Enhancing Endocannabinoid Control of Stress with Cannabidiol

The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.

Divisive normalization unifies disparate response signatures throughout the human visual hierarchy

Neural processing is hypothesized to apply the same mathematical operations in a variety of contexts, implementing so-called canonical neural computations. Divisive normalization (DN) is considered a prime candidate for a canonical computation. Here, we propose a population receptive field (pRF) model based on DN and evaluate it using ultra-high-field functional MRI (fMRI). The DN model parsimoniously captures seemingly disparate response signatures with a single computation, superseding existing pRF models in both performance and biological plausibility. We observe systematic variations in specific DN model parameters across the visual hierarchy and show how they relate to differences in response modulation and visuospatial information integration. The DN model delivers a unifying framework for visuospatial responses throughout the human visual hierarchy and provides insights into its underlying information-encoding computations. These findings extend the role of DN as a canonical computation to neuronal populations throughout the human visual hierarchy.

m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Papillary Thyroid Carcinoma

Recently, immune response modulation at the epigenetic level is illustrated in studies, but the possible function of RNA 5-methylcytosine (m5C) modification in cell infiltration within the tumor microenvironment (TME) is still unclear. Three different m5C modification patterns were identified, and high differentiation degree was observed in the cell infiltration features within TME under the above three identified patterns. A low m5C-score, which was reflected in the activated immunity, predicted the relatively favorable prognostic outcome. A small amount of effective immune infiltration was seen in the high m5C-score subtype, indicating the dismal patient survival. Our study constructed a diagnostic model using the 10 signature genes highly related to the m5C-score, discovered that the model exhibited high diagnostic accuracy for PTC, and screened out five potential drugs for PTC based on this m5C-score model. m5C modification exerts an important part in forming the TME complexity and diversity. It is valuable to evaluate the m5C modification patterns in single tumors, so as to enhance our understanding towards the infiltration characterization in TME.

A scoping review on emotion regulation mechanisms employed in the control of Dharaneeya vegas (emotions that should be restrained) in light of Modern psychology and Ayurveda

Experiencing positive emotions are now becoming one among the highest virtues. It becomes important for individuals to develop emotional intelligence competencies. There are many ways through which positive emotions can be reinforced. Modern psychology also encourages cultivation of emotional regulation capacity. This article describes modern as well as Ayurvedic mechanisms for emotional regulation to cultivate healthy emotion regulation competency. After database search from PUBMED, total 14 articles, 11 from modern psychiatry and 3 Ayurveda were reviewed and following results are obtained. There are five instances in which emotion regulation may occur: Situation Selection, Situation Modification, Attention Deployment, Cognitive Change and Response Modulation. Ayurveda observes that the main reason for mental disequilibrium is taking extreme or minimal stance in mano-arthas. Ayurveda perceive that dhee, dhriti and smrithi are tripods that helps a person regulate his inclination towards mano-arthas. Ayurveda advices certain conducts to be followed by every person irrespective of Manasa prakriti. Ayurveda insist to control certain urges and those urges are termed as dharaneeya vegas. It preached some conducts to strengthen dhee, dhrithi and smrithi and they can be collectively called sadvrittam. Sadvrittam advocates human to always engage in learning (education) all existing science, persuades a person with ultimate aim of salvation by following right conduct, incentivisation with incentives health and prosperity, coercion through fear of diseases, rebirths, bad offspring’s, training through detachment, restriction by morality, environmental restructuring by execution in community level, modelling by showing aptas and enablement by teaching it to every one irrespective of inequality.

The Bezold-Jarisch Reflex and The Inflammatory Response Modulation in Unanesthetized Endotoxemic Rats

Evidence indicates that the activation of the parasympathetic branch of the autonomic nervous system may be effective in treating inflammatory diseases. Previously, we have described that baroreflex activation displays anti-inflammatory properties. Analogous to the baroreflex, the Bezold-Jarisch reflex also promotes parasympathetic activation with simultaneous inhibition of the sympathetic system. Thus, the present study aimed to evaluate whether the activation of the Bezold-Jarisch reflex would also have the ability to reduce inflammation in unanesthetized rats. We used lipopolysaccharide (LPS) injection (5mg/kg, i.p.) to induce systemic inflammation in male Wistar Hannover rats and phenylbiguanide (PBG) administration (5μg/kg, i.v.) to activate the Bezold-Jarisch reflex. Spleen, heart, hypothalamus, and blood samples were collected to determine the levels of cytokines. Compared to baseline, PBG reduced the arterial pressure (115±2 vs. 88±5mmHg) and heart rate (380±7 vs. 114±26bpm), immediately after its administration, confirming the activation of the parasympathetic system and inhibition of the sympathetic system. From the immunological point of view, the activation of the Bezold-Jarisch reflex decreased the plasma levels of TNF (LPS: 775±209 vs. PBG + LPS: 248±30pg/ml) and IL-6 levels in the spleen (LPS: 39±6 vs. PBG + LPS: 24±4pg/mg of tissue). However, it did not change the other cytokines in the plasma or the other tissues evaluated. These findings confirm that the activation of the Bezold-Jarisch reflex can modulate inflammation and support the understanding that the cardiovascular reflexes regulate the immune system.

Heterogeneous side-effects of cortical inactivation in behaving animals

Cortical inactivation represents a key causal manipulation that allows the study of cortical circuits and their impact on behavior. A key assumption in these studies is that the neurons in the target area become silent while the surrounding cortical tissue is only negligibly impacted. However, individual neurons are embedded in complex local circuits comprised of excitatory and inhibitory cells with connections extending hundreds of microns. This raises the possibility that silencing one part of the network could induce complex, unpredictable activity changes in neurons outside the targeted inactivation zone. These off-target side effects can potentially complicate interpretations of inactivation manipulations, especially when they are related to changes in behavior. Here, we demonstrate that optogenetic inactivation of glutamatergic neurons in the superficial layers of monkey V1 induces robust suppression at the light-targeted site, but destabilizes stimulus responses in the neighboring, untargeted network. We identified 4 types of stimulus-evoked neuronal responses within a cortical column, ranging from full suppression to facilitation, and a mixture of both. Mixed responses were most prominent in middle and deep cortical layers. Importantly, these results demonstrate that response modulation driven by lateral network connectivity is diversely implemented throughout a cortical column. Furthermore, consistent behavioral changes induced by optogenetic inactivation were only achieved when cumulative network activity was homogeneously suppressed. Therefore, careful consideration of the full range of network changes outside the inactivated cortical region is required, as heterogeneous side-effects can confound interpretation of inactivation experiments.