Canada

**AutMultiple sclerosis (MS) is primarily characterized by demyelination within the central nervous system; however, the sustained clinical deficits associated with progressive forms of the disease are correlated with neuronal degeneration and death. Several mechanisms occurring within the MS lesion environment have been associated with axonal damage, including oxidative stress, hypoxic stress and glutamate excitotoxicity. Currently, there are no therapies preventing the neurodegeneration underlying chronic disability in progressive MS. Accordingly, biomarkers of neuronal damage that may suggest novel therapeutic targets and serve as prognostic indicators of disease progression are of great need. microRNAs (miRNA) are small, non-coding RNA molecules that inhibit translation of messenger RNA. They are often secreted from cells within extracellular vesicles (EVs), which are highly stable in circulation and abundant in human blood samples. Here, we use a reductionist in vitro culture system to profile miRNA expression in EVs released from human iPSC-derived neurons challenged with MS-relevant stimuli. We show that iPSC-derived neurons degenerate upon exposure to toxic stimuli and that EV miRNAs can be reproducibly obtained from degenerating neurons for sequencing. We aim to identify regulated EV miRNAs in our in vitro assays which can then be compared to neuronally-derived EVs isolated from MS patient plasma. We hope to identify a conserved miRNA signature that can be used to monitor neurodegeneration and disease progression in MS, while defining new neuroprotective strategies.

CAN-ACN 2021

Profiling EV microRNAs from degenerating neurons to identify biomarkers for multiple sclerosis

exosome

extracellular vesicle

mirna

neurodegeneration

biomarker

multiple sclerosis

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

Background: Experiencing child abuse (CA) is considered as one of the strongest predictors of depression and suicide. Childhood and adolescence are characterized by critical periods (CP) of heightened cerebral plasticity, in which neural circuits can be more easily modified by experience. The closure of these CP is driven by the development of perineuronal nets (PNNs) around certain neurons in the brain. We hypothesize that CA occurring during these CP alters the recruitment and maintenance of PNNs in brain regions involved in emotional regulation. Methods: Well-characterized brain samples of ventromedial prefrontal cortex (vmPFC) from adult depressed suicides with or without a history of CA and matched controls were provided by the Douglas-Bell Canada Brain Bank. Immunofluorescent staining was performed with different combinations of cellular markers (PV, NeuN, Westeria Floribunda Lectin). Fluorescent in situ hybridization (RNAScope®) was performed to identify the phenotype of neurons enwrapped by PNNs. Whole slide and confocal images were analyzed using QuPath and FIJI. Results: As previously reported, PNNs were found to be covering PV+ interneurons and, to a lesser extent, pyramidal neurons (SLC17A7+). CA was found to be associated with higher densities, intensity and coverage of PNNs in the lower layers of the vmPFC. Conclusions: These results suggest that a history CA has a lasting impact on vmPFC circuitry. This may represent a mechanism through which early-life adversity increases vulnerability to psychopathologies and suicide. Experiments are under way to determine the mechanisms underlying this phenomenon, namely through an examination of proximal microglia, which have been shown to be implicated in the regulation and maintenance of PNNs in animal models.

Perineuronal nets in the ventromedial prefrontal cortex of depressed suicides with a history of child abuse

A history of child abuse (CA) strongly increases the lifetime risk of suffering from major depression and predicts an unfavorable course for the illness. Severe CA has been specifically associated with a widespread, robust, and lasting inhibition of oligodendrocyte function, coupled with impaired myelination of small caliber axons in white matter of the human anterior cingulate cortex (ACC). Given that myelin is extremely lipid-rich, one possible explanation for this finding could be a disruption of the lipid profile that composes the myelin sheath. Furthermore, the composition of fatty acids (FA) in myelin phospholipids has been demonstrated to influence its stability and permeability. Therefore, the objective of this study was to quantify and compare FA concentrations in postmortem ACC white matter in the choline glycerophospholipid pool (ChoGpl), a key myelin phospholipid pool, between adult depressed suicides with a history of CA matched depressed suicides without CA and healthy non-psychiatric controls. Total lipids were extracted according to the Folch method and lipids were separated into respective classes using thin-layer chromatography. FA methyl esters from the ChoGpl fraction were quantified using gas chromatography. Our analysis revealed significant differences in FA concentrations between groups, primarily involving the FAs in the arachidonic acid synthesis pathway, which is further corroborated with ACC RNA-sequencing data. Furthermore, the concentration of most FAs was found to decrease with age. These findings are the first to associate a history of early-life adversity with ChoGpl dysregulation in the human brain.

A history of child abuse associates with fatty acid dysregulation in the anterior cingulate cortex of depressed suicides

Interictal epileptiform discharges (IEDs) and Sharp Wave ripples (SWR) are pathological and physiological events in patients with temporal lobe epilepsy. Although these two events may display similar temporal frequency patterns, they carry different energy in different frequency bands. We study a group of epilepsy patients with medically resistant epilepsy (MRE) at the Lawson Research Center at UWO, implanted with SEEG depth electrodes (DE) to identify interictal abnormalities IEDs and differentiate them from SWRs using a new algorithm. The data were cleaned, denoised, montaged and segmented, such as sleep intervals and observed Ictals. The signal waveform and its power were extracted symmetrically in non-overlapping intervals of 500 milliseconds for event detection. Each waveform's power across all detected spikes was computed and clustered based on their energy distributions. The recordings included more than 720 hours of extracellular recordings from three patients with 450 hours of non-sleep data extracted from four hippocampus electrodes anterior and posterior hippocampus. Results indicate that IEDs carrying the largest power in the bands [30-45] Hz, SWR, on the other hand, are distributed between and [25-40] and [90-110] Hz. Our algorithm detected and successfully distinguished IED from SWRs based on their carrying energy during non-sleep periods. The waveforms' energy is more significant in sleep than awake (non-ictal) periods, and was this characteristic was used as an informative feature to cluster these two events.

Physiological and Pathological transients in temporal lobe Epilepsy patients during intracranial recordings

Mutations in the ATP-dependent chromatin remodeller chromodomain, helicase, DNA binding (CHD) 7 are the primary cause of CHARGE syndrome (CS) and have been associated with autism spectrum disorder (ASD). CHARGE is an acronym for the most characteristic features presented by patients: coloboma of the eye, heart defects, atresia chonae, retardation in growth and development, genital abnormalities, and ear defects. Although not included in the diagnostic criteria CS features often include neurological and behavioural problems such as hyperactivity, seizure, intellectual disability and autism. Little is known about the molecular mechanisms that underlie these neurological symptoms. Further, there is no known treatment yet either for patients with CS or for the neurological symptoms shared between CS and ASD. To investigate this, we generated a novel CRISPR/cas9 zebrafish chd7−/− model. We show that chd7 knockout zebrafish larvae exhibit a small head phenotype, defects in craniofacial cartilage development and display aberrant axonal network development. Further the chd7 mutants have less GABAergic neurons and exhibit a hyperactivity behavioural phenotype. Using an unbiased whole transcriptomic approach, we found that the GABAergic neuron defect was at least in part due to the downregulation of a CHD7 target gene, paqr3b and the subsequent upregulation of the MAPK/ERK signalling pathway, which is also dysregulated in CHD7 mutant human cells. Through a phenotype-based screen in chd7−/− zebrafish and C. elegans, we show that the small molecule ephedrine restores MAPK/ERK signalling and improves both GABAergic defects and behavioural anomalies. This work provides insight into the neuropathogenesis in CS and identifies a promising compound for further preclinical studies.

Chd7 loss of function in zebrafish impairs GABAergic network development through MEK/ERK signalling: CHARGE syndrome and beyond

BACKGROUND Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease with cognitive, behavioral, and psychiatric symptoms, with depression and suicidality present in a large proportion of CTE cases. Pathologically CTE is defined by a distinctive accumulation of hyperphophorylated tau (pTau) predominately involving the frontal and temporal cortices, medial temporal lobe, and brainstem. However, the association between pathology in particular brain regions and psychiatric CTE symptoms is unknown. METHODS AND RESULTS Human postmortem brains from CTE cases and controls were obtained from the VA-BU-CLF Brain Bank. Trained neuropathologists examined each brain for gross and microscopic pathology, and provided semi-quantitative assessments. Regions of interest (including frontal, temporal, limbic, and brainstem structures) were sectioned and stained for pathological markers of interest (e.g. pTau, β-amyloid, α-synuclein, pTDP43, etc). Stained slides were scanned and traced digitally, with staining quantified using a Leica Aperio system. Preliminary analyses suggest alterations in specific cortical, limbic, midbrain, and white matter structures may associate with depressive and suicidal features in CTE. In particular, cortical white matter loss as well as hippocampal and midbrain pathology were associated with psychiatric features. We have also found myelination and inflammation-associated changes in the anterior cingulate cortex of depressed CTE cases. CONCLUSIONS This investigation is the first to explore associations between neuropathology in particular brain regions and specific psychiatric features in CTE. Preliminary results suggest neurodegenerative pathology, loss of white matter, neuroinflammation, and gliosis could underlie psychiatric phenotypes in CTE.

Pathological correlates of psychiatric phenotypes across brain regions in chronic traumatic encephalopathy

**AMajor depressive disorder (depression) involves different mechanisms and brain scales. Altered cortical inhibition is associated with treatment-resistant depression, and reduced dendritic inhibition by somatostatin-expressing (SST) interneurons is a key component of the pathology. Electroencephalography (EEG) is an important source of biomarkers for depression to improve diagnosis and inform personalized treatments. However, whether the effects of reduced SST inhibition on microcircuit activity have signatures detectible in EEG remains unknown. We used detailed models of human cortical layer 2/3 microcircuits with normal or reduced SST inhibition to simulate resting-state activity together with the EEG signals in health and depression. We show that the healthy microcircuit models had emergent properties that reproduced key features of resting-state EEG theta-alpha frequency bands. We found that simulated EEG from depression microcircuits showed a significant increase in theta rhythmic activity and increased broadband power. Neuronal spiking showed a spike preference of EEG peak phase, and did not differ between conditions. We also showed using a realistic head model that the EEG signal biomarkers were mostly localized. Our study thus used detailed computational models to identify EEG biomarkers of reduced SST inhibition in cortical microcircuits in depression, which may serve to improve the diagnosis and stratification of depression subtypes, and in monitoring the effects of pharmacological modulation for treating depression.

Biomarkers of reduced inhibition in human cortical microcircuit signals in depression

Only recently has the scope of parental research expanded beyond maternal contributions to include the paternal sphere. Epidemiological studies have suggested that paternal stress, nutrition, and alcohol consumption, all impact neurobiological and behavioural characteristics in offspring. Given their high prevalence and comorbid use, a severely understudied domain in paternal research includes caffeine, alcohol use, and exercise. In this experiment, sires received seven weeks of regular tap water (placebo) or caffeine and/or ethanol (drug) and were housed in regular static cages (no ex) or cages with running wheels attached (ex). Beginning at P40, offspring were administered RmTBIs or sham injuries, followed by a behavioural test battery designed to assess post concussive symptomology. Post-mortem qRT-PCR was used to assess gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc). Paternal experience did not improve or exacerbate RmTBI outcomes. However, female and male offspring displayed unique responses to RmTBI and paternal experience, resulting in sex-dependent changes in physical, behavioural, and molecular outcomes. Injury and paternal exercise drove significant changes in female offspring, whereas male offspring were affected by paternal exercise and drug treatment. Our findings add valuable insight into paternal experience and epigenetic inheritance in offspring. While not directly exacerbating or improving recovery from RmTBI, paternal experience affected male and female offspring in a sexually dimorphic manner.

Rathletes do not give you wings: How paternal exercise, caffeine, and/or alcohol affects offspring pathophysiology and behaviour following repetitive mild traumatic brain injury (RmTBI)

Background Coronavirus disease 2019 (COVID-19) frequently disturbs the nervous system. However, COVID-19's neurological disease requires a detailed characterization. Furthermore, we do not know what predicts poor neurological outcomes in patients. Previous reports have linked neurological disturbances to COVID-19's increased mortality. Here, we describe the clinical alterations in COVID-19 patients presenting with neurological manifestations and correlate neurological outcomes with disease severity. Methods We retrospectively analyzed clinical, neurological, neuroimaging (CT or MRI scans) and cerebrospinal fluid (CSF) laboratory data from 33 confirmed COVID-19 hospitalized Brazilian patients subjected to CSF sampling as clinically indicated. Findings COVID-19 was associated with a broad spectrum of neurological diseases in mild and severe cases. Headache was the only symptom associated with mild disease. In a bivariate analysis, severe patients had an 18-fold increased risk of presenting neuroimaging alterations. CSF findings do not differ in severe and mild cases. Only four patients presented increased CSF white blood cell counts. CSF levels were high for protein in 12 patients and glucose in six patients. Interpretation These findings strengthen the notion that COVID-19-induced neurological disease is heterogeneous and manifests regardless of patient state. It will be most important to determine the time course of neurological disease and whether it is permanent or alleviated over time so that COVID-19 patients with neurological alterations can be adequately treated.

COVID-19 is associated with a broad spectrum of neurological disease

Loss-of-function variants in the human Zdhhc9 gene are identified in 2% of patients diagnosed with X-linked intellectual disability. These patients exhibit striking reductions in white matter volume and altered microstructure of white matter tracts. To further understand the role of Zdhhc9 in the brain and to elucidate how disrupting Zdhhc9 function contributes to phenotypes observed in patients, we have characterized a Zdhhc9 knockout mouse line. We demonstrate that Zdhhc9 is enriched in oligodendrocytes and is approximately two-fold higher in the corpus callosum than in any other region of the mouse brain. Zdhhc9 knockout mice exhibit significant reduction in myelin/oligodendrocyte associated markers, as well as reductions in the palmitoylation of these proteins, suggesting palmitoylation of myelin proteins may be required for their stability. RNA sequencing of different brain regions from control and Zdhhc9 knockout mice demonstrate differential expression of oligodendrocyte marker genes, suggesting a larger population of immature oligodendrocytes and fewer mature oligodendrocytes in knockout brains. This work provides a new perspective into the role of Zdhhc9 in oligodendrocytes and provides evidence that palmitoylation contributes to the development of white matter.

The role of palmitoylating enzyme, zDHHC9, in intellectual disability

*Bipolar disorder (BD) is characterized by different functional changes in the brain. BD adversely affects human behavior, speech, and cognition. However, the neural basis of BD is still poorly understood. In this study, we apply graph theory analysis to compare functional brain networks features between BD and normal control individuals. Twenty-one individuals in each BD and control groups were participated in this study. Resting state electroencephalography (EEG) was recorded in the resting state condition for each participant in both groups. Then functional brain networks (derived from calculation of lagged coherence between source localized current densities) were compared between groups. Using graph theoretical analysis, we found that BD group exhibited significant reduction in clustering coefficient, global efficiency, largest eigenvalue, and the second smallest eigenvalue in the theta (4-8 Hz) and alpha bands (8-12 Hz). These results suggest that BD is associated with alterations in segregation, integration, synchronizability and robustness of functional brain networks. According to these results, BD group exhibited reduced neural information processing in global brain network scales and specific modules that can be associated with cognitive/behavioral deficits in BD.

Profiling EV microRNAs from degenerating neurons to identify biomarkers for multiple sclerosis

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