The Djavad Mowafaghian Centre for Brain Health Kickstart Grants are intended to encourage research that demonstrates new collaborations, directions, and technological developments. They support new projects that generate preliminary data for future grant applications to external funding agencies.
Congratulations to the DMCBH researchers and their teams who have received this year’s Kickstart Grants! Learn more about the four funded projects below.
Deciphering the mechanism of divergent SETD2 neurodevelopmental disorders
Principal investigator: Dr. Carol Chen
Co-PI: Dr. Annie Ciernia
Epigenetic modifications are crucial for controlling gene activity and are especially important for brain development. Problems in this process can lead to various neurodevelopmental disorders and childhood brain cancers. SETD2, an enzyme that adds a specific modification to histones (H3K36me3), plays a key role in this process by preventing unwanted gene activity within gene bodies. SETD2 is vital during early brain development, particularly in the formation of the neural tube, which eventually becomes the central nervous system.
In mice, a lack of SETD2 causes severe brain development issues and early death, while brain-specific removal leads to abnormal brain structure and behaviour. In humans, mutations in the SETD2 gene can cause different neurodevelopmental disorders such as Luscan-Lumish Syndrome and Rabin-Pappas Syndrome, which are characterized by various developmental defects.
While much is known about SETD2’s role in cells, the exact reasons why different mutations in SETD2 lead to distinct developmental outcomes in the brain remain unclear. The research team believes that different SETD2 mutations may cause varying changes in the brain’s epigenome, leading to different gene activity patterns and developmental outcomes.
Effects of Psilocybin on Hippocampal Cognitive Map Stability and Plasticity
Principal investigator: Dr. Manu Madhav
Co-PI: Dr. Catharine Winstanley
Recent research has shown that psychedelics, particularly psilocybin (found in magic mushrooms), have potential as breakthrough treatments for various psychiatric disorders such as depression, anxiety, substance abuse and anorexia. However, while there is a growing interest in psilocybin’s effects, much remains unknown about how it works beyond its interaction with the serotonin 5HT2A receptor. The REBUS (relaxed beliefs under psychedelics) model suggests that psychedelics increase brain network flexibility, allowing for a temporary state where the brain can break free from rigid thought patterns associated with mental health issues. This idea is supported by brain imaging studies in humans.
The proposed study aims to test this model by examining psilocybin’s effect on the hippocampus (a brain area important for navigation and memory) in rodents. Using advanced techniques to measure brain activity, the research team will investigate if psilocybin makes the brain’s cognitive maps less stable initially and more responsive to changes in external stimuli, thereby enhancing brain plasticity and adaptability.
Does Dopamine Encode Reward-Prediction Errors in Frontal Cortex?
Principal investigator: Dr. Jeremy Seamans
Co-PI: Dr. Anthony Phillips
Dopamine (DA) is a key brain chemical involved in functions like movement, motivation, reward, learning and attention, and also plays a role in diseases such as Parkinson’s, addiction, and schizophrenia. A popular theory suggests that DA signals ‘Reward Prediction Errors’ (RPEs) – increases in DA when things go better than expected and decreases when things go worse – which help the brain learn from experiences. This theory, supported by many experiments using specific DA pathways and tasks, is widely accepted. However, there are doubts because most evidence comes from limited scenarios, and DA-boosting drugs often don’t improve learning tasks. Additionally, DA signals in the cortex are too slow to work as precise teaching signals, and both good and bad outcomes increase cortical DA levels equally. An alternate theory suggests DA helps with attention rather than RPEs.
A new technology called fiber photometry can now measure DA in the cortex accurately and quickly, allowing researchers to test if the RPE theory applies to this part of the brain. This research project aims to use this technology, along with microdialysis, to explore this question.
Salience Network Plasticity in Female Youth with Depression Induced by Accelerated Theta Burst Stimulation
Principal investigator: Dr. Fidel Vila-Rodriguez
Co-PIs: Dr. Tamara Vanderwal, Dr. Roberto Sassi
Major depressive disorder (MDD) is the leading cause of disability worldwide, with 12% of Canadians experiencing it in their lifetime and 1.76 million affected annually. Depression typically starts in the late teens or early twenties, impacting education, work, and relationships. The prevalence of depression among youth has been rising, especially among young women, increasing from 8.1% in 2009 to 28% in 2022. Despite early onset, there is an average 11-year delay in seeking help due to barriers like lack of time, privacy concerns, and a preference for non-drug treatments.
Repetitive transcranial magnetic stimulation (rTMS) is a leading treatment for adults with treatment-resistant depression, offering benefits without memory, sexual, or metabolic side effects. Recent advancements show that multiple daily sessions can shorten treatment duration without additional side effects. rTMS affects various brain networks, including the salience network, which is linked to depression symptoms.
This study aims to test the feasibility of accelerated rTMS for youth, examine its neuroplastic effects on the salience network, and investigate its interaction with brain network changes during the menstrual cycle in young women with depression.
