A Brief Description of Currently Funded Research Grants 2025 – 2026

Investigating inhibitory function in the auditory midbrain to unravel sound sensitivity in autism

Dr. Ning Chen
University of Calgary
Calgary, AB

Co-applicants: Dr. Jun Yan, University of Calgary and Dr. Kartikeya Murari, University of Calgary

Introduction: Autism spectrum disorder (autism) is a neurodevelopmental condition for which there are currently no broadly effective approaches to reduce the negative impact on the affected individuals. Atypical sensory response is common in autism, with sound sensitivity being one of the most prevalent and disabling features. In one of the very first description of autism, children `petrified of the vacuum cleaner’ were a common observation in the group. Since then, it has been established that autistic individuals often perceive common sounds as painfully loud, leading to distress and safety concerns. Meta-analyses estimate approximately 60.58% of individuals with autism exhibit signs of sound sensitivity at some point in their lives, which is much higher than being reported in the general population. Consistent with this, up to 60% of children seeking specialist care for sound sensitivity have autism diagnoses. This sensitivity significantly impairs participation in educational, social, and workplace activities, and persisting from childhood into adulthood. Despite its prevalence and impact, there are currently no effective approaches for sound sensitivity in autism, due to lack of understanding of its neurobiological basis.
It has been proposed that imbalances between excitatory (E) and inhibitory (I) function in the brain may drive autistic phenotypes. Yet, whether E/I imbalance occurs in the auditory system and contributes to sound sensitivity in autism remains largely unclear. Our team discovered that in the midbrain auditory center of a well-established mouse model of autism, response profiles to sound stimuli, which were designed to probe the underlying molecular and cellular function, were altered, and the observations suggested reduced inhibitory function.
Objectives: We will test the hypothesis that reduced specific inhibitory function in the auditory midbrain contributes to auditory hypersensitivity in this autism model, using an integrative approach that incorporates in vivo electrophysiology, pharmacological manipulation, behavioural assays, and imaging methods to provide novel and complementary insights from different angles.

Outline of research: We will quantify neuronal firing and adaptation in response to sound stimulation using electrophysiological recording, and compare the autism model with the control mice. We will pharmacologically modulate neurotransmission mediated by GABA, the main inhibitory neurotransmitter in the brain, and observe the effects on response profiles. We will also test the effects by the pharmacological modulators of GABA on behavioural responses to auditory stimuli that model sound sensitivity in autism. We will further measure population level activities from inhibitory and excitatory neurons in response to sound stimulation.

Project benefits and application of findings: “Headphones are my armor against the world”: many autistic people currently rely on headphones to block out distressing noises or avoid loud environments altogether. Yet, despite temporary relief, these practices can further aggravate social isolation. Our research will provide new knowledge on the underlying reasons for sound sensitivity in autism by identifying the critical brain regions as well as the molecular pathways and specific cell types, and could lead to more options for managing this prevalent and challenging sensory issue. This could potentially lead to improving quality of life and expanding opportunities for autistic individuals to engage in various activities.

Distributed metacognitive representations in rodent models of ASD

Dr. Paul Masset
The Royal Institution for the Advancement of Learning / McGill University
Quebec, QC

Introduction: Whenever we take a decision, we instinctively develop a sense of confidence in our decision. We use this sense of confidence, also termed metacognition (the ability to think about our thoughts and actions), to guide future behavior. Recent work has developed behavioral tasks to study this sense of confidence in non-verbal subjects including rodents. These works have identified key regions in the prefrontal cortex in which the activity of single neurons carries an abstract representation of this confidence signal. However, many questions remain about how the circuits of the brain build up these representations from sensory perception and how these representations are changed with psychopathologies and developmental disorders such as autism (ASD).

Objectives: Our objective is to develop a new approach to study how sensory and cognitive information is integrated to construct abstract cognitive representations such as decision confidence. This new approach will allow us to compare and differentiate distributed processing across brain areas and how it is changed in rodent models of ASD.

Outline of research: We will refine state-of-the-art behavioral tasks in rats and use cutting-edge electrophysiology techniques to simultaneously record hundreds of neurons from multiple brains areas from rats performing complex decision-making tasks. We will compare these distributed representations across wild type rats and two ASD models.
Aim 1: Develop a task to measure confidence in rats performing multi-sensory decision making
In order to measure confidence in a non-verbal subject, we need a behavioral task in which we can directly relate a behavioral measurement to the sense of confidence. We will build on previous work to design a new version of a task measuring confidence in decisions based on ambiguous olfactory, auditory, or multi-sensory information. Confidence will be assessed through the rat’s willingness to wait for a reward, which has been previously shown to correspond to a signature of decision confidence. Introducing multi-sensory stimuli into this paradigm will allow us to quantify at the single subject level how well animals can combine sensory streams to guide both choice and confidence behavior.
Aim 2: Develop a computational pipeline to compare neural representations of confidence within and across brain areas.
To uncover the underlying neural computations, we will record neural activity while rats are performing the task. We will use NeuroPixel probes to simultaneously record hundreds of identified single neurons from auditory cortex, piriform cortex (the primary olfactory area), posterior parietal cortex (implicated in sensory based decision-making), and orbitofrontal cortex (known to have single neuron abstract representations of confidence). We will develop a pipeline to compare neural representations both at the single neuron and at the population levels using machine learning tools that combine dimensionality reduction and clustering methods. This will allow us to understand how neural information present in sensory cortices is combined into more abstract representations in higher order areas.
Aim 3: Compare behavioral and neural representations across ASD models.
Altered sensory processing is a known phenotype of ASD. Our task measures several aspects of sensory perception, including auditory and olfactory discrimination and the ability to perform cue combination to guide behavior as well as the capacity to integrate sensory information into a confidence estimate. We will use the behavioral task and computational tools to compare behavior and neural representations in two rat models of ASD developed by the Simons Foundation Autism Research Initiative. We will use the Cntnap2 and the Nrxn1 knockout lines as these two genes have been implicated in sensory deficits in humans and animal models. We will use balanced cohorts of young and adult rats, both female and male, to measure how age and sex affects behavior and neural representations in ASD models.

Project benefits: The project would transform our understanding of confidence representations across brain areas and how it is altered in ASD. Going beyond simple sensory perception differences but understating how the sensory information is transformed into cognitive variables such as confidence would potentially open the way to develop novel behavioral therapies to train these associations in patients.

Investigating a potential therapeutic target for TDP-43 proteinopathies

Dr. Silvia Pozzi
Université Laval
Québec, QC

Introduction: Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) belongs to a neurodegenerative disease continuum characterized by motor and cognitive impairments1. A common hallmark of ALS/FTD is TDP-43 proteinopathy – the cytoplasmic accumulation of the protein TDP-43 – which induces neuronal death, and the activation of glial cells, i.e. neuroinflammation. Previous studies showed that TDP-43 interacts with the nuclear factor kappa B (NF-kB). Activation of NF-kB leads to TDP-43 proteinopathy, whereas its inhibition reduces TDP-43 proteinopathy as well as cognitive and motor impairments in mice.
In a pure ALS mouse model, with motor-impairments-only and no TDP-43 proteinopathy, we identified the PPIA/EMMPRIN interaction as a crucial NF-kB inducer in cells. EMMPRIN is a multi-functional protein, expressed by different cell types, that is activated by the extracellular protein PPIA8,9. Activation of EMMPRIN in motoneurons leads to their death, whereas PPIA-mediated EMMPRIN activation in astrocytes, the most abundant glial cell population, prompts them toward a pro-inflammatory phenotype7. An anti-EMMPRIN antibody reverts the activated phenotype of astrocytes, and reduces motoneuronal death and neuroinflammation in ALS mice, increasing their survival and slowing disease progression.
Interestingly, we recently found that PPIA is abundant in the cerebrospinal fluid of a mouse model of ALS/FTD, that presents motor and cognitive impairments and TDP-43 proteinopathy. In these mice, we also found increased levels of EMMPRIN in the spinal cord, and a specific localization with neurons and astrocytes.
Our observations thus position the PPIA/EMMPRIN pathway as a possible mediator of NF-kB activation also in TDP-43 proteinopathy conditions. However, the role of this pathway in TDP-43 proteinopathy, neurotoxicity and glial activation has never been investigated, nor has the possibility that its inhibition may have beneficial effects on motor and cognitive impairments due to TDP-43 proteinopathy.

Objectives: Our goal is to demonstrate that the activation of the PPIA/EMMPRIN/NF-kB pathway contributes to TDP-43 proteinopathy and can become a novel therapeutic target for cognitive and motor impairments associated with TDP-43 proteinopathy.
To fulfill our goal, we will:
Aim 1: Demonstrate that the activation of the pathway exacerbates TDP-43 proteinopathy in neurons and astrocytes.
Aim 2: Validate the therapeutic potential of inhibiting EMMPRIN in an ALS/FTD mouse model.

Outline of Research: For this project we will use a mouse model, namely the transgenic TDP-43^A315T mice, that shows TDP-43 proteinopathy, neuroinflammation, motor and cognitive impairments as ALS/FTD patients. We will first test the effect of EMMPRIN activation or inhibition on TDP-43 proteinopathy, neuronal toxicity and astrocytic activation in mouse-derived primary cells. Then, we will infuse the anti-EMMPRIN antibody in TDP-43A315T mice and evaluate its therapeutic potential in reducing cognitive and motor impairments as well as neurodegeneration and neuroinflammation associated with ALS/FTD.
Projected Benefits and Application of Findings: We expect to demonstrate that the PPIA/EMMPRIN/NF-kB pathway exacerbates TDP-43 proteinopathy, and we aim at providing evidence that EMMPRIN inhibition can reduce cognitive and motor impairments, as well as neuronal death and neuroinflammation in a mouse model of ALS/FTD.
Our project will be performed in a well-known mouse model overexpressing the human TDP-43^A315T mutation, representing the first step to understand the role of the pathway in TDP-43 proteinopathy. Future perspectives include its investigation in other conditions characterized by TDP-43 proteinopathy. This pathological event indeed is not exclusive to ALS/FTD but it is present also in mouse models and patients with Alzheimer’s diseases (AD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and vascular dementia.
Our project has therefore the potential to unravel the role of a yet unexplored molecular mechanism involved in different pathologies interested by TDP-43 proteinopathy. In doing so, it will provide the first evidence on the therapeutic use of an antibody-based approach to reduce cognitive and motor impairments in a broad spectrum of neurodegenerative conditions.

Experimental Medicines Targeting Sensory Adaptation in Mouse Models of Autism

Dr. Tevye Stachniak
Memorial University of Newfoundland
St. John’s, NL

Introduction: A disruption to the balance of excitation and inhibition in the brain has been proposed to underlie autism. The proposed research focuses on the role of one type of inhibitory interneuron that expresses the marker protein, somatostatin. A pair of synaptic proteins, Elfn1 and mGluR7, create the characteristic properties of this interneuron population. These properties are critical for the feedback inhibition produced by somatostatin interneurons when activity is elevated and are thus critical for the balance of excitation and inhibition in the brain. Correspondingly, loss of function of these proteins results in hyperexcitability and brain disorders, both in mouse models and in humans (epilepsy, ADHD, and autism). We have also found that loss of Elfn1 produces deficits in sensory adaptation (a reduction in neural responses to a repeated sensory stimulus) in mice. Sensory adaptation deficits are present in autism patients, which may contribute to their sensory hypersensitivity and risk of epilepsy.

Objectives: The proposal links the physiology of somatostatin interneurons to an electrophysiological signature present in autism patients. It will further examine the ability of benzodiazepines (antiepileptic drugs that enhance brain inhibition) to improve sensory adaptation deficits and suppress epileptic seizures in mouse models. We will preferentially enhance the activity of somatostatin interneurons using selective pharmacology to enhance inhibitory GABA A receptors that contain the alpha5 subunit, which are present at somatostatin neuron synapses. We expect that these compounds will reduce hyperexcitability and correct the altered electrophysiological signature. Specifically, we will evaluate the hyperexcitability arising during sensory stimulation due to deficits in sensory adaptation.

Outline of Research: Previous work and preliminary findings indicate that loss of Elfn1 results in both sensory adaptation deficits and increased spread of cortical excitation in mouse cortex. We will confirm these findings in another mouse model that has a point mutation identified in autism patients, mGluR7(I154T). We will establish whether benzodiazepines and other antiepileptics alter sensory adaptation in wildtype, Elfn1 knockout (KO) or mGluR7(I154T) mice. We will also evaluate the effects of these compounds on sensory evoked seizures in these mouse lines.

Projected Benefits: The proposal examines a neural circuit mechanism that can contribute to both epilepsy and autism symptoms, including sensory hypersensitivity. Dysfunction in this circuit may also contribute to sensory adaptation deficits. Using sensory adaptation as a hallmark of circuit dysfunction could help segregate autism patient populations based on the biology that underlies their individual condition, with implications for responsiveness to benzodiazepines or other potential therapies. By exploring responses to pharmacology for both sensory adaptation and epilepsy, we hope to gain a mechanistic understanding of the disruption of a neural circuit that is relevant to autism. In doing so, this work will also allow me to launch my new lab in autism research with support for both a basic and a translational scientific program, which will open a wide range of opportunities for further development. Finally, this work has the potential to successfully match drug treatments to responsive patient populations based on the patient’s biology.

Exploring a-synuclein heterogeneity in Multiple System Atrophy: A step towards precision medicine in synucleinopathies

Dr. Naomi Visanji
University of Toronto
Toronto, ON

Introduction: Multiple system atrophy (MSA) is a fatal disease involving deposition of alpha synuclein (aSyn) in the brain. MSA symptoms vary significantly. There are likely many subtypes of the disease that differ by age of onset, rate of progression, pattern of aSyn deposition, and severity of motor and cognitive symptoms. This makes MSA diagnosis difficult and creates a challenge for the future use of targeted therapies.

A critical unknown in the basic biology of MSA is understanding how misfolding of the same protein (aSyn) is associated with such a variable disease.

aSyn is unstable and misfolds adopting several different structures (strains). When misfolded, aSyn seeds the misfolding of other aSyn proteins, causing an exponential increase in misfolded aSyn, aggregation and deposition. We believe different strains of aSyn might account for the different subtypes of MSA. To study this, we developed an assay to measure the seeding capacity of aSyn in MSA and other diseases involving aggregation of aSyn called Lewy Body Diseases (LBD). Using our aSyn seeding amplification assay (SAA) we found 10-fold differences in the seeding capacity of aSyn between different MSA patients. We also found comparable differences in the seeding activity of aSyn in LBD. We found that the structure of aSyn likely differs between high seeder (HS) and low seeder (LS) cases, and in LBD, we identified many biological pathways that differed between HS and LS cases.

Objective: Our findings suggest that differences in aSyn seeding activity might contribute to diversity in MSA. However, as these studies are in post-mortem brains, we cannot conclude if aSyn seeding activity is a cause or consequence of MSA diversity. To address this requires studies in living animal models.

Our objective is to test the hypothesis that diversity in the seeding activity of aSyn is a cause of clinical and pathological heterogeneity in MSA.

We will explore this hypothesis with the following specific aims:
Aim 1: To determine if brain extracts of MSA patients characterized as “high seeders” exhibit distinct strain-like properties compared to aSyn extracted from “low seeders”.
Aim 2: To investigate whether aSyn is the primary determinant of variation in MSA.
Aim 3: To uncover molecular pathways involved in the strain-specific effects of MSA aSyn.

Outline of Research: We will use transgenic mice (M83) commonly used to study aSyn seeding by injecting their brains with extracts of human MSA brain. One female and one male MSA case with high seeding activity, one female and one male with low seeding activity and one female and one male with no disease will be used. Extracts will be injected into the brains of M83 mice and their locomotor behaviour, as well signs of neurological illness will be monitored.
Aim 1: We will measure the time for animals to develop neurological illness that constitutes a humane endpoint. At endpoint, brains will be removed for analysis. We hypothesize that animals injected with HS-MSA extracts will develop neurological illness before animals injected with LS-MSA or control extracts.
Aim 2: To study if seeding activity of aSyn alone is sufficient to drive differences we will prepare extracts from HS-MSA, LS-MSA and control brains where the aSyn has been removed using a method called immunoprecipitation. The same studies in Aim 1 will be conducted. We hypothesize that animals treated with immunodepleted samples will not develop any neurological illness nor any aSyn deposition in their brains.
Aim 3: We will perform proteomics in mouse brains treated with HS-MSA, LS-MSA and control brain extracts. As we saw in our previous study in human LBD brains, we hypothesize this will reveal molecular pathways that differ between HS and LS MSA cases.

Projected benefits and application of findings:
This study aims to offer vital insight into the biological processes through which variations in aSyn seeding activity may contribute to the diverse manifestations of MSA. The pathways identified will shed light on potential molecular subtypes of MSA and represent a step towards the development of Precision Medicine in MSA.