neurological disorder. Unfortunately, current treatments for epilepsy are unable to control seizures in many patients. For this reason, identification of new methods for seizure control is a high priority. Here we will test the ability of a brain circuit to restrain seizures and prevent the development of epilepsy by activating endogenous neural circuitry that functions to resist and prevent the propagation of seizure activity. We propose to determine if recently developed optogenetic methodologies can be deployed in these structures to suppress seizures. We will explore this using several of seizures and epilepsy and simultaneously use the optogenetic approach to dissect the critical basal ganglia pathways for seizure control and identify the mechanisms by which basal ganglia can suppress seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS097762-02
Application #
9310268
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2016-07-15
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Santos, Victor R; Kobayashi, Ihori; Hammack, Robert et al. (2018) Impact of strain, sex, and estrous cycle on gamma butyrolactone-evoked absence seizures in rats. Epilepsy Res 147:62-70
André, Emily A; Forcelli, Patrick A; Pak, Daniel Ts (2018) What goes up must come down: homeostatic synaptic plasticity strategies in neurological disease. Future Neurol 13:13-21
Aguilar, Brittany L; Malkova, Ludise; N'Gouemo, Prosper et al. (2018) Genetically Epilepsy-Prone Rats Display Anxiety-Like Behaviors and Neuropsychiatric Comorbidities of Epilepsy. Front Neurol 9:476
Lee, Yichien; Rodriguez, Olga C; Albanese, Chris et al. (2018) Divergent brain changes in two audiogenic rat strains: A voxel-based morphometry and diffusion tensor imaging comparison of the genetically epilepsy prone rat (GEPR-3) and the Wistar Audiogenic Rat (WAR). Neurobiol Dis 111:80-90
Dunn, Raymond; Queenan, Bridget N; Pak, Daniel T S et al. (2018) Divergent effects of levetiracetam and tiagabine against spontaneous seizures in adult rats following neonatal hypoxia. Epilepsy Res 140:1-7
Elorette, Catherine; Forcelli, Patrick A; Saunders, Richard C et al. (2018) Colocalization of Tectal Inputs With Amygdala-Projecting Neurons in the Macaque Pulvinar. Front Neural Circuits 12:91
Aguilar, Brittany L; Forcelli, Patrick A; Malkova, Ludise (2018) Inhibition of the substantia nigra pars reticulata produces divergent effects on sensorimotor gating in rats and monkeys. Sci Rep 8:9369
Forcelli, Patrick A (2017) Applications of optogenetic and chemogenetic methods to seizure circuits: Where to go next? J Neurosci Res 95:2345-2356