Canada

Chronic stress is a risk factor for anxiety and depression and all are linked to reduced cognitive performance and neuronal atrophy. In these, there is reduced number of GABAergic neurons, reduced GABA release and altered GABAA receptor (GABAAR) functioning. GABAARs contain α subunits that essentially dictate functional outcome: sedation with α1 subunit potentiation, anxiolytic effects with α2/α3 and cognition with α5. Common GABAergic drugs, like benzodiazepines, act at α1/2/3/5-GABAARs but have side effects (sedation, dependence) mixed with mild anxiolytic effects and no cognitive benefits. Therefore, a therapy designed to increase α2/3/5 activity while also devoid of α1 activity has significant clinical relevance and potential. We investigated two enantiomers separately, GL-I-54 and GL-II-73, as well as their combined use as a racemic mixture (termed GL-RM) because of the desirable positive allosteric modulation profile when combined (α2/3/5 and α5 respectively). Using the unpredictable chronic mild stress (UCMS) model in C57BL6 mice (50% female; N=48 per study), anxiolytic, anti-depressant and pro-cognitive effects of GL-RM were assessed after acute or chronic administration. GL-RM reduced stress induced anxiety-like phenotypes and overcame stress induced cognitive deficits. Golgi staining after chronic GL-RM found GL-RM rescued dendritic spine density after UCMS in the PFC and CA1. Results support the value of a therapy with a α2/3/5 GABAAR selective profile to overcome chronic stress-induced mood symptoms and cognitive deficits, and detriments in neuronal morphology.

CAN-ACN 2021

GABAA receptor positive allosteric modulation has symptomatic and disease modifying effects in a mouse model of chronic stress

gabaa receptor

stress

cognition

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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.

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14th Canadian Neuroscience Meeting from August 23rd-25th

uthorDespite being implicated in various functions, the structural organization of the claustrum remains largely unknown. It is crucial that we first understand the intrinsic neural organization of the claustrum to better elucidate its functional complexity. Thus, we sought to investigate the transcriptomic breakdown of the claustrum through single cell RNA-sequencing (scRNA-seq). In our analysis, we uncovered a previously unknown excitatory neuronal subtype, suggesting the claustrum is composed of 2 transcriptomically distinct excitatory neurons. To investigate the spatial organization of these subtypes, we used multiplexed single-molecule fluorescence in situ hybridization (smFISH), targeting RNA from 12 different marker genes in individual brain sections. We found that the gene expression patterns of the claustral neurons correlated strongly with the scRNA-seq predictions, organizing into a "core-shell" spatial configuration that was consistent across the anterior-posterior axis. To determine if these transcriptomic signatures corresponded to specific projection neuron populations within the claustrum, multicolour retrograde tracing in conjunction with smFISH was performed. Here, we found the core and shell subtypes correlated with distinct projection targets from the retrosplenial cortex and lateral entorhinal cortex, respectively. Thus, the claustrum exhibits a "core-shell" spatial organization with distinct molecular and circuit properties, which may drive its functional complexity. This spatial heterogeneity can be used in the future to examine subtype-specific function.

Spatially patterned excitatory neuron subtypes and circuits within the claustrum

At the onset of Alzheimer's disease (AD), accumulation of oligomeric amyloid-β (Aβ) correlates with local hyperexcitability, possibly due to dyshomeostasis of extracellular glutamate. However, the interplay between Aβ oligomers and extracellular glutamate accumulation remains unresolved. We use an in silico approach to characterize the putative underpinnings of Aβ-dependent modulations of extracellular glutamate. We first consider how Aβ modifies the expression of astrocytic glutamate transporters (GLT1) and how it impacts extracellular glutamate time course. Accordingly, we develop a mathematical model for glutamate diffusion and uptake at synaptic terminals and their surroundings. Our model predicts that above a threshold Aβ concentration, astrocytic GLT1 transporters cannot prevent the accumulation of extracellular glutamate. This, in turn, promotes a positive feedback on synaptic glutamate release that favors excitotoxicity and neuronal hyperactivity. Next, we complement our model including calcium-dependent Aβ production and glutamate release. The interaction of multiple positive feedback loops of signaling can account for different tissue states, overcoming the traditional dichotomy of healthy and excitotoxic conditions. Specifically, changes in the basal firing activity can promote intermediate conditions useful to either predict AD's degeneration or offer new therapeutic perspectives. Our results support the notion of AD as a multistage pathology where transitions can follow multiple pathways, such as Aβ accumulation, excitotoxicity, or calcium dysregulation.

Aβ-dependent alteration of astrocytic GLT1 expression can trigger the multistage progression of Alzheimer's disease

Dendritic spines are responsible for relaying excitatory input and regulating signalling between neurons and their morphology can give insight into synaptic function. Excitotoxicity brought on by brain injury results in synaptic dysfunction, as intracellular Ca2+ increases. This increase in intracellular Ca2+ over-activates various cellular kinases and proteases responsible for microtubule stabilization. Previous work in our lab has shown that after an impact, there is an increase in tensile strain within the depths of the porcine cingulate sulcus. Moreover, there was a marked decrease of the microtubule stabilizing protein MAP2 specifically within the apex of the sulcus. In our current work, we explored whether changes in spine morphology were associated with our impact model. The Golgi-Cox staining method was used to visualize dendritic spine morphology. Following impact, coronal slabs were placed into Golgi-Cox solution for 2 weeks. Cortical pyramidal neurons within the sulcus apex and arm were reconstructed. Preliminary data revealed a shift towards mushroom-type spines, compared to thin and stubby-type spines within the sulci of the brain after impact. These findings suggest a shift towards an excitatory synapse shortly after impact. Along with our previous findings of changes in MAP2 properties, the shift towards an excitatory synapse could implicate activation of kinases and proteases responsible for regulating MAP2 dynamics and altering spine morphology.

Assessing dendritic integrity and spine morphology following impact in the porcine cortex

Repeated mild traumatic brain injury (rmTBI) disrupts hippocampal function and can lead to long-lasting episodic memory impairments. We hypothesized that these deficits could arise as a result of microvascular damage and microglia activation leading to impaired synaptic plasticity. Using our Awake Closed Head Injury (ACHI) Model for repeated (8x over 4 days) head injury, we found that animals showed impaired neurological function after the first hit, that was sustained throughout all 8 impacts. Histological analysis showed that animals experienced diffuse microbleeds in the brain, including the hippocampus, and that this was accompanied by fibrinogen release and microglia activation. Furthermore, animals that experience rmTBI showed impaired bilateral synaptic plasticity, with the magnitude of both long-term depression (LTD) and long-term potentiation (LTP) of synaptic efficacy being impaired in the hippocampus. This work indicate that rmTBI can produce diffuse microbleeds, microglia activation, and impaired synaptic plasticity, giving insights into the mechanisms that can underlie the memory impairments that can accompany rmTBI. This work was supported by grants from the Canadian Institutes for Health Research (CIHR) to BRC.

Repeated traumatic brain injury causes diffuse microvascular damage and impairs bidirectional synaptic plasticity

Schizophrenia (SZ) is a serious mental disorder characterized by hallucinations, delusions, and impaired cognitive behavior. Substantial heterogeneity in the clinical phenotypes complicates its diagnosis and treatment. The pathogenesis results from a complex interaction between genetic vulnerability and environmental factors, altering neuronal development particularly. Indeed, several genes and proteins associated with neurite growth, neuronal migration, and synaptic development are altered in SZ. However, the processes of neurodifferentiation and functional maturation of neuronal networks are still largely unexplored. Therefore, the exploration with multimodal optical imaging tools of the in vitro of cortical neural cell generation using iPSCs from SZ patients and controls will help measure the maturation and organization of these cultured neuronal networks. Human iPSCs lines were differentiated into mixed cortical neural cells and characterized by flow cytometry, immunostaining, western blot, and patch-clamp techniques. To explore functional and morphological properties, we use quantitative phase digital holographic microscopy (QP-DHM) combined with fluorescence imaging. QP-DHM is a high-resolution, non-invasive technique allowing to assesse cell structure and dynamics with axial sensitivity at the nanoscale. These tools will serve to explore the excitatory and inhibitory (E/I) balance of these cultured neural networks. Such a multimodal imaging approach coupled with human iPSCs disease models holds great promises to identify cellular risk biomarkers for major psychiatric disorders, including schizophrenia.

Exploring neurodifferentiation and maturation process of iPSCs derived from schizophrenia patients with multimodal optical microscopy

The ventral tegmental area (VTA) contains a heterogenous population of GABA neurons, making up about 30% of cells in the VTA. These GABA neurons regulate the activity of VTA dopamine neurons, affecting the release of dopamine in the nucleus accumbens (NAc). The release of dopamine in the NAc plays an important role in energizing goal directed behaviour towards food. GABA neurons, projecting from the lateral hypothalamus (LH), have been shown to preferentially synapse with VTA GABA neurons. Activation of LH GABA disinhibits the VTA GABA circuit to stimulate the release of dopamine in the NAc, resulting in consummatory behaviour. Acute fasting (AF) increases the incentive motivation for food. Despite the LH GABA to VTA GABA circuit being a powerful driver for food consumption, how it is affected by AF is unknown. Using patch clamp electrophysiology in midbrain slices expressing channelrhodopin in LH GABAergic terminals in the VTA, we demonstrate that following AF, LH GABA neurons have reduced inhibition of VTA GABA neuronal firing. Through train stimulations and strontium-induced asynchronous release, we show that this weakening of the LH GABA input is due to a scaling down of inhibitory postsynaptic current (IPSC) responses. Following AF, release probability of GABA from LH GABA neurons is decreased in female by not male mice. Taken together, these results show that the LH GABA to VTA GABA circuit is affected by acute energy deprivation and that males and females respond differently.

Effect of fasting on lateral hypothalamus GABA to ventral tegmental area GABA synapses

Bipolar disorder (BD) is characterized by alternating cases of depression and mania. Although deviations in neurodevelopment are suspected to contribute to the pathophysiology of BD, the precise molecular underpinnings remain unknown. In cells, calcium plays an influential role in development via signalling cascades. As such, calcium accumulates in the endoplasmic reticulum (ER) from where it can be rapidly released in response to a second messenger. Calcium levels are, therefore, tightly regulated through store-operated calcium entry (SOCE)--a mechanism that promotes calcium influx through ORAI channels when the ER is depleted. Recently, we found striking evidence of aberrant SOCE activity in BD patient-derived induced pluripotent stem cells (iPSCs) differentiated into neural progenitor cells (NPCs) in comparison to iPSC-NPCs derived from healthy control individuals. This led us to discover unsuspected cellular phenotypes. Here, we first summarize calcium imaging data revealing the sharp difference in SOCE between BD patient-derived and control iPSC-NPCs. Second, we show that lower SOCE activity in BD cells correlates with reduced STIM/Orai puncta formation. Third, we reveal decreased proliferation in BD-derived progenitors, which we then connect to a premature neuronal differentiation phenotype affecting migration. Finally, we support this dysregulated development with cerebral organoid modelling. Together, our findings suggest a contribution of SOCE to BD through dysregulation in the neurodevelopment of NPCs.

Neurodevelopmental impact of aberrant calcium mobilization in bipolar disorder patient-derived iPSC-neural progenitor cells

Naked mole-rats (NMRs; Heterocephalus glaber) are among the most hypoxia-tolerant mammals. If and how these organelles tolerate ischemia and how ischemic stress impacts mitochondrial energetics and redox regulation is unknown. We hypothesized that mitochondria fundamentally contribute to in vitro ischemia resistance in NMR brain. To test this, we treated NMR (1-2 years) and CD-1 mouse (14-16 weeks) brain sheets with an in vitro ischemic mimic and evaluated mitochondrial respiration capacity and redox regulation following 15- or 30-mins ischemia or ischemia/reperfusion (I/R). We did not observe differences between sexes (4 males and 4 females) for either species, so we pooled data from both sexes for statistical analysis. We found that, relative to mice, NMR brain largely retains mitochondrial function and redox balance post-ischemia and I/R. Specifically: i) ischemia reduced complex I and II -linked respiration ~50-70% post-ischemia in mice, versus ~20-40% in NMR brain, ii) NMR but not mouse brain maintained relatively steady respiration control ratios and robust mitochondrial membrane integrity, iii) electron leakage post-ischemia was lesser in NMR than mouse brain and NMR brain retained higher coupling efficiency, and iv) free radical generation during and following ischemia and I/R was lower from NMR brains than mice. Overall, these findings support the hypothesis that hypoxia-tolerant NMR brain is also ischemia-tolerant and suggest that NMRs may be a natural model of ischemia-tolerance in which to investigate evolutionarily derived solutions to ischemic pathology.

Naked mole-rat brain mitochondria tolerate in vitro ischemia

Q175/B6 is a knock-in mouse model of Huntington's disease, a neurodegenerative disorder characterized by chorea, loss of motor control and cognitive deficits. The primary site of neurodegeneration in HD is the striatum, a brain region important for motor learning. Studies have revealed motor and cognitive deficits in Q175 mice on the open field, accelerating rotarod and water T-maze tasks. This study aims to replicate these findings in Q175 mice while conducting more detailed analyses on the specific patterns of behaviour during these tests using the DeepLabCut tracking software and the new Behavioral Segmentation of Open Field in DeepLabCut (B-SOiD) machine learning program. 10-month-old Q175 mice engaged in less locomotion and sniffing behaviours and more grooming and rearing as compared to wild-type during the open field. HD mice also showed motor deficits on the rotarod, with a reduced latency to fall and a greater number of foot slips. In mice that used a striatum-dependent response learning strategy during training of the water T-maze, Q175 animals took significantly longer to reach the hidden platform during both training and reversal phases of the task. These findings reveal that Q175 mice show notable motor and cognitive deficits at 10 months of age, including reduced exploratory behaviour and potentially increased anxiety-like behaviours in the open field. Experiments with 3-month-old Q175 mice are also underway. Future studies that examine striatal signalling during performance of these tasks are needed for evaluation of potential therapeutic treatments in HD. Funding provided by the Canadian Institutes of Health Research Foundation grant (Fdn-143210).

Behaviour characterization of the Q175/B6 Huntington's disease mouse model

Huntington disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons involved in motor function degenerate leading to motor & cognitive problems. Dysregulation of synaptic function & Ca2+ handling is common in many neurodegenerative diseases. One level of Ca2+ regulation is at the endoplasmic reticulum (ER), & this regulation is abnormal in HD. The ER is also suggested to be involved in nuclear Ca2+ signaling, & I hypothesize that this signaling pathway is altered in HD. Sigma-1 receptors (S1Rs) - proteins located on the ER - play an important role in Ca2+ regulation & thus gene transcription. Interestingly, activating S1Rs has been shown to normalize this Ca2+ handling & restore synaptic function in HD mouse models. The goal of this project is to determine the link between S1Rs, Ca2+ handling, Ca2+ dependent gene expression, & synaptic function to better understand the pathophysiological mechanisms of HD & to find new potential treatments. Cortico-striatal co-cultures & imaging techniques were used. Our data shows interesting contributions of different Ca2+ channels to nuclear Ca2+ signaling. Ca2+ imaging also suggests impairments in nuclear Ca2+ signaling in HD spiny projection neurons in co-cultures. Furthermore, Activin A, a protein whose expression is Ca2+ dependent, is decreased in HD culture media, & its overexpression normalizes aspects of synaptic function. This project will help us understand the complex pathogenesis of HD & elucidate the roles of key therapeutic targets toward developing disease-modifying treatments.

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Spatially patterned excitatory neuron subtypes and circuits within the claustrum

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