Charting and comparing Tunisia's, Algeria's, Morocco's and Mauritania's political development over the past 10 years, this book offers fresh and original insight into their contrasting experiences as ...well as extending Levitsky and Way's model.
Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system ...is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.
We offer best-practice recommendations for journal reviewers, editors, and authors regarding data collection and preparation. Our recommendations are applicable to research adopting different ...epistemological and ontological perspectives—including both quantitative and qualitative approaches—as well as research addressing micro (i.e., individuals, teams) and macro (i.e., organizations, industries) levels of analysis. Our recommendations regarding data collection address (a) type of research design, (b) control variables, (c) sampling procedures, and (d) missing data management. Our recommendations regarding data preparation address (e) outlier management, (f) use of corrections for statistical and methodological artifacts, and (g) data transformations. Our recommendations address best practices as well as transparency issues. The formal implementation of our recommendations in the manuscript review process will likely motivate authors to increase transparency because failure to disclose necessary information may lead to a manuscript rejection decision. Also, reviewers can use our recommendations for developmental purposes to highlight which particular issues should be improved in a revised version of a manuscript and in future research. Taken together, the implementation of our recommendations in the form of checklists can help address current challenges regarding results and inferential reproducibility as well as enhance the credibility, trustworthiness, and usefulness of the scholarly knowledge that is produced.
Abstract The Leap Motion Controller (LMC) is a low-cost, markerless motion capture device that tracks hand, wrist and forearm position. Integration of this technology into healthcare applications has ...begun to occur rapidly, making validation of the LMC's data output an important research goal. Here, we perform a detailed evaluation of the kinematic data output from the LMC, and validate this output against gold-standard, markered motion capture technology. We instructed subjects to perform three clinically-relevant wrist (flexion/extension, radial/ulnar deviation) and forearm (pronation/supination) movements. The movements were simultaneously tracked using both the LMC and a marker-based motion capture system from Motion Analysis Corporation (MAC). Adjusting for known inconsistencies in the LMC sampling frequency, we compared simultaneously acquired LMC and MAC data by performing Pearson's correlation (r) and root mean square error (RMSE). Wrist flexion/extension and radial/ulnar deviation showed good overall agreement (r=0.95; RMSE=11.6°, and r=0.92; RMSE=12.4°, respectively) with the MAC system. However, when tracking forearm pronation/supination, there were serious inconsistencies in reported joint angles (r=0.79; RMSE=38.4°). Hand posture significantly influenced the quality of wrist deviation (p<0.005) and forearm supination/pronation (P<0.001), but not wrist flexion/extension (P=0.29). We conclude that the LMC is capable of providing data that are clinically meaningful for wrist flexion/extension, and perhaps wrist deviation. It cannot yet return clinically meaningful data for measuring forearm pronation/supination. Future studies should continue to validate the LMC as updated versions of their software are developed.
Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; ...however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.
Posttraumatic stress disorder, an area of large unmet medical needs, is characterized by persistence of fear memories and maladaptive stress responses. In rodents, elevation of the endocannabinoid ...anandamide due to inhibition of fatty acid amide hydrolase (FAAH) facilitates fear extinction and protects against the anxiogenic effects of stress. We recently reported that elevated anandamide levels in people homozygous for a loss-of-function FAAH mutation are associated with a similar phenotype, suggesting a translational validity of the preclinical findings.
In this double-blind, placebo-controlled experimental medicine study, healthy adults were randomized to an FAAH inhibitor (PF-04457845, 4 mg orally, once daily; n = 16) or placebo (n = 29) for 10 days. On days 9 and 10, participants completed a task battery assessing psychophysiological indices of fear learning, stress reactivity, and stress-induced affective responses.
FAAH inhibition produced a 10-fold increase in baseline anandamide. This was associated with potentiated recall of fear extinction memory when tested 24 hours after extinction training. FAAH inhibition also attenuated autonomic stress reactivity, assessed via electrodermal activity, and protected against stress-induced negative affect, measured via facial electromyography.
Our data provide preliminary human evidence that FAAH inhibition can improve the recall of fear extinction memories and attenuate the anxiogenic effects of stress, in a direct translation of rodent findings. The beneficial effects of FAAH inhibition on fear extinction, as well as stress- and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for posttraumatic stress disorder.
Brain sex differences are established developmentally and generate enduring changes in circuitry and behavior. Steroid-mediated masculinization of the rat amygdala during perinatal development ...produces higher levels of juvenile rough-and-tumble play by males. This sex difference in social play is highly conserved across mammals, yet the mechanisms by which it is established are unknown. Here, we report that androgen-induced increases in endocannabinoid tone promote microglia phagocytosis during a critical period of amygdala development. Phagocytic microglia engulf more viable newborn cells in males; in females, less phagocytosis allows more astrocytes to survive to the juvenile age. Blocking complement-dependent phagocytosis in males increases astrocyte survival and prevents masculinization of play. Moreover, increased astrocyte density in the juvenile amygdala reduces neuronal excitation during play. These findings highlight novel mechanisms of brain development whereby endocannabinoids induce microglia phagocytosis to regulate newborn astrocyte number and shape the sexual differentiation of social circuitry and behavior.
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•Microglia are more phagocytic in the male amygdala during neonatal development•Androgen-induced endocannabinoids increase phagocytosis in males•Microglia engulf viable newborn astrocytes in a complement-dependent manner•Developmental phagocytosis produces a sex difference in juvenile social play
VanRyzin et al. demonstrate that microglia in the developing amygdala engulf and kill otherwise viable newborn astrocytes, establishing sex differences in social circuits. This process, which depends on gonadal hormones and endocannabinoid signaling, promotes juvenile play by males.
Previous studies of the ferret visual cortex indicate that the development of direction selectivity requires visual experience. Here, we used two-photon calcium imaging to study the development of ...direction selectivity in layer 2/3 neurons of the mouse visual cortex in vivo. Surprisingly, just after eye opening nearly all orientation-selective neurons were also direction selective. During later development, the number of neurons responding to drifting gratings increased in parallel with the fraction of neurons that were orientation, but not direction, selective. Our experiments demonstrate that direction selectivity develops normally in dark-reared mice, indicating that the early development of direction selectivity is independent of visual experience. Furthermore, remarkable functional similarities exist between the development of direction selectivity in cortical neurons and the previously reported development of direction selectivity in the mouse retina. Together, these findings provide strong evidence that the development of orientation and direction selectivity in the mouse brain is distinctly different from that in ferrets.
► In mouse but not ferret, direction selectivity develops without visual experience ► In mouse but not ferret, the earliest selective neurons are direction selective ► Surprising similarities in direction selectivity development in cortex and retina
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