Canada

Exposure to early adversity increases the risk for non-transmittable diseases, but also psychiatric conditions, and these common developmental risk factors suggest overlapping underlying mechanisms. The dopamine neurons constitute a system underlying the brain response to environmental conditions and functional variations of this system may be linked to long-term unfavorable outcomes in response to early adversity. We created an expression-based polygenic score for the dopamine transporter gene network (ePRS-DAT1) on the prefrontal cortex and striatum, to explore the role of dopamine on the long-term effects of early life adversity on these outcomes. The ePRS-DAT1 reflects genes co-expressed with DAT1 gene in the PFC and STR in a combined manner, being calculated using the effect size of the association between the individual SNPs from those genes and gene expression (GTEx). Using large datasets (UKBiobank for adulthood and ALSPAC for childhood/adolescence), we demonstrate that the ePRS-DAT1 moderates the impact of early life adversity on the risk for both psychiatric and cardiometabolic comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the ePRS suggesting these regions as critical dopaminergic targets for psychiatric/metabolic comorbidities. These results reveal that psychiatric and metabolic comorbidities showed share common developmental pathways and underlying biological mechanisms.

CAN-ACN 2021

A mesocorticolimbic dopamine gene network moderates the effect of early adversity on the risk for metabolic and psychiatric comorbidities

gene network

metabolic and psychiatric comorbidities

early life adversity

dopamine

gene expression

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

Cortical astrocytes are highly heterogeneous cells with distinct gene expression profiles, phenotypes, and functions. They are born from neural stem/progenitor cells (NSPCs) during embryonic development starting at E15 and undergo a period of rapid expansion in the first postnatal week. Whether time of astrocyte birth from NSPCs determines their position within the murine cerebral cortex is not known. To determine whether time of birth influences astrocyte distribution in the upper (UL) vs. lower (LL) cortical layers, we permanently labelled ventricular-subventricular zone (V-SVZ) NSPCs and their progeny via in utero electroporation with PiggyBac (PB)-CAG-EGFP at E15, 16, and 17 and sacrificed animals at P21. Immunohistochemistry (IHC) for the astrocyte lineage marker SOX9 was performed and EGFP+SOX9+ or EdU+SOX9+ astrocytes were quantified and compared between UL and LL cortical layers within each timepoint. PB-based labelling of EGFP+SOX9+ astrocytes showed that E15- and E16-born astrocytes were mostly found in the UL at P21; this bias was lost in E17-born astrocytes. As an alternative birth dating method, 5-ethynyl-2'deoxyuridine (EdU) was administered to pregnant mice at E16 and tissue was collected at P3 prior to astrocyte expansion. EdU labelling confirmed that SOX9+ astrocytes born at E16 were mostly found in the UL at P3. Altogether, our results suggest that the distribution of SOX9+ cortical astrocytes is influenced by birth date.

Cortical layer distribution of SOX9+ astrocytes from V-SVZ neural stem/progenitor cells depends on time of birth

Exposure to early life stress in humans and animals confers long-term consequences, affecting brain structure and function and increasing the risk for neuropsychiatric pathology. Early life stress can take different forms, such as parental loss, abuse, or poverty. The limited bedding (LB) paradigm has been used in animal models to simulate stress related to the lack of resources, affecting maternal care of her offspring. However, it is still unclear how the LB paradigm affects neonatal brain development, whether the reaching of specific neurodevelopmental milestones is modified differently in male and female offspring and whether a specific domain is preferentially affected. We examined daily reaching of physical, sensory, and motor milestones between P1-15 in offspring from LB and normal bedding (NB) mothers. We later tested open field locomotion and conditioned fear learning using the same animals as juveniles (P28). Animals subjected to the LB condition showed significant delays in achieving physical milestones, such as auditory canal opening; sensory milestones, such as ear twitching reflex and auditory startle response; and motor milestones, such as grasping reflex and surface righting reflex, compared to NB animals. Sex had no significant effect on some of these delays. At the juvenile stage, locomotor activity and conditioned fear response were comparable between groups and sex, suggesting that some of the maturational delays were compensated for after weaning for at least some behaviors. Supported by CIHR PJT162376 to CDW.

Early adversity modifies physical, sensory and motor neurodevelopmental milestones in rat pups

Aim: Youth nicotine exposure is a continued concern due to the growing use of electronic cigarettes and their largely unknown addiction liability, especially during vulnerable periods such as adolescence. Thus, the aim of the following research is to assess developmental differences in nicotine vapour-associated reward and withdrawal. Methods: Experiment 1 - adult and adolescent rats (n = 5-6/group) were exposed to either nicotine (JUUL, 5% nicotine) or vehicle (30:70 propylene glycol to glycerol) vapour using the open-source vapour exposure apparatus, OpenVape, for 10 minutes at 3 doses (2, 4, or 8 minutes of active vapour puffs). To evaluate the reward-like properties of nicotine, a biased place conditioning paradigm was implemented. Experiment 2 - adult and adolescent rats of both sexes (n = 7-8/group) were exposed to either JUUL or vehicle vapour for 10 minutes 3 times a day for 2 weeks. 16 hours following their final exposure, rats were injected with 1.5 mg/kg mecamylamine. 20 minutes following injections, rats were scored for somatic signs of withdrawal for a period of 10 minutes. Results: Experiment 1 - Two-Way ANOVA revealed a significant effect of age (F(1,45) = 9.872, p < 0.003) and dose (F (3,45) = 7.098 p < 0.001). Both adult and adolescent male rats showed significant increases in place preference for the nicotine-paired side, with adolescents displaying significant increases at lower doses than adults. Experiment 2 - Three-Way ANOVA revealed a significant effect of treatment (F(1,51) = 15.99, p < 0.0002) and Sex (F(1,51) = 15.91, p < 0.002) but not age (F(1,51) = 1.151, p = 0.2880). Conclusions: Our results support the notion that adolescence is a period that is more sensitive to the rewarding effects of, but not withdrawal from, nicotine.

Effects of nicotine vapour exposure on reward and withdrawal in adolescent and adult rats

Puberty is a critical period of sexual maturation that is vulnerable to the development of metabolic disorders. Metabolic disorders like Type-1 diabetes are more likely to develop in youths near the onset of puberty. Diabetes onset occurs later in boys than girls, mirroring average sex differences in pubertal onset. Attempts to control diabetic symptoms at their onset may improve prognosis and disease management. Lactate-producing probiotics improve glucose tolerance in adults, but it is unclear if this effect extends to pubertal individuals. Administration of lactate-producing probiotics may assist with glucose management at a vulnerable period of metabolic development. As of 5 weeks of age, 80 male and female CD-1 mice were given ad libitum access to either a control broth, or one of two probiotic solutions (Lacidofil or Cerebiome) for 14 days. Lacidofil and Cerebiome are proprietary blends of Lacticaseibacillus rhamnosus, Lactobacillus helveticus, and Bifidobacterium longum. Weight change and blood glucose and L-lactate concentrations were assessed with an oral glucose tolerance test prior to and after the probiotic treatment period. Pubertal male and female mice displayed less blood glucose, weight gain, and more blood L-lactate after Lacidofil treatment. Pubertal female mice displayed significantly less blood glucose, weight gain and more blood L-lactate after Cerebiome treatment. Our findings indicate that lactate-producing probiotics improve glucose tolerance in mice in a sex-specific manner and may assist in managing metabolic impairments consistent with diabetic development in pubertal groups.

Lactic-acid probiotics enhance glucose tolerance and weight gain in a pubertal mouse model

Background: ProstaglandinE2 (PGE2) is a lipid signalling molecule involved in healthy neurodevelopment. Abnormal PGE2 levels due to genetic or environmental factors are linked to autism spectrum disorders (ASD). Our lab has shown that maternal PGE2 exposure results in differential developmental gene expression, and autism-like behaviours in offspring, including social deficits, and repetitive and anxious behaviours. Our goal was to examine the sex-dependent effect of prenatal PGE2 exposure on cerebellar dendritic morphology and related motor coordination. Methods: Cerebellums of PGE2 and Saline-injected C57BL/6 (WT) offspring at postnatal day 30 were stained with the GOLGI-COX method to measure dendrite length, branching, and the odds of observing dendritic loops. We also examined cerebellar-related motor function using adhesive sticker, grid walking, and cylinder tests. Results: PGE2 mice (males and females) had greater dendritic arborization closer to the soma and higher odds of observing dendritic loops than WT controls. Dendrite length was greater in WT Females (WTF) than in Males (WTM) with no significant differences observed in PGE2 Males (PGE2M) and Females (PGE2F). In the adhesive sticker test, we saw no significant differences in first sticker removal attempt times but more attempts per second in PGE2M. In the grid walking test, PGE2M slipped through the grid more than PGE2F, despite no WT sex differences. While WTM escaped faster than WTF, PGE2M escaped slower than PGE2F. In the cylinder test sex differences in rearing and wall touching in WT mice were lost in PGE2 mice. We saw a reduction in steps in PGE2M compared to WTM. We show that prenatal PGE2 signalling disruptions result in sex-dependent abnormalities in cerebellar development and behaviour.

Prenatal PGE2 exposure causes abnormal cerebellar dendritic morphology and cerebellar related motor coordination in mice

There is a clear male bias in the prevalence of neurodevelopmental disorders (NDDs). Certain environmental factors have been shown to contribute to the etiology of these NDDs, including exposure to antipyretic drugs. To investigate the molecular mechanisms by which environmental factors may contribute to the male bias in NDDs, we focused on two genetic models that mimic antipyretic drug exposure, namely cyclooxygenase-2 knockin (COX-2-) and COX-2 knockout (COX-2-/-) mice. Illumina and Affymetrix GeneChip arrays were used to profile gene expression in brain samples obtained from COX-2-/- mice during prenatal development. Impaired COX-2 activity was found to downregulate the expression of various neuroimmune markers in the brain of males, whereas markers of ribosomal activity were upregulated in females. Further investigations using Real-Time qPCR on postnatal brain samples also revealed that gene markers linked to distinct subtypes of astrocytes were dysregulated in male and female COX-2- mice. While males exhibited an increased prevalence of neurotoxic A1 astrocytes, females exhibited an increased prevalence of neuroprotective A2 astrocytes. Our findings offer novel insight into the sex-dependent effects of antipyretic drugs, which may ultimately facilitate the discovery of therapeutic targets for NDDs exhibiting a male bias.

The impact of impaired cyclooxygenase-2 activity during mouse brain development: a focus on sex differences

Purpose:Impaired attention is the most common and debilitating cognitive deficit following traumatic brain injury (TBI), leading to rehabilitation barriers and long-term disability. Few studies have explored a standardized and evidence-based rehabilitation pathway for impaired attention after TBI. The aim of this study was to gather expert opinion and identify key elements of rehabilitation pathway for attention deficits after TBI. Methods: First, a survey was conducted among 49 rehabilitation experts from designating teaching hospitals to identify the priority in developing the pathway. Second, evidence and priority-based elements of the pathway were set up for acute and post-acute TBI patients. Thirdly, content validity was evaluated by the Modified Delphi technique on 16 neurorehabilitation professionals. Finally, a qualitative study was conducted, using a focus group interview. Results: 'Successful return to the community' and 'development and dissemination of an attention rehabilitation manual' were academic issues of the highest priority in terms of importance and urgency, respectively. Elements of acute pathway included classification of TBI severity, history and physical exam, clinical testing, assessment and management of postconcussion symptoms and neuropsychiatric sequelae in mild TBI, and disorder of consciousness and post-traumatic confusional state in moderate to severe TBI, cognitive rehabilitation, and outcomes. The post-ac pathway highlighted comprehensive and evidence-based assessment, cognitive rehabilitation programs, medication, and education. Conclusion: Implementation of the rehabilitation pathway for attention impairment after TBI may improve a physiatrists' practice and patients' outcome by decreasing the clinical variances, length of hospi

Key elements of rehabilitation pathway for impaired attention after traumatic brain injury in Korea

Background: Prostaglandin E2 (PGE2) is a bioactive lipid molecule involved in healthy brain development, including neuronal differentiation, migration and plasticity. Exposure to various environmental factors during pregnancy such as infections, inflammation, acetaminophen or misoprostol leads to abnormal PGE2 levels and has been linked to Autism Spectrum Disorders (ASD). We have previously determined that maternal exposure to PGE2 results in differential expression of developmental genes and associated autism-like behaviours, including social and motor deficits, repetitive and anxious behaviours. This study investigates sex-dependent effects of a maternal PGE2-exposure at embryonic day 11 (E11) on the morphology of dendrites of C57bl/6 mice offspring. Methods: The hippocampi of PGE2 and Saline-injected wildtype (WT) male and female offspring at postnatal day 30 were stained using the Golgi-Cox method, followed by confocal microscopy to examine dendritic arborization, length, branch order and the odds of observing dendritic loops. Results: We show that compared to matched WT controls PGE2-exposed males and females (PGE2M and PGE2F) had a statistically greater dendritic arborization closer to the soma, had greater primary branching and increased odds of observing dendritic loops. Also, dendrite length was greater only in PGE2M, compared to the controls. Overall, this study provides new evidence that single maternal PGE2 exposure during the critical time in prenatal development contributes to sex-dependent changes in dendritic architecture in the hippocampus of offspring.

Maternal exposure to prostaglandin E2 affects hippocampal dendritic morphology in C57bl/6 mice offspring - link to autism spectrum disorder (ASD)

The neurobiology of depression can increase the risk of developing Alzheimer disease (AD) in later life. The depression-related enzyme monoamine oxidase (MAO) has been implicated in the earliest lesions in the progression of AD. The two isoforms of MAO, e.g. MAO-A and MAO-B, catalyze the degradation of monoaminergic neurotransmitters (e.g. serotonin, dopamine, and noradrenaline) and MAO-mediated neurocytotoxicity may involve hydrogen peroxide (a reaction byproduct). MAO protein expression and catalytic activity often do not correlate and an unrecognized pool of inactive MAO could bias results and give rise to misleading conclusions. Perhaps this explains why MAO inhibition has been only modestly successful in clinical AD populations. It is impossible to differentiate active from inactive MAO protein in cells and tissues. Activity-based probes (ABPs) are probes designed to attach to the catalytic sites of active enzymes. Exploring this concept, our team has synthesized three fluorescent ABPs and using recombinant MAO-A and MAO-B proteins, endogenous (LnCAP cells) and overexpressed (N2a cells) MAO proteins, and confocal microscopy, we demonstrate that these probes bind irreversibly and selectively to MAO-A. This will benefit future live-cell imaging studies. ABPs, especially highly selective candidates, will give us a better understanding of the function of MAO-A and MAO-B in health and could help define a role for MAO in pathology and provide for a stage-specific therapeutic intervention strategy with benefit for clinical depression as well as AD.

Developing selective fluorophore-tagged activity-based probes for live-cell imaging of active monoamine oxidase

BACKGROUND AND AIM Several functions, motor or sensory, rely on the ability of neurons to modify their discharge pattern to faithfully encode the characteristics of a sensory stimulus or to reflect a rhythmic motor control for example. Changes in firing pattern often involve particular ion channels and are intimately related to the function of the circuit. Astrocytes are increasingly recognized as key regulators of neural activity, through release of gliotransmitters. An increasing number of studies have documented how they affect synaptic and network functions. However, their contribution to neuronal computations is still poorly understood. METHODS: Whole cell patch recordings of neurons and astrocytes was combined to Ca2+-imaging and optogenetic manipulations in either brainstem or cortical slices from rats and transgenic mice. RESULTS: Here I will describe a mechanism first identified in a brainstem trigeminal circuit where neuronal firing pattern depends on particular Na+ channels sensitive to the extracellular Ca2 + concentration which is regulated by astrocytes through release of the calcium-binding protein, S100ß. The same mechanism also contribute to inputs integration and influences the input-output function of cortical layer 5 pyramidal neurons, and of primary afferents neurons. I will also describe how astrocytic coupling define functional domains and determines synchronization and coordination of neuronal firing within these domains. CONCLUSIONS Neuron-glia interactions are most often thought to occur at or near synapses. Our results suggest that astrocytes control neural activity by acting directly on or near the neuronal ionic channels, a largely unexplored form of communication between astrocytes and neurons. The S100β-dependent mechanism adds up to the previously reported conventional gliotransmitters such as glutamate, GABA, and ATP. Beyond increasing our understanding of how astrocytes contribute to neuronal computations an important value of our findings resides in the increased understanding of the role of S100β which is abnormally regulated after trauma and in many neurological disorders including epilepsy, depression, Parkinson's and Alzheimer's diseases. We propose that abnormal S100β control may have a wide impact by leading to abnormal extracellular ionic environment, abnormal neural activities, and thus pathological states.

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Cortical layer distribution of SOX9+ astrocytes from V-SVZ neural stem/progenitor cells depends on time of birth

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