Biology subjects

Khokhar, J. Y.

Publications and source records attributed to Khokhar, J. Y..

11 recordsLinked to original sources

bioRxiv2026

Cannabis THC:CBD Composition Affects Oligodendrocyte Progenitor Cell Characteristics Following Acute Cannabis Vapor Inhalation in Adult Male and Female Mice

Cannabis is one of the most widely consumed substances in the world. Consumers seek out cannabis cultivars with varying levels of phytocannabinoids, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The effects of THC, CBD or the combination of THC:CBD have distinct outcomes on cognitive processes, cellular functions, and phytocannabinoid pharmacokinetics. The majority of research on cannabis effects on the brain has focussed on neurons, and few studies have investigated the impact of different cannabis cultivars on glia. In particular, the impact of varying levels of THC:CBD on oligodendrocyte lineage cells, which play numerous support roles in the brain essential to proper neuronal communication, is relatively unknown. This study set out to examine the acute impact of different cultivars of vaporized cannabis on oligodendrocyte lineage cells in the forceps minor of adult male and female mice. Mice were exposed to vapor from cannabis flower high in THC, high in CBD or balanced in THC:CBD over 15 minutes, and brains were fixed 30 minutes post-cannabis onset. Using immunofluorescence microscopy, we observed significant changes to oligodendrocyte progenitor cell (OPC) morphology in mice exposed to balanced cannabis, and, using correlative light and electron microscopy, we observed alterations to OPC mitochondria. The alterations observed (i.e., enlarged soma and nucleus volume, reduced density and increased area of mitochondria in the soma) in OPCs due to balanced cannabis are reminiscent of the very early changes seen during OPC differentiation. This study highlights the differing effects of cannabis cultivars on OPCs and the rapidity of the OPC response to inhaled phytocannabinoids.

neuroscience↗

bioRxiv2025

Developing a model of temporomandibular disorder in the common marmoset using nerve growth factor

Developing an animal model that more closely represents the human multidimensional pain experience is an important step towards addressing the current chronic pain crisis. The common marmoset has potential as this model species given its biological, neurological and phylogenetic similarity to humans. Here, we developed a model of myofascial temporomandibular disorder (TMD) in the marmoset by injecting nerve growth factor (NGF) into the superficial masseter. Following injection, animals showed reduced mechanical withdrawal thresholds at 5 g and 10 g doses of NGF and changes in circadian rhythm and feeding initiation following injection of 10 g of NGF. Animals did not show evidence of jaw dysfunction, masticatory alterations, or grimace during novel behavioural assays. The model is transient, with pain resolution occurring approximately 7 days after onset, which allows for repeated testing on the same animal. This same NGF-TMD model has been previously validated in rodents and humans and presents an opportunity for forward and reverse translation to examine mechanisms, develop relevant pain assessment tools, and ultimately test novel treatments for TMD and other musculoskeletal pain conditions. New & NoteworthyWe developed a long-lasting but transient ([~]7 days) model of myofascial temporomandibular disorder pain in marmosets. Mechanical hypersensitivity and changes to circadian activity and spontaneous eating behaviours were observed. There was no evidence of jaw dysfunction, altered food preference or changes in grimace. The NGF-TMD model can be translated to the marmoset with the potential for investigating mechanisms and novel interventions for TMD.

neuroscience↗

bioRxiv2024

Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic-pituitary-adrenal (HPA) axis responsivity in female and male mice

RationaleClinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior. ObjectivesWe aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice. MethodsC57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol. ResultsCompared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC. ConclusionsCBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.

neuroscience↗

bioRxiv2024

Acute nicotine vapor normalizes sensorimotor gating and reduces locomotor activity deficits in HIV-1 transgenic rats

RationaleDespite improved life expectancy of people with HIV (PWH), HIV-associated neurocognitive impairment (NCI) persists, alongside deficits in sensorimotor gating and neuroinflammation. PWH exhibit high smoking rates, possibly due to neuroprotective, anti-inflammatory, and cognitive-enhancing effects of nicotine, suggesting potential self-medication. ObjectivesHere, we tested the effects of acute nicotine vapor exposure on translatable measures of sensorimotor gating and exploratory behavior in the HIV-1 transgenic (HIV-1Tg) rat model of HIV. MethodsMale and female HIV-1Tg and F344 control rats (n=57) were exposed to acute nicotine or vehicle vapor. Sensorimotor gating was assessed using prepulse inhibition (PPI) of the acoustic startle response, and exploratory behavior was evaluated using the behavioral pattern monitor (BPM). ResultsVehicle-treated HIV-1Tg rats exhibited PPI deficits at low prepulse intensities compared to F344 controls, as seen previously. No PPI deficits were observed in nicotine-treated HIV-1Tg rats, however. HIV-1Tg rats were hypoactive in the BPM relative to controls, whilst nicotine vapor increased activity and exploratory behavior across genotypes. Cotinine analyses confirmed comparable levels of the primary metabolite of nicotine across genotypes. ConclusionsPrevious findings of PPI deficits in HIV-1Tg rats were replicated and, importantly, attenuated by acute nicotine vapor. Evidence for similar cotinine levels suggest a nicotine-specific effect in HIV-1Tg rats. HIV-1Tg rats had reduced exploratory behavior compared to controls, attenuated by acute nicotine vapor. Therefore, acute nicotine may be beneficial for remediating sensorimotor and locomotor activity deficits in PWH. Future studies should determine the long-term effects of nicotine vapor on similar HIV/NCI-relevant behaviors.

neuroscience↗

bioRxiv2023

FARESHARE: An Open-source Apparatus for Assessing Drinking Microstructure in Socially Housed Rats

Social factors have been shown to play a significant and lasting role in alcohol consumption. Studying the role of social context on alcohol drinking is important to understand the factors that contribute to initiation or maintenance of casual and problematic alcohol use, as well as those that may be protective. A substantial body of preclinical research has shown that social environment such as housing conditions and social rank plays an important role in alcohol consumption and preference, though the extent of these effects have been obfuscated by methodological differences and technical challenges. Robust individual differences in alcohol intake in socially housed animals are difficult to track when animals share a common fluid source. Commercial solutions are prohibitively expensive and are limited by proprietary software and hardware (including caging systems). Here we describe an affordable, open-source solution for tracking fluid consumption in socially housed rats.

animal behavior and cognition↗

bioRxiv2023

Neural and behavioral correlates of edible cannabis-induced poisoning: characterizing a novel preclinical model

Accidental exposure to {Delta}9-tetrahydrocannabinol (THC)-containing edible cannabis, leading to cannabis poisoning, is common in children and pets; however, the neural mechanisms underlying these poisonings remain unknown. Therefore, we examined the effects of acute edible cannabis-induced poisoning on neural activity and behavior. Adult Sprague-Dawley rats (6 males, 7 females) were implanted with electrodes in the prefrontal cortex (PFC), dorsal hippocampus (dHipp), cingulate cortex (Cg), and nucleus accumbens (NAc). Cannabis poisoning was then induced by exposure to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg). Subsequently, cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24 h after THC exposure. In another cohort (16 males, 15 females), we examined the effects of cannabis poisoning on learning and prepulse inhibition, and the serum and brain THC and 11-hydroxy-THC concentrations. Cannabis poisoning resulted in sex differences in brain and serum THC and 11-hydroxy-THC levels over a 24-h period. It also caused gamma power suppression in the Cg, dHipp, and NAc in a sex- and time-dependent manner. Cannabis poisoning also resulted in hypolocomotion, hypothermia, and anti-nociception in a time-dependent manner and impairments in learning and prepulse inhibition. Our results suggest that the impairments in learning and information processing may be due to the decreased gamma power in the dHipp and PFC. Additionally, most of the changes in neural activity and behavior appear 2 hours after ingestion, suggesting that interventions at or before this time might be effective in reversing or reducing the effects of cannabis poisoning.

neuroscience↗

bioRxiv2021

Prevalence and Characteristics of Cannabis-induced Toxicoses in Pets: Results from a Survey of Veterinarians in North America

Cannabis legalization in North America has coincided with an increase in reports of cannabis-induced toxicosis in pets, but the magnitude of this problem, as well as outcomes of these incidents remain unknown. Therefore, we examined the frequency, diagnostic criteria, clinical signs, and prognoses of cannabis toxicoses in pets in North America. We conducted an online survey between January, 2021 and April, 2021 targeting veterinarians practicing in Canada and the United States (US). Out of the 251 study participants, 191 practiced in Canada. Cannabis toxicosis was most commonly reported in dogs (n=226 veterinarians), and the number of toxicosis cases increased significantly in Canada (p<0.0001) and the US (p=0.002) after October, 2018. Frequently reported clinical signs of cannabis toxicosis included: urinary incontinence (n=195), disorientation (n=182), ataxia (n=178), lethargy (n=150), hyperesthesia (n=134), and bradycardia (n=112). Edibles were most commonly suspected to be the cause of toxicosis (n=116). The most common route of exposure was ingestion (n=135), while the most cited reason was ingestion while unattended (n=135). Cannabis toxicosis was mostly diagnosed using supportive clinical signs (n=229), the most common treatment was outpatient monitoring (n=182), and pets were most often treated as out-patients (n=103). The legalization of cannabis use in Canada and the US is likely an important factor associated with the increased cannabis toxicosis cases in pets; however, the legal status may also increase reporting. The medicinal use of cannabis by pet-owners for pets may also contribute to a portion of the reported toxicoses. Most pets that experienced cannabis toxicosis recovered completely, suggesting that most cannabis toxicoses do not result in long-term ill effects. Even though some deaths (n=16) were reported in association with cannabis toxicosis, the presence of confounders such as toxins, and underlying conditions cannot be ruled out, emphasizing the need for rigorous controlled laboratory studies to investigate this important issue.

pharmacology and toxicology↗

bioRxiv2021

Cannabis Vapour Exposure Alters Neural Circuit Oscillatory Activity In A Neurodevelopmental Model Of Schizophrenia: Exploring The Differential Impact Of Cannabis Constituents

Cannabis use is highly prevalent in patients with schizophrenia and worsens the course of the disorder. To understand the causal impacts of cannabis on schizophrenia-related oscillatory disruptions, we herein investigated the impact of exposure to cannabis vapour (containing delta-9-tetrahydrocannabinol [THC] or balanced THC and cannabidiol [CBD]) on oscillatory activity in the neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia. Male Sprague Dawley rats underwent NVHL or sham surgeries on postnatal day 7. In adulthood, electrodes were implanted targeting the cingulate cortex (Cg), the prefrontal cortex (PFC), the dorsal hippocampus (HIP), and the nucleus accumbens (NAc). Local field potential recordings were obtained following exposure to two strains of vapourized cannabis flower (with ~10% THC or ~10% balanced THC:CBD) in a cross-over design with a two-week wash-out period between exposures. Compared to controls, NVHL rats had reduced baseline gamma power in the Cg, dHIP, and NAc, and reduced high-gamma coherence between the dHIP-Cg. THC-only vapour broadly suppressed oscillatory power and coherence, even beyond the baseline suppressions observed in NHVL rats. Balanced THC:CBD vapour appeared to ameliorate the THC-induced impacts on power and coherence in both sham and NVHL rats. For NVHL rats, THC-only vapour also normalized the baseline dHIP-Cg high-gamma coherence deficits. NHVL rats also demonstrated a 20ms delay in dHIP theta to high-gamma phase coupling, which was ameliorated by both exposures in the PFC and NAc. In conclusion, THC-only cannabis vapour suppressed oscillatory activity in NVHL and sham rats, while balanced THC:CBD vapour may ameliorate some of these effects.

neuroscience↗

bioRxiv2020

Chronic Chemogenetic Manipulation of Ventral Pallidum Targeted Neurons in Rats Fed an Obesogenic Diet.

Current treatments for obesity are unable to reliably reduce weight over time and alternative treatments need to address this challenge. New interventions that target the nervous system could manipulate brain networks underlying reward, metabolic rate and behavior. Here, the ventral pallidum was evaluated as a target of manipulation due to its established role in the networks underlying motivation, pleasure and behavioral output. Chronic inhibitory or excitatory chemogenetic activation was used to modulate the activity of ventral pallidum (VP) targeted neurons in rats on an obesogenic diet. We hypothesized that inhibition of VP activity would decrease the salience of the rats high-sugar, high-fat diet and lead to reduced food consumption and weight gain over time. Paradoxically, measurements of weight, water and food consumption revealed significantly increased weight gain in both groups receiving VP targeted manipulation that was not readily explained by food or water consumption. We theorize that the complex reciprocal feedback between ventral striatal structures (e.g., VP) and metabolic centers of the hypothalamus and brainstem, demonstrated by prior research, likely underpin our findings. This study suggests that the treatment of appetitive disorders (e.g., obesity) with chronic neuromodulation-based interventions could be burdened by the delayed onset of outcomes that are difficult to predict from related prior studies that used acute interventions.

neuroscience↗

bioRxiv2018

An unbiased decoding of ventral striatal oscillations in a rat model of binge eating: Finding the balance between model complexity and performance.

The ventral striatum (VS) is a central node within a distributed network that controls appetitive behavior, and neuromodulation of the VS has demonstrated therapeutic potential for appetitive disorders. Local field potential (LFP) oscillations recorded from deep brain stimulation electrodes within the VS are a pragmatic source of neural systems-level information about appetitive behavior that could be used in responsive neuromodulation systems. Here, we recorded LFPs from the bilateral nucleus accumbens core and shell (subregions of the VS) during limited access to palatable food across varying conditions of hunger and food palatability in male rats. We used standard statistical methods (logistic regression) as well as the machine learning algorithm lasso to predict aspects of feeding behavior using VS LFPs. These models were able to predict the amount of food eaten, the increase in consumption following food deprivation, and the type of food eaten. Further, we were able to predict whether the initiation of feeding was imminent up to 42.5 seconds before feeding began and classify current behavior as either feeding or not-feeding. In classifying this behavior, we found an optimal balance between model complexity and performance with models using 3 LFP features primarily from the alpha and high gamma frequencies. As shown here, unbiased methods can identify systems-level neural activity linked to symptoms of mental illness with potential application to the development and personalization of novel treatments.\n\nAuthor SummaryAs neuropsychiatry begins to leverage the power of computational methods to understand disease states and to develop better therapies, it is vital that we acknowledge the trade-offs between model complexity and performance. We show that computational methods can elucidate a neural signature of feeding behavior and show how these methods could be used to discover neural patterns related to other behaviors and used as therapeutic targets. Further, our results helps to contextualize both the limitations and potential of applying computational methods to neuropsychiatry by showing how changing the data being used to train predictive models (e.g., population vs. individual data) can have a large impact on how model performance generalizes across time, internal states and individuals.

neuroscience↗

bioRxiv2018

Machine learning based classification of deep brain stimulation outcomes in a rat model of binge eating using ventral striatal oscillations.

Neuromodulation-based interventions continue to be evaluated across an array of appetitive disorders but broader implementation of these approaches remains limited due to variable treatment outcomes. We hypothesize that individual variation in treatment outcomes may be linked to differences in the networks underlying these disorders. Here, Sprague-Dawley rats received deep brain stimulation separately within each nucleus accumbens (NAc) sub-region (core and shell) using a within-animal crossover design in a rat model of binge eating. Significant reductions in binge size were observed with stimulation of either target but with significant variation in effectiveness across individuals. When features of local field potentials (LFPs) recorded from the NAc were used as predictors of the pre-defined stimulation outcomes (response or non-response) from each rat using a machine-learning approach (lasso), stimulation outcomes could be predicted with greater accuracy than expected by chance (effect sizes: core = 1.13, shell = 1.05). Further, these LFP features could be used to identify the best stimulation target for each animal (core vs. shell) with an effect size = 0.96. These data suggest that individual differences in underlying network activity may contribute to the variable outcomes of circuit based interventions and that measures of network activity have the potential to individually guide the selection of an optimal stimulation target and improve overall treatment response rates.

neuroscience↗