Assistant Professor of Neurology
Appointed McNair Scholar January 2023
Our cognitive functions arise from the orchestrated activity of highly interconnected circuits of neurons. In a healthy brain, neural activity levels are maintained in an optimal range. In epilepsy, healthy circuit activity patterns are disturbed and replaced by hypersynchronous activity that interfere with cognitive functions and can transform into seizures.
Epilepsy affects 50 million people worldwide. Current treatment options (including medication and surgical resection) leave more than one third of people with epilepsy without adequate seizure control. The shared underlying cause of epilepsies, whether of genetic or acquired origins, is neuronal hyperexcitability. Such hyperexcitability is a pathomechanism of epilepsy and several related brain disorders, including Alzheimer’s disease and autism. Therefore, developing treatments for hyperexcitability is critically important. However, the precise mechanisms that cause epileptic circuit activity remain poorly understood. As a result, despite decades of research, multiple generations of antiseizure medications have failed to reduce the proportion of patients with treatment-resistant epilepsy.
Our mission at the Laboratory of Neural Circuit Modulation is to advance a mechanistic understanding of the circuit mechanisms that regulate neuronal activity to enable developing neuromodulatory interventions for inhibiting epilepsy. In the following years, we will primarily focus on the inhibitory circuit elements involved in the generation and termination of seizures.
Inhibition is often described as a counterweight to excitation, and impaired inhibition contributes to epilepsy. However, inhibition is complicated. There are dozens of types of GABAergic inhibitory interneurons, with important cellular and molecular differences. Our prior research identified functionally distinct interneuron types that are recruited in distinct brain states, including physiological brain states during behavior, and pathological states (seizures) in epilepsy.
We aim to develop innovative approaches that will allow us and the field to map the recruitment of distinct inhibitory cell types in seizures and target such types (including types that remained out of reach) with neuromodulatory intervention. We use rodent models of epilepsy along with non-epileptic controls and carry out large-scale, cell type-specific recording of neuronal activity using in vivo 2-photon microscopy. This approach uses a multiphoton microscope to take high-resolution images of fluorescence reporters inside the brain of awake, behaving mice at a rate of dozens of frames per second. Genetically encoded fluorescent reporters of neuronal activity (calcium, neurotransmitters, neuromodulators and endocannabinoids) are expressed in the cell types of interest using genetic targeting. Optical recordings are combined with correlated measurement of electrical activity (such as depth EEG) and behavioral features to detect and ultimately predict seizures. There are three advantages of this approach critical for our mission: First, the ability to simultaneously record from hundreds of neurons is realized without losing the ability to distinguish between neuronal types. Second, the procedures that establish our optical access to the brain enable the application of both invasive and non-invasive neuromodulatory interventions during recording. Optogenetic methods use genetically encoded light-sensitive ion channels, and low-intensity focused ultrasound takes advantage of the differences in cell-intrinsic properties between cell types and cell states. These stimuli allow selectively activating or inhibiting the targeted cell types. Moreover, stimuli can be triggered by a closed loop system, enabling strategies that aim to prevent or interrupt seizures without interfering with baseline brain activity. Lastly, as these experiments are carried out in awake mice, the approach allows us to challenge the subjects with behavioral tasks during recording and stimulation. Thus, the impact of the neuromodulatory interventions on both seizures and cognitive function can be evaluated with great resolution and specificity.
