Canada

Spikes are usually initiated at the axon initial segment (AIS), the most excitable site of a neuron. Yet other regions of the neuron are also excitable. While there are many studies on somatic and dendritic excitability, axon excitability has yet to be thoroughly investigated in most neurons because the small size of the axon precludes intracellular recordings. Using a novel optogenetic approach, recent experiments from our lab have shown that axon spikes transiently in response to sustained depolarization. Although the optogenetic method has many advantages, it still has some limitations: first, light is not focused on one point, meaning stray light may hit other regions of the neuron; second, since voltage changes are recorded from the soma, the location of spike initiation must be inferred indirectly. These experimental limitations necessitated simulations to definitively interpret the experimental results. We built a multicompartment model of a CA1 pyramidal neuron with a detailed myelinated axon that reproduced our experimental data. The model confirmed the site of spike initiation based on the shape (kinkiness) of spikes recorded in the soma. Simulations also confirmed that even when targeting the axon for photostimulation, a small degree of stray light can hit the dendrites and evoke spikes in the AIS. The results ultimately confirm that the AIS spikes repetitively during sustained depolarization, consistent with analog to digital transduction of information, whereas the axon responds with transient spiking only during abrupt changes in depolarization. Simulations show that the stimulus the axon receives during spike propagation is a very intense and short depolarization, which is precisely the input to which it is tuned to respond.

CAN-ACN 2021

Transient spike initiation supports digital information transfer in axons: simulations in a biophysically detailed model

excitability

axon

computational modeling

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

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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

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Listen to internationally known plenary speakers, attend sessions, workshops, and special activities. Attending the virtual summer meeting is an excellent opportunity to share your expertise and learn from and network with leaders in the field.

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AAPT SM21

poster

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.

Optogenetic-mediated spatiotemporal control of α-synuclein aggregation mimics Lewy body formation and triggers neurodegeneration

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.

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

Adult hippocampal neurogenesis (AHN) is the process that generates neurons from neural progenitor cells (NPCs) in the adult hippocampus. AHN is important for proper learning, memory, cognition, and mood regulation but is severely decreased in memory and mood disorders. Understanding how AHN is regulated may lead to treatments for these conditions. AHN entails multiple cell stages involving NPC proliferation and differentiation, followed by neuron maturation. The transition of these cell stages is regulated by expression of specific transcription factors. We found that the transcription factor capicua (CIC) is expressed in NPCs but is downregulated during NPC differentiation. Contrastingly, CIC is upregulated during neuron maturation. Such expression changes suggest CIC might play a role in AHN. Here we find that deleting CIC in the hippocampus, including the adult hippocampal neuronal lineage, results in reduced NPCs due to increased differentiation into immature neurons. These immature neurons have impaired dendrite complexity and abnormal migration, with delayed progression to fully matured granule neurons. Together, our results show that CIC plays a critical role in NPC differentiation and neuron maturation in AHN. Our study identifies a previously unknown role for CIC in AHN. Given that decreased AHN is associated with mood and memory disorders, future investigations into the genes and pathways that CIC regulates may reveal crucial molecular inroads and therapeutic entry points into these conditions.

Capicua is required for the regulation of adult hippocampal neurogenesis

The adult brain has a remarkable capacity to produce new cells that migrate and integrate into pre-existing neuronal circuits throughout the lifespan of animals. Adult neural stem cells (NSCs) in subventricular zone (SVZ) are a largely quiescent population and their activation and proliferation is modulated by a number of physical and chemical cues from different sources. However, the mechanisms that integrate those signals and regulate quiescent/proliferative (Q/A) states transition are poorly understood. In this study, using ex-vivo calcium imaging, we revealed the universal Ca2+ signature that characterize activated (aNSCs) and quiescent (qNSCs) NSCs states. We showed that qNSCs are characterized by higher frequency of Ca2+ fluctuations and lower intracellular Ca2+ level, compared to aNSCs. This different Ca2+ dynamics were regulated by intracellular IP3-sensitive Ca2+ stores. Pharmacological inhibition of IP3-sensitive stores decreased the frequency of Ca2+ fluctuations and increased intracellular Ca2+ level of qNSCs. Similarly, CRISPR-Cas9 mediated deletion of Itpr2, specifically in SVZ NSCs resulted in the same characteristic differences in the Ca2+ dynamics. Importantly, these changes were accompanied with increase in proliferation indicating a causal relationship between internal store-dependent Ca2+ dynamics and NSCs Q/A transition. We also showed that anti-proliferative pathways are keeping NSCs quiescent by modulating calcium dynamics. For instance, pharmacological inhibition of the melatonin signaling pathway activates NSCs by reducing the frequency of Ca2+ fluctuations and increasing intracellular Ca2+ levels. Altogether, our data suggest that Ca2+ signaling in NSCs may integrate and decode different signals to regulate NSCs Q/A transition.

Quiescent and proliferative states of adult neural stem cells are characterized by different Ca2+ dynamics and steady-state intracellular levels

Haploinsufficiency of Syngap1 gene encoding the Synaptic Ras- GTPase Activating protein is associated with intellectual disability, autism spectrum disorder and epilepsy. Haploinsufficiency of Syngap1 leads to alterations in synaptic plasticity, behavioral abnormalities and cognitive deficits in mouse models. In particular, several studies have shown that Syngap1 regulates the time course of the maturation of dendritic spines and glutamatergic synapses in excitatory neurons; In contrast, the role of Syngap1 in inhibitory, GABAergic neurons is relatively uncharted. GABAergic neurons are a diverse class of neurons with different morphology, connectivity and physiological properties. They play an important role in neural circuit development and plasticity. Parvalbumin (PV)-expressing interneurons, one of the major classes of cortical GABAergic interneurons, form synapses onto the soma and proximal dendrites of pyramidal cells and are involved in the synchronization of the firing rate of pyramidal cell populations. Our aim is to study the role of Syngap1 in PV cell development In vivo, in establishing balanced synaptic connectivity and proper network in contributing to the behavioral endophenotype and cognition in mouse model by techniques like immunolabelling the synapses and behavioral studies. Preliminary data suggest that alteration in synaptic connectivity of PV cells in different cortical regions do contribute to observed overall behavioral and cognitive deficits. A better understanding of the role of Syngap1 in GABAergic cell development may shed light on the involvement of GABAergic circuit alterations in the cognitive deficits caused by Syngap1 haploinsufficiency in humans.

Understanding the role of SYNGAP1 in GABAergic circuit development and function

Astrocytes are involved in diverse and highly specialized functions in the brain. They display morphological and molecular heterogeneity that is reflective of the microenvironments in which they reside. Astrocytes also become reactive in many brain disorders and diseases, and contribute to disease progression. To better understand how astrocytes develop and specialize within brain microenvironments, we transplanted mouse astrocytes into the mouse cortex in the first postnatal week, and assessed their integration in the host brain at various time points. We found that transplanted astrocytes developed complex morphologies typical of cortical protoplasmic astrocytes and displayed tiling arrangements with astrocytes from the host brain. Also, at 110-130 days post-transplantation, transplanted astrocytes expressed the same levels of GLAST/EAAT1, GLT1/EAAT2, and GFAP as astrocytes in the host brain. Similarly, spatial territories covered by transplanted astrocytes displayed the same density of pre-synaptic terminals as territories covered by host brain astrocytes. Finally, transplanted astrocytes developed endfeet with high AQP4 expression that were tightly associated with capillaries, similar to what we observed with astrocytes in the host brain. Our results indicate that transplanted astrocytes successfully integrate and survive long-term within the mouse brain when transplanted in the immature cortex. These findings open the possibility of using transplanted astrocytes to monitor changes in brain activity/function, and potentially as therapeutic tool to tackle brain diseases.

Transplanted astrocytes develop, mature, and survive long-term in the mouse cortex

Though cannabis use during pregnancy has increased, our understanding of its effects on offspring is incomplete. Gestational THC injection studies found altered goal-directed behaviour and mesolimbic dopamine reward circuitry in offspring of various ages. To investigate whether oral cannabis exposure during pregnancy alters ventral tegmental area (VTA) dopamine neuron activity, mice were exposed to 5 mg/kg THC cannabis extract in peanut butter or peanut butter alone from GD0-PD10. Whole cell patch clamp electrophysiology was performed in VTA slices from adolescent (P42-P46) offspring. Maternal weight gain, food intake, litter size, frequency of miscarriages, or maternal behaviour in a pup retrieval test were not different between groups, suggesting the effects of cannabis are not secondary to poor maternal care or health. VTA dopamine neurons of male mice exposed to cannabis from GD0 to PD10 had a more depolarised resting membrane potential, increased spontaneous firing, decreased latency to fire, and increased after-hyperpolarisation potential height, but not width. In contrast, dopamine neurons from female mice had shorter after-hyperpolarisation potentials, without changes in resting membrane potential, spontaneous firing frequency or other firing properties. Consistent with previous injection studies, prenatal exposure to oral cannabis differently alters the firing properties of male and female VTA dopamine neurons. Future research will examine synaptic changes and the behavioural implications of cannabis-induced differences in VTA dopamine neuronal activity.

Prenatal cannabis exposure alters the firing properties of adolescent ventral tegmental area dopamine neurons

Astrocytes express different neurotransmitter receptors that serve to integrate these cells into neuronal networks. Many of these receptors, when sensing neuronal activity, induce elevations in intracellular astrocyte Ca2+, which leads to the release of gliotransmitters that modulate nearby neurons. Ionotropic N-methyl-D-aspartate (NMDA) receptors are found on astrocytes and are activated by glutamate and D-serine or glycine, and conduct Ca2+ into astrocytes. In brain slices, astrocyte NMDAR activation causes depolarization and Ca2+ elevations. However, its role in astrocytes Ca2+ transients and feedback modulation to neurons in vivo is not characterized. Therefore, we used a novel NMDAR knockdown (KD) construct to reduce NMDAR expression specifically in cortical astrocytes. Then, using dual calcium imaging of astrocytes and neurons each expressing a unique genetically encoded calcium indicator (Lck-GCaMP6f and RCaMP1.07 respectively) we determined the impact of astrocytes NMDARs on astrocytes Ca2+ transients and nearby neuronal activity. Two-photon microscopy of the barrel cortex of awake mice revealed that NMDAR KD reduced Ca2+ responses to whisker stimulation in both astrocytes and neurons. This highlights the importance of NMDAR in astrocyte Ca2+ signalling and astrocyte-neuron communication and suggests that astroglial NMDAR KD could cause deficits in sensory perception. This work contributes to a deeper knowledge of mechanisms underlying astrocyte Ca2+ signalling and provides novel directions to study the role of astrocytes in neuronal circuits.

Transient spike initiation supports digital information transfer in axons: simulations in a biophysically detailed model

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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

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