Canada

Chemotherapy-induced neuropathic pain (CINP) is a treatment-limiting complication of several classes of anticancer agents, including the taxanes, platins, vinca alkaloids, and bortezomib. It negatively affects the quality of life of patients, and unfortunately, there is no effective treatment at present. The current treatment approaches utilize antidepressant drugs, which offer only mild improvement. Despite several research efforts in the past, the underlying mechanism behind CINP is not clear, which poses a major hurdle in developing effective therapies. In this study, we explored if neuroinflammation has any role in inducing CINP. We considered the frequently used chemotherapy agents paclitaxel and cisplatin in this study. Intraperitoneal administration of either paclitaxel or cisplatin demonstrated robust mechanical allodynia in male CD-1 mice. Co-administration of an anti-inflammatory agent, dexamethasone, significantly reversed mechanical allodynia in these models. We further investigated the impact of these drugs on neurite outgrowth of DRG cultures established from paclitaxel/cisplatin treated animals and did not observe any significant effect. However, these drugs induced hind paw denervation in these animals, and dexamethasone reversed the loss of the nerve extremities in the paws, as evident from increased PGP9.5 labeling of nerve fibers. Evaluation of macrophages&#39; response to these drug treatments in the DRGs and nerve extremities is ongoing. Overall, our findings suggest that local inflammatory response at the nerve extremities contributes to CINP.

CAN-ACN 2021

Neuroinflammation facilitates chemotherapy induced neuropathic pain

axon degeneration

sensory neurons

cinp

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

Chemotherapy-induced neuropathic pain (CINP) is a treatment-limiting complication of several classes of anticancer agents, including the taxanes, platins, vinca alkaloids, and bortezomib. It negatively affects the quality of life of patients, and unfortunately, there is no effective treatment at present. The current treatment approaches utilize antidepressant drugs, which offer only mild improvement. Despite several research efforts in the past, the underlying mechanism behind CINP is not clear, which poses a major hurdle in developing effective therapies. In this study, we explored if neuroinflammation has any role in inducing CINP. We considered the frequently used chemotherapy agents paclitaxel and cisplatin in this study. Intraperitoneal administration of either paclitaxel or cisplatin demonstrated robust mechanical allodynia in male CD-1 mice. Co-administration of an anti-inflammatory agent, dexamethasone, significantly reversed mechanical allodynia in these models. We further investigated the impact of these drugs on neurite outgrowth of DRG cultures established from paclitaxel/cisplatin treated animals and did not observe any significant effect. However, these drugs induced hind paw denervation in these animals, and dexamethasone reversed the loss of the nerve extremities in the paws, as evident from increased PGP9.5 labeling of nerve fibers. Evaluation of macrophages' response to these drug treatments in the DRGs and nerve extremities is ongoing. Overall, our findings suggest that local inflammatory response at the nerve extremities contributes to CINP.

poster

Growing evidence indicates that during early stages of Alzheimer's disease (AD) abnormal brain activity occurs due to disruption of GABAA-mediated transmission. While disrupted GABAA signaling may result from several mechanisms, recent evidence points to deficits in the potassium-chloride cotransporter KCC2, responsible for maintaining low intracellular chloride in neurons to maintain robust inhibition. In this study, we validate whether KCC2 is downregulated in two transgenic mouse lines that develop AD-like amyloid-beta pathology and symptoms. Further, we examine whether by restoring KCC2 function we can alleviate deficits associated with AD. We found a decrease in the global and membrane protein levels of KCC2 in layer II/III of the prefrontal cortex of 5xFAD mice. In addition, ex vivo chloride imaging revealed impaired Cl- transport in the 5xFAD mice. Moreover, the power of hippocampal gamma oscillations was decreased in the APPNL-G-F mice, as predicted from deficits in KCC2. Consistent with this prediction, treatment with CLP290, a KCC2 activity enhancer, restored the power of the higher band gamma oscillations. Finally, short-term administration of CLP290 in the 5xFAD mice improved spatial memory in the Morris Water Maze (MWM) test whereas it improved learning performance in the MWM and episodic memory in the Contextual Fear Conditioning test in the APPNL-G-F mice as compared to vehicle-treated controls. These results indicate that KCC2 may be a viable target for reversing deficits in GABAA-mediated inhibition in AD and attenuating several symptoms associated with AD pathology.

Enhancing the potassium chloride co-transporter KCC2 reverses functional deficits associated with Alzheimer's disease-related mutations in mice

Early life seizures (ELS) are often refractory to conventional anticonvulsant treatments, and can result in later life epilepsy and severe cognitive deficits. Our recent study demonstrated that ELS acutely reduced the excitatory synaptic inputs onto hippocampal fast-spiking (FS) interneurons through affecting presynaptic neurotransmitter release, which plays a crucial role in ELS pathophysiology. Thus, enhancing excitatory synaptic afferents onto FS interneurons will represent a logical approach to normalize the function of FS interneurons in ELS. BDNF regulates excitatory circuit development in FS interneurons through TrkB receptors. Therefore, we hypothesize that activation of TrkB receptors will alleviate ELS-induced dysfunction of excitatory afferents onto hippocampal FS interneurons. ELS were induced in P10-12 mice. We found that activation of TrkB receptors using a partial TrkB receptor agonist, LM22A-4, significantly increased the frequency of AMPA receptor mediated sEPSCs, but not sEPSC amplitude in CA1 FS interneurons in slices from 1 hour post-ELS mice, through increasing the probability of neurotransmitter release as evidenced by increased paired pulse ratio of evoked AMPAR EPSCs. Furthermore, LM22A-4's effects were abolished by co-administration of the TrkB receptor antagonist, ANA-12. These data strongly support a critical role of TrkB receptors in mediating ELS-induced dysregulation of hippocampal fast-spiking interneurons, and provide a potential therapeutic option for early life epilepsy.

Trkb receptor activation alleviates early seizure-induced dysfunction of hippocampal fast-spiking interneurons

Studies of perception and cognition in schizophrenia (SCZ) show neuronal background noise (ongoing activity) to intermittently overwhelm external stimulus processing. This increased relative noise results in temporal imprecision and higher variability of behavioral responses. What, however, are the neural correlates of temporal imprecision in SCZ behavior? We report EEG decrease in signal-to-noise ratio (SNR) in two SCZ groups (but not in depression) in broadband, theta, and alpha bands. SCZ also show lower intertrial phase coherence (ITPC) relative to stimulus onset in theta which, as computational simulations show, is due to phase-based temporal desynchronization. Reduced SNR and ITPC are related and show a relationship to temporal precision on the behavioral level, namely reaction times. In conclusion, we demonstrate how diagnostic-specific temporal imprecision in SCZ neural activity - reduced relative signal strength and phase coherence - mediates temporal imprecision on the behavioral level. Temporal imprecision may underlie the altered neuro-cognitive processing in SCZ.

It's in the timing: reduced temporal precision in neural activity of schizophrenia

Disturbance of the central serotonin system has long been thought of playing a leading role in major depressive disorder. The main serotonergic nucleus of the brain, the dorsal raphe nucleus (DRN), integrates inputs from multiple brain regions, a large fraction of which is coming from the lateral hypothalamic area (LHA). In this study, we have examined whether plasticity at the LHA-DRN pathway contributes to the development of depressive or resilient phenotypes in mice undergoing chronic social stress. To activate LHA terminals in DRN, an AAV-ChR2-YFP was injected in the LHA of 6 weeks old C57BL/6J male mice. Two weeks later, these mice were subjected to chronic social defeat stress (CSDS) protocol. 24-h after CSDS, mice were classified as either susceptible or resilient when evaluated in a social interaction test, and acute brain slices encompassing the DRN were prepared. During whole-cell patch-clamp recordings of DRN neurons, 5 ms blue light pulses were delivered to activate LHA axons terminals, and postsynaptic currents were measured to investigate pre- and postsynaptic plasticity. In resilient mice, we found a significant increase in paired-pulse ratio at GABAergic synapses, indicating the decreased GABA release probability. In susceptible mice, we measured an important trend toward a decrease in the AMPAr/NMDAr ratio, indicating synaptic depression at the LHA-DRN pathway caused by CSDS. These results suggest that synaptic dysfunction may play an important role in the behavioral phenotype found in depression.

Dissecting the lateral hypothalamic input to the dorsal raphe nucleus and its role in major depression

Microglia activation is a critical component of the post-stroke inflammatory response; however, an accumulation of pro-inflammatory activated microglia can have a detrimental effect and lead to cognitive decline. Strokes that affect the basal ganglia can impair behavioural flexibility, an important component of executive function. An association between activated microglia in the white matter tracts and executive dysfunction has been established but not sufficiently evaluated in the context of stroke. Minocycline is a tetracycline derivative shown to effectively inhibit microglia activation. In this study, we used a rat model to investigate the effects of acute post-stroke minocycline treatment on cognitive outcomes and white matter pathology. Stroke was induced in 8-10-month-old male wildtype Fischer 344 rats by injection of endothelin-1 into the right dorsal striatum. Minocycline was administered for 4 days post-stroke prior to testing for behavioural flexibility, learning and memory using an operant conditioning-based set-shifting task and the Morris water maze. Brains were histologically examined at 28 days post-stroke to assess microglia activation, astrogliosis and infarct size. Results indicate a link between white matter activated microgliosis and behavioural outcomes post-stroke suggesting that modifying microglia activation post-stroke could protect the brain and improve cognitive outcomes.

Targeting post-stroke white matter microgliosis using minocycline to prevent cognitive decline in the rat

Background: The in vitro characterization of transitional microglial states in the context of neurodegeneration is lacking; therefore, we report a novel classification system that tracks microglial activation state and potential neurotoxicity. Furthermore, we were interested in the role of leucine rich repeat kinase2 (LRRK2) in this regard, given its importance in inflammatory processes and that it is implicated in Parkinson's Disease (PD). Methods: Differentiated neuronal SH-SY5Y cells were pre-stressed with sub-toxic levels of glutamate prior to co-culture with lipopolysaccharide-activated microglial BV2 cells or primary microglia. Both transwell co-cultures and mixed live-cell imaging was used to asses microglial transition through various morphological phenotypes and their impact on SH-SY5Y cells. Results: Healthy neurons were resistant to microglial-mediated inflammation but pre-stressed neurons were highly susceptible. Pre-stressed neurons actively recruited microglia, which expressed high levels of oxidative stress and formed large cellular aggregates. LRRK2 kinase and WAVE2 inhibitors (MLi2 and CK-869, respectively) stunted microglial activation and reduced pro-inflammatory cytokines. Conclusion: LRRK2 and WAVE2 may be important mediators in microglial-induced neurotoxicity and these data may be mechanistically important for better understanding neuron-microglial crosstalk and its role in neurodegenerative conditions.

LRRK2 mediated microglial phenotype and neurotoxicity in a novel two-hit in vitro model of neurodegeneration

Ischemic stroke is a devastating neurological disease caused by a reduction in blood flow to the brain that results in neuronal cell death. Subsequent neuroinflammation is mediated by central nervous system resident immune cells and peripheral immune cells. Evidence suggests that stroke-induced gut dysbiosis results in priming of pro-inflammatory immune cells in the intestine that migrate to the stroke lesion and contribute to neuroinflammation. Currently, it is unknown whether gut dysbiosis and the migration of gut-derived immune cells to the stroke lesion persist in the chronic phase following injury. In this study, we aimed to characterize; (I) stroke induced gut dysbiosis and (II) the contribution of gut-derived immune cells to neuroinflammation, over time in a rodent model of ischemic stroke. Using 16s rRNA sequencing we observed that gut dysbiosis is observed at D4 following injury in both males and female animals. Interestingly, females exhibit a return to baseline microbial composition at D20 while males continue to exhibit gut dysbiosis. In addition, we injected a lipophilic cell-tracking dye (Cm-DiI) into peyer's patches at various timepoints following injury to observe whether gut derived immune cells migrate to the brain beyond D3. Using immunohistochemical analyses, we observed Cm-DiI+/CD45+/DAPI+ cells in the stroke injured hemisphere at D4 and D9 following ischemic stroke induction. These findings suggest that stroke induced gut dysbiosis and the migration of gut-derived immune cells to the stroke lesion are phenomena that persist beyond the acute phase of injury.

Characterizing gut dysbiosis and the gut derived immune response to ischemic stroke

Alzheimer's Disease (AD) remains the major form of Dementia. Progressive neuronal loss is the major cause for the disease; however, the etiology of AD remains a controversial topic. Excessive oxidative stress, Tau hyperphosphorylation and formation of intracellular neurofibrillary tangles, as well as accumulation of extracellular Amyloid beta plaques represent the main targets for finding a cure. There is currently no effective treatment available for AD. Loss of cellular antioxidants including Thioredixin-1 (Trx1) is observed in AD tissue samples. Trx1 is a small redox reductase protein responsible for maintaining the oxidized proteins. Examining the importance of Trx1 depletion in pathology of AD, we have previously shown that pharmacological and genetic inhibition of Trx1 impairs autophagy, a vital housekeeping process responsible for protein homeostasis in neurons. We also have identified that loss of Trx1 is an important upstream event in induction of neuronal nuclear lamina invagination. Nuclear lamina damage or laminopathy is a newly identified mechanism in pathophysiology of AD. In the current studies we use genetic inhibition of Trx1 in human neuroblastoma cells and examine the effect on nuclear events. Our results indicate that downregulation of Trx1 is sufficient for induction of NL damage. These results lead to histone modification and changes in nuclear chromatin methylation. These studies were also complemented in hippocampi tissues from a mouse model of neuronal specific Trx1 knockout. Downregulation of Trx1 in these mice was associated with nuclear lamina damage and accumulation of amyloid beta and Tau hyperphosphorylation. Our studies provide a mechanistic link between oxidative stress and the key downstream events observed in AD pathology.

Nuclear Laminopathy and oxidative stress in Alzheimer's Disease

Alzheimer's Disease (AD) is more common in women, while low free testosterone has been associated with increased AD risk in men. However, treatment with testosterone has yielded mixed results in improving AD-related cognitive decline. Previous in vitro studies have shown that a major neurometabolite of testosterone: 5α-androstane-3α,17β-diol (3α-diol) inhibited the prolonged extracellular signal-regulated kinase (ERK) phosphorylation associated with oxidative stress. The role of 3α-diol in vivo remains unknown. We therefore examined the effects of continuous 3α-diol treatment on protein markers associated with AD progression in a triple transgenic (3xTg) mouse model. 3-month-old wild-type and 3xTg mice received subcutaneous implants of a 1 cm long Silastic capsule containing either 3α-diol dipropionate, or a blank capsule. Brains were collected at 6 and 9 months of age to analyze changes in expression of hippocampal ERK, MAP Kinase Phosphatase 3 (MKP3), plus phosphorylated (Ser202) and total tau. 3α-diol had no significant effect on the ratio of phosphorylated: total tau, at either age. No significant differences in ERK phosphorylation were observed at 6 months, but at 9 months sex and genotype-dependent differences were observed, with 9-month 3xTg females exhibiting higher ERK phosphorylation as well as markedly higher MKP3 expression. Treatment with 3α-diol had no effect on ERK phosphorylation, but significantly reduced MKP3 at 9 months, to levels indistinguishable from those observed in 3xTg males. 3α-diol may contribute to sex differences in AD susceptibility.

Effect of 5α-androstane-3α,17β-diol on ERK and MKP3 in a mouse model of Alzheimer's Disease

Reduced ability of the salience network (SN) to control switching between the central executive and default mode network (DMN) is linked to deterioration of cognitive functioning in normal aging, mild cognitive impairment (MCI) and AD dementia (He et al., 2014). In the current study, we compared functional connectivity between SN and the anterior DMN amongst older adults with subjective cognitive decline (SCD), MCI, and normal cognition (NC). Participants were 72 older adults [39 females, mean age=71.5] who were classified as either NC (n=26), SCD (n=29), or MCI (n=17). Participants underwent a 6-minute resting state functional magnetic resonance imaging using gradient-echo EPI BOLD at 3T (TR=2000ms, TE=30ms). Seed-based analysis using CONN with an anterior cingulate cortex (ACC; [0, 22,35]) seed, a key node in the SN, was conducted to assess functional connectivity between the SN and the anterior DMN within each group. Groups did not differ in age, years of education, or sex distribution [F(2,69)=0.415, p=0.66; F(2,69)=2.20, p=0.12; X² (2, N=72)=1.89, p=0.39, respectively]. Significant functional connectivity was found between ACC and medial prefrontal cortex (mPFC) in SCD and MCI groups (T(28)=2.39, p-FDR=0.04; T(16)=2.89, p-FDR=0.02, respectively) but not in the NC group. These findings show support for increased functional connectivity in SCD and MCI between SN and anterior DMN compared to NC. This finding is consistent with evidence of increased functional connectivity between the posterior DMN and mPFC in individuals with MCI and AD, an alteration that is believed to be a compensatory response to decreased functional connectivity between the posterior DMN and other brain regions such as the medial temporal lobe, responsible for memory formation and processing.

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Enhancing the potassium chloride co-transporter KCC2 reverses functional deficits associated with Alzheimer's disease-related mutations in mice

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