Canada

Behavioural neuroscience researchers continue to seek relevant rodent paradigms that mimic human patterns of cannabis use. Injected Δ9-tetrahydrocannabinol (THC) is commonly used to assess acute cannabis effects in rodents despite pharmacokinetics varying greatly between injection and inhalation. In addition, tasks used to assess behaviour following cannabis exposure often lack strong translational relevance to human tasks. Therefore, in the present experiment, we investigated cognitive effects of acute exposure to cannabis smoke in two rodent tasks highly translatable to human tasks for measuring working memory, attention, and impulsivity. Male Long-Evans rats were trained in two cognitive tasks using touchscreen-equipped operant conditioning chambers: (1) the trial-unique, delayed nonmatching-to-location (TUNL; n=16); (2) the five-choice serial-reaction time task (5CH; n=16). Trained rats received: (i) combusted cannabis smoke (two strains: Mohawk, high-THC; Treasure Island: low-THC) using a 4-chamber pump-driven system; or (ii) injected THC (3.0mg/kg; i.p.) and behaviour was immediately assessed on the tasks. Interestingly, we failed to observe any effects of cannabis smoke on performance of TUNL or 5CH; however, injected THC significantly reduced accuracy and number of trials completed during TUNL, plus a notable (albeit insignificant) increase in omissions during 5CH. These data support a growing literature showing distinct differences between cannabis strain and method of administration, highlighting a continued need to investigate cannabinoid effects on cognition.

CAN-ACN 2021

Effects of smoked cannabis and injected Δ9-tetrahydrocannabinol on touchscreen-based tasks for measuring working memory, attention, and impulsivity in male Long Evans rats

behavioral neuroscience

cannabis

rats

cognition

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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

Previous studies have focused on the encoding of the first-order features of vestibular stimuli, but few studies, to date, have studied the encoding of the second-order attribute that consist of changes in vestibular stimuli amplitude or envelope. Because envelopes are critical for perception, we investigated if and how vestibular only neurons in the vestibular nuclei, known to mediate self-motion perception, encode the envelope attribute of the head motion stimulus. Specifically, we studied neural responses to stimuli consisting of a noisy waveform whose envelope varied sinusoidally at lower frequency. Importantly, stimulus amplitude was kept low such as not to elicit static nonlinearities from afferents (e.g., rectification, saturation). Our results show that the envelope attribute of the stimulus is encoded at single-neuron level in the vestibular nuclei. On average, we found that the gain of the neuron's response to the envelope remained constant across frequencies (p = 0.24). Moreover, the neuron's response shows a slight phase lead that increases as the frequency of the envelope increases (p=0.01). We found that static nonlinearities do not account for neural envelope response. Finally, we calculated the discrimination threshold and found higher values than that found in the Thalamus and for perception. Overall, our results will have important implication in our understanding of how early processing of vestibular signal can encode second-order attributes of head motion that will further be used to ensure stable perception of the world and accurate motor control.

Second-order attribute of head motion is encoded at single-neuron level in the vestibular nuclei

Self motion is composed of both rotational and translational motions which occur with characteristic statistics in everyday life. In the context of rotation, we have previously shown that neurons at the first central stage of vestibular processing (VN) are adapted to match their tuning curves to the statistics of natural rotation. This strategy effectively removes redundancy in the neural response, and produces responses which are independent of frequency (i.e. temporally whitened). However, unlike for rotation, translation sensitive neurons display significantly more heterogeneity in their tuning curves to artificial stimuli, and their responses to natural stimuli which cover the full physiological range of motion frequencies has not been explored. Here we investigated whether and, if so, how the responses of translation sensitive vestibular-only (otolith VO) cells in the VN of awake behaving macaques are adapted to naturalistic translation stimuli. Our results indicate that otolith VOs are not consistently matched to natural statistics in the same way as their rotation-sensitive counterparts, and instead fall roughly into 3 categories covering a range from strongly low-pass filtered to optimally whitened responses. This study is the first to examine the responses of otolith VO neurons in the context of natural self-motion, and suggests that low-pass filtered, faithful reconstruction, and optimally encoded representations of the stimulus may each be implemented in the translational vestibular system via parallel encoding strategies.

Neuronal sensitivity and variability mediate 3 parallel strategies for encoding natural translations in the primate vestibular system

Clinical data proposes that the common street drug MDMA (ecstasy) increases water intake by inducing the sensation of thirst and promoting fluid retention by the kidney. These effects account for the high incidence of hyponatremia (low blood sodium and excel water in serum) in patients visiting hospital emergency departments as a result of experiencing headaches and dizziness (and other signs of hyponatremia) following ingestion of MDMA. Clinical as well as rodent studies also reveal an increase in serum vasopressin levels when MDMA is ingested or administered, which is likely a key factor in fluid retention. To investigate the neurophysiological mechanisms underlying these effects brain slices obtained from transgenic rat brains were prepared at a specific angle to preserve circuitry important for the regulation of thirst and vasopressin release. Whole cell current and voltage clamp recordings from identified vasopressin neurons revealed that a bath application of MDMA causes an excitatory response; mediated by membrane depolarization. Moreover, a proportion of tonically active vasopressin neurons were observed to transition to a phasic firing pattern known to facilitate peptide release. These results suggest that MDMA can act directly on neurons controlling vasopressin thereby increasing the likelihood of fluid retention.

Mechanisms of MDMA induced vasopressin release in rats

Our research group has recently reported that nicotine, cocaine, and their conditioned contextual stimuli (CS), enhance object memory consolidation via noradrenergic and dopaminergic receptors. This suggests the hypothesis that the neuropharmacology of unconditioned and conditioned memory modulation is not influenced by drug class. To test the hypothesis, male Sprague-Dailey rats received infusions of the nicotinic receptor antagonist mecamylamine (MEC) within the perirhinal cortex (PRh); a cortical region well known to be involved in consolidation object memory. To establish the drug CSs, rats were confined for 2 h in a chamber (the CS+) after injections of 0.4 mg/kg nicotine or 20 mg/kg cocaine, and in another chamber (the CS−) after injections of vehicle. This was repeated over 10 d (5 drug/CS+ and 5 vehicle/CS− pairings in total). Surprisingly, it was found that the memory enhancing action of post-sample 0.4 mg/kg nicotine, but not 20 mg/kg cocaine, was blocked by intra-PRh infusions of 10 and 30 μg/side MEC. Moreover, the memory enhancing effects of the nicotine CS, but not cocaine CS, were also blocked by 30 μg/side MEC. Overall, these data indicate that a nicotine CS promotes memory consolidation by enhancing PRh cholinergic activity similar to the central effects of nicotine itself, but this is not the case for cocaine and cocaine CSs. These results suggest that in addition to mimicking the behavioural effects of drugs, drug CSs also possess the ability to mimic the neurochemical effects of the drugs themselves on object memory consolidation. Supported by NSERC.

Role of nicotinic receptors in the perirhinal cortex in memory modulation by nicotine, cocaine, and their conditioned stimuli

Functional Magnetic Resonance Imaging (fMRI) and functional Near Infrared Spectroscopy (fNIRS) are neuroimaging techniques that can measure changes in blood flow in response to external stimuli. fNIRS is a portable imaging device and considered to be the optical equivalent of fMRI. The objective of this preliminary work is to investigate the ability of fNIRS to detect brain activity during a median nerve stimulation task in healthy controls and to compare the results to fMRI findings. To date, 25 healthy controls have been recruited to the fMRI task, of which 10 have also participated in the fNIRS task. Median nerve stimulation was conducted while brain activity was recorded with fMRI and fNIRS (tests done sequentially). Both the left and right hand were stimulated, successively, at a current that sustained thumb abduction (8-35 mA). A block design with eight cycles of stimulation 'on' and seven cycles of 'rest' was used. At the group level, for both fMRI and fNIRS, significant brain activity was observed in the contralateral primary and bilateral secondary somatosensory areas for each hand being stimulated. At the single subject level, the results demonstrate an 80% agreement between fMRI and fNIRS results where fMRI is considered ground truth. The overall good agreement between the two techniques is promising, and future work will focus on recruiting additional participants to better assess the sensitivity between modalities. Ultimately, this work adds to the growing body of research highlighting fNIRS as a suitable alternative to fMRI, as it affords the advantage of being portable and low-cost to maintain.

A quantitative comparison of fMRI and fNIRS activity to a median nerve stimulation task

The role of the hippocampus in representing space is widely supported. Neurons that increase their firing rate when an animal occupies a certain region, 'Place Cells,' have been thoroughly identified and studied in multiple species. This unique population of neurons has been thought to support a cognitive-map like representation of space in the brain; however, little is known about how these representations are formed in the common marmoset during free navigation in a 3D environment. Moreover, whether these representations are modulated by spatial view or movement kinematic has yet to be determined. In this work, we sought to identify the firing properties of neurons in the CA fields of the hippocampus while we register spatial and view information of freely navigating marmosets as they engage in a variety of foraging behaviors in 3D space. For this purpose, we habituated the experimental subjects to freely move inside a plexiglass recording chamber with four vertical levels while wearing affixed infrared reflective markers on top of skull implants that allowed for 6 degrees of freedom position and head direction camera tracking (Optitrack, Natural Point Inc, USA). Using MRI-guided neuro-navigation techniques, we chronically implanted 32ch microwire arrays in the hippocampus, and we were able to record single-unit activity during the aforementioned behaviors wirelessly. We analyzed data from 2 animals; spatial view and occupancy rate maps were constructed using 20cm3 bins. Spatial Information Content (SIC) was calculated independently for place and view for 200 total cells. SIC was higher for the spatial view than body position. We also found cells whose firing rate was highly correlated for both body velocity and head angular velocity.

Representation of 3D space in the hippocampus of freely moving marmosets

While the SARS-CoV-2 virus is well known for its impact on the respiratory system, neurological symptoms such as headache, anosmia, and cognitive impairments have been observed. Most strikingly, anosmia is reported in around 50% of COVID-19 cases. Male golden hamsters are used to study the outcomes of SARS-CoV-2 infection and therefore may also be used to model the neurological and behavioural effects of following virus challenge. To this end, we are developing a behavioural battery that could easily be run by any scientific group in containment level 3 to assess behavioral changes in hamsters following SARS-CoV-2 infection. All tasks rely on rodents' innate preference for novelty and are conducted without extensive training or rule learning. Briefly, hamsters are exposed to two copies of a stimulus (odour or object) in a training trial. Following a brief delay, the hamsters are re-exposed to a third copy of the now familiar stimulus, and a novel stimulus. Results indicate that hamsters show a preference for novel odours; however, they are unable to perform the object-based task. In a sociability task, male hamsters were found to preferentially explore a novel hamster more than a novel object, as well as discriminate between a novel and familiar hamster in a similar paradigm. Experiments to refine these tasks are ongoing, with a goal of incorporating them into SARS-CoV-2 vaccine trials at the Vaccine and Infectious Disease Organization/Intervac in the fall of 2021.

Development of spontaneous tests of olfactory, object, and social discrimination behaviour in male golden hamsters: use in rodent models of SARS-CoV-2 infection?

Perineuronal nets (PNNs) are extracellular matrices that preferentially surround parvalbumin-positive (PV+) interneurons. Since PV+ neurons shape neural dynamics and plasticity, PNNs surrounding PV+ neurons have been proposed to regulate neural function. Much of the research on PNNs has centered on their role in sensory circuits, and little is known about how PNNs in sensorimotor structures affect behavioral expression. Here, we analyze the relationship between PNN and PV expression in sensorimotor systems and vocal performance in songbirds. Because songbirds, like humans, learn their vocalizations and use auditory feedback for vocal learning and control, songbirds are powerful animal models to reveal neural mechanisms of sensorimotor plasticity and function. We specifically relate PNN expression around PV+ neurons in forebrain and basal ganglia circuitry to the performance of learned vocalizations in the zebra finch. We hypothesize that, just as PNNs in sensory processing areas consolidate the sensory representations, PNNs in sensorimotor structures could consolidate sensorimotor commands for vocalizations. In this respect, we propose that more PV+ neurons are surrounded by PNNs in birds that produce more stereotyped vocalizations. Given that developmental exposure to song and age affect song stereotypy, we investigate this relationship in juvenile and adult birds that are either reared normally or deprived of song exposure throughout development. Our studies hope to provide further insight into the influence of PNNs on behavioral control and plasticity.

Investigating the influence of perineuronal nets surrounding parvalbumin-positive neurons in sensorimotor circuitry on motor performance

With the recent legalization of cannabis in Canada, there is concern that its use may perpetuate negative outcomes in mental health and impact executive brain functions like working memory (WM). The endocannabinoid (eCB) system regulates the homeostasis of the circuitry underlying memory processes. We were interested in investigating the effects of acute cannabis smoke (Mohawk strain, high-THC; Treasure Island strain, low-THC) exposure on adult male Long-Evans rats' WM capacity. We used a validated object paradigm to evaluate visuospatial WM capacity. Then, we developed a novel odour-based paradigm for assessing olfactory WM capacity as it is rodents' primary sense. An identical (IOT) and differential (DOT) version of the paradigms allowed us to evaluate various cognitive loads on WM capacity using 3 and 6 items. The spontaneous WM tasks used capitalize on rodents' innate preference for novelty and the time spent exploring familiar stimuli in the sample phase, and novel stimuli introduced in the test phase, was analyzed. In both the object and odour paradigms, a load-dependent effect on memory was found whereby more stimuli notably decreased WM function in the DOT, but not IOT, versions. Following acute smoke exposure, no overall disruption in WM function was observed in the object paradigm. However, WM deficits were observed in the odour paradigm after acute exposure to Mohawk, but not Treasure Island, smoke in both the IOT and DOT task. Due to this olfaction-based WM disruption, the task shows promise to model the cognitive impacts of cannabis consumption in humans.

Use of spontaneous object- and odour-based working memory (WM) tasks to evaluate the effects of acute cannabis smoke exposure on WM capacity in male rats

It has been hypothesized that cell assemblies represent mental or perceptual entities, forming the basis of neural coding and computation. We investigated how the number of cell assemblies was related to the age of the rats and spontaneous remapping, using unit recordings of CA1 pyramidal cells in six young and six old rats while they learned a place-dependent eyeblink conditioning task (Schimanski et al., 2013). To control the dependence of cell assembly detection on different number of recorded neurons, we selected 30 pyramidal cells randomly from each recording session and repeated the procedure 25 times. This generated >8000 data sets. The number of cell assemblies was estimated by a recently proposed method (Russo and Durstewitz, 2017). We found that young rats had significantly more cell assemblies than old ones (median for young = 166.7, median for old = 87.4, Mann-Whitney test, p = 3.1 x 10-8). Significantly more cell assemblies were also detected in non-remapping rats than remapping ones (median for non-remapping = 192.1, median for remapping = 90.9, Mann-Whitney test, p = 8.4 x 10-13). Interestingly, cell assemblies were most abundant in the first few days of recording if rats were grouped into non-remapping, young or old, but not in remapping. Taken together, we showed that significantly more cell assemblies were detected in young and non-remapping rats. Reduction of cell assemblies over training in non-remapping rats suggests that efficient neural codes may be generated by learning and hence a reduced number of cell assemblies is sufficient.

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Second-order attribute of head motion is encoded at single-neuron level in the vestibular nuclei

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