Josephine McGowan, PhD
Research Projects
Ketamine as a prophylactic
In a study I was a part of in 2014 when I first joined Dr. Denny's lab, we were the first to discover that a single administration of (R,S)-ketamine in mice prevents against stress-induced depressive-like behaviors (Brachman et al., 2016, Biological Psychiatry). This was a paradigm-shift in the field of psychiatry, as it was the first to demonstrate that a drug can be administered before a stressor in a vaccine-like fashion to prevent stress-induced psychiatric diseases such as major depressive disorder (MDD) or post-traumatic stress disorder (PTSD).
In a follow-up study, I found that there is a dose- (30 mg/kg) and time- (1 week) specific window to administer (R,S)-ketamine to effectively buffer fear expression in mice (McGowan et al., 2017, Neuropsychopharmacology). These data indicate that stress resiliency can be pharmacologically increased. Several human studies have found a similar effect, in that (R,S)-ketamine prevents stress-induced psychopathology (McGhee et al., 2008, Journal of Trauma; Ma et al., 2019, Psychiatry Research).
However, because of the abuse potential of (R,S)-ketamine, its reputation as a club drug, and its psychomimetic effects, research in the lab has since been focused on understanding the neurobiological mechanisms of resilience enhancement to inform the development of more efficacious therapeutics. Several candidate novel drugs can be administered before or at the time of stress to increase stress resilience.
Neurobiological mechanisms of ketamine's fear buffering effects
Dr. Denny's group discovered that (R,S)-ketamine's prophylactic effect on buffering fear is mediated by the ventral CA3 (vCA3) region of the ventral hippocampus, a region of the brain important for anxiety and fear behaviors (Mastrodonato et al., 2018, Biological Psychiatry). We also found that AMPA bursts in this region are attenuated 1 week after (R,S)-ketamine administration, long after the drug's 2.5h half life. However, the limitation of these studies is that they measure changes at a single timepoint: after the mouse is sacrificed. No studies have yet uncovered changes dynamically across time, from administration, to the experience of a stressor, to the recall of that stressor.
For my dissertation work, I used Inscopix in vivo calcium imaging and in vivo micro dialysis to uncover how the ventral hippocampus, and specifically vCA3, is changing throughout prophylactic (R,S)-ketamine treatment. These data will reveal novel therapeutic targets to prevent fear disorders such as post-traumatic stress disorder (PTSD).
The full dissertation and publication showcasing my exciting discoveries will soon be available here.
Change in resiliency and therapeutic potential across the lifespan
I have participated in several studies to uncover the utility of (R,S)-ketamine across the lifespan, how memory changes as we age, as well as to review the literature on stress resiliency and implications for the aged population.
Biomarkers of prophylactic treatment efficacy
In a paper published in 2018 (McGowan et al., 2018, Neuropsychopharmacology), we discovered that purine and pyrimidine metabolism was altered in both brain and plasma following a single dose of (R,S)-ketamine and stress.
These data indicate that it may be possible to obtain a biomarker to prophylactics against stress-induced psychiatric disease using a simple blood test. The applications of these findings were patented in 2018 (see Achievements).
The impact of traumatic brain injury (TBI) on fear behavior and memory traces
Using Dr. Denny's ArcCreER^T2 x EYFP mice, we are currently working to uncover how a traumatic brain injury (TBI) in mice impacts fear behavior and how fear memory traces are altered post-impact.
Post-doctoral direction: Translational studies on the interaction between stress and sleep
During my post-doctoral fellowship at McLean Hospital, I will learn novel translational approaches to uncover how stress impacts sleep architecture, and what may be mediating this interaction in both mice and humans.
Stay tuned for publications related to this work.
The McGowan Lab Premise (Projected 2026)
As neuroscientists, we are privileged to be able to peek into the labyrinth of our minds using innovative new tools. In my own lab, my focus will be on uncovering the biological impacts of stress-induced psychiatric disorders and how we can treat and prevent these disorders. I will develop a research program to accomplish translational, clinically relevant research rooted in rigorous basic neuroscience experiments. My goal is to one day have a real-world impact on human health and to understand fundamental principles about mood, emotion, fear, and ultimately, what makes us who we are.
Some lingering overarching questions I’d love to address in my career (just a sampling; it is constantly growing):
TRANSLATION: How can we develop better animal models of human disease? How can we align data better from mice to humans? How do we apply neural circuit preclinical data and start applying them to the clinic?
BEYOND THE BRAIN: What is the role of the periphery in neuropsychiatric diseases?
COMPUTATION: How can we leverage machine learning and other sophisticated AI and statistical approaches to tackle big data (e.g., -omics) in neuroscience and psychiatry?
PRECISION MEDICINE: Can we match individuals to treatments that would benefit them most using precision medicine approaches (via brain activity, biomarkers, behavioral readouts, self-reports, etc.)?
GENERAL CURIOSITY: What are the long-term effects of COVID-19 and how can we combat them (inflammation, stress, lack of sleep, persistent symptomatology, etc.)?