Canada

Brain development and function are exceptionally reliant on the adequate development and maintenance of vascular networks. As such, early impairments in vascular health can lead to neurodevelopmental defects. Despite a wealth of knowledge on neuronal mechanisms of autism spectrum disorders (ASD), very few studies have considered the role played by the brain vasculature in ASD. ASD are viewed as neurodevelopmental conditions associated with genetic origins such as the common 16p11.2 deletion which leads to haploinsufficiency of 27 conserved genes. We undertook an extensive study to investigate the cerebrovascular contributions to ASD and revealed that 16p11.2 deletion induced endothelial-dependent structural and functional neurovascular abnormalities, establishing a novel vascular link to ASD. While this study associated dysfunctional endothelial cells (ECs) with 16p11.2 deletion syndrome, the endothelial aspects leading to these dysfunctions remain to be elucidated. We are using an untargeted metabolomics approach, as well as assessing mitochondrial function, to decipher core features of brain ECs isolated from a mouse model of 16p11.2 deletion syndrome. We identified an energetic failure in 16p11.2 deficient ECs compared to WT ECs, as shown by altered concentration of high energy metabolites involved in the Krebs cycle as well as in energy supply. This research program will provide new insight into key players in ASD pathogenesis, which is an essential pre-requisite for the development of transformative therapeutic strategies.

CAN-ACN 2021

Metabolic defects in brain endothelial cells from 16p11.2 deletion autism mice

cerebrovasculature

autism spectrum disorders

development

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

Memory reactivation (RA) can facilitate trace destabilization, enabling memory updating. Some memories, however, are resistant to modification. Specifically, elderly individuals display deficits in declarative memory updating. There is currently no treatment to target this cognitive impairment, likely because factors mediating RA-based memory updating remain unclear. We propose that cholinergic signalling supports RA-based memory changes. Recent findings in our lab suggest that M1-muscarinic acetylcholine receptor (mAChR) signalling within perirhinal cortex supports object memory destabilization and RA-based updating. Correspondingly, aging research indicates a decline in cholinergic transmission across the lifespan. Therefore, we hypothesize that age-related cholinergic system dysfunction underlies memory updating deficits in elderly individuals. To test this, we used a post-RA object memory modification (PROMM) task--where a reactivated object memory is updated with new contextual information--to assess object memory updating in 3-, 6-, and 12-month-old male mice. 3-month-old mice showed intact PROMM task performance, 6-month-old mice showed a mild impairment, while 12-month-old mice were severely impaired. Subsequently, we administered the M1-selective agonist CDD-0102A prior to object memory RA in the PROMM task in the 12-month-old male mice; remarkably, pre-RA systemic M1-mAChR agonism enhanced PROMM task performance. These results therefore suggest a promising neural target for promoting the modification of inflexible memories in aged populations.

Systemic M1 muscarinic acetylcholine receptor activation can restore aging-related object memory updating deficits in mice

Current hypotheses propose that sleep/wake regulation depends on both the circadian clock and a homeostatic process. The glycogen synthase kinase-3 beta (GSK3b) regulates the activity of key circadian transcription factors (e.g., BMAL1, CLOCK). GSK3b is also involved in long-term depression and metaplasticity. Moreover, FXR1, a GSK3b substrate, has recently been shown to affect both cell-autonomous homeostatic plasticity and system-level response to sleep loss in a GSK3b-dependent manner. This project thus aims to investigate a potential role of GSK3b in circadian and homeostatic sleep/wake regulation by verifying how its knockdown (KD) in cortical neurons impacts vigilance states under normal (baseline: BL) and sleep-deprived (SD) conditions. A neuron-specific KD of Gsk3b was achieved in adult male mice via dual adeno-associated virus delivery of a CRISPR/Cas9 system. Cortical viral injections and electrocorticography (ECoG)/electromyography (EMG) electrodes implantation surgeries were done simultaneously 3 weeks prior to ECoG/EMG recording, which comprises 24 h of BL, 6 h of SD, and 18 h of recovery. Analyses notably include vigilance state duration/distribution and ECoG spectral activity. Gsk3b KD did not affect the time spent in wakefulness and sleep states nor the alternation between states. However, the KD of Gsk3b in the motor cortex decreased gamma (30-50 Hz) activity during wakefulness and alpha (8-10 Hz) activity during slow-wave sleep (SWS). Moreover, a SD-induced increase in beta/gamma (20-50 Hz) activity during SWS was found in the visual cortex only under Gsk3b KD. These results support a role for GSK3b in the regulation of ECoG activity during wakefulness and sleep, and bring a deeper insight on molecular mechanisms controlling vigilance state quality.

Knocking down glycogen synthase kinase-3 beta (GSK3b) in cortical neurons affects the mouse electrocorticogram across vigilance states

Bipolar disorder (BD) is associated with language disturbances such as speech pressure and poverty of speech. However, little is known about the neurophysiology underlying language deficits in BD. In a previous study, we extracted three functional brain networks (i.e., a linguistic processing network - LPN, default mode network - DMN, and motor response network - RESP) involved in the lexical decision (LD) task by manipulating the "word-likeness" of LD stimuli combined with a multivariate functional connectivity analysis in healthy adults. Here, we applied the same techniques to determine if these three networks could be extracted in people with BD. The BD patients (n = 25) were also compared to controls (n = 21) to assess possible difficulties in LD task performance and abnormal activity in the three functional networks in BD. There were no differences between BD patients and controls in their accuracy or reaction times in the LD task. We replicated our previous work in healthy subjects as we were able to separate the LPN from the DMN and RESP. LPN activity did not differ between the groups, which is in line with the lack of significant differences in LD task performance between BD and control. BD was associated with sustained activity in the RESP, which involves activations in left-dominant pre- and post-central gyri and juxtapositional lobule cortex, as well as bilateral activations in superior and inferior lateral occipital cortex, superior parietal lobule, and occipital fusiform gyrus. Impairment in RESP may be observed in any task and could potentially be a biomarker for BD.

Altered activity in functional brain networks involved in lexical decision in bipolar disorder

It has been proposed that a context paired with ketamine (KET) can elicit an antidepressant response through principles of Pavlovian conditioning. This raises the question as to whether this conditioned antidepressant response is unique to KET, or whether it can be generalized to other antidepressant drugs with known pharmacological mechanisms like the serotonin reuptake inhibitor, escitalopram (ESC), or the norepinephrine-dopamine reuptake inhibitor, bupropion (BUP). Thus, the current study investigated whether a context paired with KET, ESC, or BUP could influence the immobility response to forced swimming stress (FSS; 10 mins/session, 3 sessions total), which is a preclinical tool used to assess the antidepressant efficacy of drugs. To do this, male Sprague-Dawley rats were injected with 0.9% saline (w/v; SAL) and placed in a vehicle-paired context (CS-) and injected with SAL, KET (10 or 20 mg/kg, IP), ESC (10 mg/kg, IP), or BUP (10 mg/kg, IP) and placed in a drug-paired context (CS+) on alternating days (10 days total, 5 pairings each in the CS- and CS+). One week later, rats were exposed to 3 sessions of FSS over 3 consecutive days (FSS1-3; exposure to CS- and CS+ prior to FSS2 and FSS3, respectively). Exposure to a KET-paired context prior to FSS3 significantly reduced immobility without affecting general locomotor activity in comparison to contexts paired with SAL or BUP, but not ESC. These findings support the notion that a KET-paired context elicits a conditioned antidepressant response, and that this response may partially involve serotonergic mechanisms.

Conditioned effects of a ketamine-paired context: implications for its antidepressant mechanism

Ancient medicine drugs containing the alkaloid rhynchophylline (RHY) increase sleep duration and quality in humans. Although treatment with RHY alone has not been tested in humans, rodent studies suggest that it modulates cellular pathways involved in sleep/wake regulation by targeting ion channels and kinases. Interestingly, RHY can inhibit EphA4, and EphA4-/- mice have sleep alterations. We thus studied effects of RHY on sleep and related molecular mechanisms. The electrocorticogram was recorded in male and female mice receiving 50 or 100 mg/kg of RHY (or saline) at light onset and 1h before light offset. Sleep architecture and spectral activity were examined. Additional groups had their brains sampled 3h after each injection to assess changes in the transcriptome with a high spatial resolution. In both sexes, RHY decreases wake and increases NREM sleep during the dark period, and reduces REM sleep during the light period. Moreover, RHY shortens individual bouts of wake and NREM sleep. RHY also enhances activity in low frequencies in wake and modifies the time-course of NREM sleep delta and sigma activity. Preliminary results in females suggest that Rhy affects the expression of genes such as Sgk1 similarly at the beginning of the light and dark periods, while its impact on mitochondrial genes and genes expressed in the hypothalamus appears time-dependent. RHY modifies sleep in manners similar to EphA4-/- mice, but additional effects may suggest EphA4-independent mechanisms. The transcriptomic approach will help defining how RHY impacts wake/sleep regulatory circuits.

The traditional Chinese medicine component Rhynchophylline modifies sleep and the brain spatial transcriptome in mice

It has been established that exposure to drug conditioned stimuli (CS) can enhance memory consolidation, indicating that drug CSs not only produce changes in behaviour, but can also impact cognition. Therefore, it is possible that conditioned memory modulation, like other conditioned responses, will display extinction. The current study used classical and operant conditioning techniques to test this hypothesis in male Sprague-Dawley rats performing an object location (OL) memory task. To establish the CS in Experiment 1, rats were injected with heroin (0, 0.3, 1 mg/kg, S.C.) and immediately placed in operant chambers for 1 hr, once a day for 5 consecutive days. It was found that exposure to the heroin-CS four days after conditioning dose-dependently enhanced object location memory. In addition, when tested after 6 exposures to the CS without receiving heroin, the CSs ability to modulate memory was significantly reduced. In Experiment 2, rats were trained to self-administer heroin (0.05 mg/kg/inf) on a continuous reinforcement schedule for 12 days. It was found that exposure to the heroin-CS four days after training enhanced object location memory, and when tested after 6 exposures to the CS without receiving heroin, the CSs ability to modulate memory was significantly reduced. Taken together, these results support the idea that conditioned memory modulation occurs in parallel with conditioned responses that are mediated by conditioned stimuli.

Extinction of conditioned memory modulation

Maternal immune activation (MIA) in mice can be used to investigate the link between perinatal infection and early-life developmental disorders such as cerebral palsy and autism spectrum disorder. Studies have shown that adult mice exposed to a bacterial or viral immune response during early- to mid-embryonic development display reduced social communication and interaction, and increased repetitive stereotypic behaviour. To date however, few studies have looked at the effects of MIA on early behaviours and developmental milestones in mice. In the current study, pregnant CD-1 dams were injected at embryonic day 11.5 with either lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (PolyIC) to stimulate aspects of a bacterial or viral immune response, respectively. Offspring were then assessed from post-natal day 2-21 using a modified Fox developmental behavioural test battery to assess reflexive and morphological developmental milestones. Additionally, grooming, homing to maternal bedding, and activity/exploration in the open field were evaluated. Overall, accelerated development and alterations in behaviour were observed in the MIA mice compared to sham-injected controls. These results suggest that MIA results in differential physiological and behavioural characteristics that emerge during early post-natal development, and further highlight the need for research that focuses on the effects of MIA during this developmental period.

The effects of maternal immune activation on early developmental milestones and behaviour in outbred CD-1 mice.

Background: Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite Orientation Dispersion and Density Imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructure. NODDI maps can be calculated for neurite density index (NDI), orientation dispersion index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, being more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations.Aims: We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS.Methods: Three reviewers conducted the literature search of four electronic databases (Medline, Embase, Scopus, and PubMed). We performed a random-effect meta-analysis. The extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger's tests were used to assess publication bias.Result: We identified 7 studies analysing 374 participants (202 MS, 172 controls). NDI in WM lesions and NAWM were significantly reduced compared to healthy WM. The standardised mean difference was -3.08 (95%CI -4.22 to (-1.95), p=<0.00001, I2=88%) and -0.70 (95%CI -0.99 to (-0.40), p=<0.00001, I2=35%) respectively. There was no statistically significant difference of ODI in MS WM lesions and NAWM compared to healthy controls. The standardised mean difference was -0.44 (95%CI -1.60 to (-0.71), p=0.45, I2=95%) for WM lesions and -0.46 (95%CI -2.07 to (-1.15), p=0.58,

Investigating microstructural changes in white matter in multiple sclerosis: A systematic review and individual participant data meta-analysis of neurite orientation dispersion and density imaging

Microglia are functionally dynamic brain immune cells known to adapt their morphology depending on their environment. These context-dependent morphologies are extensively measured to inform changes in function. However, current manual morphological analyses, while informative, are often time-consuming and fail to detect subtle differences in cell architecture. To solve these limitations, we tested the sensitivity of an open-source quantitative method to measure microglial morphology called Fractal Analysis, adapted into a manual analysis of cell perimeter and area. Using the automated FracLac Plugin (ImageJ), we calculated the fractal dimension (FD) and lacunarity (LA), complementary indices, of two sets of immunohistochemical stainings (fluorescent and non-fluorescent) of hippocampal microglia and infiltrating bone marrow-derived macrophages (BMDM) from healthy postnatal mice. By creating a macro, we were able to combine our manual methodology to the fractal analysis, and find that FD and LA were more sensitive to changes in morphology than measurements of area and perimeter. In our dataset, FD and LA were both significantly increased in microglia compared to BMDM, while only LA was significantly higher in microglia among the ventral compared to the dorsal part of the hippocampus, possibly indicating increased process ramification. The detection of these differences in healthy tissue emphasizes the diverse regional morphology of microglia compared with infiltrating immune cells, but also the sensitivity of this automated methodology to detect subtle morphological changes.

Testing available quantitative methods to analyze brain immune cell morphology

α-synuclein (α-syn) aggregation into insoluble deposits, referred to as Lewy bodies (LBs) is the paramount pathological hallmark of Parkinson's disease (PD) and related α-synucleinopathies. However, how these aggregates affect neuronal homeostasis leading to neurodegeneration remains elusive. This gap in knowledge is mainly due to the lack of proper cellular and animal models to undertake such investigations. We have addressed this limitation by developing a light-inducible protein aggregation system (LIPA). This application is based on the use of a mutant form of the Arabidopsis thaliana photoreceptor cryptochrome 2 (CRY2), which when stimulated with blue light, mutant CRY2 undergoes rapid, reversible and robust protein clustering or aggregation. The use of this application allows for real-time induction of α-syn inclusions formation with remarkable spatial and temporal resolution in both cell culture and in vivo paradigms. We used a gene therapy approach, based on the use of adeno-associated virus (AAV), to overexpress our LIPA system directly into the brains of naive mice. For the delivery of the blue light necessary for the induction of the aggregation and propagation of α-syn, we used implantable micro-devices developed by Amuza Inc. We report on the development of a light-inducible protein aggregation (LIPA) system that enables real-time induction of α-syn inclusion formation with remarkable spatial and temporal resolution in living cells. In vivo, LIPA-α-syn aggregates compromised the nigrostriatal transmission, induced dopaminergic neuronal loss and PD-like behavioral impairment. Our system provides a novel, dependable and invaluable tool to generate, visualize and dissect the role of protein aggregates in PD and possibly other neurodegenerative disorders.

Metabolic defects in brain endothelial cells from 16p11.2 deletion autism mice

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