Canada

During the dynamic process of brain development, the neurite formation and elongation are essential to establish a complex neural network in the central nervous system. Somatostatin (SST), a growth hormone inhibitory peptide, is known to play a critical role in neurotransmission, neurite formation, migration and maturation. In the present study, we examined the time-dependent (at day 1, 3, 5 and 7) developmental changes in the expression of crucial marker that govern the functional activity of neurons, including SST, choline acetyltransferase, and tyrosine hydroxylase, brain nitric oxide synthase, GABA and synaptophysin in non-differentiated and all-trans retinoic acid (RA)-induced differentiated SH-SY5Y cells. We also determined SST-mediated modulation of subcellular distribution and expression of neurotransmitter and Synaptic markers using immunocytochemistry and western blot analysis. Our results suggest a distinct response of RA and SST alone or in combination in regulating different neurotransmitter markers during the transition of SH-SY5Y cells from non-neuronal entity to neuronal phenotype. Here we present markers specific and time-dependent changes in differentiated cells when compared to non-differentiated SH-SY5Y cells. These data suggest that SST in SH-SY5Y cells might be associated with the stabilization and migration of neurotransmitter markers to neurites. Taken together, results described here support the role of SST in neurogenesis with a possible implication in neurological disease exhibiting interrupted neuronal communication and loss of cognitive function.

CAN-ACN 2021

Role of somatostatin in regulating developmental changes of neurotransmitters in retinoic acid-induced differentiated SH-SY5Y cells

neurotransmitter phenotype

cell differentiation

sh-sy5y

somatostatin

neurite outgrowth

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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.

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/

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We hope you enjoy this program, and look forward to welcoming you, virtually.

Shernaz Bamji

President of the Canadian Association for Neuroscience

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Please head to https://can-acn.org/meeting-2021/registration-2021/ to register. 

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

Hearing loss is a chronic health condition affecting ~466 million people worldwide, with excessive exposure to loud noise as a leading cause. Epidemiological studies have identified hearing loss as a major risk factor for age-related cognitive decline; however, the brain regions mediating the link between the two remain elusive. Although previous studies have reported molecular changes in the hippocampus and striatum following noise exposure, it is unknown whether such changes contribute to cognitive decline associated with noise-induced hearing loss. To that end, we noise-exposed 6-month old rats, and then assessed their hearing and cognitive function at 7, 10 and 13 months of age. Rats underwent cognitive testing on the Morris water maze to assess hippocampal-dependent learning and memory, and on a striatal-dependent visuomotor associative learning task. Consistent with human studies, noise exposure resulted in mild, high-frequency hearing loss. The noise-exposed rats did not exhibit significant deficits in striatal-dependent visuomotor associative learning, yet they had a faster reaction time compared to the sham-exposed rats. Moreover, a subset of noise-exposed older rats demonstrated hippocampal-dependent spatial learning deficits, suggesting that some animals are more vulnerable to the effects of noise exposure with age. Ultimately, these novel findings expand our understanding of how brain regions outside of the auditory pathway are affected by noise exposure; findings that should be considered when investigating the link between hearing loss and cognitive decline.

Investigating the link between hearing loss and age-related cognitive decline in a rodent model

The ability to alter previously established behaviours is key for survival. Two ways in which reductions in conditioned behaviours can be achieved is through overexpectation and extinction. In both cases the expected outcome, be it aversive or appetitive, is greater than that delivered, thus generating a negative prediction error and downregulating established expectations. In overexpectation, the expectation of the outcome is manipulated by inflating it through summation, whereas in extinction it is outcome delivery that is manipulated by omitting it altogether. Our previous work showed that the lateral orbitofrontal cortex (lOFC) is critical for learning from overexpectation but less so in learning from extinction. When studying the effects of lOFC function on extinction, we found a mild effect of lOFC inactivation only in initial but not subsequent extinction learning. This albeit mild effect led us to assess the generality of the role of the lOFC in overexpectation by studying the order of learning episodes. Specifically, we examined the effect of lOFC inactivation on learning from overexpectation in animals that have undergone either initial extinction or overexpectation training with a different cue. Our findings confirm that inactivation of the lOFC prior to compound training in overexpectation disrupted the reduction in responding seen on test, regardless of the order of learning and prior experience. Additionally, silencing the lOFC only resulted in a mild impairment in initial extinction. Together, these results extend and replicate our prior work to provide additional evidence that the lOFC consistently regulates the reduction of learned fear responses driven by overexpectation.

The lateral orbitofrontal cortex consistently regulates learning from overexpectation of fear

Chronic stress, the main environmental risk factor for major depressive disorder (MDD) is linked to intestinal barrier deterioration via gut-brain signaling in gastrointestinal disorders. MDD shows high comorbidity with gastrointestinal disorders including patterns of microbiome dysbiosis and inflammatory peripheral markers, suggesting increased intestinal permeability in these patients. We investigate how the effects of chronic stress can influence manifestations of intestinal permeability in both male and female mouse models of depression. The prevalence of MDD is two-fold higher in women, however, chronic social defeat stress (CSDS) experiments have been conducted exclusively in male mice. We hypothesize that stress induces changes to gut barrier integrity in a sex-specific manner, playing a role in vulnerability or resilience. Accordingly, mice were subjected to various stress paradigms: 6-day or 28-day chronic variable stress, or 10-day CSDS. 16S rRNA sequencing assessed microbial populations pre- and post-stress. Gene and protein expression analysis of tight junctions from intestinal tissues shows alterations related to the type and duration of stress with sex-specific effects. Furthermore, CSDS induces changes in tight junction expression associated with resilience or susceptibility to chronic social stress, corresponding to phenotype severity. Our results provide evidence for the effects of chronic stress in disrupting intestinal barrier homeostasis in conjunction with the manifestation of depression-like behaviours.

Sex-specific effects of chronic stress on intestinal permeability and depression-like behaviors

We present the Py-based SYstem for Chronic monitoring of rOdent SpeciesPy-(PSYCO) Mouse Tracker (PNMT): an affordable, open-sourced, and customizable/scalable behavior recording software for small foot-print Raspberry Pi-based acquisition computers and subsequent offline analysis tools capable of recording and tracking multiple mice for extended periods of time, respectively. Video tracking coupled with radio frequency identification (RFID) was employed to track multiple mice in a modified home-cage setting for up to four days. Video and RFID recordings were completed utilizing a Raspberry Pi 3B+ or Pi4 micro-computer. During offline analysis performed on a PCdesktop computers, mice were tracked using You Only Look Once version 4 (Yolov4) algorithm coupled with the Simple Online and Realtime Tracking (SORT) for mice tracking, respectively. RFID readings recorded in the system were then associated with the best-matched mouse that was tracked. For evaluation, PMTNMT performance was compared to a human manual validation of video recordings containing one to four mice. PMTNMT maintained a minimum of 70% identities tracked among mice detected with an overall accuracy >above 90 %. Moreover, we also showed that PMTNMT can be adapted to other behavior apparatus such as an open field like arena or sociability chamber to track mice. Furthermore, the PSYCO tracker can incorporate inputs from popular open-sourced packages such as Deeplabcut and Traja for postures estimation and travel trajectory analysis, respectively. Overall, our group demonstrated the performance of a newly developed multiple animal tracking system capable of tracking mice for extended periods of time and adaptable to the use case of individual investigators.

PSYCO:Py-based SYstem for Chronic monitoring of rOdent Species, an open-sourced python based system for homecage mouse tracking and image processing

Evidence indicates that neurodegeneration (NDG) is a prominent feature and the primary cause of disability in multiple sclerosis (MS). Yet, knowledge of the molecular mechanisms of NDG in MS, as well as treatment options for NDG are lacking. Published data from our lab indicates that dysfunction of the RNA binding protein heterogeneous ribonucleoprotein A1 (A1) may contribute to MS pathogenesis. Therefore, to examine A1 dysfunction, we utilized an in vitro, blue light (BL) induced, optogenetic protein self-association expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, to examine the effects of MS-associated somatic A1 mutations (P275S and F281L) on A1 localization, cluster kinetics and stress granule (SG) formation in real-time. Using BL stimulation followed by a period of recovery, which promotes protein self-association and dissociation dynamics (imitating a cell stress event that occurs during MS relapse), revealed that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. Additionally, mutant A1 protein clustering also caused SG formation to occur more quickly and frequently in response to BL stimulation. Overall, this study establishes a live cell optogenetic imaging system to probe localization and association dynamics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote SG formation, which supports the hypothesis that A1 dysfunction may exacerbate NDG in MS.

Optogenetics defines the effects of multiple sclerosis-associated hnRNPA1 mutations on hnRNPA1 dynamics and stress granule formation

Early-life stress (ELS) has profound and enduring effects on cognition and behaviour. Stressors activate the hypothalamic-pituitary-adrenal axis and increase glucocorticoid (GC) levels. GCs are important for neurodevelopment; however, high GC levels increase neuron death and dendritic atrophy. Rodent models of ELS use stressors such as maternal deprivation, limited bedding and nesting material, and endotoxin exposure. Alternatively, some ELS studies administer corticosterone systemically (p.o., i.p. or s.c.) to neonatal rodents. No studies have administered corticosterone in vivo directly to the neonatal brain. Here, we developed a simple and robust method to administer corticosterone to the neonatal mouse brain by intracerebroventricular (icv) injection into the lateral ventricle. We applied a local analgesic to the scalp of postnatal day 5 (PND5) C57BL/6J mice. We then delivered 2 uL of 5, 10, 15, or 45 ng/uL solutions of corticosterone with a single icv injection. 2uL of sterile saline was injected as a vehicle control. After 2.5 hr, we collected the brain, whole blood, and liver. Corticosterone levels in microdissected brain regions, blood, and liver were measured via liquid chromatography tandem mass spectrometry (LC-MS/MS). With higher doses of corticosterone, brain corticosterone levels rose accordingly while peripheral corticosterone levels did not. Our study outlines a novel paradigm of injecting corticosterone into the brain of non-anesthetized PND5 mice that can be used to elucidate the impact of locally elevated corticosterone in the brain and model ELS.

Novel method for intracerebroventricular injection in neonatal mice

Nearly 50 different retinal ganglion cell (RGC) types sample the visual scene for distinct features such as motion direction or line orientation. RGC feature selectivity arises from its synapses with a specific subset of amacrine (AC) and bipolar cell (BC) types, but how their dendrites arborize and collect input from these specific subsets remains poorly understood. We developed a method that combines calcium imaging and post hoc histology that revealed a family of circuits that express the adhesion molecule Sidekick 1 (Sdk1) which include a novel RGC type (S1-RGC) that responds to local edges. Genetic and physiological studies revealed that Sdk1 loss selectively disrupts S1-RGC visual responses which result from a loss of excitatory and inhibitory inputs on this neuron. These phenotypes were specific to S1-RGCs and were accompanied by selective deficits in their dendritic growth. We conclude that Sdk1 shapes dendrite growth and wiring to help S1-RGCs become feature selective.

The cell adhesion molecule Sdk1 shapes assembly of a retinal circuit that detects localized edges

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by a mutation in the gene MECP2. MeCP2 protein is found to be most abundant in neurons where it binds to DNA to act as an A-D global transcriptional regulator. Previous work has shown neurons with MECP2 mutations exhibited morphological and functional hypoconnectivity at a single neuron level. We hypothesized this hypoconnectivity between MECP2¬-mutant neurons will result in altered network development and function. Excitatory neurons derived from iPSCs from a RTT patient, two control patients, and isogenic pairs were generated. Neurons were plated on a multielectrode array and electrophysiology was measured over 6 weeks. Spatiotemporal analyses were used to quantify the electrophysiological features and computational network modeling was used to explore mechanisms driving the differences seen in vitro. iPSC-derived cultures exhibited bursting patterns that went from sparse firing to asynchronous bursting to synchronous bursting across development - quantified through burst frequency. As neuronal cultures developed, mutants grew increasingly different in their burst frequency compared to isogenic controls. Spiking network modelling revealed adaptation currents had the greatest influence on bursting. As adaptation currents increased, the burst frequency shifted to lower values. Simulated knockout experiments supported these results. This suggest that RTT networks may be mediated by adaptation currents, and various regulators for channels involved in adaptation may be implicated as downstream targets of MeCP2.

Electrophysiological characterization of Rett Syndrome in iPSC-derived neuronal networks using computational network modeling

Fragile-X syndrome (FXS), the leading genetic cause of intellectual disability, occurs when the Fmr1 gene on the X-chromosome is silenced, reducing the levels of Fragile-X mental retardation protein (FMRP). This loss of FMRP hinders neurodevelopment and leads to several neurological pathologies, one of which is learning and memory deficits that are attributed to dysregulated hippocampal neurogenesis. The purinergic signalling pathway, where cells use ATP and its metabolites as signalling molecules, is essential for neurogenesis but has yet to be considered in the FXS hippocampus. However, our lab has discovered abnormal purinergic signalling in the FXS cortex, suggesting FMRP regulates this pathway. We hypothesize that purinergic signalling abnormalities exist in the FXS hippocampus and contribute to the dysregulation of neurogenesis. To begin our investigation, we used the Fmr1-KO mouse model to characterize the expression of purinergic receptors known to be involved in neurogenesis. After performing Western Blots on hippocampal tissue at postnatal day 1 (P1), P7, P14, and P21, we found that the P2X7 receptor was upregulated at P7. In mice, P7 is when hippocampal neurogenesis peaks; therefore, overexpression of P2X7 at this critical time point may have increased consequences for the adult mouse. Because P2X7 can play several roles in neurogenesis, it is unclear what those long-term consequences may be. Our next step is to determine which cells overexpress the P2X7 receptor to determine which aspect(s) of neurogenesis this P2X7 overexpression may impact.

Purinergic signalling is altered in the Fmr1-KO mouse hippocampus

Based on the 2016 Survey on Drug use and Health in the USA, 4.9% of pregnant women 15-44 years old reported recent cannabis use. Studies on the long-term outcomes of gestational cannabis exposure (GCE) are limited. Although cannabis ingestion triggers short-term hyperphagia, the incidence of obesity is lower in frequent cannabis users. It is unknown whether GCE will influence the metabolic dysfunction associated with high-fat diet (HFD) consumption in adult offspring. Pregnant female mice received edible cannabis extract, equivalent to THC (5mg/kg/day) or vehicle from GD1.5 till PD10. At least 9 litters culled to 6 mice/litter from each group were examined. Daily body weight and food intake of the dams were recorded during pregnancy and lactation. Body weight and locomotor activity of the pups were monitored at several age points. Adult offspring (7 weeks old) received HFD or control diet (CD) for 12 weeks. Body weight, adiposity, glucose tolerance, insulin sensitivity, and gut microbiota composition are examined. While GCE did not alter the dams' weight gain, food intake, pregnancy duration, or litter size, it reduced the pups' body weight at PD6 and PD11, but not at later ages and decreased their locomotor activity at PD10. GCE female but not male offspring that received CD were more insulin resistant but not heavier or more glucose intolerant than their controls. HFD induced more insulin resistance independent of weight gain in GCE male but not female offspring. Perinatal cannabis exposure negatively impacts insulin sensitivity of adult offspring in a sex-specific manner.

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Investigating the link between hearing loss and age-related cognitive decline in a rodent model

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