Canada

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.

CAN-ACN 2021

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

neural stem cells

zebrafish

immune cells

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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.

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Shernaz Bamji

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14th Canadian Neuroscience Meeting from August 23rd-25th

The ability to store new information and to adapt to new environments is a crucial neurobiological process underlying our everyday life. This capability has been linked to modifications of the efficacy of synaptic transmission that are partly due to activity-dependent structural alterations of dendritic spines. We propose a computational pipeline to reconstruct and analyse dendritic spines from confocal microscopy images into a 3D mesh model. First, we acquired confocal, high resolution images of distal dendritic segments from adult born neurons in the olfactory bulb (OB) after odour learning using a simple and complex go/no-go odour discrimination paradigm and after sensory deprivation. The reconstruction of dendritic spines images was performed in 4 steps i) correction of image stacks via deconvolution and diffraction correction, ii) 3D segmentation, iii) reconstruction into a 3D mesh and iv) automatic extraction of spines and measure of features. Recent papers suggest that clusterization instead of classification is more appropriate to describe spines because spine morphologies are continuous. Thus, instead of manually categorizing spines, we assessed several spine features such as the length, surface, open angle, etc., and analysed these features with machine learning. We performed dimension reduction and we then identified some clusters associated with spines' morphological features. We report a significant increase in surface and in open angle as well as a decrease in Hull ratio in the mice of odour learning group as compared to control animals.

Clustering dendritic spines morphological properties after odour stimulation and learning

Cholinergic modulation of the prefrontal cortex is essential for higher brain function. Changes in cholinergic markers have been reported in brains of healthy aged adults and those with dementia. Disturbances in fibers, enzymes, and receptors are hypothesized to underlie age-related cognitive dysfunctions; however, their integrated impact on cortical cholinergic signalling is not well understood. Here, we use optogenetics and whole cell electrophysiology to investigate functional properties of cholinergic synapses across a broad age range in adulthood. We use prefrontal brain slices from transgenic mice expressing excitatory opsin in cholinergic basal forebrain neurons whose axons project to the cortex and release acetylcholine when stimulated with light. We demonstrate that pyramidal neurons in the aged brain show changes in the properties of their responses to optogenetically-released acetylcholine. Direct excitation of cholinergic receptors on pyramidal neurons declines with age. Ongoing experiments are probing the impact of aging on specific contributions of presynaptic and postsynaptic components of the synapse. In addition, we are investigating age-dependence in the sensitivity of cholinergic signalling to allosteric modulation and other treatment interventions. Understanding the impact of aging on synaptic mechanisms of cholinergic transmission is important to understand cognitive resilience and gain a better appreciation for effective targets to treat cognitive impairment.

Functional impact of aging on mouse prefrontal cholinergic synapses: an optophysiological investigation

Schizophrenia (SZ) is a psychiatric disease affecting about 1% of the population. Increasing evidence shows that cortical alterations of the maturation and function of inhibitory systems inducing perturbations in the excitatory/inhibitory (E/I) balance are likely to be involved in the pathogenesis of SZ. We propose that a delay of the GABA switch from excitatory to inhibitory during neurodevelopment could explain the perturbations of the E/I balance and represent a cellular phenotype of SZ. To assess this assumption, we aim to use a multimodal imaging approach including Digital Holographic Microscopy (DHM) to explore the neuronal functional maturation in in vitro cellular models. During early neurodevelopmental stages, GABA-mediated depolarization induces calcium (Ca2+) influx through voltage-gated Ca2+-channels. As a first step, Ca2+ responses to GABA stimulation have then been monitored at different ages in primary cultures of rat cortical neurons. The percentage of neurons responding to GABA decreased overtime suggesting a loss of GABA depolarizing action during neuronal maturation. We are now evaluating the relationship between Ca2+ responses and the label-free DHM measurements of transmembrane water fluxes related to GABAA receptors and (N)KCC cotransporters activities. We aim to use this methodology to explore the maturation of iPSC-derived cortical neurons obtained from patients with SZ, high-risk offspring and controls. Such non-invasive detections of functional alterations during the neurodifferentiation process could help to identify risk biomarkers of SZ.

Exploration of inhibitory system maturation in neuronal cultures with multimodal imaging techniques: toward a methodology to identify cellular biomarkers of schizophrenia

The dorsal and ventral hippocampus (DH and VH) are dramatically different structures. The DH is involved in cognition and undergoes robust synaptic plasticity while the VH functions in emotional processing and naturally exhibits poor plasticity. N-methyl-D-aspartate receptors (NMDARs) assemble as functionally diverse heterotetramers with essential roles in synaptic plasticity. Incorporation of the GluN3A subunit into NMDARs alters conventional NMDAR properties, delays synapse maturity, and opposes synaptic plasticity. Consistent with recent reports, we show that GluN3A remains elevated, mainly in extrasynaptic locations, in the adult VH but not the DH. Despite GluN3A persistence, VH spines matched the maturity level observed for the DH. As presynaptic and postsynaptic GluN3A-NMDARs can facilitate glutamate release and limit Ca2+ permeability, we performed real-time glutamate and calcium imaging to further understand the consequences of GluN3A persistence in the adult VH. Compared to the DH, the VH accumulated more glutamate during afferent stimulation yet exhibited less NMDAR-mediated Ca2+ influx. We then hypothesized that prolonged GluN3A expression limits synaptic plasticity in the VH. Indeed, in wildtype mice, long-term potentiation (LTP) was significantly lower in the VH compared to the DH. In contrast, GluN3A knockout (KO) mice exhibited strong VH LTP that now exceeded the magnitude of LTP in the DH. In sum, our data show that GluN3A persistence limits VH plasticity in adulthood, perhaps serving a protective role to prevent overexcitation of anxiety and fear circuitry.

Atypical NMDA receptors limit synaptic plasticity in the adult ventral hippocampus

Dynorphin A and enkephalin are opiate peptides that are found in the direct and indirect pathway Medium spiny neurons respectively. Although the opioid system in the striatum plays a crucial role in reward processing, the opioidergic modulation of striatal interneurons is still poorly understood. Furthermore, the nitrergic low threshold spikes (LTS) and the cholinergic interneurons are striatal neurons that modulate the final striatal output. The nitrergic (LTS) interneurons secrete many neurotransmitters (i.e. somatostatin, GABA, NO, and NPY). While the cholinergic interneurons are the main source of acetylcholine in the striatum. In this study, we aimed at studying of the effect of δ and κ opiate receptor agonists on the nitrergic and the cholinergic interneurons. We used transgenic mice in which the NPY is marked with a green fluorescent protein (GFP). Moreover, we carried out whole-cell and cell-attached recordings from mice brain slices maintained in vitro. Our data report that δ receptor agonist (DPDPE; 1 µM) and κ receptor agonist (U-50488 hydrochloride; 10 µM) reversibly inhibited the nitrergic and the cholinergic interneurons. This inhibitory effect on the nitrergic interneurons persisted in the presence of nicotinic and muscarinic receptor antagonists, and tetrodotoxin (TTX) (1µM). Finally, we found that DPDPE but not U-50488 inhibited the GABAergic transmission on the LTSIs. Taken together our results demonstrate that δ & κ opioid peptides exert direct and indirect effects on the nitrergic LTSIs. These results help us to understand more about striatal microcirculatory and how opioid peptides can modulate striatal output.

Opioid peptides exert direct and indirect effects on striatal nitrergic low threshold spiking (LTS) interneurons

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 C. elegans 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.

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Clustering dendritic spines morphological properties after odour stimulation and learning

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