Canada

Pain synesthesia is an extreme form of empathy where an individual can personally feel the pain of another within their own body. The experience of pain synesthesia has been noted in populations who have experienced physical trauma (acquired synesthesia). Pain synesthetes typically experience pain in a pre-sensitized region of the body (i.e., a previously broken leg), when observing or imagining others in pain. However, the influence of social factors, such as perceived social support and adverse childhood experiences have not been explored in pain synesthesia. In this experiment, 137 healthy undergraduate students were asked to complete a series of questionnaires to assess various social and psychological factors along with past pain experiences (e.g., Multidimensional Scale of Perceived Social Support, Post-Traumatic Stress Diagnostic Scale, West Haven-Yale Multidimensional Pain Inventory, etc.). Participants were then shown a series of coloured photographs displaying right hands and right feet in painful versus non-painful scenarios. Participants were asked to rate each image for perceived pain experienced by the scenario and whether the images triggered synesthetic pain. The results will help us understand whether social factors influence individual susceptibility to synesthetic pain and whether viewing still images of hands and feet trigger synesthetic pain in pre-sensitized regions.

CAN-ACN 2021

Pain synesthesia as a trigger for pain in pre-sensitized regions of healthy undergraduates

synaesthesia

empathy

pain

Colleagues and Friends:

I am very happy to welcome you to the 14th annual Canadian Neuroscience Meeting, and to the first virtual edition of our meeting. I want to highlight the important work the CAN meeting chair, **Roger Thompson** and co-chair, **Alyson Fournier**, did to put together the great program we are offering this year. Moving to a virtual format required a complete re-design of the program, and both Roger and Alyson did a splendid job in providing us with an appealing and well adapted program for our first virtual event. I wish to thank them for this very important effort.

Highlights of this year’s scientific meeting include invited speakers **Michael Hausser, Franck Polleux, Gwyneth Card, Magdalena Götz**and Brain Prize winner **Huda Zoghbi**. Plenary and parallel symposia, proposed by our members complete our diverse [scientific program.](https://can-acn.org/meeting-2021/program-2021/)

The 2021 Advocacy session, chaired and organized by CAN advocacy committee chair **Karun Singh**, will feature a special lecture and question period with Member of Parliament and past Science Minister **Kirsty Duncan**. This will be followed by a short overview of CAN’s advocacy activities over the last year. We invite you to participate in this session for insight from Dr. Duncan on the workings of Parliament Hill, and to learn more about what CAN has been doing to promote neuroscience research in Canada.

We are also excited to host **Lisa Willis** in the Equity Diversity and Inclusion session, organized by EDI committee chair **Jibran Khokhar**.

A special highlight of our meeting will be the lectures by award-winning young neuroscientists. We are please to host the CAN 2020 Young Investigator Award winner **Mihaela Iordanova**, and CAN 2021 Young Investigator Award winners **Aaron Phillips** and **Tabrez Siddiqui**. Highlights will also include presentation by the top three winners of the CAN-CIHR-INMHA Brain Star Award winners, **Claire Gizowski, Nuria Daviu Abant** and **Lukas Tamayo-Orrego**.

Independently organized satellite symposia complement and complete this exciting program, check them out here: https://can-acn.org/meeting-2021/2021-satellite-symposia/

Some of the most engaging sessions are always the poster sessions featuring the work of our trainees, so make sure to log in to Gather Town during the poster sessions to chat with the presenters.
We hope you enjoy this program, and look forward to welcoming you, virtually.

Shernaz Bamji

President of the Canadian Association for Neuroscience

![](https://assets.underline.io/uploads/markdown_image/1/image/b9aea25343a87d5aac3b9367dc780974.jpg)



Please head to https://can-acn.org/meeting-2021/registration-2021/ to register. 

14th Canadian Neuroscience Meeting from August 23rd-25th

poster

Stroke constitutes a major cause of death and disability of the adult population in the industrialized world. Ischemic stroke (IS), which occurs as a result of a sudden obstruction within a cerebral artery due to an embolus or thrombus, accounts for the majority of cases. After IS, it has been observed a deactivation of the Canonical Wnt pathway. Interestingly, DKK1 levels are elevated in IS brain in patients and animals' models. DKK1 inhibits the canonical Wnt pathway by preventing Wnt ligands from binding the receptor complex formed by Frizzled (Fzd) and low-density lipoprotein receptor-related protein-5/6 (LRP5/6). Wnt ligands binding to Fzd/LRP5/6 stabilizes β-catenin in the cytosol and stimulates its subsequent translocation to the nucleus to regulate transcription of target genes implicated in a wide range of physiological processes in the brain. Our study aimed to elucidate DKK1 role following IS. For this purpose, TOPGAL-iDKK1, which induce DKK1 by doxycycline administration and C57BL/6 mice were used. C57BL/6 mice were treated intraperitoneally with a DKK1 inhibitor, WAY262611 (5 and 10 mg/kg 24h after IS and every 2 days until sacrifice at 1 week) following middle cerebral artery occlusion (MCAO) which simulate IS. WAY262611 administration had reduced infarct volume and edema compared to the control mice as well as improved sensorimotor functions in a battery of behavioral tests whereas DKK1 induction impaired them. In addition, WAY262611 attenuate neuronal degeneration in treated-mice brain whereas DKK1 induction had the opposite effect. Taken together, our data suggest that pharmacological inhibition of DKK1 could be an elegant therapeutic target after IS.

Dickkopf-1 induction impairs short- and long-term structural and functional recovery after ischemic stroke

Schwann cells (SCs) support peripheral nerve regeneration, but the efficacy of this regeneration is limited. Introducing exogenous SCs to the site of peripheral nerve injury is an ongoing avenue of investigation as a cellular therapy to enhance regeneration. Approaches that utilize an accessible source of a patient's own cells would greatly facilitate clinical translation. Previous work demonstrates that skin-derived SCs are able to promote axonal growth and remyelination in murine models of nerve injury, however, it is not clear whether skin-derived and nerve-derived SC are functionally equivalent. To this end, we isolated SCs from small skin samples and then subjected them to high resolution single-cell mRNA sequencing (scRNA-seq) followed by battery of in vitro and in vivo assays. Our genomic analyses revealed close to 95% similarity between skin and nerve SCs at differential gene level while gene network analysis showed mostly overlapping profiles between the two cell types with the exception of immune regulatory family (eg. IRF) upregulated in skin SCs. In vitro assays revealed similarity in proliferation, migration and expression of epidermal growth factor between the two cell types, which is in alignment with our genomic analysis. However, we observed subtle difference such as higher expression of VEGF and collagen content in skin SCs and higher expression of TGF-alpha in nerve SC. Overall, our results showed that skin and nerve Schwann cells share mostly identical properties with subtle differences, suggesting that skin may be a viable source of Schwann cells to improve nerve repair.

Human skin and nerve derived Schwann cells exhibit subtle transcriptomic and functional differences

While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in Parkinson's disease (PD), early causal pathogenic events are not clear. Converging findings point at endolysosomal (EL) system dysfunction as the early mechanism and key pathway affected in PD. However, the exact mechanism by which alpha-synuclein (aSyn) aggregates, also called Lewy Bodies (LBs), disrupt the EL system remain elusive. To answer this question, our group created a new optogenetic-based model of PD that allows for the real-time induction of aSyn aggregates under the blue light control, mimicking all cardinal LBs features. This Light-Inducible Protein Aggregation (LIPA) system allows us to explore unsolved questions related to early interactions between the EL system, LBs and PD pathogenesis. Using the LIPA inside living cells, we were able to study the direct impact of our aggregates on vesicle homeostasis by investigating the interactions between our LIPA aggregates and the EL system using the super-resolution microscopy STED in combination with transmission electron microscopy (TEM). STED microscopy offered us a better understanding of the interactions between LBs and trafficking vesicles showing early interactions with vesicles such as the early endosomes (EEA-1) but also the degradation vesicles (LAMP1/2A) characterized by multiple co-localization with those markers. Interestingly, those vesicles were differentially interacting with aSyn aggregates overtime. The TEM realized on our purified aggregates, revealed that they are composed of multiple vesicles and shown distorted organelles. Those results allowed us to better understand how aSyn aggregates impact the trafficking of the vesicles inside the cell overtime.

Unveiling the role of the endolysosomal system in the pathogenesis of Parkinson's disease

ncreasing evidence suggest that phosphorylation plays an important role in the aggregation and toxicity of amyloid beta (Aβ) resulting from the amyloid precursor protein (APP) cleavage, and Tau, the major neuropathological hallmarks of Alzheimer´s disease (AD). Our laboratory has reported an accumulation of Polo-like kinase 2 (PLK2) in the brains of AD patients. Thus, the aberrant accumulation and activity of PLK2 may contribute to AD. Our goal is focused on examining the effect of PLK2 pharmacological inhibition on APP and Tau accumulation and toxicity in cells and transgenic mouse models of AD. HEK293T cells were used to examine the effect of PLK2 and its inhibition on APP and Tau protein levels by immunoblotting. In vivo, behavioral analysis incorporated evaluation of different learning and memory tasks. Biochemical and histological analysis of AD neuropathology (APP, Tau, their phosphorylated forms, and synaptic dysfunction) were performed using immunoblotting and immunohistochemistry. We observed that PLK2 overexpression decreases APP and Tau levels in a PLK2-concentration dependent manner, counteracted by PLK2 pharmacological inhibition in cells. In vivo, our results showed cognitive decline and AD hallmarks in symptomatic mice, as well as a decrease in some pathological aspects upon PLK2 inhibition in a sex-dependent manner, both at the behavioral and molecular levels. Overall, this project will shed light onto novel mechanisms by which phosphorylation regulates Tau and APP aggregation and toxicity, providing a novel therapeutic target for AD and related dementia.

Pharmacological inhibition of Polo-like kinase 2 modulates Alzheimer's disease pathology in a sex-dependent manner

The microtubule-associated tau protein is essential to the stabilization of neuronal microtubule networks and impaired function has been associated with disease. Indeed, tau hyperphosphorylation and conformational abnormalities are hallmarks of tauopathies - a subclass of neurodegenerative diseases characterized by the deposition of abnormal tau proteins in brain tissue. Accumulating evidence has suggested that tau contributes to Huntington's disease (HD) pathology - a neurodegenerative disease caused by the formation of a mutant huntingtin protein (mHtt) and characterized by motor, psychiatric and cognitive deficits. Specifically, studies have reported that (i) tau aggregates form within several brain structures in HD patients, (ii) in a transgenic HD mouse model, behaviors were improved with a tau deletion and therefore that (iii) this disease could be a secondary tauopathy. HYPOTHESIS. Tau protein could aggravate and/or accelerate the onset of behavioral and neuropathological phenotype of HD. Reducing tau expression will improve behavioral phenotype of the zQ175 mouse model of HD. METHODS. zQ175 mice were crossed with tau knockout (mTKO) mice and behavioural tests were performed at 3, 6, 9 and 12 months to assess the evolution of anxiety, cognitive and motor deficits in relation to the presence or absence of tau. RESULTS. Our preliminary results suggest that loss of tau induces a worsening of behaviors in HD mice. To understand our results, we targeted a hypothesis: mHtt can block the compensatory mechanism of tau deletion in HD mice. CONCLUSION. Based on these early findings, tau appears to play an essential role in HD. This project will contribute to a better understanding of the relationships between tau, mHtt and the development of deficits in HD.

Investigating the impact of tau deletion in a Huntington's disease mouse model

Major Depressive Disorder (MDD) is one of the leading causes of disability worldwide. MicroRNA's (miRNA) are well known epigenetic regulators that are disrupted in MDD and are packaged into extracellular vesicles (EVs). EVs have emerged as means of intercellular communication, transferring miRNA, as well as other molecules such as proteins between cells, altering cell function in recipients. Therefore, we hypothesize that EV cargo from the anterior cingulate cortex will have a disease specific profile that could mediate disease development in MDD subjects compared to healthy controls. EVs were isolated from post-mortem human brain tissue using size exclusion chromatography. The quality was assessed by western blots and transmission electron microscopy (TEM). RNA was extracted and sequenced using the Illumina Platform. Proteins were also extracted and profiled using LC-MS/MS. Western blots showed no contamination with cellular debris, along with enrichment of the exosomal marker CD9. TEM images showed vesicles mostly between 30 and 200 nm in size. Preliminary differential analyses revealed that both the miRNA and proteomic profiles of the EVs are dysregulated in MDD. This will be the first study to profile brain-derived EV miRNA and protein in the context of depression. Future studies will be needed to determine the effect of the dysregulated EV cargo in MDD. This could provide novel mechanistic insights into the potential role of EVs in the pathophysiology of MDD, which could be a starting point for the development of targeted therapeutic strategies and prevention measures.

Extracellular vesicles: a window into the etiology of major depressive disorder

Lipid dysregulation is a core component of neurodegeneration in Alzheimer's Disease (AD). Gangliosides are members of the glycosphingolipid family enriched in the central nervous system. The healthy brain maintains a homeostatic balance of gangliosides. GM1, the most abundant ganglioside in the adult brain, is enriched within neuronal membrane rafts and exerts neuroprotective effects. In contrast, accumulation of GM2 and GM3, degradative by-products of GM1, can directly cause neurodegeneration, suggesting that ganglioside dysregulation is a key contributor in AD pathology. Our current gap in knowledge is whether ganglioside dysregulation is worsened by, or contributes, to beta-amyloid (Aβ) accumulation in the brain. Thus, anatomical-specific distributions of gangliosides were investigated in the amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mouse model of AD that develops age-dependent Aβ plaques. Hypothesis: Aβ accumulation leads to increased levels of simple gangliosides GM2 and GM3 contributing to neurodegeneration in the AD brain. Methods: Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was performed on brains of wildtype and transgenic mice aged 4, 8, 12, and 18 months to quantify ganglioside distribution across anatomical regions. Results: Our data demonstrate an age-dependent increase in simple gangliosides that are exacerbated in the Tg mice. Aged Tg mice showed higher levels of simple gangliosides as compared to Wt in the cortex and hippocampus, brain regions of initial amyloid deposition. Significance: This work identifies a potential interplay between Aβ and simple gangliosides in driving neurodegeneration, highlighting a rationale for evaluating glycosphingolipid modifying approaches in AD treatment.

Mass spectrometry imaging of gangliosides in Alzheimer's Disease

The tau protein implicated in microtubule stabilization exists in six isoforms resulting of alternative splicing of the tau gene. In several conditions collectively referred to as tauopathies, tau becomes hyperphosphorylated and accumulates into various pathological forms. It has been recently reported that the expression of 4R tau isoforms is increased in patients with Huntington's disease (HD), suggesting that this disorder may be a secondary tauopathy. We hypothesize that the introduction of tau to cell and animal models of HD leads to an exacerbation of intracellular huntingtin (HTT) aggregation with consequences on cellular and behavioral functions. Human synthetic recombinant tau is introduced to an HD neuronal cell line (StHdh cells) and various aspects of toxicity are assessed. The uptake of tau is observed by immunocytochemistry, metabolic activity using an MTT assay and HTT aggregation is measured by filter retardation assays. To evaluate the influence of tau on behavioral impairments, 3-month old wild-type and HD (zQ175) mice received intracerebral stereotaxic injections of tau into the hippocampus and prefrontal cortex and several behavioral tests were performed. Low dose tau fibrils significantly decrease the metabolic activity of healthy and HD cells while the 3R forms of tau increase HTT aggregation in the HD cells. In vivo, 4R monomers and 3R fibrils exacerbate behavioral phenotypes in WT mice notably anxiety-like behavior; whereas 4R monomers tend to worsen cognition in zQ175 mice. Although preliminary, tau seems to alter cellular features associated to HD and worsen behavioral phenotypes in mice. Ongoing experiments will allow us to link the cellular alterations to the behavioral aspects observed, shedding light on the role of tau in this disease.

Investigating the contribution of tau to Huntington's disease pathology

Many pathological changes associated with epilepsy can be recast as decreases in cell and circuit heterogeneity. We hypothesize that epileptogenesis can be recontextualized as a process where reduced cellular heterogeneity renders neural circuits less resilient to seizure-like transitions, for which we provide experimental, computational, and mathematical support. Patch clamp recordings on human cortical pyramidal neurons from resected epileptogenic and non-epileptogenic tissue revealed a significant decrease in heterogeneity in intrinsic neuronal excitability amongst epileptogenic neurons. In a computational spiking excitatory-inhibitory (E-I) cortical neural network, networks with epileptogenic heterogeneity levels were uniquely vulnerable to ictogenesis-like sudden transitions into a synchronous and hyper-active state. These dynamics were explained via mathematical analysis of the corresponding mean-field system, revealing a unique bifurcation structure in networks with low heterogeneity. Interestingly, experiments also revealed a surprising decrease in single-cell excitability, quantified via the frequency-current (FI) relationship, in epileptogenic neurons, which can be explained by the mathematical consequences of decreased heterogeneity on input-output relationships. This interdisciplinary study represents the first investigation of the role of neural heterogeneity in epilepsy, experimentally identifying decreased heterogeneity associated with the disease and computationally and mathematically connecting it to the onset of seizure-like dynamics.

Lost neural heterogeneity in human epilepsy is a fundamental principle unifying epileptic etiologies

Amyloid-β (Aβ) is a key molecule involved in the pathogenesis of Alzheimer's disease (AD), the most common neurodegenerative disease. Earlier researches have showed that amyloid deposition in the cerebellum only occurred in late stage of AD. Furthermore, cerebellar neurons are resistant to the neurotoxic effects of Aβ oligomers (AβOs). Interestingly, we have previously identified that AβOs bind to the alternative splicing site 4 (SS4) of neurexins (NRXs). NRXs are presynaptic molecules that orchestrate synapses development in the brain by engaging with several ligands to form extracellular protein networks. Among those ligands, cerebellin 1 (Cbln1) promotes synapse formation in the cerebellum by bridging NRX and postsynaptic GluD2. Interestingly, Cbln1 binds to NRXs through the SS4, the same domain responsible for AβOs interaction. We thus hypothesize that endogenous Cbln1 is preventing AβO accumulation in cerebellum by blocking the interaction between AβOs and NRX. Indeed, our results revealed that treatment with soluble Cbln1 completely abolished the binding of AβOs to NRX-expressing COS7 cells. Interestingly, application of AβOs did not interfere NRX-Cbln1 binding suggesting that NRX-Cbln1 complex is resistant to AβOs. Furthermore, AβOs treatment in Cbln1 KO cerebellar neurons showed a significant increase of AβOs deposition on axons compared to wild-type neurons suggesting that endogenous levels of Cbln1 could protect cerebellum neurons in AD. This study may uncover a new mechanism that promote selective cerebellar resistance to Aβ-induced pathological mechanism in AD.

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