Canada

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&#39;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.

CAN-ACN 2021

Investigating the impact of tau deletion in a Huntington&#39;s disease mouse model

animal behavior

tau protein

huntington's disease

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://s3.eu-west-1.amazonaws.com/underline.prod/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

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

poster

Huntington's disease (HD) is an adult onset neurodegenerative disease caused by a trinucleotide CAG repeat expansion in the HTT gene. While the pathogenesis of HD is incompletely understood, mitochondrial dysfunction is thought to be a key contributor. In this work, we used C. elegans models to elucidate the role of mitochondrial dynamics in HD. We found that expression of a disease-length polyglutamine tract in body wall muscle, either with or without exon 1 of mutant huntingtin, results in the disruption of mitochondrial networks. While the mitochondrial network in young worms form elongated tubular networks as in wild-type worms, mitochondrial fragmentation occurs as expanded polyglutamine protein forms aggregates. To correct the deficit in mitochondrial morphology, we reduced the levels of DRP-1, the GTPase responsible for mitochondrial fission. Surprisingly, we found that disrupting drp-1 can have detrimental effects, which are dependent on how much the expression is decreased. To avoid potential negative side effects of disrupting drp-1, we examined whether decreasing mitochondrial fragmentation by targeting other genes could be beneficial. Through this approach, we identified multiple genetic targets that rescue movement deficits in worm models of HD. Three of these genetic targets, pgp-3, F25B5.6 and alh-12, ameliorated movement deficits in the HD worm model and restored mitochondrial morphology to wild-type. This work demonstrates that disrupting the mitochondrial fission gene drp-1 can be detrimental in animal models of HD, but that decreasing mitochondrial fragmentation by targeting other genes can be protective. Overall, this study identifies novel therapeutic targets for HD aimed at improving mitochondrial health.

Decreasing mitochondrial fragmentation is protective in <i>C. elegans</i> models of Huntington's disease

Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs, using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride did not interfere with the antinociceptive effect of opioids in rat models of neuropathic pain. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish, in a fashion akin to the effects of finasteride. Our results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new option for this disorder.

The 5alpha-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder

Admission hyperglycemia is a common concern in patients with ischemic stroke, predicting poor prognosis. Thioredoxin interacting protein (TXNIP) is intimately responsive to hyperglycemia, to drive oxidative damage partly through interacting with NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome. In this in-vitro study, we demonstrate whether verapamil, an established TXNIP inhibitor, provides direct neuroprotection against hyperglycemic reperfusion. Oxygen glucose deprivation (OGD) was induced in primary cortical neural (PCN) cultures prepared from mice fetus brain. Cell survival experiment was performed at 24 h ischemic reperfusion (I/R) injury in cultures exposed to different verapamil concentrations in hyperglycemic medium. Immunoblotting and immunoprecipitation experiments were carried out to analyze the effect of glucose or verapamil on TXNIP expression or interaction with NLRP3 inflammasome. Based on our findings, increasing glucose concentration (2.5, 5 and 10 mM) directly correlates with TXNIP expression in PCN culture exposed to OGD, followed by reduced PCN survival at high glucose (HG) concentration (25 mM). Verapamil (100 Nm) produced significant protection against PCN cells injury at HG, along with reduced TXNIP expression. This was associated with moderate reduction in TXNIP interaction with NLRP3 inflammasome. These findings underline verapamil protection against HG-induced TXNIP upregulation as a potential therapy in hyperglycemic stroke.

Verapamil provides neuroprotection against hyperglycemic ischemic-reperfusion injury in primary neural cells: Involvement of thioredoxin interacting protein

Spinal cord injury (SCI) causes sensorimotor and autonomic impairment that reflects loss of neurons at the epicenter and penumbra of the injury. Strategies aimed at enhancing neuronal protection are critical to attenuate neurodegeneration and improve neurological recovery after SCI. In rat SCI, we previously discovered that tissue levels of neuregulin-1beta 1 (Nrg-1β1) is acutely and persistently downregulated in the spinal cord and restoring its declined levels fosters oligodendrogenesis and promotes an anti-inflammatory, pro-regenerative response in glia and leukocytes, which culminates in improved functional recovery after SCI. While Nrg-1β1 is well-known for its critical roles in the development, maintenance and physiology of neurons and glia, its specific effects and mechanisms on neuronal injury remain unknown. In the present study, using a compressive/contusive rat SCI model and an in vitro model of glutamate toxicity in primary neurons, we demonstrate Nrg-1β1 provides early neuroprotection through attenuation of reactive oxygen species, lipid peroxidation, necrosis and apoptosis in acute and subacute stages of SCI. Mechanistically, availability of Nrg-1β1 following glutamate challenge protects neurons from caspase-dependent and independent cell death that is mediated by modulation of mitochondria associated apoptotic cascades and MAP kinase signaling pathways. Altogether, our work provides novel insights into the role and mechanisms of Nrg-1β1 in neuronal injury after SCI and introduces its potential as a neuroprotective target for this neurological condition.

Availability of neuregulin-1beta1 protects neurons in spinal cord injury and against glutamate toxicity through caspase dependent and independent mechanisms

Background. Males and females respond differently to chronic stress. The medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses and sends projections to other limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, whether these pathways are differently involved in depressive-like behaviors following chronic stress in males and females is still unclear. Methods. We used chronic variable stress (CVS) to induce depressive-like behaviors in males and females and recorded electrophysiological measures in both projections. Chemogenetic was used to validate behavioral contribution of mPFC-NAc pathways to the expression of depressive-like behaviors. Finally, using RiboTag mice, we performed RNAseq to screen pathways specific transcriptional profiles. Results. CVS in females increases the frequency of sEPSCs in NAc and VTA projecting neurons. In males, CVS raises the frequency of sEPSCs only in VTA projecting mPFC neurons. These functional changes were accompanied by sex-specific morphological alterations. We showed that the chemogenetic activation of mPFC-NAc pathway increases stress susceptibility in both sexes while the inhibition of this pathway reverses stress-induced behavioral deficits in females only. Finally, our analysis revealed pathway-specific transcriptional alterations in males and females induced by CVS. Conclusion. Our results suggest that chronic stress impacts the corticoaccumbal and corticotegmental pathways differently through sex-specific morphofunctional alterations in mPFC neurons.

Sex-specific cellular and molecular adaptations to chronic stress in the corticoaccumbal and corticotegmental pathways

Spinal cord injury (SCI) is a life changing condition affecting individuals within Canada and worldwide with no effective treatment to date. A limitation in humans, like other mammals, is that they cannot repair the damaged central nervous system. By contrast, the zebrafish model has a remarkable ability to regenerate the brain and spinal cord after injury, due to populations of ependymoglia. Previous work has shown that for ependymoglia-driven neural regeneration to occur in zebrafish, immune cells are a key requirement. This opposes the immune response in mammals that demonstrates a prolonged pro-inflammatory phase that prevents recovery after SCI. How the activation of the zebrafish immune response results in successful spinal cord repair remains poorly characterized. In this study, we hypothesized that the inflammatory response following SCI in zebrafish is regulated by a longer anti-inflammatory response that is important for successful regeneration. By studying the spatiotemporal dynamics of immune cells post-SCI, we observed that overtime immune cells infiltrate into the injury site, correlating with a peak in proliferation of ependymoglia. Interestingly, analysis of pro- and anti-inflammatory cytokines from our initial qRT-PCR experiments suggest that anti-inflammatory cytokines remain stable across multiple time-points post-SCI in comparison to pro-inflammatory cytokines. These findings propose that in order for successful spinal cord regeneration to occur, a shorter pro-inflammatory response that is tightly controlled by anti-inflammatory cytokines is necessary.

Investigating the role of the immune cell response for successful spinal cord regeneration in the zebrafish model

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.

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

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Decreasing mitochondrial fragmentation is protective in <i>C. elegans</i> models of Huntington's disease

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