Canada

Circadian rhythms, 24-hour oscillations within an organism generated by biological clocks, keep temporal order of molecular, physiological, and behavioral processes with respect to daily changes in the environment, thus enabling systemic homeostasis and proper function of the biological system. A multi-oscillatory network of circadian pacemakers, comprising a central clock in the suprachiasmatic nucleus of the hypothalamus, and peripheral clocks located in other brain regions and tissues throughout the body, sustains tissue-specific rhythms, such as in the striatum. The striatum, a region of the basal ganglia that receives dopaminergic input from the midbrain, controls motor functions and behavioral processes related to mood and reward. Proper function of the striatum is presumably maintained by a mutual interaction of components of the circadian clock and the dopamine signalling pathway. Using a conditional knockout of the core clock gene Bmal1 within medium spiny neurons (MSNs) of the striatum, we assessed the molecular, physiological, and behavioural consequences of striatal clock malfunction. Male and female knockout mice showed deficits in motor coordination and control, but were less affected in mood-related tests. Daily rhythms of gene expression, primarily targeting the circadian clockwork and cell signalling pathways, were also studied, in addition to measurements of mitochondrial respiration in MSNs. Preliminary results indicate changes in molecular and physiological processes in MSNs of knockout animals, that may contribute to the observed behavioural phenotypes.

CAN-ACN 2021

Molecular and behavioural consequences of a striatal bmal1 knockout in mice

striatum

clock genes

circadian rhythms

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

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Please head to https://can-acn.org/meeting-2021/registration-2021/ to register. 

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

poster

The upper hearing limit of humans is 20kHz, and sounds having frequencies above 20kHz are considered ultrasonic. Ultrasonic frequencies are important to a variety of species, many of which have a well-defined and much higher hearing limit compared to humans. A common model used for auditory research is the domestic cat (Felis catus). Even though it is generally accepted that cats can hear ultrasonic frequencies, there are notable discrepancies in the literature regarding the full extent of the cat's hearing abilities. Here, auditory brainstem responses (ABRs) are used to evaluate the ultrasonic hearing abilities of cats. The ABR is an objective test used to assess the physiological integrity of the auditory pathway from the cochlea up through the brainstem. Wideband stimuli (clicks) as well ultrasonic pure tones are presented to the subject. Each stimulus leads to electrical responses that reflect the neurophysiological activity in the auditory nerve and the auditory nuclei in the brainstem. This work evaluates the amplitude and latencies of the ABRs to the different stimuli presented. Since cats are a common animal model in hearing research, it is crucial to validate and expand our current understanding of their hearing abilities. By using ABR data in conjunction with data from psychoacoustic experiments to investigate specifically the ultrasonic hearing abilities of cats, we can elucidate uncertainties and ultimately better our understanding of brain regions responsible for the cat's ability to perceive these high frequency signals. Supported by a grant from NSERC.

Using auditory brainstem responses to evaluate the ultrasonic hearing abilities of the domestic cat

Spinal and brain stimulation approaches are complementary in the treatment of motor disorders related to spinal cord injuries (SCI). Nevertheless, no study has directly compared their single and combined effect over immediate modulation of walking. To address this unmet need, we developed a neuroprosthesis that allows stimulating the brain and spinal motor circuits in phase-coherence with walking. Six rats were implanted with electromyographic electrodes (EMGs) within hindlimb muscles, a multi-electrode array within the hindlimb motor cortex and epidural electrodes over the lumbar (L2) and sacral (S1) spinal segments. After obtaining baselines for kinematics/EMGs on a treadmill, rats received a spinal hemisection at T9 that paralyzed one leg. The immediate effects of cortical and/or spinal stimulation over treadmill locomotion were evaluated in the intact state and after SCI. We characterized the effect of stimulation parameters such as stimulus amplitude, frequency, and duration. Gait analysis demonstrated that each stimulation technique independently modulated walking. Both cortical and L2 stimulation, when delivered in synchrony with foot lift, increased leg flexion. S1 stimulation, when delivered 80ms after the foot lift, increased leg extension. Combined cortical and spinal stimulation approaches resulted in maximal increase in foot clearance, step height and swing velocity, before and after SCI. These experiments demonstrated that cortico-spinal neuroprosthesis has the potential to reduce motor deficits and enable targeted rehabilitation protocols after SCI.

Combining the effects of cortical and spinal stimulation to improve walking after spinal cord injury

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Coordinating speed and steering is essential to navigate the environment. Speed is controlled by the Mesencephalic Locomotor Region (MLR), which generates forward motion by symmetrically activating a set of reticulospinal neurons. Recent studies uncovered that steering is controlled at least in part by distinct reticulospinal neurons controlled by the superior colliculus, which processes visuomotor transformations. Whether animals can brake and turn during ongoing MLR stimulations is poorly documented. Using in vivo optogenetics, we show that mice can brake and turn during stimulation of the cuneiform nucleus, a subpart of the MLR. Using deep learning-based movement analysis, we show that the footfall pattern and limb kinematics are normal during optogenetically-evoked locomotion. We also show that increasing laser power increased locomotor speed. In the open field arena, mice could perform sharp 90° turns when approaching a corner during stimulation of the cuneiform nucleus. Turns were associated with a slowdown that was scaled to the locomotor speed when entering the corner. Mice used less sharp turning angles at faster speeds. Our results indicate that the animal could integrate environmental cues during MLR-evoked locomotion to adjust speed and motion direction, thus ensuring smooth navigation. Our study suggests that stimulation of the cuneiform nucleus may be a relevant clinical target to improve locomotor performance without restricting the ability to perform braking and steering maneuvers in pathological states such as Parkinson's disease.

Optogenetic activation of glutamatergic neurons in the cuneiform nucleus controls locomotor speed without preventing braking or turning maneuvers in mice

The sound-induced flash illusion (SIFI), the misperception of flash number when presented with an incongruent number of clicks, has been studied almost exclusively using a forced-choice task. Compared to forced-choice tasks, Go/No-Go tasks remove the need for response selection. Understanding the audiovisual interaction under different cognitive loads will pave the way for studies in different development trajectories (e.g. cochlear implant). The task was to discriminate 1 vs. 2 flashes of Gabor stimuli at threshold contrast while ignoring the sound of clicks (0, 1 or 2). Participants were told to make two-alternative forced-choice 2AFC (i.e. left-for-1 and right-for-2) or Go/No-Go responses (either Go-for-1 or Go-for-2) in three separated blocks with order counterbalanced between participants. In all conditions, participants reported more "two-flash" in 2-click trials and vice versa in 1-click trials, when compared to 0-click trials. Furthermore, the effect in 2-click trials was larger in the Go-for-1 task compared to the Go-for-2 and 2AFC tasks. The effect in 1-click trials did not differ among tasks. Repeated measures model indicates that both click number (F1,19=42.06, p<.001) and task type (F1,19=38.00, p<.001) have significant impacts on accuracy. Despite the SIFI being established for 20 years, there has yet to be a departure from the forced-choice task design measuring the illusion. The differences in SIFI effect based on different task designs show that how the illusion is measured can affect the outcome. The basis for this difference is the subject of future work.

Sound-induced flash illusion in forced-choice and go/no-go tasks

During early postnatal development the visual system exhibits a heightened capacity for neural plasticity in which the structure and function of neural circuits can be modified by changes in visual experience. The composition of the N-methyl-D-aspartate receptor (NMDAR) plays a major role in regulating the capacity for neural plasticity by altering the threshold for synaptic modification. The current study was designed to examine the role that the NMDAR subunit composition plays in the enhancement of plasticity that results from brief immersion in complete darkness. A novel method employing multiplex immunolabeling was developed to quantify NMDAR subunit composition in thin tissue slices from the cat visual system. This approach preserves in situ protein distribution and permitted an investigation of layer-specific receptor changes. Receptor subunit composition was examined in a group of age-matched normal control cats, as well as cats that were exposed to a short (10 day) period of darkness to eliminate visually-driven activity and enhance plasticity capacity. We found that darkness shifted NMDAR subunit composition toward the neonatal isoform in both visual cortex and the lateral geniculate nucleus. This was a generalized shift observed across cortical and thalamic layers. These results further implicate modifications of the NMDAR subunit composition, stimulated by reduced neural activity, as a factor underlying the enhancement of plasticity linked to dark immersion.

Investigation of darkness-induced modification of NMDA receptors within the primary visual pathway

Despite its known importance in most other sensory systems, the role of synchrony remains to be explored in somatosensation. Spike synchrony is vital for signal propagation between low-threshold mechanoreceptors (LTMRs) and their postsynaptic targets, but the influence of different tactile stimuli on LTMR spike synchrony remains unclear. In response to a periodic stimulus like vibration, synchronous spiking across neurons relies on the timing of spikes relative to the phase of the stimulus cycle (i.e. precision) and the probability of a spike occurring on each cycle (i.e. reliability). As such, through in vivo extracellular recordings in rodents, we measured the reliability and precision of rapid adapting (RA)- and slow adapting (SA)-LTMR responses to vibrotactile stimuli to infer synchronization of spiking across neurons. Results showed that SA and RA afferents synchronize at different frequency ranges. Interestingly, population synchrony was lost at low and high frequencies due to a loss of spiking precision or reliability, respectively. To explore the mechanisms supporting synchrony loss at each frequency extreme, we developed generalized linear models of LTMRs. Differences in the fitted model parameters demonstrate that a shorter refractory period gives RAs the unique ability to respond to and synchronize at high frequencies. The findings of this study strengthen our understanding of synchrony in somatosensory coding and the resulting models allow for efficient exploration of the mechanisms underlying tactile signal processing.

The role of synchronous spiking in the encoding of vibrotactile stimuli by low-threshold mechanoreceptors

Peripheral nerve injury elicts plastic changes in spinal nociceptive circuits, resulting in allodynia and the development of chronic neuropathic pain (CNP). Eventually, this state causes maladaptive changes in nociceptive circuits in the brain, frequently leading to increased anxiety and depression comorbidities in CNP patients. Little is known about the precise role of spinal projection neurons in the transmission of CNP-evoked plastic changes from the spinal cord to the brain. We recently characterised a population of spinal dorsal horn projection neurons that express the transcription factor Phox2a, whose spinal cord-specific loss (Phox2aSpC) results in impaired innervation of brain targets and a reduction of nocifensive behaviours that require such connections. To determine the role of this molecularly defined population of projection neurons in CNP, spared nerve injury (SNI) was induced in Phox2aSpC and control mice. The development of mechanical and thermal hypersensitivity, as well as increase in neuronal cFos expression at spinal levels did not differ significantly between these two groups. However, SNI-evoked licking response to cold allodynia was attenuated in Phox2aSpC mice, compared to controls. The analysis of the impact of SNI on neuronal and microglial activity in the parabrachial nucleus and cognitive behaviours in Phox2aSpC mice is pending. Together, our results argue that the normal function of spinal Phox2a projection neurons are required for the development of supraspinal effects of SNI and may constitute a therapeutic target for relief of CNP.

Spinal Phox2a projection neurons relay spared nerve injury-induced neuronal plasticity changes from the spinal cord to the brain

Neurons of the hypothalamic arcuate nucleus (ARC) integrate nutritional signals to modulate energy balance. Evidences suggest that the underlying mechanisms involve the release of fatty acids (FA) from intracellular lipid droplets (LD). This model is supported by data from our lab showing that neurons can form and accumulate triglycerides in LD. In addition, our data and single-cell RNAseq studies show that Adipose Triglyceride Lipase (ATGL) is expressed in ARC pro-opiomelanocortin (POMC) neurons that play a crucial role in energy balance. Thus, we propose that ATGL in ARC POMC neurons is involved in energy balance control by regulating LD lipolysis. To test this, we quantified LD and oxidation of FA in hypothalamic neurons (cell lines and primary cultures) treated with oleate, forskolin (ATGL activator in adipose tissues), or Atglistatin (ATGL inhibitor). Also, we generated POMC specific ATGL KO mice (Cre-Lox) which were subjected to metabolic phenotyping. Our results show that hypothalamic neurons accumulate LD in response to Atglistatin/oleate, forskolin decreases LDs via ATGL and Atglistatin decreases the oxidation rate of LD-derived FA. Our lipidomics data show that palmitate and oleate are the major FA in neuronal LD. In our mouse model, ATGL KO in POMC neurons does not affect body weight or food intake in chow-fed males. These animals will be subjected to metabolic challenges (high fat diet) to assess the role of ATGL in adaptive metabolic responses. Our data show for the first time that hypothalamic neurons can accumulate LD and that ATGL activates LD lipolysis.

Feeling hungry? The role of fat stores in hypothalamic neurons on energy balance

Social defeat is a preclinical model to study the effects of chronic psychosocial stress in rodents, as it recapitulates many stress-induced pathologies observed in humans, including metabolic changes. This model, however, is based off male territorial aggression that is not applicable to female rodents. To investigate how females respond to psychosocial stress, we tested two adaptations to the social defeat paradigm to study the effect of chronic stress on metabolism in females. In the first paradigm, fighting females, a female and castrated male CD-1 are cohoused for several days, priming the CD-1 female to display territorial behaviors towards an intruding C57 female mouse. In the second paradigm, non-discriminatory social defeat, we introduced a C57 male and female simultaneously to a CD-1 male mouse. The intruding male provokes territorial aggression towards both the male and female mice. We tested both paradigms for 21-days and gave mice access to chow and a high fat diet, ad lib. Females in the non-discriminatory model displayed changes to hormone levels and metabolism commonly associated with chronic stress. These mice increased their consumption of the standard chow diet, high in carbohydrates, when stressed and had elevated ghrelin and corticosterone levels. Females from the fighting female's paradigm, however, did not display the same markers of chronic stress. Our results highlight discrepancies in the magnitude of stress elicited by each paradigm, with the second paradigm inducing metabolic changes in females commonly observed in males following social defeat.

Molecular and behavioural consequences of a striatal bmal1 knockout in mice

Next from CAN-ACN 2021

Using auditory brainstem responses to evaluate the ultrasonic hearing abilities of the domestic cat

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