Canada

Spinal locomotor circuits have the intrinsic capability of producing the rhythmic activity needed to underlie repetitive locomotor movements. Locomotor rhythm generation can be shaped by the specific ionic conductances that spinal neurons express. Since the emergence of the larval zebrafish as an attractive vertebrate model to the study of locomotion, appreciable progress has been made in uncovering the cell types and connectivity patterns that make up zebrafish spinal locomotor circuits; however, little is known regarding their mechanisms for locomotor rhythm generation. IM, a persistent subthreshold potassium current, has been demonstrated to be involved in regulating neuronal bursting and recent evidence demonstrates that it is involved in locomotor rhythm generation in the neonatal rat. We sought out to determine whether IM could be involved in shaping the locomotor rhythm in larval zebrafish which, to our knowledge, has remained uninvestigated. Our ex vivo electrophysiological recordings of motor nerves during spontaneous swimming activity of 4 days post fertilization larvae in the presence of ICA-069673 and XE-991 - agonist and antagonist, respectively, of the IM-mediating Kv7.2/7.3 channels - reveal that IM may limit the amplitude and promote rhythmicity of tails beats produced during swimming activity. These findings further detail the mechanisms by which locomotor rhythm generation is governed in the larval zebrafish, highlighting that the role IM plays in locomotor rhythm generation may be similar across species.

CAN-ACN 2021

A role for a persistent subthreshold K+ current in generating rhythm within larval zebrafish spinal locomotor circuits

spinal circuits

zebrafish

locomotion

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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

Lysosomes are acidic organelles that contain a myriad of hydrolytic enzymes. In neurons, lysosomes traffic throughout the axons and dendrites to deliver catabolic enzymes to distal regions of the cell and maintain local degradative demands. Of the various lysosomal enzymes, glucocerebrosidase (GBA) is of particular interest due to its relationship with synucleinopathies such as Parkinson's Disease and Dementia with Lewy Bodies. Mutations in GBA are the most common genetic risk factor for synucleinopathies, but the mechanistic relationship is unclear. GBA cleaves the glycolipid glucosylceramide (GC) into glucose and ceramide, but mutations in GBA, or its catalytic inhibition, can disrupt the composition of the lysosomal membrane. The lysosomal membrane serves as the platform to which trafficking complexes are recruited and activated. Thus, we investigated if the prolonged catalytic inhibition of GBA by Conduritol B Epoxide (CBE) could interfere with lysosomal trafficking dynamics in axons. In human iPSC-derived cortical neurons treated with CBE for 10 days, we did not observe a change in the motile fraction, velocity, or run length of LAMP1-GFP vesicles. Additionally, we did not find any alterations in lysosomal size or density in the axon, dendrites, or neuronal cell bodies, despite complete inhibition of enzymatic activity. These results suggest that CBE-mediated inhibition of GBA in neurons does not directly impact lysosomal dynamics or size in the time course of our experiments.

Lysosomal transport dynamics in GBA-inhibited iPSC-derived human neurons

The previous study from our group has identified that after peripheral nerve injury there is an increase of kynurenine in the plasma, which seems to be involved in the maintenance of neuropathic pain. However, the mechanisms which peripheral kynurenine (Kyn) mediates neuropathic pain is unknown. Therefore, the aim of the present study was to test the hypothesis that peripheral Kyn reaches the spinal cord and maintain neuropathic pain by KMO metabolism, leading to downstream nociceptive metabolites. Methods: Spared Nerve Injury (SNI) model of neuropathic pain was induced in C57BL/6 mice and the following test and methods were used: von Frey filaments nociceptive test, Real-time PCR and western blotting, inhibition of KMO activity. This study was approved by the Local Ethical Commission in Animal Research (045/2013). Results: SNI induced mechanical allodynia in a time-dependent manner, which peaked from 7 up to 21 days. SNI- induced mechanical allodynia was associated with an increase in the expression of KMO in the spinal cord, mainly at day 10 and 14 after injury. KMO expression was restricted to spinal cord astrocytes. Functionally, pharmacological inhibitor against KMO injected intrathecally after SNI, reduced mechanical allodynia. Also, kyn injected systemically (i.v) promoted mechanical allodynia, which was educed when KMO was pharmacologically inhibited. In summary, these results indicated that after peripheral nerve injury spinal astrocytes-expressing KMO plays a critical role in the development of neuropathic pain. In conclusion, the kynurenine metabolic pathway is a critical link in the neuroimmune response after peripheral nerve injury in the maintenance of neuropathy.

Meningeal dendritic cells interactions with astrocytes elevate the kynurenine metabolic pathway to sustain neuropathic pain

Multiple sclerosis (MS) is a neurodegenerative disease which is largely associated with progressive disability. It is characterized by multiple focal demyelinating lesions where the extent of myelin loss correlates with the advancement of disease and also age. Substantial work has focused on preventing demyelination from occurring, but the alleviation of MS symptoms through regeneration of myelin, or remyelination, remains an under-researched area. Remyelination is associated with less clinical disability and linearly declines with age. This process is dependent upon microglia, the resident immune mediators of the central nervous system (CNS). Microglia are a heterogeneous phenotype, forming subpopulations that vary across development, anatomical regions and disease. Using advanced analytical tools and bioinformatic techniques, we show that a subpopulation of microglia arises at the onset of remyelination in a mouse model of MS which presents acute demyelination followed by spontaneous, but robust, remyelination. These remyelination-associated microglia (RAM) change their transcriptional signature throughout remyelination, moving from an Igf1/Irf7 dominated phenotype to one that is characterized by genes responsible for regeneration, such as Meg3. We have validated this by showing the expression of Igf1 and Irf7 within mouse lesions using RNA scope. We are currently sequencing microglia from aged, lesioned environments to assess how microglia responses differ through ageing

Phenotypic profiling of microglia across remyelination and ageing

The lateral entorhinal cortex (LEC) is the site of tau accumulation in early stages of Alzheimer's disease and has projections downstream to the dentate gyrus (DG) of the hippocampus. The pathological form of tau has the ability to propagate across synapses, spreading to connected brain regions and correlating with memory deficits and synaptic loss. The DG is the site of ongoing adult neurogenesis, with new granule neurons added showing enhanced plasticity and increased survival compared to older neurons. Thus, we are interested in examining neuron age for vulnerability to tau pathology in the LEC-DG circuit. We use an inducible cre-recombinase transgenic mouse model to label neurons born at different ages (development vs. adulthood) with TdTomato, and viral AAV tau injections into the LEC to mimic early tau pathology. Following a 4-month incubation, animals are tested for memory deficits with Novel Object Recognition (NOR) and Novel Place Recognition (NPR) and tissue is immunohistochemically processed to analyze tau levels and cellular morphology in TdTomato-labelled DG neurons. We assess synaptic changes in DG neurons via measuring dendritic spines, dendritic complexity and mossy fibre boutons. Preliminary findings show a trend for tau animals to perform worse on NOR compared to healthy controls, while no difference found for NPR. Morphological results show adult-born neurons have an increase in immature thin dendritic spines and decrease in mushroom spines (mature, functional spines) in tau animals relative to healthy controls, as well as reduced mossy fibre bouton filopodia length. Our initial results demonstrate the effect of tau on the LEC-DG circuit, with altered synaptic connectivity and memory performance.

Vulnerability to tau pathology in the entorhinal-hippocampal circuit

Neurodegeneration (NDG), hallmarked by neuronal cell body and axonal loss, occurs in progressive Multiple Sclerosis (MS) in the absence of overt relapses and inflammatory episodes. Heterogeneous nuclear ribonucleoprotein A1 (A1) is an RNA binding protein that is key in cellular RNA metabolism, but is mislocalized from nuclei to cytoplasm in the neurons from brains of people with progressive MS, and from spinal cords of mice with experimental autoimmune encephalomyelitis (EAE), a model for MS. We hypothesized that this mislocalization impacts the A1 RNA binding profile to promote NDG. To test this, we compared the A1 RNA binding profile from the spinal cords of naïve mice to those of mice with EAE, using crosslinking-immunoprecipitation/RNA sequencing (CLIPseq). We confirmed that the global RNA transcriptome from EAE mouse spinal cords is distinct from that of naïve mice, and further found that severity of EAE disease resulted in a greater alteration in the global transcriptome, with a number of differentially-expressed genes involved in neurodegeneration. We have also generated a first-of-its-kind profile of homeostatic A1 RNA targets in spinal cord. Further, the A1 RNA binding profile is drastically dysregulated in EAE mouse spinal cords, losing interaction with ~40% of homeostatically bound RNAs and instead enriching for non-coding RNAs. We are in the process of mapping the A1 binding "footprint" on these RNAs to provide insight into its specificity. Together, these data will form the foundation of our understanding of the role A1 dysfunction plays in NDG in MS.

RNA binding of heterogeneous nuclear ribonucleoprotein A1 is dysregulated in a mouse model of Multiple Sclerosis

To provide us with a complete sensory experience, our brain naturally merges information from our various senses (e.g., vision and hearing). The brain's ability to integrate auditory and visual information is not static; studies have shown that recent sensory experience can influence the accuracy and sensitivity of one's perception. To better understand the neural mechanisms underlying this process, we set out to develop and validate rodent models of audiovisual temporal and synchrony perception. Rats were trained on one of two perceptual judgment tasks: (1) a temporal order judgment (TOJ) task where rats reported whether the auditory or visual stimulus was presented first, or (2) a synchrony judgment (SJ) task where rats reported whether the auditory and visual stimulus were presented at the same moment in time or different times. To test for sensory adaption, rats were passively exposed to either synchronous or asynchronous stimuli prior to undergoing an experimental test session. Consistent with human studies, both tasks showed a psychophysical relationship between stimuli timing offsets and performance. Interestingly, prior disclosure to asynchronous audiovisual stimuli resulted in a shift of the psychophysical curve in the direction of the stimulus offset in rats performing the TOJ task, but not the SJ task. Additional testing is underway using the SJ task to further investigate synchrony perception in rats. Our collective results suggest that rats represent a suitable model for future studies aimed at studying the neural mechanisms underlying audiovisual perception.

Using novel rodent models of audiovisual perception to assess the influence of prior sensory exposure on audiovisual perceptual judgments

Introduction: Rats with complete spinal cord injury (SCI) exhibit good plantar stepping in the upright posture 5weeks after complete SCI without any training. Spontaneous reorganization of spinal circuits transmitting afferent input from the sole of the foot via the Tibial nerve (TIB) is a main contributor to this locomotor recovery. The purpose of this study was to examine changes in afferent pathways of the TIB at different times after SCI. Methods: Cord dorsum potential responses to graded electrical TIB stimulation were measured in 17 rats at different levels of the lumbar spinal cord. Intra-spinal field potentials were recorded (6 rats) after graded TIB stimulation. The amplitude of the different components of these potentials were normalized and compared in rats with intact cords (x), injured cords at 1 week (y) and at 5 weeks (z) post SCI. Results: The TIB group I muscle afferents evoked maximal response at the L4-L5 level in both intact and spinalized animals. The group II muscle afferents evoked surface potentials that decreased at L4 at 1 week after SCI compared to responses in intact rats. By 5 weeks post SCI, the group II responses became similar to those seen in the intact rats coinciding with upright walking development. Intraspinal field potentials from the dorsal horn also showed a similar reduction and recovery pattern. Conclusion: The reduction observed in cord dorsum and intraspinal field potentials evoked by group II afferent stimulation of the TIB at 1 week SCI suggests that dorsal horn interneurons with group II input are compromised at this time.

Afferent input "re-organization" after a complete thoracic spinal cord injury in rats

Background: Less exploratory gaze behaviour has been reported in individuals with visual height intolerance (vHI) compared to controls standing at high heights (Kugler et al., 2014); however, it is unclear if this gaze behaviour persists with different gaze conditions and how this compares to non-threatening settings. Therefore, this study aimed to investigate changes in gaze behaviour between low and high heights in individuals without vHI. We hypothesized less gaze exploration under conditions of postural threat. Methods: 14 healthy young adults without vHI (5 F; mean age=25) stood on a forceplate for 5 minutes at low (0.8m) and high (3.2m) heights facing a featureless canvas 2.6m away. Eye movements normalized to eye level and center of view were measured with a Dikablis eye-tracking system and used to calculate mean position and variance of gaze and number and duration of fixations and saccades. Results: Repeated measures ANOVAs revealed significant changes in postural and emotional-cognitive outcomes. Number of fixations (p<0.05, η²p=0.27) and saccades (p<0.05, η²p=0.31) significantly decreased with height. There were non-significant trends for increased fixation length and decreased saccade amplitude with increased height (η²p=0.20; 0.14, respectively). Likewise, there were non-significant trends for decreased horizontal variance and lower mean gaze position with increased height (η²p=0.19). Conclusions: Individuals without vHI demonstrated less gaze exploration under threatening conditions, characterized by fewer and longer fixations within a smaller horizontal area.

Gaze behaviour with height-induced postural threat

Short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) occur when the motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS) is reduced by the delivery of a preceding peripheral nerve stimulus. However, the intra-individual variability in these measures is significant, and normative values would facilitate the interpretation of SAI and LAI in future studies. In the present analysis, we pooled data from studies published by our lab between 2014 and 2020. We present individual data from each study and investigate patterns in the depth of inhibition with respect to age, biological sex, and time of testing. Further, we quantified the reliability of the data for studies with repeated baseline SAI and LAI measurements. Our data show no relationship between the depth of inhibition for SAI and LAI with either time of day (SAI: rho = 0.089, p = 0.280; LAI: rho = 0.152, p = 0.102) or age (SAI: rho = -0.003, p = 0.973, n =113; LAI: rho = 0.095, p = 0.398, n = 81). Further, there was no significant difference in SAI or LAI between males and females (p > 0.05). Intra-class correlation coefficients (ICC) for repeated measurements of SAI and LAI ranged from moderate (ICC = 0.523) to strong (ICC = 0.882). This retrospective study explores normative values and reports the reliability of these measures as assessed in our lab with the goal of facilitating the interpretation of SAI and LAI data.

A retrospective investigation of short- and long-latency afferent inhibition data from six years of published studies

It has been shown that the nervous system implies descending pathways to efficiently encode sensory input of low contrast natural stimuli. However, the underlying mechanisms and their impact on perception and behavior remain poorly understood. Here we investigate the effects of descending pathways (feedback) on population coding and perception of 2nd order stimuli ("envelopes") within the hindbrain of the weakly electric fish Apteronotus leptorhynchus. These fish constitute an excellent model system for studying these important questions as our previous work has shown that descending pathways mediate the perception of low contrast sensory input. Here we will instead ask whether such mechanisms also apply to higher contrasts. To do so, we used envelope stimuli with different frequencies as well as intensities and tested behavioral responses while simultaneously recording from a population of sensory neurons. We then blocked feedback and compared behavioral and neural responses. Preliminary results show that while behavioral responses could be reduced by blocking feedback, neuronal responses remained similar at high but not low contrasts. This suggests that for low contrasts changes in behavior can be explained by feedback mechanisms, whereas this is not the case for high contrasts. This leads to the question as to the mechanisms in downstream brain areas and what decoder can explain this discrepancy. Our results thus can uncover mechanisms underlying coding and consequences on perception of stimuli with different statistics that are likely to be shared across sensory systems and across species.

Next from CAN-ACN 2021

Lysosomal transport dynamics in GBA-inhibited iPSC-derived human neurons

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