Canada

Spinal and brain stimulation approaches are complementary in the treatment of motor disorders related to spinal cord injuries (SCI). Nevertheless, no study has directly compared their single and combined effect over immediate modulation of walking. To address this unmet need, we developed a neuroprosthesis that allows stimulating the brain and spinal motor circuits in phase-coherence with walking. Six rats were implanted with electromyographic electrodes (EMGs) within hindlimb muscles, a multi-electrode array within the hindlimb motor cortex and epidural electrodes over the lumbar (L2) and sacral (S1) spinal segments. After obtaining baselines for kinematics/EMGs on a treadmill, rats received a spinal hemisection at T9 that paralyzed one leg. The immediate effects of cortical and/or spinal stimulation over treadmill locomotion were evaluated in the intact state and after SCI. We characterized the effect of stimulation parameters such as stimulus amplitude, frequency, and duration. Gait analysis demonstrated that each stimulation technique independently modulated walking. Both cortical and L2 stimulation, when delivered in synchrony with foot lift, increased leg flexion. S1 stimulation, when delivered 80ms after the foot lift, increased leg extension. Combined cortical and spinal stimulation approaches resulted in maximal increase in foot clearance, step height and swing velocity, before and after SCI. These experiments demonstrated that cortico-spinal neuroprosthesis has the potential to reduce motor deficits and enable targeted rehabilitation protocols after SCI.

CAN-ACN 2021

Combining the effects of cortical and spinal stimulation to improve walking after spinal cord injury

spinal stimulation

neuroprostheses

cortical stimulation

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

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.

Endogenous cerebellin 1 prevents amyloid-β oligomers accumulation in the cerebellar granule cells

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.

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

In Canada, 80000 people live with spinal cord injury (SCI), with roughly 1400 individuals added to this population each year. These individuals live with lost motor function, multiple secondary complications and disuse-related diseases that arise from severe inactivity imposed by the injury. Dysregulation of the sympathetic nervous system is common in SCI individuals as connections between the autonomic command centres in the brainstem are severed from spinal sympathetic preganglionic neurons (SPNs) that regulate sympathetic outflow. SPNs are found in intermediate lamina and central autonomic nuclei of T1-L2 spinal cord and depending on the site of injury, some or all sympathetic activity is affected, such as hindering the ability to sweat or increase energy metabolism to meet increased metabolic demands of the body. Recently, epidural stimulation has been shown to restore voluntary movements in people with SCI and improves autonomic function. However, the neurons and neural pathways that allow for both locomotor and autonomic function recovery are unknown. We hypothesize that ventrally derived propriospinal interneurons (INs) that are involved in locomotion, and are termed V3 INs, relay ascending motor commands to SPNs to ensure adequate sympathetic activity during increased metabolic demands such as locomotion. Our preliminary data has demonstrated that lumbar V3s project to and synapse throughout the IML of thoracic spinal cord. Our continuing work focuses on if there are greater V3 synaptic densities innervating the heart region of the thoracic spinal cord (T1-T5).

Sympathetic preganglionic neuron innervation by locomotor related V3 spinal neurons

Bats exhibit several traits associated with human communication, including vocal learning and complex social communication--traits that are rare among mammals. Here, we use a bat model to investigate the cortical representation of the larynx to begin studying the motor control of complex vocal behaviours. In anesthetized Egyptian fruit bats (Rousettus aegyptiacus), we applied ICMS to the frontoparietal cortex to evoke muscle contractions. We tested for the presence of a larynx representation in M1, S1, and adjacent cortex by recording electromyographic (EMG) activity from the cricothyroid muscle in the larynx. In order to correct for EMG artifacts introduced by the ICMS signal itself, we systematically varied ICMS circuitry (e.g. return lead placement, current sense resistor) to minimize contamination. This method also reduces the need for "blanking" techniques, which can lead to signal loss. Our corrections reduced the artifact by ~90% and increased the EMG signal-to-noise ratio, providing a robust laryngeal signal. Here we report ICMS activation of the larynx at two rostromedial sites in M1--each of which had a distinct latency (20 vs 190 ms)--in a case study of Rousettus. Ongoing experiments will focus on denser mapping of this region to determine whether latency differences reflect modules within M1 or distinct cortical fields, perhaps with different roles in the control of vocal behaviour.

Larynx motor representation in fruit bats located with intracortical microstimulation (ICMS) optimized for detection of weak electromyographic (EMG) signals

The upper hearing limit of humans is 20kHz, and sounds having frequencies above 20kHz are considered ultrasonic. Ultrasonic frequencies are important to a variety of species, many of which have a well-defined and much higher hearing limit compared to humans. A common model used for auditory research is the domestic cat (Felis catus). Even though it is generally accepted that cats can hear ultrasonic frequencies, there are notable discrepancies in the literature regarding the full extent of the cat's hearing abilities. Here, auditory brainstem responses (ABRs) are used to evaluate the ultrasonic hearing abilities of cats. The ABR is an objective test used to assess the physiological integrity of the auditory pathway from the cochlea up through the brainstem. Wideband stimuli (clicks) as well ultrasonic pure tones are presented to the subject. Each stimulus leads to electrical responses that reflect the neurophysiological activity in the auditory nerve and the auditory nuclei in the brainstem. This work evaluates the amplitude and latencies of the ABRs to the different stimuli presented. Since cats are a common animal model in hearing research, it is crucial to validate and expand our current understanding of their hearing abilities. By using ABR data in conjunction with data from psychoacoustic experiments to investigate specifically the ultrasonic hearing abilities of cats, we can elucidate uncertainties and ultimately better our understanding of brain regions responsible for the cat's ability to perceive these high frequency signals. Supported by a grant from NSERC.

Next from CAN-ACN 2021

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

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Sympathetic preganglionic neuron innervation by locomotor related V3 spinal neurons