A Brief Description of Currently Funded Research Grants 2026 – 2027

Defining the role of M1 muscarinic Acetylcholine receptor signaling in Alzheimer’s disease

Dr. Khaled S. Abdelrahman
University of British Columbia (Djavad Mowafaghian Centre for Brain Health)
Vancouver, BC

Introduction: Alzheimer’s disease is a condition that gradually damages the brain and is one of the most common causes of memory loss in older adults. It affects millions of people worldwide, including over 700,000 Canadians, and has a profound impact not only on those diagnosed but also on their families and care partners. People with Alzheimer’s often experience difficulties with memory, thinking, and everyday tasks, and these challenges worsen over time.
For many years, Alzheimer’s research has focused on the buildup of a harmful protein in the brain called beta-amyloid, which is known to damage brain cells. However, scientists are still working to understand exactly how this damage happens. More recently, researchers have discovered that problems with blood flow in the brain are also an important part of the disease. Because the brain relies on a steady supply of blood to deliver oxygen and nutrients, even small reductions in blood flow can make it harder for brain cells to function and may contribute to memory problems.
What remains unclear is whether and how beta-amyloid drives these changes in blood flow, and resolving this link may be critical for developing more effective treatments for Alzheimer’s disease.

Objectives: The goal of our research is to better understand how blood flow in the brain is controlled and why it is disrupted in Alzheimer’s disease. We are particularly interested in a protein called the M1 receptor. This receptor acts like a small “switch” on brain cells that helps regulate communication between brain cells and may also play a role in controlling blood flow.
We want to find out whether these M1 receptors stop working properly in Alzheimer’s disease and whether this contributes to reduced blood flow and memory issues. We also want to know if targeting these receptors with drugs could help restore normal brain function.
In addition, Alzheimer’s disease affects women more often than men, so we will explore whether M1 receptors behave differently in males and females. We will also study how sex hormones, such as estrogen and testosterone, may influence these processes.

Outline of research: To answer these questions, we will carry out a series of carefully designed studies using mice.
First, we will study brain cells isolated from male and female mice and grown in the laboratory. This allows us to closely examine how beta-amyloid affects M1 receptors in a controlled setting. By doing this, we can better understand what goes wrong at the smallest, cellular level in both sexes.
Next, we will study mice that develop Alzheimer’s-like symptoms. In these mice, we will use genetic approaches to remove M1 receptor and see how this affects the brain as a whole. We will measure blood flow in the brain and test memory to understand how these changes lead to problems with thinking and behavior.
We will also compare male and female mice to determine whether there are important differences between them. Because hormones can affect how the brain works, we will also look at what happens when levels of hormones like estrogen and testosterone are changed by surgically removing the ovaries or testes. This will help us better understand how the M1 receptor influences blood flow in the brain in both sexes.
The proposed experiments will help us determine whether improving M1 receptor function can restore healthy blood flow and improve memory in both male and female mice.

Project benefits and application of findings: This research will help us better understand why the brain does not receive enough blood in Alzheimer’s disease and how this contributes to memory loss. By focusing on M1 receptors, we may uncover a new and important piece of the puzzle that has not been fully explored before.
If we find that M1 receptors play a key role, this could open the door to new types of treatments aimed at improving blood flow in the brain. Unlike current therapies, which mainly manage symptoms without addressing the underlying problems, this approach could target a root cause of brain dysfunction in Alzheimer’s disease.
In addition, by studying differences between males and females, our work could support more personalized treatments that are better tailored to each individual.
Overall, this research has the potential to lead to new strategies for slowing or improving memory loss, enhancing quality of life for people living with Alzheimer’s disease, and reducing the emotional and financial burden on families.

The role of hilar mossy cells in hippocampal circuit dysfunction and behavioural deficits in a mouse model of autism spectrum disorder.

Dr. Justin J. Botterill
University of Saskatoon
Saskatoon, SK

Introduction: Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder that affects approximately 1 in 50 Canadian children and youth. The major features of ASD include difficulties in social interaction or communication, repetitive behaviours, altered sensitivity to stimuli (touch, lights, sounds), difficulties in processing emotions, and altered cognition. Although the causes of ASD remain unclear, genetic and environmental factors are believed to play a major role. ASD is also characterized by complex changes in the circuitry, excitability, and function of several brain regions. For example, one major brain region of interest in ASD is the hippocampus, a seahorse-shaped structure located in the temporal lobes of the brain that is considered critical for cognitive, emotional, and social behaviours. Notably, ASD is associated with significant alterations of hippocampal volume, excitation-inhibition balance, and circuitry that are thought to disrupt hippocampal function and lead to impaired cognition, emotional processing, and sociability. Unfortunately, there remains a relatively poor understanding of the hippocampal cells and circuits that contribute to ASD. Recent studies have shown that an understudied cell population in the hippocampus known as hilar mossy cells are critical for diverse hippocampal functions such as cognition, emotion, and social behaviour. Mossy cells are thought to support such behaviours through their complex circuitry that modulates hippocampal excitation-inhibition balance. Interestingly, mossy cell dysfunction is well documented in conditions that are highly comorbid with ASD, such as epilepsy, major depressive disorder, and anxiety disorders. It was also recently reported that mossy cell dysfunction contributes to hippocampal excitability in Fragile X Syndrome, which is the most prevalent single-gene disorder for intellectual disability and ASD. However, no study to date has selectively studied whether mossy cells are dysfunctional in ASD. This is a critical knowledge gap that if clarified, could lead to a better understanding of the neurobiological mechanisms underlying ASD.

Objectives: In this study, we propose to test the hypothesis that mossy cells contribute to hippocampal circuit dysfunction and behavioural deficits in a mouse model of ASD. First, we will record electrical activity from mossy cells in ASD mice and healthy controls to compare their physiological properties. We will then determine whether an early-life intervention restores mossy cell deficits in ASD. Lastly, we will test whether selectively manipulating the activity of mossy cells in young adulthood improves cognitive, emotional, and social behavioural deficits associated with ASD.

Outline of research: All experiments will use a widely used mouse model of ASD known as Contactin-associated protein-like 2 knockout (Cntnap2 KO). In Aim 1, we will use brain slice electrophysiology to test the hypothesis that mossy cell physiology is abnormal in Cntnap2 KO mice compared to wild-type C57Bl/6J mice (controls). We will then determine whether early-life intervention (postnatal days 14 to 21) with an immunosuppressant (rapamycin) that was previously shown to be effective at improving symptoms in mouse models of ASD can restore mossy cell physiology. We will also use fluorescence microscopy on brain tissue to determine whether rapamycin treatment protects mossy cells from neurodegeneration. In Aim 2, we will inject light-sensitive proteins into the hippocampus of young adult Cntnap2 KO mice. We will then selectively activate mossy cells via light (optogenetics) during a variety of rodent behavioural tests relevant to ASD. Specifically, we will evaluate whether mossy cell stimulation improves hyperactivity, compulsive-like behaviours, sociability, and hippocampal-dependent learning and memory. Collectively, these experiments will investigate mossy cells at the cellular, synaptic, anatomical, and behavioural levels in ASD.

Project benefits: The results of this research will provide new knowledge about the specific hippocampal cells and circuits that underlie ASD. Understanding the complex neurobiological mechanisms of ASD could lead to the discovery of new therapeutic targets and interventions that restore hippocampal dysfunction and improve the debilitating behavioural deficits associated with ASD.

Investigating altered synaptic integration in a mouse model of Alzheimer’s disease.

Dr. Stephen D. Glasgow
Brock University
St. Catharines, ON

Introduction: Dementias, including Alzheimer’s disease (AD), are severe neurodegenerative disorders that affects 8.4% of the Canadian population over the age of 65. Care of patients diagnosed with neurodegenerative disease states has been estimated to cost the health care system in Canada $10 billion a year and is projected to increase to $16.6 billion per year by 2031. Understanding how typical memory is formed is necessary to develop treatments for neurodegenerative diseases characterized by memory dysfunction. The most common form of dementia is AD, which is characterized by a progressive deterioration of various forms of memory, including the ability to remember new environments, whichwhich suggests that AD may be due, in part, to dysfunction of the brain circuits responsible for navigation. Early stages of AD show decreases in levels of the classic neurotransmitter acetylcholine in the parasubiculum (PaS), a brain region that contributes to our ability to store information about our external environment. The overall aim of this proposal is to examine how acetylcholine impacts activity in the PaS in the healthy and AD brain.

Objectives: We propose the following aims:
i. What brain regions send inputs to the PaS?
ii. Does the neurotransmitter acetylcholine modify activity in the PaS?

Outline of Research: Levels of acetylcholine in PaS are lower in neurodegenerative disease states compared to the healthy brain, suggesting that reduced levels of acetylcholine in the PaS might contribute to memory loss in AD. However, little is known about how brain cells in the PaS are affected by acetylcholine in the healthy brain. To address this, we will use a unique molecule-to-behaviour approach that will help dissect the role of acetylcholine in the PaS and assess how it contributes to spatial memory.

Projected Benefits and Application of Findings: The proposed program will investigate how the brain forms new memories and assess the role of the classic neurotransmitter acetylcholine in spatial memory. The studies proposed here will help us understand how the PaS contributes to spatial memory and will lead to the development of therapeutic approaches to treat symptoms associated with memory problems. In combination with early detection, directed therapies aimed at promoting levels of acetylcholine in the PaS may help slow disease progression in AD.

Decoding Mutation-Specific Chromatin Dysregulation in SRCAP-Associated Neurodevelopmental Disorders

Dr. Gilda Stefanelli
University of Ottawa
Ottawa, ON

Introduction: Neurodevelopmental disorders, such as autism and intellectual disability, arise when the brain does not develop properly. These conditions can affect learning, behaviour, and social interactions, and together they impact millions of individuals and families worldwide. Many neurodevelopmental disorders are caused by changes in genes that control how DNA is organized and used in cells. This process, known as gene regulation, ensures that the right genes are turned on or off at the correct time during development. When this regulation is disrupted, brain development can be altered.
One gene involved in this process is SRCAP, which plays a key role in controlling how genes are activated during early brain development. Mutations in SRCAP are linked to different neurodevelopmental disorders. However, an important and unresolved question is why some mutations lead to severe physical and cognitive symptoms, while others mainly affect behaviour. Understanding this difference is essential for improving diagnosis and treatment.

Objectives: This project aims to understand how different types of SRCAP mutations disrupt early brain development. Rather than treating all mutations as equivalent, we will investigate whether distinct classes of mutations interfere with gene regulation in different ways.
By identifying how specific mutations alter gene activity during development, we aim to explain why patients with SRCAP mutations can experience a wide range of symptoms. Ultimately, this work will help connect genetic changes to their biological and clinical consequences.

Outline of Research: To address these questions, we will use human stem cells derived from patients carrying SRCAP mutations. These cells can be grown in the laboratory and guided to become brain cells, allowing us to model the earliest stages of human brain development in a controlled and reproducible way. In addition, we will generate three-dimensional brain-like structures, known as organoids, which more closely mimic the organization and diversity of the developing human brain.
Using these models, we will examine how SRCAP mutations affect the way DNA is organized and how genes are turned on and off over time. We will track these changes across different stages of brain cell development to understand when and how disruptions occur. We will also assess how these molecular changes influence the types of brain cells that are produced, their proportions, and their developmental trajectories.
A key strength of this project is the direct comparison of different classes of SRCAP mutations. By studying these mutations side by side in the same experimental system, we will determine whether they disrupt gene regulation through distinct biological mechanisms. This approach will allow us to move beyond simply identifying defects, and instead uncover how different mutations lead to different developmental outcomes.

Projected Benefits: This research will provide new insight into how genetic changes disrupt brain development at both the molecular and cellular levels. By linking specific mutations to their effects on gene regulation and brain cell development, this work will help explain why patients with SRCAP mutations can present with very different symptoms.
In the long term, these findings may improve how neurodevelopmental disorders are classified and diagnosed, moving toward approaches that consider the underlying biological mechanisms rather than just clinical symptoms. This could help identify more precise patient subgroups and support the development of targeted therapeutic strategies aimed at restoring normal gene regulation during development.
More broadly, this project will establish a human model system for studying how gene regulation controls brain development. Because disruptions in gene regulation are a common feature of many neurodevelopmental disorders, the knowledge gained from this work will have relevance beyond SRCAP, contributing to a better understanding of brain development and disease.

Hippocampal Mechanisms of Associative Learning Deficits in Schizophrenia

Dr. Jiannis Taxidis
The Hospital for Sick Children
Toronto, ON

Introduction: Schizophrenia is a serious psychiatric illness affecting approximately 1% of the population worldwide. While it is best known for symptoms such as hallucinations and delusions, many patients also suffer from cognitive problems that profoundly affect their ability to function in daily life. One important but poorly understood cognitive problem is associative learning: the ability to learn that a cue in the environment predicts a meaningful outcome. Patients struggle to learn which cues genuinely predict reward or other significant events, while assigning too much importance to cues that are irrelevant or neutral. This imbalance is thought to contribute directly to psychotic symptoms and is not treated by current medications.
A particularly important form of associative learning is linking a cue to an outcome that follows after a brief delay. This ability requires the brain to maintain information about the cue across the delay and connect it to the later event. Evidence from both patients and animal studies points to the hippocampus, a brain region critical for memory, as a key structure for this type of learning. How hippocampal dysfunction in schizophrenia disrupts this process, however, remains unknown.

Objective: Our objective is to determine how hippocampal dysfunction in schizophrenia impairs the ability to link a sensory cue to a delayed reward, and to identify the circuit mechanisms responsible. We will test the hypothesis that abnormal hippocampal activity fails to form stable representations of cues and to link them with outcomes across short delays. Specifically, we will ask whether cue-related and reward-expectation signals in the hippocampus are unstable in schizophrenia, whether this instability is driven by abnormal inhibitory control, and whether restoring normal hippocampal activity can improve associative learning.

Outline of Research: We will use a well-established genetic mouse model, called Df(16)A, carrying a deletion equivalent to the human 22q11.2 deletion, one of the strongest known single genetic risk factors for schizophrenia. These mice already show brain and behavioural abnormalities closely relevant to the disorder, particularly in the hippocampus. We will train these mice, alongside healthy controls, on a behavioural task in which one odour predicts a small water reward after a short delay, while another odour does not. Mice must learn which odour predicts reward and withhold responding to the other. This task is specifically designed to isolate the brain’s ability to bridge a cue and an outcome across time.
We will use multiple state-of-the-art neuronal imaging and manipulation methods to study hippocampal circuits throughout learning this task. First, we will record activity from thousands of hippocampal neurons across days of training to test whether Df(16)A mice show unstable neuronal responses during odour cues or during the delay preceding the expected reward. Second, we will record the activation of a specific class of inhibitory neurons with exceptional temporal precision, to determine whether abnormal inhibition disrupts hippocampal representations during learning. Third, we will selectively reactivate specific neurons to restore hippocampal activity patterns and test whether this improves learning. Together, this three-step design moves from identifying the abnormality, to finding its cause, to testing a potential correction.

Projected benefits and application of findings:
This project directly addresses a disabling cognitive symptom of schizophrenia: the inability to reliably learn which cues in the environment are meaningful. By combining a clinically relevant behavioural task with the most advanced tools in modern neuroscience, we will identify the specific hippocampal activity patterns and circuit mechanisms that go awry in this genetic model of the disorder. Our findings will establish a powerful new framework for studying schizophrenia at the level of defined neural circuits rather than symptoms alone. They could guide the development of future circuit-based targeted treatments, addressing a dimension of schizophrenia that current medications leave almost entirely untouched.