Canada

Cancer is a multi-stage disease caused by sequential mutations; however, the molecular mechanism generating cancer-initiating mutations for many cancers is not well understood. Using the developing cerebellum as model system, here we delineate a molecular mechanism for tumor initiation in medulloblastoma (MB), the most frequent malignant pediatric brain tumor. Activation of the Sonic hedgehog (SHH) pathway is frequent in MB, with mutations in the tumor suppressor PTCH1 (a negative regulator of SHH signaling) being the most common initiating event for SHH-MB. However, how SHH as a developmental mitogen promotes early carcinogenesis in the cells of origin, granule cerebellar progenitors (GCPs), remains to be determined. 
Here we report that physiological exposure of GCPs to Shh causes a distinct form of DNA replication stress, altering DNA replication dynamics to increase both origin firing and fork velocity. Shh promotes DNA helicase loading and activation in GCPs, with increased levels of Cdc7-dependent replication origin firing. S-phase duration is reduced and hyper-recombination consequently occurs. Such elevated recombination causes copy-number neutral LOH, an event seen frequently at the PTCH1/ptch1 locus. Moreover, Cdc7 inhibition to attenuate origin firing in a MB mouse model is sufficient to reduce somatic recombination and preneoplastic tumor formation. We therefore establish that tissue-specific replication stress induced by Shh acts to promote LOH, which in tumor-prone Ptch1+/- GCPs can result in loss of this tumor suppressor, as an early cancer initiating event.


CAN-ACN 2021

Sonic hedgehog causes replication stress promoting cancer initiation in medulloblastoma

medulloblastoma

dna replication stress

sonic hedgehog

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://s3.eu-west-1.amazonaws.com/underline.prod/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


IWSSIP is an international conference that brings together researchers and developers from both academia and industry reporting the latest scientific and theoretical advances to discuss and debate major issues and state-of-the-art aspects on systems, signals and image processing.

###### For the session discussion, each author will be seated at individual breakout tables.  Please find which table they will be at here:
###### [QA table assignments in Gather.town](https://drive.google.com/file/d/1hBHOD_KF7NSsaTcpYcHCZslXJvQVxJQe/view?usp=sharing)

IWSSIP 2021

keynote

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.

The role of descending pathways in population coding of 2nd order electrosensory stimuli

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.

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

The ability of organisms to sense and respond to temperature in their ambient environment as well as in their own bodies is critical for survival. Thermoregulation occurs as an essential homeostatic process Currently there exists a paucity of information on the involvement of the afferent mechanism of thermoregulation in ectotherms. Here we investigate thermoregulation and the involvement of a family of thermosensing proteins known as the transient receptor potential (TRP) channels in the ectotherm Xenopus laevis. Using Xenopus larvae as an in vivo model, and a melanophore cell line as an in vitro model, our data indicate that within skin melanophores pigments known as melanosomes aggregate in cool temperatures and disperse at warmer temperatures. Our in vivo model suggests that this aggregation of skin pigments occurs as a systemic response. We identified TRP family genes in the Xenopus genome via RT-PCR, including a candidate (TRPM8) from the TRPM subfamily, which has been characterized previously as a cold sensor. Using immunohistochemistry, we visualized TRPM8 expression in Xenopus melanophores and the skin, and found that TRPM8 is co-localized with melanophores using a melanophore-specific marker. To investigate the function of TRPM8, we treated cultured melanophores and Xenopus larvae with an agonist (WS12), which resulted in aggregation of pigment in the absence of cool temperature. Our results suggest that in Xenopus larvae temperature alterations regulate skin pigmentation, a process that depends on a member(s) of the TRPM channel family. (Support from the Natural Sciences and Engineering Research Council, Canada)

The coordination of thermoregulation by circadian and thermosensory mechanisms

Weakly electric fish actively sense their environment using a self-generated electric field. Objects with electrical properties differing from those of the surrounding water cause small perturbations that are detected by electroreceptors distributed over their skin surface. When sensing conditions are unfavourable, fish appear to increase several movements (tail-bending and back-and-forth swimming) that are thought to improve electrosensory acquisition. However, these movements are variable and not reliably identified. Recently, unbiased data-driven approaches have been used to extract fundamental poses, combinations of which can be used to describe any animal behaviour. Here, we apply these approaches as a first step towards testing the hypothesis that specific movements can enhance electrosensory information acquisition. We find that fish behaviour can be explained by combinations of only a few fundamental basis shapes. Then, along with a newly developed model for quantifying the electric field, we characterize the spatiotemporal properties of natural electrosensory inputs and identify how they are affected by body pose and movement.

The effect of self-motion on electrosensory inputs

To learn more on the factors that govern the development of neural circuits, both in structural and functional terms, we use whole brain two-photon imaging on larval zebrafish that express a pan-neuronal genetically-encoded calcium indicator GCaMP6s. Using a resonant scanner and piezo driven objective, we record neural activity (GCaMP6 fluorescence) from up to ~50% of the whole neuronal population (~100,000 neurons), while simultaneously conveying visual stimulation using a screen oriented towards the head-restrained larva in agarose. This experimental paradigm leverages the early-developing visual system of the zebrafish to evoke reproducible neuronal responses and behavioral outputs across individuals. Abrupt changes in illumination induce navigational tail movements, which are monitored using a high-speed camera to identify distinct behavioral modules and their neural correlates. By varying the temporal properties of visual stimuli, we also probe the neural mechanisms of habituation and anticipation. Using graph theory, functional networks are generated from spontaneous brain activity recordings, which are then paired with the zebrafish structural connectome (Kunst et al., Neuron, 2019) in order to gain fundamental insight on the interaction between structure and function in vertebrate brain networks. Our dual spontaneous/stimulus-evoked experimental framework will be used to compare fish across different developing conditions, namely germ-free fish, to observe the impact of gut microbiota on brain connectivity, sensorimotor integration and behavior.

Whole-brain optical imaging in zebrafish larvae to investigate neural circuit development and connectivity

The subventricular zone neurogenic niche receives neuronal inputs from many areas of the brain. Although these inputs are known to regulate neurogenesis through neurotransmitter release at synapse-like connections between neuronal axon terminals and neural stem and progenitor cells (NPCs), few studies have examined how neuronal modulators at these synapse-like connections affect SVZ NPC function. Our recent work identified monoacylglycerol lipase (Mgll), a hydrolase that breaks down endocannabinoid 2-AG, as an extrinsic factor to regulate SVZ NPC function in culture. 2-AG is a well-known retrograde modulator that controls neurotransmitter release. To date, it remains unknown how Mgll-modulated 2-AG signaling in the SVZ niche regulate SVZ NPC behavior in vivo. In this regard, we propose to examine the role of neuronal Mgll activity from distinct brain region in regulating SVZ NPC function. Using retrograde monosynaptic rabies virus tracing and anterograde tracing, we identified direct synapse-like connections between hypothalamic arcuate nucleus (ARC) neuron axon terminals and a subpopulation of NPCs residing in the ventral SVZ microdomain as previously reported. Intriguingly, specific removal of Mgll expression in ARC neurons using virally transfected Cre recombinase in Mgll-floxed mice resulted in a decrease of SVZ NPCs in this microdomain and a subsequent reduction of proliferating cells in this microdomain. These findings provide an understanding of how long-range neuronal Mgll activity regulates adult SVZ NPC function in a microdomain-specific fashion.

Long-range hypothalamic neuronal projections to the subventricular zone neurogenic niche regulates neural stem cell function through endocannabinoid signaling

Sonic hedgehog causes replication stress promoting cancer initiation in medulloblastoma

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Sonic hedgehog causes replication stress promoting cancer initiation in medulloblastoma

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Next from CAN-ACN 2021

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

Similar lecture

Viewpoint selection for fibrous structures in a pre-operative context: application to cranial nerves surrounding skull base tumors

Stay up to date with the latest Underline news!

PRESENTATIONS

CONFERENCES

COMPANY

RESOURCES

Downloads