The endocannabinoid neurotransmitters possess a unique set of synaptic properties

Similar to Fig. 3, without the analyzer, we can see clearly two horizontally shifted LCP and RCP images, as shown in Fig. 4 I– L. The separation between two images determines how sharp the edge can be resolved, which is also confirmed by the final edgedetection images shown in Fig. 4 M–P. The highest resolution achieved is around 2 μm , close to the diffraction limit of the optical system, by using a meta surface with Λ of 8,000 μm. It is worth to note here that these results are taken under the condition of a planar object at the focal plane. Therefore, for thick 3D object, multiple measurements need to be taken by scanning the focal plane over the objects and combine each focal plane result together. In the case of the samples with circular birefringence inclusions, the LCP and RCP components will gain different phases, so that the combined LP components in the overlapped area may not be completely canceled out after the second linear polarizer. Although this indicates the contrast between the edge and the background will be compromised, additional circular birefringence information can be revealed.Social behavior is a human hallmark. People spend an enormous amount of time engaging in social interactions. They form loose relationships with acquaintances or strong relationships with friends and family members. Together, these connections form social networks that range from schools and companies to ethnic identities and nationalities. The social nature of humans has been recognized since Aristotle . Its crucial role in human life has been studied in a spectrum of fields in the social sciences. Only recently, however, have biological approaches been used to study the underlying physiology of social behavior. These approaches have contributed to understanding the neural signaling that may regulate social behavior as well as the impact of social factors on mental and physical health. These lines of research have given rise to the aggregated field of social neuroscience . Firstly, this field has emphasized the importance of social relationships.

Social contact is essential for the health of the brain and the body . For example, social isolation in critical periods of life wreaks havoc on cognition, vertical racking system emotion and immune responses. Second, social support is a crucial factor for neuropsychiatric and bodily diseases, both in susceptibility and recovery . Examples abound: abnormal social development predicts addictive behaviors and conduct disorder; social support buffers against not only mental illnesses such as depression but also physical ailments such as chronic pain and recovery from myocardial infarction. The multitude of health problems associated with social factors also highlights the complexities and fragilities involved in a growing person navigating the social sphere. The nature of social relationships changes significantly over a lifespan, requiring the development of unique social skills. For instance, a child must transition from a strong maternal attachment to mostly peer contact over the course of adolescence, the young adult must transition from single hood to a state of attachment with a significant other, while the elderly must take on new roles imposed by accrued experience and reduced physical strength. These distinct types of experiences involve a range of cognitive and emotional processes that undoubtedly impact brain development. The impact is likely mutual, as proper development is crucial for ongoing social function. Such mutual interactions must be finely tuned. To date, the neural processes underlying these transitions and the neural systems that regulate social behavior are largely unknown. Perhaps the best biological account so far has been the study of oxytocin. Oxytocin is a peptide, comprised of nine amino acids, that has long been known for its peripheral hormonal effects in parturition and lactation . More recently, research has elucidated its central effects in affiliative behaviors and social reward. Tom Insel, Larry Young, and colleagues performed seminal studies in prairie voles . They compared these rodents, which display monogamous pair bonding, to the genetically similar but polygamous montane voles , and found distinct differences in their oxytocin systems .

One key difference is that compared to montane voles, prairie voles have increased oxytocin receptors in the nucleus accumbens, a brain region important for reward signaling. In a series of pharmacological and genetic studies, these authors elaborated the crucial roles of oxytocin in social memory and pair-bond formation. Since then, work on oxytocin remains an active area of ongoing investigation. Modern neuroscience tools have been used to examine the circuit dynamics of oxytocin signaling. For example: oxytocin neurons of the paraventricular nucleus of the hypothalamus project to the amygdala to modulate evoked fear ; oxytocin neurons coordinate with serotonergic neurons from the dorsal raphe nucleus tocontrol peer social reward ; oxytocin in the hippocampus controls signal-tonoise ratio for information processing ; oxytocin receptors are left-lateralized in the auditory cortex to enable maternal retrieval of separated pups . Human studies have been hampered by the difficulty in delivering oxytocin to the brain, but this obstacle was partly removed by the recent development of an intranasal oxytocin spray. Although the pharmacokinetics of intranasal oxytocin is still unclear, its central effects have been widely documented in numerous high-profile publications. For example, intranasal oxytocin impacts one’s trust of others . Intranasal oxytocin is also being tested in ongoing trials for indications including anxiety, autism spectrum disorder, and drug addiction. Drug development is still at an early stage , but a first a sign of success on sociability in autism-spectrum patients was reported .More recent studies of marijuana use in humans are also in line with the assumption that this drug may affect social behavior. In a survey of students who were experienced marijuana users, more than 70 percent said that intoxication makes them want to interact more with others, because the group takes on ‘a much greater sense of unity, or real social relationship’ . More than 80 percent reported that they felt more insightful and empathetic of others but they are also less able to play social games, which suggests that marijuana makes users more intuitive and social but hinders their social skills .

Worth noting, however, is that, a substantial portion of experienced users also preferred to ingest the drug in isolation, perhaps because they like to feel ‘isolated from things around me’ . This contrasts with more casual users who typically ingest the drug in a social setting. Experimental studies have also found that marijuana alters social behavior. In a study of aggression, two groups were given a shared task with a frustration stimulus. Compared to placebo, the group given marijuana provided self-rated reports of higher cooperativity and decreased hostility . Interestingly, the authors also note that marijuana may have been disinhibitory, such that the users were more willing to express their feelings. Similarly, an experimental study in a small group setting found that active marijuana changed the distribution of social activities by decreasing time spent in verbal exchanges while increasing time spent in co-actation, i.e. engaging in a shared activity, such as playing a game . Together, these studies indicate that active marijuana use can exert powerful effects on social interactions. They also imply that the effects likely depend on the dose, stressful stimuli, and the past experience of the user. Interestingly, the studies note differential effects on the emotional aspects of social experiences versus the skills needed for social interaction . Thus, the neurobiological consequences of marijuana likely involve a range of dissociable effects throughout the engagement and ongoing development of social interactions.The endocannabinoid system, a modulatory neurotransmitter system in the brain, mediates the effects of the psychoactive principle in marijuana, Δ9 -tetrahydrocannabinol. Work on the endocannabinoid system in social behavior remains limited and has emerged more recently. Meanwhile, indoor grow facility the more established roles of this system in anxiety, reward, pain, and cognition have hinted at overlapping functions in social behavior. The endocannabinoid system consists of lipid-derived messengers called ‘endocannabinoids’ whose actions in the brain are mainly, albeit not exclusively, mediated through CB1 cannabinoid receptors. A series of enzymes catalyze the biochemical synthesis and degradation of endocannabinoids to control their signaling activity . These cascades typically start with the release of particular lipid species from phospholipid membranes, involve multiple biochemical pathways, and end with recycling or the directing of products to alternative biochemical signaling cascades. The canonical route for the synthesis ofanandamide is thought to involve a calcium-dependent phospholipase D that releases anandamide by hydrolysis of the phospholipid precursor N-arachidonoylphosphatidylethanolamine . Whether and how other enzymes may be involved is unknown, making the molecular mechanisms and localization of anandamide signaling unclear. Anandamide is mainly degraded via intracellular hydrolysis by the enzyme fatty acid amide hydrolase . On the other hand, the mechanisms of synthesis for the other endocannabinoid 2-arachidonoyl-sn-glycerol are clearer. 2-AG is generated via the hydrolysis of the intracellular second messenger 1,2-diacylglycerol, by diacylglycerol lipase-α . DGL-α can be coupled to different receptors upstream for the activation of 2-AG by different signaling systems. For example, in glutamatergic neurons, DGL-α forms a complex with the type-1 metabotropic glutamate receptor, mGluR5, which is scaffolded by proteins such as Homer-1a .

The efficiency of coupling in this complex represents a molecular mechanism for signaling regulation. 2-AG is mainly degraded by the serine hydrolase monoacylglycerol lipase . Both anandamide and 2-AG are unconventional in the sense that they act in a retrograde manner to suppress presynaptic firing . In this regard, they can be thought of as ‘synaptic circuit breakers’ to curb incoming depolarization . In line with this idea, 2-AG, for example, is generated upon glutamate spillover to the ‘perisynaptic’ region rather than within the post-synaptic density proper – an anatomical feature that allows homeostatic negative feedback. This is not to say, however, that this type of synaptic feedback is the only mode of endocannabinoid signaling. Another unique property of the system is that endocannabinoids can also act as diffuse localmessengers. Anandamide possesses properties of a volume transmitter – diffusing and affecting multiple neighboring cells – whereas 2-AG is thought of more as a point-to-point synaptic transmitter. Accordingly, a third property is that, when the messengers work in concert, their temporal profiles may differ during signaling. For example, when an animal is subjected to acute stress, 2-AG increases within minutes in the periaqueductal grey whereas anandamide rises in the course of an hour to mediate stress-induced analgesia . In other situations, the directionality of changes in 2-AG and anandamide may actually be opposing. For example, non-contingent alcohol exposure increases extracellular 2-AG levels in the nucleus accumbens , but reduces anandamide . In the brain, 2-AG is almost 1000-fold more abundant than anandamide. Although this difference could in part be accounted for by structural, intermediary, or otherwise signaling-incompetent pools of 2-AG, the substantial difference nevertheless suggests dichotomous patterns for signaling action. A fourth unique property is that, as lipid mediators, the endocannabinoids are not stored in traditional vesicles but instead ‘demobilized’ in phospholipid membranes at baseline; they become ‘mobilized’ during signaling activity as they are synthesized ‘on-demand’. This means that molecular mechanisms for their recruitment must involve synthetic enzymes for mobilization. This necessity has implications for understanding interactions between systems, from the circuit down to the molecular level. If the synthetic machinery for anandamide is less well known, for example, it becomes difficult to dissect the molecular interactions needed for its recruitment. This can be seen in the contrast between several well-documented cases of 2-AG recruitment by various G-protein-coupled receptors versus only one for anandamide. G-protein-coupled receptors that recruit 2-AG include type-1metabotropic glutamate receptors , type 1/3 muscarinic acetylcholine receptors , and type-1 orexin receptors . D2 receptors in the dorsal striatum have been shown to recruit anandamide .The brain distribution of components of the endocannabinoid system is consistent with a role in social behavior. CB1 receptors are highly expressed in associational cortical regions of the frontal lobe and subcortical structures that underpin human social-emotional functioning . For example, the behavioral variant of frontotemporal dementia, characterized by indifference to social conflict and eccentric social conduct, involves neurodegeneration of regions in salience networks, including the anterior cingulate cortex, frontoinsular cortex, prefrontal cortex, striatum, and thalamus .

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