Sex differences in the neural and behavioral effects of acute high-dose edible cannabis consumption in rats.

The consumption of D9-tetrahydrocannabinol (THC)- or cannabis-containing edibles has increased in recent years; however, the behavioral and neural circuit effects of such consumption remain unknown, especially in the context of ingestion of higher doses resulting in cannabis intoxication. We examined the neural and behavioral effects of acute high-dose edible cannabis consumption (AHDECC). 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). Rats were provided access to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg) for 10 minutes, during which they voluntarily consumed all of the provided Nutella and THC mixture. Cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24-h after exposure. In another cohort (16 males, 15 females), we examined the effects of AHDECC on learning and prepulse inhibition, and serum and brain THC and 11-hydroxy-THC concentrations. AHDECC resulted in higher brain and serum THC and 11-hydroxy-THC levels in female rats over 24 h. AHDECC also produced: 1) Cg, dHipp, and NAc gamma power suppression, with the suppression being greater in female rats, in a time-dependent manner; 2) hypolocomotion, hypothermia, and anti-nociception in a time-dependent manner; and 3) learning and prepulse inhibition impairments. Additionally, most neural activity and behavior changes appear 2 h post-ingestion, suggesting that interventions around this time might be effective in reversing/reducing the effects of AHDECC. Significance Statement The effects of high-dose edible cannabis on behaviour and neural circuitry are poorly understood. We found that the effects of acute high-dose edible cannabis consumption, which include decreased gamma power, hypothermia, hypolocomotion, analgesia, and learning and information processing impairments, are time- and sex-dependent. Moreover, these effects begin 2 h after AHDECC and last for at least 24 h, suggesting that treatments should target this time window in order to be effective.

Cannabidiol Exerts Anticonvulsant Effects Alone and in Combination with Δ9-THC through the 5-HT1A Receptor in the Neocortex of Mice.

Cannabinoids have shown potential in drug-resistant epilepsy treatment; however, we lack knowledge on which cannabinoid(s) to use, dosing, and their pharmacological targets. This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC), as well as (iii) the serotonin (5-HT)1A receptor's role in CBD's mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 µM CBD alone and combined with Δ9-THC was evaluated. To examine CBD's mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD's effect was evaluated. An amount of ≥30 µM CBD alone exerted significant anticonvulsant effects while 10 µM CBD did not. However, 10 µM CBD combined with low-dose Δ9-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD's effects. Thus, our results demonstrate the efficacy of low-dose CBD and Δ9-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD's mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.

Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation.

Human cerebral organoids resemble the 3D complexity of the human brain and have the potential to augment current drug development pipelines for neurological disease. Epilepsy is a complex neurological condition characterized by recurrent seizures. A third of people with epilepsy do not respond to currently available pharmaceutical drugs, and there is not one drug that treats all subtypes; thus, better models of epilepsy are needed for drug development. Cerebral organoids may be used to address this unmet need. In the present work, human cerebral organoids are used along with electrophysiological methods to explore oxygen-glucose deprivation as a hyperexcitability agent. This activity is investigated in its response to current antiseizure drugs. Furthermore, the mechanism of action of the drug candidates is probed with qPCR and immunofluorescence. The findings demonstrate OGD-induced hyperexcitable changes in the cerebral organoid tissue, which is treated with cannabidiol and bumetanide. There is evidence for NKCC1 and KCC2 gene expression, as well as other genes and proteins involved in the complex development of GABAergic signaling. This study supports the use of organoids as a platform for modelling cerebral cortical hyperexcitability that could be extended to modelling epilepsy and used for drug discovery.

The use of L-phenylalanine ammonia lyase inhibitors in plant ecophysiological studies / Zastosowanie inhibitorów amoniakoliazy L-fenyloalaniny w badaniach ekofizjologii roslin.

Phenylalanine ammonia lyase (PAL) is a key enzyme controlling the biosynthesis of phenolic compounds in plants. PAL catalyzes ammonia elimination from L-phenylalanine in a reaction that yields cinnamic acid, a precursor of a large group of phenylpropanoid compounds. Phenylpropanoids and their derivatives play an important role in regulating plant resistance mechanisms under environmental stresses. By reducing the level of phenolic compounds, PAL inhibitors can induce changes in plant metabolism. This paper presents the current state of knowledge on the use of PAL inhibitors in plant biology, and draws attention to the possibilities of using PAL inhibitors in agriculture in the context of the witnessed climate changes which increase the frequency and intensity of some disasters such as droughts, floods and storms. By reducing the level of phenolic compounds, PAL inhibitors can induce changes in plant metabolism. This paper presents the current state of knowledge on the use of PAL inhibitors in plant biology, and draws attention to the possibilities of using PAL inhibitors in agriculture in the context of the witnessed climate changes.

Toward resilient agriculture and environmental protection: The role of cell wall-bound phenolics.

Due to their unpredicted scope, duration, and effects, soil droughts pose a serious threat to agriculture. Gradual steppe formation and desertification of farming and horticultural lands are the consequences of climate change. Irrigation systems for field crops do not offer the most viable solution, as they depend heavily on freshwater resources, which are currently scarce. For these reasons, it is necessary to obtain crop cultivars that are not only more tolerant to soil drought, but also capable of effective use of water during and after drought. In this article, we highlight the importance of cell wall-bound phenolics in the efficient adaptation of crops to arid environments and protection of soil water resources.

Cell dehydration of intergeneric hybrid induces subgenome-related specific responses.

The aim was to identify subgenome-related specific responses in two types of triticale, that is, of the wheat-dominated genome (WDG) and rye-dominated genome (RDG), to water stress induced in the early phase (tillering) of plant growth. Higher activity of the primary metabolism of carbohydrates is a feature of the WDG type, while the dominance of the rye genome is associated with a higher activity of the secondary metabolism of phenolic compounds in the RDG type. The study analyzed carbohydrates and key enzymes of their synthesis, free phenolic compounds and carbohydrate-related components of the cell wall, monolignols, and shikimic acid (ShA), which is a key link between the primary and secondary metabolism of phenolic compounds. Under water stress, dominance of the wheat genome in the WDG type was manifested by an increased accumulation of the large subunit of Rubisco and sucrose phosphate synthase and a higher content of raffinose and stachyose compared with the RDG type. In dehydrated RDG plants, higher activity of L-phenylalanine ammonia lyase (PAL) and L-tyrosine ammonia lyase (TAL), as well as a higher level of ShA, free and cell wall-bound p-hydroxybenzoic acid, free homovanillic acid, free sinapic acid, and cell wall-bound syringic acid can be considered biochemical indicators of the dominance of the rye genome.

The role of invasive plant species in drought resilience in agriculture: the case of sweet briar (Rosa rubiginosa L.).

Sweet briar (Rosa rubiginosa) belongs to the group of wild roses. Under natural conditions it grows throughout Europe, and was introduced also into the southern hemisphere, where it has efficiently adapted to dry lands. This review focuses on the high adaptation potential of sweet briar to soil drought in the context of global climatic changes, especially considering steppe formation and desertification of agricultural, orchard, and horticultural areas. We provide a comprehensive overview of current knowledge on sweet briar traits associated with drought tolerance and particularly water use efficiency, sugar accumulation, accumulation of CO2 in intercellular spaces, stomatal conductance, gibberellin level, effective electron transport between photosystem II and photosystem I, and protein content. We discuss the genetics and potential applications in plant breeding and suggest future directions of study concerning invasive populations of R. rubiginosa. Finally, we point out that sweet briar can provide new genes for breeding in the context of depleting gene pools of the crop plants.

An improved method for the determination of cannabidiol in topical products using ultrasound-assisted extraction and gas chromatography-mass spectrometry.

The recent surge in the sale of cannabidiol (CBD)-based topicals has risen rapidly in recent years, as it can be used to treat a multitude of skin disorders. However, there is minimal regulation concerning actual CBD content in these products. Topicals on the market may contain various concentrations of CBD and may be combined with a range of other compounds. The concentration of CBD has to be determined before the products enter the market. For this reason, a selective analytical method was developed using a 23 factorial design; and validated to determine CBD content in various topicals based on ultrasound-assisted extraction (UAE) followed by gas chromatography coupled to mass spectrometry (GC-MS). The method showed good precision (relative standard deviation ≤ 7.7%), accuracy at three concentration levels (recovery > 97.9%) for three different matrices, acceptable linearity (R2 > 0.99), and limit of detection (0.05 µg/mg). The method was successfully applied to the analysis of five commercial topicals. The proposed method is rapid, sensitive, precise, and accurate. In addition, it does not require derivatization and it is suitable for the determination of CBD in topicals for quality control purposes.

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.

Non-rolling flag leaves use an effective mechanism to reduce water loss and light-induced damage under drought stress.

BACKGROUND AND AIMS: The study reports on four different types of flag leaf rolling under soil drought in relation to the level of cell wall-bound phenolics. The flag leaf colonization by aphids, as a possible bioindicator of the accumulation of cell wall-bound phenolics, was also estimated. METHODS: The proteins of the photosynthetic apparatus that form its core and are crucial for maintaining its stability (D1/PsbA protein), limit destructive effects of light (PsbS, a protein binding carotenoids in the antennas) and participate in efficient electron transport between photosystems II (PSII) and PSI (Rieske iron-sulfur protein of the cytochrome b6f complex) were evaluated in two types of flag leaf rolling. Additionally, biochemical and physiological reactions to drought stress in rolling and non-rolling flag leaves were compared. KEY RESULTS: The study identified four types of genome-related types of flag leaf rolling. The biochemical basis for these differences was a different number of phenolic molecules incorporated into polycarbohydrate structures of the cell wall. In an extreme case of non-rolling dehydrated flag leaves, they were found to accumulate high amounts of cell wall-bound phenolics that limited cell water loss and protected the photosynthetic apparatus against excessive light. PSII was also additionally protected against excess light by the accumulation of photosynthetic apparatus proteins that ensured stable and efficient transport of excitation energy beyond PSII and its dissipation as far-red fluorescence and heat. Our analysis revealed a new type of flag leaf rolling brought about by an interaction between wheat and rye genomes, and resulting in biochemical specialization of flexible, rolling and rigid, non-rolling parts of the flag leaf. The study confirmed limited aphid colonization of the flag leaves with enhanced content of cell wall-bound phenolics. CONCLUSIONS: Non-rolling leaves developed effective adaptation mechanisms to reduce both water loss and photoinhibitory damage to the photosynthetic apparatus under drought stress.

Altered Brain Activation in Youth following Concussion: Using a Dual-task Paradigm.

A concussion is known as a functional injury affecting brain communication, integration, and processing. There is a need to objectively measure how concussions disrupt brain activation while completing ecologically relevant tasks.The objective of this study was to compare brain activation patterns between concussion and comparison groups (non-concussed youth) during a cognitive-motor single and dual-task paradigm utilizing functional near-infrared spectroscopy (fNIRS) in regions of the frontal-parietal attention network and compared to task performance.Youth with concussion generally exhibited hyperactivation and recruitment of additional brain regions in the dorsal lateral prefrontal (DLPFC), superior (SPC) and inferior parietal cortices (IPC), which are associated with processing, information integration, and response selection. Additionally, hyper- or hypo-activation patterns were associated with slower processing speed on the cognitive task. Our findings corroborate the growing literature suggesting that neural recovery may be delayed compared to the restoration of behavioral performance post-concussion.Concussion, near-infrared spectroscopy, dual-task paradigm, cognitive, motor, brain activation.

Grip Strength in Youth Ice Hockey Players: Normative Values and Predictors of Performance.

Toong, T, Wilson, KE, Urban, K, Paniccia, M, Hunt, AW, Keightley, M, and Reed, N. Grip strength in youth ice hockey players: Normative values and predictors of performance. J Strength Cond Res 32(12): 3503-3511, 2018-Grip strength is a simple, valid, and reliable tool for estimating overall muscular strength, a key component of health-related fitness and sport performance. To date, there is a paucity of up-to-date and developmentally sensitive grip strength norms specific to youth-athlete populations. The objectives of this study are to (a) establish normative grip strength values in youth ice hockey players, (b) descriptively compare these values with existing Canadian pediatric norms, and (c) explore the relationship between age, sex, body mass, and hockey playing level on grip strength performance. A sample of 690 male and female youth ice hockey players between the ages of 10 and 16 years were included. Participants completed assessments of maximal grip strength using a hand dynamometer on both hands. In addition, age, sex, body mass, and hockey playing level were collected. Maximal absolute grip strength, stratified by age and sex, was higher than previously published Canadian pediatric norms. Grip strength increased with age in both sexes. Males and females performed similarly until 12 years of age, after which point males had greater strength. Individuals with greater body mass had greater strength. For the nondominant hand, competitive players had greater strength than those playing house league or select. This study describes normative grip strength values in youth ice hockey players according to age, sex, body mass, and playing level. These athlete-specific norms may be used to help evaluate and monitor changes in grip strength over time in youth ice hockey players.

Default Mode Network Oscillatory Coupling Is Increased Following Concussion.

Concussion is a common form of mild traumatic brain injury. Despite the descriptor "mild," a single injury can leave long-lasting and sustained alterations to brain function, including changes to localized activity and large-scale interregional communication. Cognitive complaints are thought to arise from such functional deficits. We investigated the impact of injury on neurophysiological and functionally specialized resting networks, known as intrinsic connectivity networks (ICNs), using magnetoencephalography. We assessed neurophysiological connectivity in 40 males, 20 with concussion and 20 without. Regions-of-interest that comprise nodes of ICNs were defined, and their time courses derived using a beamformer approach. Pairwise fluctuations and covariations in band-limited amplitude envelopes were computed reflecting measures of functional connectivity. Intra-network connectivity was compared between groups using permutation testing and correlated with symptoms. We observed increased resting spectral connectivity in the default mode network (DMN) and motor networks (MOTs) in our concussion group when compared with controls, across alpha through gamma ranges. Moreover, these differences were not explained by power spectrum density within the ICNs. Furthermore, this increased coupling was significantly associated with symptoms in the DMN and MOTs-but once accounting for comorbidities (including, depression, anxiety, and ADHD) only the DMN continued to be associated with symptoms. The DMN plays a critical role in shifting between cognitive tasks. These data suggest even a single concussion can perturb the intrinsic coupling of this functionally specialized network in the brain, and may explain persistent and wide-ranging symptomatology.

Cortical Thickness Changes and Their Relationship to Dual-Task Performance following Mild Traumatic Brain Injury in Youth.

Mild traumatic brain injury (mTBI) is common in youth, especially in those who participate in sport. Recent investigations from our group have shown that asymptomatic children and adolescents with mTBI continue to exhibit alterations in neural activity and cognitive performance compared with those without a history of mTBI. This is an intriguing finding, given that current return-to-learn and return-to-play protocols rely predominately on subjective symptom reports, which may not be sensitive enough to detect subtle injury-related changes. As a result, youth may be at greater risk for re-injury and long-term consequences if they are cleared for activity while their brains continue to be compromised. It is currently unknown whether mTBI also affects brain microstructure in the developing brain, particularly cortical thickness, and whether such changes are also related to cognitive performance. The present study examined cortical thickness in 13 asymptomatic youth (10-14 years old) who had sustained an mTBI 3-8 months prior to testing compared with 14 age-matched typically developing controls. Cortical thickness was also examined in relation to working memory performance during single and dual task paradigms. The results show that youth who had sustained an mTBI had thinner cortices in the left dorsolateral prefrontal region and right anterior and posterior inferior parietal lobes. Additionally, cortical thinning was associated with slower reaction time during the dual-task condition in the injured youth only. The results also point to a possible relationship between functional and structural alterations as a result of mTBI in youth, and lend evidence for neural changes beyond symptom resolution.

Functional near-infrared spectroscopy reveals reduced interhemispheric cortical communication after pediatric concussion.

Concussion, or mild traumatic brain injury (mTBI), is a growing concern, especially among the pediatric population. By age 25, as many as 30% of the population are likely to have had a concussion. Many result in long-term disability, with some evolving to postconcussion syndrome. Treatments are being developed, but are difficult to assess given the lack of measures to quantitatively monitor concussion. There is no accepted quantitative imaging metric for monitoring concussion. We hypothesized that because cognitive function and fiber tracks are often impacted in concussion, interhemispheric brain communication may be impaired. We used functional near-infrared spectroscopy (fNIRS) to quantify functional coherence between the left and right motor cortex as a marker of interhemispheric communication. Studies were undertaken during the resting state and with a finger-tapping task to activate the motor cortex. Pediatric patients (ages 12-18) had symptoms for 31-473 days, compared to controls, who have not had reported a previous concussion. We detected differences between patients and controls in coherence between the contralateral motor cortices using measurements of total hemoglobin and oxy-hemoglobin with a p<0.01 (n=8, control; n=12 mTBI). Given the critical need for a quantitative biomarker for recovery after a concussion, we present these data to highlight the potential of fNIRS coupled with interhemispheric coherence analysis as a biomarker of concussion injury.