Canada

The prevalence of many chronic pain syndromes differs across sex. Recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn (SDH), direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund&#39;s Adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between loss of inhibition and NMDA receptor potentiation within SDH neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator BDNF failed to downregulate inhibitory signalling elements and upregulate excitatory elements in female rats, resulting in no effect of ex vivo BDNF on synaptic NMDA receptor responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in SDH neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain phenotype. The discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment of pain for both sexes.

CAN-ACN 2021

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

nmdar

spinal cord

sex differences

pain

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

The prevalence of many chronic pain syndromes differs across sex. Recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn (SDH), direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund's Adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between loss of inhibition and NMDA receptor potentiation within SDH neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator BDNF failed to downregulate inhibitory signalling elements and upregulate excitatory elements in female rats, resulting in no effect of ex vivo BDNF on synaptic NMDA receptor responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in SDH neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain phenotype. The discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment of pain for both sexes.

poster

**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.

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

Introduction: Olfactory dysfunction (OD) is a well-established consequence of traumatic brain injury (TBI). Most of the studies reported OD in patients with moderate and severe TBI in the acute phase. However, inconsistent results have been found on OD in patients with mild traumatic brain injury (mTBI). This study aims to investigate olfactory perception in patients with mTBI in the acute phase. Method: We measured olfactory capacities in 53 patients with mTBI between 2 and 4 weeks following their trauma and in 53 healthy controls (HC). More specifically, we administered a well-established olfactory test (Sniffin'Sticks) and we measured odor detection (yes/no paradigm) and odor perception of 4 common odorants (eucalyptol, benzaldehyde, parmesan cheese, geraniol), by using a computer controlled automated odor presentation device (olfactometer). Results: We did not observe any group difference in the Sniffin'Sticks test scores. However, compared to HC, mTBI patients showed more difficulty detecting odors (p= .001) and perceived them as more intense (p= .015). Furthermore, depending on the odorant (interaction odor * group: p= .001), mTBI patients perceived odors as less pleasant than HC. Conclusion: These findings show that patients with mTBI suffer from altered olfactory detection and perception from the first weeks following their trauma. However, well-established olfactory tests such as the Sniffin'Sticks test may not be sufficiently sensitive to these changes. 

Patients with a mild traumatic brain injury: what happens to their sense of smell in the acute phase?

Circadian clocks are ubiquitous throughout tissues and organs in mammals, forming a multioscillatory network that controls daily rhythms in physiology and behavior. A brain region expressing circadian clock genes is the striatum; a basal ganglia structure receiving dopaminergic input plays a major role in motor control. It is composed of distinct populations of medium spiny neurons (MSNs), either expressing Dopamine receptor D1 (DRD1) of the direct (stimulatory) or Dopamine receptor D2 (DRD2) of the indirect (inhibitory) pathway. Components of the dopamine signalling pathway and circadian clock genes mutually influence one other in striatal MSNs, which are key in the role of behaviorial control. Thus, we hypothesize that appropriate motor responses to a selective dopaminergic stimulation of either direct or indirect pathway depends on proper striatal clock function. Experiments were carried out on mice with a conditional knockout (KO) of the core clock gene Bmal1 from MSNs. Under baseline conditions, male and female Bmal1 KO mice display a hyperactive phenotype. To determine whether dopamine signaling was altered in the MSNs, mice were treated with a D1 and D2 receptor agonist and their locomotor activity were recorded in the context of the open field. KOs of both sexes display an attenuated response to the D1 agonist relative to controls, whereas the D2 agonist suppresses activity similarly in KO and control animals of both sexes. Data suggest that disrupted clock function in MSNs influences the locomotor outputs of the basal ganglia, particularly within the direct pathway.

Disrupted circadian clock function in the striatum affects dopamine-related motor responses

Introduction: Intracellular Cl- concentration ([Cl-]i) is high in primary sensory neurons due to the activity of the Na+-K+-Cl- cotransporter 1 (NKCC1), causing greater Cl- accumulation than typically seen in CNS neurons. Consequently, central terminals of primary afferents in the spinal dorsal horn experience depolarization upon activation of GABAA receptors (GABAAR). Thus, regulation of [Cl-]i in these terminals may significantly affect transmitter release. Determining the exact [Cl-]i in C-fiber terminals is pivotal to understand sensory processing. Methods: To image [Cl-]i we used the genetically-encoded ratiometric Cl- sensor, superclomeleon, using 2-photon microscopy in acute spinal cord slices. Superclomeleon was virally transduced selectively in C-fibers in NaV1.8-cre mice. The GABAAR agonist and antagonist muscimol and bicuculline, as well as the NKCC1 antagonist bumetanide, were used to modulate [Cl-]i in afferent terminals in the dorsal horn. NKCC1 mRNA levels in the dorsal root ganglia was evaluated with RNAScope. Results: We found that [Cl-]i in C-fibers was significantly higher in males than females. Bumetanide significantly decreased [Cl-]i in males but not in females. Bicuculline did not significantly affect [Cl-]i in C-fibers indicating a minimal contribution of tonic GABAA signaling to [Cl-]i. NKCC1 mRNA was also significantly lower in females than males, consistent with the functional data. Conclusion: Presynaptic inhibition appears to be under distinct control by GABAergic inhibition between sexes, which should be taken into consideration in future studies.

Sex differences in chloride homeostasis of c-fiber primary afferents in the spinal cord dorsal horn

Perineuronal nets (PNNs) are extracellular matrices that surround various types of neurons and are thought to restrict the plasticity of the neurons they surround. For example, the increased expression of PNNs around parvalbumin (PV) interneurons in sensory areas are thought to consolidate mechanisms of sensory processing. Given their effects on neural function, it is important to better understand the characteristics of neurons associated with PNNs (i.e., to predict which neurons will be surrounded by PNNs), as such neurons might be most important for adaptive brain functioning. Given the importance of PV to neural plasticity, we tested the hypothesis that PNNs were more likely to be associated with neurons with more intense PV expression. To this end, we analyzed PV intensity in PV neurons with or without PNNs in sensory and sensorimotor brain structures. We first examined this pattern in adult zebra finches, a songbird with discrete sensory and sensorimotor brain circuits for vocal learning and control. Consistent with our hypothesis, PV intensity was greater in PV neurons surrounded by PNNs than in PV neurons without PNNs in sensorimotor brain areas. We are currently extending these analyses across development, between sexes, and in other species (e.g., rodents) to assess the degree to which this pattern relates to developmental, sex, and species variation in behavioral plasticity.

Insights into neural characteristics that predict perineuronal net expression in brain circuitry

Dorsolateral prefrontal cortex (DLPFC) is associated with executive control and response selection, but the extent to which it is involved in effector-specific transformations is unclear. We addressed this question by recording single neurons from dorsolateral prefrontal cortex (DLPFC) while two trained monkeys performed a head-unrestrained reaching paradigm that allowed freely coordinated motion of gaze, head reaching in depth. Animals touched one of three central LEDs at waist level while maintaining gaze on a central fixation dot and were rewarded if they touched a target appearing at one of 15 locations in a 40° x 20° (visual angle) array. Preliminary analysis of 271 neurons in both monkeys showed an assortment of target/stimulus, gaze, pre-reach and reach-timed responses in DLPFC. We first tested for gaze, head, and hand gain fields during the different neuronal responses and found that 38% of the responses were gain modulated by initial hand position. A small fraction of neurons showed gain fields for initial eye position (4%), and for both initial eye and hand position (6%). After removing the gain field effects, we fitted the residual data against various spatial models and found that the visual response best encoded the target relative to space (Ts), whereas responses at gaze and hand onset showed a tendency towards coding hand displacement (dA). In addition, some (20%) neurons showed a preference for coding final head position or displacement. A more complete analysis will describe the complete coding and distribution of gaze, head, and reach signals in this region.

Effector-specific spatial codes in dorsolateral prefrontal cortex during a head-unrestrained reach task

The dI3 population of spinal cord interneurons (INs) is a group of excitatory INs that receive varied sensory afferent input and project to ipsilateral motoneurons. Prior experiments have discovered that the permanent silencing of dI3 INs has a minimal impact on locomotor function in intact animals, but substantially interferes with locomotor rehabilitation/recovery after spinal cord injury (SCI). To gain insight into how dI3 INs are involved with locomotor function and recovery, the inhibitory DREADD receptor (hM4Di) was expressed in dI3 INs using a hybrid line of transgenic mice (Isl1-Cre:Vglut2-Flp x FlexloxFlexFRT-hM4Di). Consistent with prior experiments, transient inhibition of hM4Di-expressing dI3 neurons with the DREADD agonist JHU37160 (0.5mg/kg) did not significantly impact locomotor function in intact animals. However, in T9-T10 SCI mice, transient silencing of dI3 INs resulted in a significant loss of flexor motor tone, demonstrated by a significant increase in the resting ankle joint angle (+43.9° ± 11.6°, n=7, t-test, p=0.0065). This coincided with decreased stepping and the qualitative appearance of hindlimb flaccidity during the treadmill locomotor task. Based on these results, dI3 INs appear to adopt a more significant role in hindlimb function after SCI, specifically the maintenance of basal motor tone in the absence of supraspinal input. Given that SCI patients often experience both hypotonia and spasticity (increased motor tone), these findings provide the impetus for targeting dI3 INs to modulate motor tone below the level of the lesion.

dI3 interneurons maintain hindlimb motor tone in mice following spinal cord injury

Multiple studies have shown that mouse higher visual areas are involved in discrimination task through intricate functional properties and complex networks. However, it remains enigmatic how this highly connected network define specialized perceptual roles in extrastriate areas and how these interact in mouse behavior. Here we sought to study the connectivity and perceptual roles of these extrastriate areas using patterned optogenetic inactivation combined with mesoscopic calcium imaging. (A) Our first goal will be to develop a novel system of photostimulation using a the digital micromirror device (DMD), which uses mirrors to precisely shape a light beam into a large surface. Such innovative technology opens new doors in optogenetics as brain areas often have complex shape and are interconnected with remote areas. Validation on Channelrhodopsin-expressing mice showed robust local and long-range activations using the red calcium indicator jrGECO1a. Our second goal (B) is to implement this novel method of stimulation to our inactivation paradigm and assess how the inactivation of a whole extrastriate area impact the functional properties of adjacent areas and on feedback connections to the primary visual cortex using calcium imaging. Our final goal (C) is to study how perceptual learning is affected during spatially integrated optogenetic inactivation. Overall, studying visual perception require rigorous knowledge on the function and the organization of visual areas and this research will have the potential to bring new light unto this interaction.

Exploring the interaction between function and organization in mouse visual cortex using a novel spatially integrated optogenetic system

Allocentric (landmark-centered) and egocentric (eye-centered) visual information are optimally integrated for goal-directed movements. This process has been observed within the supplementary and frontal eye fields, but the underlying processes for this combination remain a puzzle, mainly due to inadequacy of current theoretical models to explain data at different levels (i.e., behavior, single neuron, and distributed network). Here, we propose a physiologically inspired neural network with two major components: First, a Convolutional Neural Network (CNN) is used to extract the allocentric information (target and landmark): We used repeated (2 layers) convolution, rectifications, and normalization followed by a feature pooling layer to extract allocentric information (target and landmark). Second, a Multi-Layer Perceptron network (MLP, 3 fully connected layers) is used to incrementally transform allocentric information into an integrated motor response. We added an additional layer to transform motor responses into final gaze positions. The network was trained on both idealized and actual monkey gaze behavior. MLP output units accurately simulated prefrontal motor responses (including open-ended response fields that shifted partially with the landmark) and their decoded output achieved good correspondence (MLP: R2 = 0.80) with actual gaze behavior (Bharmauria et al. Cerebral Cortex 2020). These results suggest that our framework works and provides a suitable tool to study the underlying mechanisms of allocentric and egocentric integration. Supported by a VISTA Program fellowship.

Mechanisms for integrating allocentric and egocentric visual information for goal-directed movements: a neural network approach

Considerable regional evidence has accumulated for dorsal-ventral modularity in the visual system, but it is not clear how these modules function at the whole brain network level, or how these networks are influenced by naturally occurring saccades. We addressed these questions using graph theory analysis of fMRI data collected during a task where participants had to remember, then discriminate between two different object features. Seventeen participants judged whether a remembered object changed shape or orientation with or without an intervening saccade. BOLD activation from 50 cortical nodes was used to identify local and global network properties. A network modularity analysis revealed three sub-networks during fixation: a bilateral dorsal sub-network linking areas involved in visuospatial processing and two lateralized ventral sub-networks linking areas involved in object feature processing. Importantly, when horizontal saccades across the remembered object required visual comparisons between hemifields, the two lateralized ventral sub-networks became functionally integrated into a single bilateral sub-network. Comparisons of 'betweenness centrality' between conditions identified several significant hub regions in occipital, parietal, and frontal cortex involved in linking distant network nodes during saccades. These results provide support of a ventral and dorsal stream distinction in human perception and show how hemispheric sub-networks are modified to functionally integrate information across saccades.

Functional network topography reveals dorsal-ventral cortical modules for visual feature memory, and lateralized modules that combine for transsaccadic integration

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

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