NEW INVESTIGATOR AWARD 2023 WINNER
Dr. Justin Botterill, PhD
Assistant Professor Department of Anatomy, Physiology, and Pharmacology (College of Medicine)
University of Saskatchewan
Grant Project: Projections from the supramammillary nucleus to the dentate gyrus: a novel source of hippocampal hyperexcitability and sleep-related seizures
My interest in epilepsy research began during early adolescence when a close family member was diagnosed with epilepsy. My general interest in basic epilepsy research motivated me to pursue a PhD in Neuroscience at the University of Saskatchewan. My doctoral research used a rodent model of epilepsy to evaluate how repeated seizures induce aberrant plasticity and interictal (between-seizure) cognitive impairments. My interest in epilepsy research motivated me to pursue postdoctoral training in Dr. Helen Scharfman’s laboratory (Nathan Kline Institute). My postdoctoral research focused on the hippocampus to study neurobiological mechanisms of temporal lobe epilepsy. In January 2023, I started my independent research laboratory at the University of Saskatchewan where I will focus on studying the neurobiological mechanisms of epilepsy and its treatment.
Project Summary: Temporal lobe epilepsy (TLE) is the most common form of adult-onset epilepsy. Despite advances in drug development, 1 in 3 patients with TLE do not respond to current treatments. The high rate of treatment-resistant cases in patients in with TLE emphasizes the need to develop a better understanding of the causes of seizures so that more precise and effective treatments can be developed. The proposed research program will focus on a brain region known as the hippocampus because approximately 80% of seizures in TLE originate in the hippocampus or nearby regions. Specifically, we will evaluate excitatory projections from the supramammillary nucleus (SuM) of the hypothalamus that densely innervate the dentate gyrus (DG) subfield of the hippocampus. Recent studies have found that SuM projections to the hippocampus strongly influence patterns of hippocampal activity to support essential functions such as learning, memory, and emotion. In addition, the SuM has also been shown to strongly influence sleep and wakefulness. Despite considerable evidence that the SuM influences hippocampal function in physiological states, the SuM to DG circuit has been mostly overlooked in the context of TLE. The main goal of our study will be to determine whether the SuM to DG circuit is a major source of hippocampal hyperexcitability, seizures, and/or sleep-related dysfunction in TLE. We will use genetically modified mice and electrophysiological recordings to determine whether selectively modifying the activity of the SuM to DG circuit influences hippocampal excitability and seizures. We will also evaluate whether the SuM to DG circuit contributes to sleep-related problems which are commonly reported in people with TLE. Overall, this work will provide novel insights into whether the SuM is a major source of hippocampal excitability, seizures, and sleep-related deficits in TLE. The new knowledge gained by this project could ultimately lead to the development of new and effective therapies for patients with treatment resistant TLE.
Grant: $75,000