Canada

The resting perfusion of blood to the brain is immense and essential for proper function yet we have little understanding of how the brain regulates its basal blood supply. Astrocyte-mediated neurovascular coupling has conventionally been examined in the context of transient neuronally-evoked calcium (Ca2+) events triggering phasic changes in arteriole diameter to control blood flow. However, our group recently demonstrated that &quot;resting&quot; astrocyte Ca2+ levels control tonic, neural activity independent, brain blood flow. It was unclear if or how fluctuations in resting astrocyte Ca2+ regulated vascular tone in vivo. Using two-photon fluorescence imaging, astrocyte patch-clamp, pharmacology, chemogenetics and cre-lox gene knockdown in acute cortical brain slices and in vivo, we showed that increases in arteriole tone (vasoconstriction) caused a sustained elevation in the astrocyte endfoot Ca2+ level. Pharmacology suggested that a TRPV4-mediated Ca2+ influx initiated a Ca2+-dependent COX-1 pathway in endfeet that triggered the release of prostaglandin vasodilators. The role of endfoot COX-1 was further demonstrated with astrocyte specific cre-lox knockdown of the COX-1 gene PTGS1. Furthermore, chemogenetic control of arteriole constriction was sufficient to engage this pathway. While in brain slices this pathway appeared to be a static effect on arteriole tone, in awake mice in vivo, we found this pathway was involved in vasomotion - a pulsatile phenomenon of vascular contraction and relaxation occurring at ~0.1Hz which is important for the basal perfusion of tissue. Using an astrocyte selective AAV to overexpress a Ca2+ extrusion pump called CalEx, which clamps astrocyte free Ca2+ at a lower level and prevents increases, this largely abolished vasomotion compared to control virus. Our data demonstrated that bidirectional communication between astrocyte endfeet and arterioles is important for setting basal arteriole tone and vasomotion in vivo, which is likely an essential process for optimizing cerebral perfusion of oxygenated blood.

CAN-ACN 2021

Bidirectional communication between astrocytes and arterioles controls vasomotion

two-photon

trpv4

cox-1

in vivo

vasomotion

cerebral blood flow

astrocyte

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

The resting perfusion of blood to the brain is immense and essential for proper function yet we have little understanding of how the brain regulates its basal blood supply. Astrocyte-mediated neurovascular coupling has conventionally been examined in the context of transient neuronally-evoked calcium (Ca2+) events triggering phasic changes in arteriole diameter to control blood flow. However, our group recently demonstrated that "resting" astrocyte Ca2+ levels control tonic, neural activity independent, brain blood flow. It was unclear if or how fluctuations in resting astrocyte Ca2+ regulated vascular tone in vivo. Using two-photon fluorescence imaging, astrocyte patch-clamp, pharmacology, chemogenetics and cre-lox gene knockdown in acute cortical brain slices and in vivo, we showed that increases in arteriole tone (vasoconstriction) caused a sustained elevation in the astrocyte endfoot Ca2+ level. Pharmacology suggested that a TRPV4-mediated Ca2+ influx initiated a Ca2+-dependent COX-1 pathway in endfeet that triggered the release of prostaglandin vasodilators. The role of endfoot COX-1 was further demonstrated with astrocyte specific cre-lox knockdown of the COX-1 gene PTGS1. Furthermore, chemogenetic control of arteriole constriction was sufficient to engage this pathway. While in brain slices this pathway appeared to be a static effect on arteriole tone, in awake mice in vivo, we found this pathway was involved in vasomotion - a pulsatile phenomenon of vascular contraction and relaxation occurring at ~0.1Hz which is important for the basal perfusion of tissue. Using an astrocyte selective AAV to overexpress a Ca2+ extrusion pump called CalEx, which clamps astrocyte free Ca2+ at a lower level and prevents increases, this largely abolished vasomotion compared to control virus. Our data demonstrated that bidirectional communication between astrocyte endfeet and arterioles is important for setting basal arteriole tone and vasomotion in vivo, which is likely an essential process for optimizing cerebral perfusion of oxygenated blood.

technical paper

Physical activity and healthy eating are vital elements for establishing metabolic and mental health. We recently showed that unhealthy snacking is a strategy used to cope with stress during the coronavirus disease 2019 (COVID-19) pandemic. Here, we implemented a longitudinal survey with 319 participants in May (Phase P1) and October 2020 (P2) to assess whether physical activity can improve mood and mental health outcomes over time. There was a decrease in leisure-time physical activity, but not on-the-job activity, from P1 to P2. Lower leisure-time physical activity in P1 was associated with appraisals of uncontrollability in P2. These appraisals predicted worsened mood, and increased feelings of depression, anxiety, or stress in P2. We then conducted mediation models to determine if uncontrollability underlies the relationship between P1 leisure-time physical activity and subsequent mood and mental health outcomes in P2. Interestingly, we found that when situations were appraised as uncontrollable in P2, the level of leisure-time physical activity in P1 was predictive of worsened mood and mental health outcomes in P2. In aggregate, we surmised that physical activity at the onset of the pandemic indirectly predicted mood and mental health outcomes 4 months later. This suggests that physical activity may protect against the widespread stress and lifestyle changes inflicted by COVID-19.

Impact of physical activity at the onset of the COVID-19 pandemic on mood and mental health over time

The set of behavioral strategies we develop to manage stress stems from social interactions. Similarly, chronic stress models in rich environments in mice models, simplify the analysis of environmental and social factors using an automated assessment and tracking system. In a large group, mice are so influenced by pressures from other members of the group that over time, the evolutionary structure is formed by the social hierarchy in the group. For example, in this evolutionary structure, in rich and complex environments, group members interact with each other, sometimes play, and sometimes fight with each other to prove their dominance to the group. The behavioral ability that each mouse exhibits during daily life to control stress determines its status in the colony. The goal of this project is to develop an automated behavioral platform using machine-based units and a radio-frequency identification system (RFID) to evaluate the behaviors resulting from chronic variable stress (CVS) in male and female mice in groups ethically. To achieve our goals, we have developed two smart vivariums (1m x1m) equipped with high-quality cameras including various components such as beddings, enrichments, food, nesting material, games and toys, bridges, and ropes for each group of male and female. We control the behavioral characteristics of different groups up to a maximum of 10 people for 6 weeks by these smart vivariums at the same time for both mice groups and finally archive them in cloud data storage. To that end, we created an extensive library of several thousand images of different mice to automatically detect these individual or group behavioral characteristics by tracking them through a hybrid machine system consisting of DeepLabCut and YOLO with an RFID system.

The smart vivarium v1.0: implementation and validation

AIM: Opioid withdrawal can be associated to environmental cues through classical conditioning to produce conditioned withdrawal. Recent preclinical evidence suggests that exposure to these cues can have profound cognitive effects and can play a role in the addiction by enhancing memory consolidation. To further understand the neurobiological mechanism by which cues influence memory, this study investigated the roles of two stress neuromodulators: noradrenaline and corticotrophin-releasing factor. METHODS: In Experiment 1, 0-3 mg/kg naloxone, 0.1 - 0.6 mg/kg lofexidine (alpha-2 adrenergic agonist) and 10 - 20 mg/kg antalarmin (CRF1 antagonist) were co-administered shortly after training on the object recognition task to heroin-dependent rats (via subcutaneous osmotic mini-pumps; 3.5 mg/kg/day). In Experiment 2, heroin-dependent rats were confined for 2 hours in a context (CS ) following naloxone injections and in another context (CS-) following vehicle injections. The effects of immediate post-training exposure to the CS (or CS-) and co-administration of lofexidine and antalarmin were tested 7 days after removal pumps. RESULTS: It was found both lofexidine and antalarmin dose-dependently blocked the enhancement of object memory consolidation by post-training naloxone precipitated withdrawal and by conditioned withdrawal. CONCLUSIONS: These experiments suggest that pharmacological and psychological withdrawal have significant effects on memory storage by activating noradrenergic and CRF stress systems.

Antagonists of noradrenergic and corticotrophin-releasing factor receptors block enhancement of memory consolidation by heroin withdrawal and conditioned heroin withdrawal

Major psychiatric diseases (MPDs), including schizophrenia, are diagnosed very late, due to the lack of effective biomarkers. Post-mortem analyzes show that the lipid composition of neuronal membranes differs in people with schizophrenia. This difference is also reflected in several types of cells, including red blood cells (RBCs). RBCs are known to exhibit spectacular biomechanical properties (BPs) resulting in unique deformability capacity and spontaneous membrane vibrations at the nanoscale . It has been reported that the lipid composition of the RBC membranes affects these BPs. An accurate biomechanical characterization of RBCs could thus reveal MPD-related phenotypes. Quantitative Phase Digital Holography Microscopy (QP-DHM), providing images with a nonmetric axial sensitivity, represents a highly relevant technique to quantitatively study the RBC biomechanics. As a first step to identify MPD-related RBC phenotypes, we have started to develop a methodology based on QP-DHM to characterize RBC biomechanics. Studies are conducted in different conditions known to specifically impact RBC BPs. Concretely membrane vibrations and RBC deformations are monitored in environments controlled for temperature, ph, O2 and CO2 partial pressures. We are also going to start a biomechanical study of RBCs obtained from mice, having benefited from a strict diet allowing a control of their membrane lipid composition. Then, aiming at identifying MPD-related RBC phenotypes, we will apply this methodology on our clinical data set, composed or RBC samples collected from patients suffering for MPDs.

Exploration of the red blood cell biomechanics with digital holographic microscopy: Towards a methodology to identify cellular phenotypes related to major psychiatric disorders

Introduction: The COVID-19 pandemic has created a shift in the use of at-home spaces for work, play and research. In the present study we sought to determine if NeuroTrackerX, an anaglyph, at-home version of the three-dimensional multiple object tracking (3D-MOT) software NeuroTracker, produced similar results to the laboratory version that uses active 3D technology. Methods: 20 cognitively healthy adults (10 female, mean age = 68.3 years, SD = 6.75) were recruited for participation as the at-home training group. 20 participants, above 50 years old, who had previously completed at least 8 session of in-lab 3D-MOT, were randomly selected to serve as the in-lab control group. At-home participants were loaned the necessary equipment (e.g. 3D-glasses, computer equipment), and engaged in 10 training sessions over five weeks (2x per week). Results: No demographic differences were observed between the two groups (age, sex, MMSE score). The in-lab control group performed better on the task at session one (p < 0.05), however no differences in session scores (p > 0.05), or learning rates (p > 0.05) were observed between groups over the remaining sessions. Participants in both groups showed significant improvements in task performance across the training sessions (p < 0.001). Conclusions: These results indicate that NeurotrackerX provides a promising in-home option to use for cognitive training in cognitively healthy adults. Future studies are needed to determine if these benefits can also be observed in cognitively-challenged groups who may benefit from this form of cognitive training.

At-home cognitive training during the COVID-19 Pandemic? Validation, utility and lessons for future research

Genetic cell fate manipulation can be used to convert one cell type to another, which facilitates the production of personalized and customized human neurons for basic science applications and disease modeling. Genetic conversions often start with accessible cell types like fibroblasts, which are converted to neurons using multiple lentivirus vectors that encode neurogenic genes, such as Ascl1 and Ngn2; furthermore, for doxycycline (dox) inducibility, another vector is used to deliver a dox-dependent transcriptional regulator (e.g. rtTA or TetR). Such direct cell fate conversion approaches have the advantage of retaining some epigenetic marks, but somatic cells like fibroblasts often grow slowly, and the use of multiple viral vectors decreases conversion efficiencies. To address these limitations, we tested a range of media formulations and found that supplementing serum-based fibroblast media with basic fibroblast growth factor improved growth by 3-fold. We also found that co-expression of Ascl1 and Ngn2 from a single lentivirus vector improved neuronal conversion by approximately 45% compared to the delivery of Ascl1 and Ngn2 on separate vectors. These improvements increase both neuronal conversion efficiency and potential neuronal yield of this fibroblast-to-neuron conversion platform. We are currently developing a self-inactivating "all-in-one" lentivirus, which will express dox-inducible Ascl1-P2A-Ngn2 along with TetR and a selectable marker to isolate pure neuronal populations for studies of human neurobiology and to model disorders of the brain.

Improved methodologies for genetic conversion of human fibroblasts to neurons

State-of-the-art imaging tools rely on a restrained preparation, limiting natural behavior while measuring cellular activity via fluorescence (FL). Recently, advances in wearable microscopy expanded the range of accessible behaviors by allowing imaging of freely behaving animals. However, wearable microscopes to this day are primarily used for brain imaging and have not been adopted for imaging other parts of the body, for example the spinal cord. Furthermore, unfavorable attributes of FL indicators constrain the extent of imaging experiments, including photobleaching, autofluorescence and excitation light scattering noise especially in the parts of the body like the spinal cord due to myelination. All 3 of these issues can be eliminated while offering an increase in the imaging depth by using bioluminescence (BL) instead of the FL. Here we demonstrate our ability of imaging BL calcium indicators through the cranial window in mice as fast as 5 frames per second using redesigned open-source miniscopes. Furthermore, we present an expansion of the miniscope use towards neurovascular imaging in the spinal cord. Spinal neurovascular imaging is accomplished by integrating a custom vertebral implant with miniscope hardware that ensures mechanical stability over time. Such implants allow interchangeable imaging of the brain or spinal cord in free or restrained animals. Altogether, our work expands the imaging toolbox towards better imaging quality via BL indicators and the ability to image across multiple sites throughout the nervous system using wearable miniature microscopes.

Next generation tools for imaging in the cortex and spinal cord

The atypical spectrum of mood disorders includes a variety of phenotypes characterized by unusually high sensitivity to environmental factors as well as increased eating behaviour and weight gain. In the case of Seasonal Affective Disorder, the environmental sensitivity relates to highly predictable photoperiodic phenomena tied to the seasons of the year. In the case of DSM-defined atypical depression, the environmental sensitivity relates to the social realm as reflected in the construct of rejection sensitivity. Patients with various forms of binge eating are highly sensitive to both appetitive and non-appetitive stimuli over time. Our group has been interested in identifying gene-environment interactions that might explain why certain individuals are more prone to develop these disorders characterized by environmental sensitivity and overeating/weight gain. Our primary genetic focus has been on the seven-repeat allele (7R) of the DRD4 gene because it is a hypo-functional variant that is likely to influence dopamine system functioning over the lifespan. There is also significant evidence that the 7R allele moderates phenotypic development in the face of various environmental signals. The current talk will review various findings linking the 7R allele to increased environmental sensitivity in patients with Seasonal Affective Disorder, bulimia nervosa and to young children exposed to various levels of maternal sensitivity in the early postnatal period. The possible evolutionary and clinical significance of these findings will also be discussed.

DRD4, environmental sensitivity and weight gain across the atypical spectrum of mood disorders: A lifespan perspective

Dopamine (DA) connectivity in the prefrontal cortex (PFC) continues to unfold until early adulthood, with dramatic organizational and functional changes occurring during adolescence. This delayed development involves long-distance axonal growth of midbrain DA neurons across the adolescent period and is mediated by the Netrin-1/DCC guidance cue pathway. We examined whether repeated social stress in adolescence dysregulates the Netrin-1/DCC pathway, disrupting PFC DA innervation and cognitive control in adulthood. We used a modified accelerated social defeat stress (ASD) model and segregated mice into resilient (RES) and susceptible (SUS) groups by measuring social avoidance in a social interaction test (SIT) 24h after ASD exposure. ASD in adolescence downregulates DCC expression in DA neurons in SUS and RES groups, but its effects on PFC DA development and behavior differ between phenotypes. ASD-induced molecular, cellular and behavioral changes are not observed following ASD exposure in adulthood. While most (~60%) mice exposed to adolescent ASD show RES, most adult mice show stress SUS. Alterations in dopamine development in adolescence may mediate the established link between genetic variance within the Netrin-1/DCC pathway and psychiatric disorders of neurodevelopmental origin.

Stress in adolescence alters guidance cue pathways and impacts dopamine development

Individual differences in dopamine gene and brain systems influence the responsiveness to environmental variations and affect different types of behaviors (sensitivity to reward, decision-making, eating) over the life course. Robust evidence points to DRD4 gene but neither the characterization of context diversity and dynamics, nor the neurobiological mechanisms involved in metabolic disorders and their co-morbidity with psychiatric conditions (e.g. obesity and ADHD) are understood in sufficient depth. Evidence advancing the theoretical understanding of environmental variation characterization over the life course will first be presented. Second, studies focusing on different genomic approaches to explore the impact of variations of dopamine related genes on the brain responses to both adverse and protective environmental conditions. A recent published study that explored differential susceptibility to positive environments according to the predicted genetically-regulated gene expression of prefrontal cortex DRD4 gene will be presented, evidencing the role of positive environment as a protective factor against the development of eating disorders in children as young as 48 and 60 months of age. To be able to further investigate the role of dopamine on these gene by environment interactions, we will present new data exploring the role of the dopamine transporter gene network through a polygenic approach that reflects variation on the genes co-expressed with DAT1 gene in the PFC and STR in a combined manner. A higher chance of having co-morbidity between mental and cardio-metabolic disorders on the UKBiobank cohort was associated with the interaction between variations in the DAT1 gene network and exposure to early life adversity, confirming our initial hypothesis. Taken together these findings highlight the relevance of a dopamine-related gene network to influence the risk to develop psychiatric conditions associated with exposure to early life adversity. Combining this novel approach to developmental neuropsychology with a more theoretically rich characterization of environmental variation over the life course can guide the elaboration of more efficacious and cost-effective personalized prevention and treatment of complex metabolic and mental health and diseases, targeting individuals that would benefit the most from interventions.

The role of dopamine on the link between early life environment and lifecourse eating behavior and co-morbidity between metabolic and psychiatric disorders: Context characterization and biologically-informed genomic approaches

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Next from CAN-ACN 2021

Impact of physical activity at the onset of the COVID-19 pandemic on mood and mental health over time

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Astroglial ionotropic NMDA receptor calcium signalling and modulation of cortical neuron activity

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PRESENTATIONS

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