Canada

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by a mutation in the gene MECP2. MeCP2 protein is found to be most abundant in neurons where it binds to DNA to act as an A-D global transcriptional regulator. Previous work has shown neurons with MECP2 mutations exhibited morphological and functional hypoconnectivity at a single neuron level. We hypothesized this hypoconnectivity between MECP2¬-mutant neurons will result in altered network development and function. Excitatory neurons derived from iPSCs from a RTT patient, two control patients, and isogenic pairs were generated. Neurons were plated on a multielectrode array and electrophysiology was measured over 6 weeks. Spatiotemporal analyses were used to quantify the electrophysiological features and computational network modeling was used to explore mechanisms driving the differences seen in vitro. iPSC-derived cultures exhibited bursting patterns that went from sparse firing to asynchronous bursting to synchronous bursting across development - quantified through burst frequency. As neuronal cultures developed, mutants grew increasingly different in their burst frequency compared to isogenic controls. Spiking network modelling revealed adaptation currents had the greatest influence on bursting. As adaptation currents increased, the burst frequency shifted to lower values. Simulated knockout experiments supported these results. This suggest that RTT networks may be mediated by adaptation currents, and various regulators for channels involved in adaptation may be implicated as downstream targets of MeCP2.

CAN-ACN 2021

Electrophysiological characterization of Rett Syndrome in iPSC-derived neuronal networks using computational network modeling

neurodevelopmental disorders

rett syndrome

electrophysiology

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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

The presence of an allocentric landmark can have both explicit (instruction-dependent) and implicit influences on reaching performance (Byrne and Crawford 2010; Chen et al., 2011; Klinghammer et al. 2015, 2017). However, it is not known how the instruction itself (to rely either on egocentric versus allocentric cues) influences memory-guided reaching. Here, 13 participants performed a task with two instruction conditions (egocentric vs. allocentric), but with similar sensory and motor conditions. In both conditions, participants maintained fixation while a LED target briefly appeared (alongside a visual landmark) in one visual field. After a mask/memory delay period, the landmark re-appeared in the same or opposite visual field. In the allocentric condition, participants were instructed remember the initial location of the target relative to the landmark, and to reach relative to the shifted landmark. In the egocentric condition, subjects were instructed to ignore the landmark and point toward the remembered location of the target (50% of trials were motor-matched anti-reaches). The allocentric instruction yielded significantly more accurate pointing than the egocentric instruction, despite identical visual and motor conditions and regardless of the final pointing side. These results show that memory-guided pointing improves when participants are explicitly instructed to point relative to the landmark. This suggests that explicit attention to a visual landmark recruits allocentric coding mechanisms that are more resistant to memory decay than egocentric mechanisms.

Explicit attention to allocentric visual landmarks improves memory-guided reaching

As we read, communication across brain networks allows us to integrate the way words look, sound, and mean. Phonological (sounds) and semantic (meaning) processing are key components of skilled reading. Understanding their underlying neural systems in adults sets a foundation to explore their development in children. In this pilot study, 64-channel EEG was recorded while adults (n=14; ages=23-36; 8 male) read word pairs that were rhyming or nonrhyming (goose-juice vs. small-juice) and semantically related or unrelated (open-close vs. nest-close). The goal was to explore both the event related potentials (ERPs) associated with lexical access (the N400) and oscillatory power effects associated with brain network integration during both types of priming. While similar N400 effects were seen for both phonological and semantic priming (larger N400 for unrelated vs. related words at central/mid-line electrodes 300-550ms; ps<.001), the frequency and duration of oscillatory power effects differed. Phonologically unrelated vs. related words showed greater power in beta (13-30 Hz, 334-820ms, p<.05), and gamma (31-80Hz, 292-456ms, p<.001), while semantically unrelated vs. related words showed greater long-lasting power in theta (4-7 Hz, 42-2400ms, p<.05), alpha (8-12 Hz, 122-1040ms, p<.05) and beta (13-30 Hz, 878-1544ms and 1944-2500ms, ps<.05). In line with speech processing models, higher frequency oscillations may be associated with sound as compared to meaning processing. Oscillatory power may reveal additional insights into the brain networks important for reading than ERPs alone.

Neurocognitive processes used in phonological and semantic priming: An ERP and oscillatory power study

Major depressive disorder (MDD) will affect 20% of individuals and is now considered the leading cause of disabilities worldwide. However, most studies still investigate MDD exclusively in males. We reported that chronic social stress induces blood-brain barrier (BBB) leakiness through loss of tight junction protein claudin-5 (cldn5) in the nucleus accumbens (NAc), a mood regulation center, of male mice allowing the passage of circulating inflammatory mediators into the brain and establishment of depression-like behaviors. In rodents, exposure to chronic social defeat stress (CSDS) through physical encounter with a larger aggressive mouse induces a depression-like phenotype. A subpopulation of mice does not develop depressive behaviors and is considered resilient, allowing us to also study biological adaptations promoting stress resilience. After CSDS, cldn5 gene expression is unchanged in the NAc of stress-susceptible females but decreased in the prefrontal cortex (PFC), a brain region regulating decision making and social behaviors, when compared to controls and resilient mice. This sexual dimorphism of stress-induced neurovascular adaptations was confirmed in post-mortem human brain samples from depressed individuals, adding translational value to our findings. Viral-mediated functional manipulation confirmed the causality of cldn5 loss in the female PFC in the establishment of depressive behaviors and possibly sex-specific MDD symptomatology. This data suggests that stress-induced neurovascular changes do not occur in the same brain regions in stressed females vs males.

Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression

Hearing loss is a chronic health condition affecting ~466 million people worldwide, with excessive exposure to loud noise as a leading cause. Epidemiological studies have identified hearing loss as a major risk factor for age-related cognitive decline; however, the brain regions mediating the link between the two remain elusive. Although previous studies have reported molecular changes in the hippocampus and striatum following noise exposure, it is unknown whether such changes contribute to cognitive decline associated with noise-induced hearing loss. To that end, we noise-exposed 6-month old rats, and then assessed their hearing and cognitive function at 7, 10 and 13 months of age. Rats underwent cognitive testing on the Morris water maze to assess hippocampal-dependent learning and memory, and on a striatal-dependent visuomotor associative learning task. Consistent with human studies, noise exposure resulted in mild, high-frequency hearing loss. The noise-exposed rats did not exhibit significant deficits in striatal-dependent visuomotor associative learning, yet they had a faster reaction time compared to the sham-exposed rats. Moreover, a subset of noise-exposed older rats demonstrated hippocampal-dependent spatial learning deficits, suggesting that some animals are more vulnerable to the effects of noise exposure with age. Ultimately, these novel findings expand our understanding of how brain regions outside of the auditory pathway are affected by noise exposure; findings that should be considered when investigating the link between hearing loss and cognitive decline.

Investigating the link between hearing loss and age-related cognitive decline in a rodent model

The ability to alter previously established behaviours is key for survival. Two ways in which reductions in conditioned behaviours can be achieved is through overexpectation and extinction. In both cases the expected outcome, be it aversive or appetitive, is greater than that delivered, thus generating a negative prediction error and downregulating established expectations. In overexpectation, the expectation of the outcome is manipulated by inflating it through summation, whereas in extinction it is outcome delivery that is manipulated by omitting it altogether. Our previous work showed that the lateral orbitofrontal cortex (lOFC) is critical for learning from overexpectation but less so in learning from extinction. When studying the effects of lOFC function on extinction, we found a mild effect of lOFC inactivation only in initial but not subsequent extinction learning. This albeit mild effect led us to assess the generality of the role of the lOFC in overexpectation by studying the order of learning episodes. Specifically, we examined the effect of lOFC inactivation on learning from overexpectation in animals that have undergone either initial extinction or overexpectation training with a different cue. Our findings confirm that inactivation of the lOFC prior to compound training in overexpectation disrupted the reduction in responding seen on test, regardless of the order of learning and prior experience. Additionally, silencing the lOFC only resulted in a mild impairment in initial extinction. Together, these results extend and replicate our prior work to provide additional evidence that the lOFC consistently regulates the reduction of learned fear responses driven by overexpectation.

The lateral orbitofrontal cortex consistently regulates learning from overexpectation of fear

Chronic stress, the main environmental risk factor for major depressive disorder (MDD) is linked to intestinal barrier deterioration via gut-brain signaling in gastrointestinal disorders. MDD shows high comorbidity with gastrointestinal disorders including patterns of microbiome dysbiosis and inflammatory peripheral markers, suggesting increased intestinal permeability in these patients. We investigate how the effects of chronic stress can influence manifestations of intestinal permeability in both male and female mouse models of depression. The prevalence of MDD is two-fold higher in women, however, chronic social defeat stress (CSDS) experiments have been conducted exclusively in male mice. We hypothesize that stress induces changes to gut barrier integrity in a sex-specific manner, playing a role in vulnerability or resilience. Accordingly, mice were subjected to various stress paradigms: 6-day or 28-day chronic variable stress, or 10-day CSDS. 16S rRNA sequencing assessed microbial populations pre- and post-stress. Gene and protein expression analysis of tight junctions from intestinal tissues shows alterations related to the type and duration of stress with sex-specific effects. Furthermore, CSDS induces changes in tight junction expression associated with resilience or susceptibility to chronic social stress, corresponding to phenotype severity. Our results provide evidence for the effects of chronic stress in disrupting intestinal barrier homeostasis in conjunction with the manifestation of depression-like behaviours.

Sex-specific effects of chronic stress on intestinal permeability and depression-like behaviors

We present the Py-based SYstem for Chronic monitoring of rOdent SpeciesPy-(PSYCO) Mouse Tracker (PNMT): an affordable, open-sourced, and customizable/scalable behavior recording software for small foot-print Raspberry Pi-based acquisition computers and subsequent offline analysis tools capable of recording and tracking multiple mice for extended periods of time, respectively. Video tracking coupled with radio frequency identification (RFID) was employed to track multiple mice in a modified home-cage setting for up to four days. Video and RFID recordings were completed utilizing a Raspberry Pi 3B+ or Pi4 micro-computer. During offline analysis performed on a PCdesktop computers, mice were tracked using You Only Look Once version 4 (Yolov4) algorithm coupled with the Simple Online and Realtime Tracking (SORT) for mice tracking, respectively. RFID readings recorded in the system were then associated with the best-matched mouse that was tracked. For evaluation, PMTNMT performance was compared to a human manual validation of video recordings containing one to four mice. PMTNMT maintained a minimum of 70% identities tracked among mice detected with an overall accuracy >above 90 %. Moreover, we also showed that PMTNMT can be adapted to other behavior apparatus such as an open field like arena or sociability chamber to track mice. Furthermore, the PSYCO tracker can incorporate inputs from popular open-sourced packages such as Deeplabcut and Traja for postures estimation and travel trajectory analysis, respectively. Overall, our group demonstrated the performance of a newly developed multiple animal tracking system capable of tracking mice for extended periods of time and adaptable to the use case of individual investigators.

PSYCO:Py-based SYstem for Chronic monitoring of rOdent Species, an open-sourced python based system for homecage mouse tracking and image processing

Evidence indicates that neurodegeneration (NDG) is a prominent feature and the primary cause of disability in multiple sclerosis (MS). Yet, knowledge of the molecular mechanisms of NDG in MS, as well as treatment options for NDG are lacking. Published data from our lab indicates that dysfunction of the RNA binding protein heterogeneous ribonucleoprotein A1 (A1) may contribute to MS pathogenesis. Therefore, to examine A1 dysfunction, we utilized an in vitro, blue light (BL) induced, optogenetic protein self-association expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, to examine the effects of MS-associated somatic A1 mutations (P275S and F281L) on A1 localization, cluster kinetics and stress granule (SG) formation in real-time. Using BL stimulation followed by a period of recovery, which promotes protein self-association and dissociation dynamics (imitating a cell stress event that occurs during MS relapse), revealed that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. Additionally, mutant A1 protein clustering also caused SG formation to occur more quickly and frequently in response to BL stimulation. Overall, this study establishes a live cell optogenetic imaging system to probe localization and association dynamics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote SG formation, which supports the hypothesis that A1 dysfunction may exacerbate NDG in MS.

Optogenetics defines the effects of multiple sclerosis-associated hnRNPA1 mutations on hnRNPA1 dynamics and stress granule formation

Early-life stress (ELS) has profound and enduring effects on cognition and behaviour. Stressors activate the hypothalamic-pituitary-adrenal axis and increase glucocorticoid (GC) levels. GCs are important for neurodevelopment; however, high GC levels increase neuron death and dendritic atrophy. Rodent models of ELS use stressors such as maternal deprivation, limited bedding and nesting material, and endotoxin exposure. Alternatively, some ELS studies administer corticosterone systemically (p.o., i.p. or s.c.) to neonatal rodents. No studies have administered corticosterone in vivo directly to the neonatal brain. Here, we developed a simple and robust method to administer corticosterone to the neonatal mouse brain by intracerebroventricular (icv) injection into the lateral ventricle. We applied a local analgesic to the scalp of postnatal day 5 (PND5) C57BL/6J mice. We then delivered 2 uL of 5, 10, 15, or 45 ng/uL solutions of corticosterone with a single icv injection. 2uL of sterile saline was injected as a vehicle control. After 2.5 hr, we collected the brain, whole blood, and liver. Corticosterone levels in microdissected brain regions, blood, and liver were measured via liquid chromatography tandem mass spectrometry (LC-MS/MS). With higher doses of corticosterone, brain corticosterone levels rose accordingly while peripheral corticosterone levels did not. Our study outlines a novel paradigm of injecting corticosterone into the brain of non-anesthetized PND5 mice that can be used to elucidate the impact of locally elevated corticosterone in the brain and model ELS.

Novel method for intracerebroventricular injection in neonatal mice

Nearly 50 different retinal ganglion cell (RGC) types sample the visual scene for distinct features such as motion direction or line orientation. RGC feature selectivity arises from its synapses with a specific subset of amacrine (AC) and bipolar cell (BC) types, but how their dendrites arborize and collect input from these specific subsets remains poorly understood. We developed a method that combines calcium imaging and post hoc histology that revealed a family of circuits that express the adhesion molecule Sidekick 1 (Sdk1) which include a novel RGC type (S1-RGC) that responds to local edges. Genetic and physiological studies revealed that Sdk1 loss selectively disrupts S1-RGC visual responses which result from a loss of excitatory and inhibitory inputs on this neuron. These phenotypes were specific to S1-RGCs and were accompanied by selective deficits in their dendritic growth. We conclude that Sdk1 shapes dendrite growth and wiring to help S1-RGCs become feature selective.

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Explicit attention to allocentric visual landmarks improves memory-guided reaching

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