While this phenotype does not exclude more nuanced forms of social anxiety, it does support the idea that the modulation of stress reactivity and social behavior can be dissociable. In line with this notion, CB1 over expression in the medial prefrontal cortex alters social interactions without overtly changing the anxiety-related phenotype. In contrast to socially impaired mice, parallel experiments in normal mice indicated that increasing anandamide does not alter social approach. One explanation could be technical – namely, that the social approach test has a ceiling effect or is unable to capture more subtle qualities of social interaction. Indeed, the task is typically used as a screening tool rather than a continuous-scale measure of sociability. Another explanation could be biological – that signaling systems in a healthy brain are able to compensate for endocannabinoid enhancement in a way that socially impaired brains cannot. These explanations are in line with previous reports of different social situations in which faah-/- mice demonstrated increased direct reciprocal interactions, as well as URB597-treated juvenile rats engaging in more social play. Therefore, expanded investigation is warranted into how anandamide contributes to different social contexts and the qualities of social interactions. Nevertheless, our set of results suggests that the prosocial action of FAAH blockade is selective for social impairment in certain contexts, which may be therapeutically advantageous for the spectral nature of ASD. Based on our results and the available literature, plant grow trays we can reasonably speculate on two possible scenarios improved by anandamide signaling that may underlie social impairment in BTBR and fmr1-/- mice.
First, oxytocin-driven anandamide activity in the nucleus accumbens, which we previously demonstrated to be important for social reward, may be impaired in these mice. Consistent with this idea, BTBR mice were found to have abnormal oxytocin expression in the hypothalamus45. BTBR mice were also reported to be deficient in conditioned place preference to social interactions. However, because social conditioned place preference is a relatively new construct, and the learning impairments in these mice make interpretation problematic, further support from the literature is lacking. A second possible scenario is that anandamide might correct an imbalance of excitatory and inhibitory neurotransmission in the cortex, which has been postulated to underlie ASD. Enhancing GABAergic activity in BTBR mice ameliorates their social impairment, and negative allosteric GABA modulation in C57Bl6J mice recapitulates social impairment. This suggests that a loss of balance between inhibitory and excitatory activity might contribute to social impairment. A simplified view of this result orients us to interpret our findings as indicating that anandamide could modulate such balance. This view is consistent with the presence of CB1 receptors on presynaptic terminals of both glutamatergic projection neurons and GABAergic interneurons.In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.The use of marijuana, the most widely consumed illicit drug in the world, and synthetic cannabinoid drugs typically starts in adolescence. Its usage pattern is striking. According to the 2014 NIDA survey, Monitoring the Future, past-month usage of marijuana was at 6.5% among 8th graders, 16.6% among 10th graders, and 21.2% among 12th graders . The percentage of high school seniors who think marijuana is harmful has declined from 52.4% five years ago to only 36.4% today, indicating a possible prelude to increasing usage in the coming years .
In addition to recreational use, the accelerating prevalence of cannabinoids as a medicine, e.g. in child epilepsy and autism, is exposing growing numbers of young people to the drug. These usage trends are especially concerning within a rapidly changing social sphere, consisting of technological advancements in marijuana cultivation and cannabinoid synthesis, widespread cultural acceptance, as well as novel politics and economies. Long-term effects are likely as a consequence of the roles of the endocannabinoid system in the developing brain. This signaling system has three main components: two lipid-derived local messengers – 2-arachidonoyl-sn-glycerol and anandamide , enzymes and transporters that mediate their formation and elimination, and cannabinoid receptors that are activated by endocannabinoids and regulate neuronal activity . Endocannabinoid activity regulates processes such as neuronal genesis, migration, and differentiation, as well as in synaptic pruning and glial cell formation . With regard to the adolescent period, developmental fluctuations have been reported on the expression levels of CB1 cannabinoid receptors in corticostriatal areas and, to a lesser extent, levels of endocannabinoids. For example,levels of CB1 receptors increased in the cortex and striatum during this period , while 2-AG is reduced in these regions and anandamide continuously increases in the prefrontal cortex . These lines of evidence each emphasize the vulnerability of the developing brain to consequences of early cannabinoid exposure. However, they also highlight the knowledge gap regarding the molecular mechanisms responsible for these consequences, especially with regard to brain reward systems . In fact, it remains unknown whether disrupted endocannabinoid signaling is responsible for impairment. We hypothesized that non-physiological activation of cannabinoid receptors during adolescence persistently impairs the endocannabinoid regulation of social reward in early adulthood.We first administered a synthetic cannabinoid receptor agonist, WIN55212-2 for 2 weeks to adolescent mice at postnatal day. We chose the WIN compound at this dose because it models the effects of marijuana on cannabinoid receptors over other bio-active constituents. After a two-week washout period, at PND58, we found that whereas vehicle-treated mice developed a social place preference, WIN treated mice developed no such preference . This result suggests that improper cannabinoid receptor activation during adolescence impairs the later expression of social reward in adulthood.It is reasonable to expect that socially stimulated anandamide mobilization, which we previously found to be important in social reward , would also be disrupted by nonphysiological activation of cannabinoid receptors in early life. Indeed, we found that after a twoweek washout, at PND58, mice previously treated with WIN had increased levels of anandamide in the nucleus accumbens , medial prefrontal cortex , and ventral hippocampus . Thus, socially stimulated anandamide signaling in these regions may no longer occur properly following WIN treatment.These preliminary results require additional confirmation. Nevertheless, the results are a proof in principle that early, custom grow rooms non-physiological activation of cannabinoid receptors can persistently impair social reward, and that this impairment is due to an underlying disruption in anandamide signaling.
Future investigation should be aimed at: the critical window that leads to persistent impairment; other persistent molecular changes, such as 2-AG levels and CB1 surface expression; and whether oxytocin-stimulated anandamide signaling is also impaired. These investigations would provide a more complete picture of the molecular changes responsible for persistent impairment. They would be relevant to the long-term effects of early cannabinoid exposure on mental illness and addiction.Social interactions and social support protect against physical pain. Such protection exerts powerful effects in adaptive as well as pathological contexts, with profound consequences for pain and pain-related health outcomes . Basic neural mechanisms linking a social signal to an analgesic one, however, are poorly defined. We recently identified a mechanism through which social stimulation mobilizes the endocannabinoid neurotransmitter anandamide, which in turn enhances the saliency of the social interaction . As endocannabinoid signaling is known for its analgesic effects independently of social factors, we therefore tested the idea that social stimulation might also recruit the endocannabinoid system as a mediator of analgesia. We targeted a key area for descending pain modulation, the periaqueductal grey .We used juvenile rats in order to analyze subdivisions of the periaqueductal grey and because of previous investigation of opioids in separation distress . These models, however, have not been extensively replicated. In preliminary experiments, we isolated juvenile rats for 24 h, then re-socialized half while keeping the other half isolated for 3 additional hours. This social stimulation protocol is consistent with that which elicits an increase in anandamide in the mouse nucleus accumbens, ventral hippocampus, and medial prefrontal cortex . We found that acute social stimulation in this manner increases levels of anandamide in the ventral periaqueductal grey , but not the dorsal PAG . In a survey of other regions, we found that the cingulate and insular cortices trended toward an increase, but these results were not significant, and the nucleusaccumbens did not show a change in anandamide . Paralleling this phenomenon, we used the hot-plate test to assess for acute pain response. Animals were placed inside a large beaker which had been heated to 55 degrees on a hot plate, and their latency to withdrawal or lick their hindpaw was measured. We found that social stimulation increased the threshold for paw withdrawal . These results suggest that social stimulation induces anandamide-mediated endocannabinoid signaling in order to exert social protection against pain.These preliminary experiments illustrate the concept that socially mobilized endocannabinoid signaling is recruited to buffer against physical pain. Further investigation should be directed toward: establishing the stimulation protocol, as the profile of endocannabinoid changes between mice and rats are clearly different – it is possible that rats may be more sensitive to the rewarding effects of play and thus require a shorter stimulation; this would be needed to understand whether endocannabinoids modulate an affective component of pain through reward signaling, or actually modulates descending pain at the level of the periaqueductal grey; whether isolation and social stimulation are qualitatively different or simply opposite effects; the confounding effects of stress on pain; and whether endocannabinoid signaling elicited here is also oxytocin-stimulated and, if so, the responsible circuitry.According to the United Nations, the population of the world is expected to grow in the next century, which in turn encourages the development of innovative techniques to ensure agricultural sustainability. Agriculture on productive land is threatened not only by high levels of urbanization, uneven water distribution, and inclement weather, but also is threats to biodiversity that have unfavorable environmental impacts. Due to the anticipated drastic population growth and constraints on resources in the upcoming decades, only 10% of the demand for food is estimated to be met by expansion of productive lands, with the remainder relying on new techniques that can achieve higher yields. Therefore, developing novel methods to augment the ratio of crop production over used land is a vital issue. In recent years, the indoor vertical farming systems with artificial light are found to be a viable solution to resolve the in-creasing demands of future agricultural products. The IVFS are promising alternatives to open field or greenhouse agriculture because they have precisely monitoring environmental parameters and are insensitive to outdoor climates, which can boost annual sales volume per unit area up to 100 times compared to that of open lands. Furthermore, employment of light emitting diodes as light sources can initiate and sustain photosynthesis reactions and the optical wavelength, light intensity, and radiation intervals can further enhance growth quality . Recently, many studies have been carried out to investigate how environmental parameters, such as closed-loop control, ultrasound, and electro-degradation, affect hydroponic cultivation of leafy vegetables in these systems. One of the most influential factors affecting growth in IVFS is to maintain a uniform air flow at an optimal air current speed over plants canopy surfaces. Poor flow uniformity or variation in air velocity over culture beds destabilizes crop production rates. It has been found that inducing a horizontal air speed of 0.3–0.5 m s−1 boosts photosynthesis through more efficiently exchanging species between the stomatal cavities in plants and the flow of air. Lee et al. studied the effects of air temperature and flow rate on the occurrence of lettuce leaf tip burn in a closed plant factory system. Furthermore, it was observed that the relative humidity of the air flow can significantly influence calcium transportation in lisianthus cultivars. According to Vanhassel et al., higher levels of relative humidity can significantly decrease the occurrence of tip burn. Therefore, it is vital to maintain relative humidity in the desired range to ensure even distribution of calcium in lettuce leaves. Over the past few years, researchers have been trying to develop techniques for improving uniformity over cultivation zones. Regardless of the recent progress, the control and automation systems of IVFS bring additional costs, which makes systematic experimental investigation and optimization a challenge. Computational fluid dynamics has been utilized as a reliable tool to numerically simulate complex physical phenomena. Markatos et al. developed a CFD procedure to study velocity and temperature distribution in enclosures using buoyancy-induced physics.