Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure

Air pollution is linked to increased emergency department visits for headache and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that chronic environmental irritant exposure sensitizes the trigeminovascular system response to nasal administration of environmental irritants. Here, we examine whether chronic environmental irritant exposure induces migraine behavioral phenotypes. Male rats were exposed to acrolein, a transient receptor potential channel ankyrin-1 (TRPA1) agonist, or room air by inhalation for 4 days before meningeal blood flow measurements, periorbital cutaneous sensory testing, or other behavioral testing. Touch-induced c-Fos expression in trigeminal nucleus caudalis was compared in animals exposed to room air or acrolein. Spontaneous behavior and olfactory discrimination was examined in open-field testing. Acrolein inhalation exposure produced long-lasting potentiation of blood flow responses to a subsequent TRPA1 agonist and sensitized cutaneous responses to mechanical stimulation. C-Fos expression in response to touch was increased in trigeminal nucleus caudalis in animals exposed to acrolein compared with room air. Spontaneous activity in an open-field and scent preference behavior was different in acrolein-exposed compared with room air-exposed animals. Sumatriptan, an acute migraine treatment blocked acute blood flow changes in response to TRPA1 or transient receptor potential vanilloid receptor-1 agonists. Pretreatment with valproic acid, a prophylactic migraine treatment, attenuated the enhanced blood flow responses observed after acrolein inhalation exposures. Environmental irritant exposure yields an animal model of chronic migraine in which to study mechanisms for enhanced headache susceptibility after chemical exposure

Excitation of atomic nitrogen by electron impact

Absolute cross sections were measured for the excitation of the N I(1134, 1164, 1168, 1200, 1243, and 1743 A) multiplets by electron impact on atomic nitrogen. The presence of vibrationally excited molecular nitrogen in the discharged gas was confirmed, and its effect on the measurements is discussed. The ratio of the oscillator strengths of the 1200 and 1134 A resonance transitions is presented, as well as the branching ratio for the N I(1311/1164 A) multiplets. Striking differences in the distribution of intensity between the spectra of atomic nitrogen and molecular nitrogen excited by energetic electrons suggest an optical method for measuring the density of atomic nitrogen in the upper atmosphere

Evaluation of behavior in transgenic mouse models to understand human congenital pain conditions

BACKGROUND: Containing a brain for signal processing and decision making, and a peripheral component for sensation and response, the nervous system provides higher organisms a powerful method of interacting with their environment. The specific neurons involved in pain sensation are known as nociceptors and are the source of normal nociceptive pain signaling to prompt appropriate responses. Though acute hypersensitization can be advantageous by encouraging an organism to allow an injured area to heal, chronic pain conditions can be pathological and can markedly reduce quality of life. While a variety of genes have been associated with congenital pain conditions, two rare cases examined in this study have not had their mutated genes identified. Potassium voltage-gated channel subfamily H member 8, or KCNH8, is involved in regulating action potential production and propagation, and has not been linked with pain processing of any kind to date. Here, a male patient evaluated at Boston Children’s Hospital contains a novel single-base KCNH8 mutation and possesses an extremely low sensitivity to cold temperatures and mechanical pain, but a higher sensitivity to warmer temperatures. A separate protein, intersectin-2, or ITSN2, normally functions in clathrin-mediated endocytosis and exocytosis. A second patient at Boston Children’s Hospital expresses a previously-unseen point mutation in ITSN2 and experiences erythromelalgia, characterized by episodes of intense pain and red, swollen limbs during ambient warm temperatures. Through the use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing, this study will produce these specific genetic mutations in mouse lines to explore their effects on mammalian behavior. OBJECTIVES: This project employs two transgenic mouse models to study the behavioral phenotypes associated with rare potentially damaging mutations in KCNH8 and ITSN2 exhibited in the human patients. Through these experiments, a greater understanding of neural pain signaling and sensitivity changes can occur. METHODS: The differences in temperature preference of KCNH8 and ITSN2 mutant mice compared to wild type mice lacking these mutations was studied using thermal plates under cold and warm conditions. Direct application of acetone and von Frey filaments to mouse paws was used to study cold and mechanical sensitivity. Further testing of stamina, anxiety, coordination, and strength were also evaluated. RESULTS: A marked decrease in sensitivity to von Frey stimulation (p<0.01) and acetone administration (p<0.05) was observed in KCNH8 mutant mice. Thermal preference testing demonstrated a decreased preference for warmer temperatures as compared to wild type mice. In addition, anxiety levels were also observed to be slightly higher in these mutant KCNH8 mice (p<0.05). The mutant ITSN2 mice spent less time at cooler temperatures, though surprisingly they significantly preferred warmer conditions as compared to their wild type littermates. A full and partial reversal of these temperature preferences was demonstrated in cold and heat thermal conditions respectively after intraperitoneal gabapentin injection, which normalized the mice toward wild type behavior. CONCLUSIONS: Data from the KCNH8 mutant mouse model indicates an aversion to warmer temperatures and a decreased ability to detect cold or mechanical pressure, much like the human patient. The mutant ITSN2 mice were less likely to spend time at cooler temperatures, indicating heightened sensory sensitivity, but their preference for warmer temperatures suggests a possible desensitization of the affected nociceptors. These results often mirror the patient’s phenotype, but the preference for ambient warmer environments appears opposite to the patient. As the ITSN2 mice feel discomfort at cooler temperatures, a proposed desensitization at warmer temperatures would result in a more comfortable environment and could explain the observed preference. The trends toward normal neural firing rates achieved through gabapentin injection suggest that the aberrant responses in mutant ITSN2 mice is due to altered sensitization, but additional examination under these conditions with a larger group of mice is necessary to further unravel these signaling pathways. However, these extremely encouraging data introduce two new molecular targets for acute pain control

Hadronic Parity Violation: a New View through the Looking Glass

Studies of the strangeness changing hadronic weak interaction have produced a number of puzzles that have so far evaded a complete explanation within the Standard Model. Their origin may lie either in dynamics peculiar to weak interactions involving strange quarks or in more general aspects of the interplay between strong and weak interactions. In principle, studies of the strangeness conserving hadronic weak interaction using parity violating hadronic and nuclear observables provide a complementary window on this question. However, progress in this direction has been hampered by the lack of a suitable theoretical framework for interpreting hadronic parity violation measurements in a model-independent way. Recent work involving effective field theory ideas has led to the formulation of such a framework while motivating the development of a number of new hadronic parity violation experiments in few-body systems. In this article, we review these recent developments and discuss the prospects and opportunities for further experimental and theoretical progress.Comment: Manuscript submitted to Annual Reviews of Nuclear and Particle Scienc

Casein kinase iδ mutations in familial migraine and advanced sleep phase.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine

Orangutan Vision, Looking Preferences, and Passive Looking-Time Versus Active Touchscreen Paradigms

Key aspects of orangutan picture preference, looking paradigms, and vision were assessed in three manuscripts. These studies have important contributions to research on comparative vision and animal picture perception, as well as practical applications for orangutan research. The first manuscript assessed visual preferences for pictures of primates. Orangutan looking-time was coded as they watched simultaneous slideshows on two laptop computers. Orangutans preferred photographs of unfamiliar orangutans over unfamiliar humans, and familiar orangutans over unfamiliar orangutans. When comparing familiar orangutans, they preferred adults over infants, and males over females. These preferences were then compared to preferences reported across primates which show variable results, likely due to complex social factors and context. A second manuscript assessed passive looking-time and active touchscreen paradigms. Passive and active paradigms can produce discrepant results, and the validity of these paradigms had not been empirically assessed in animals. Three methods were compared: looking-time at slideshows on two laptops, a touchscreen that displayed pictures when touched, and simply holding up pairs of printed images. All three methods detected the expected preference for pictures of animals over non-animals. This can be considered evidence of the reliability of these paradigms, equivalence of passive and active methods, and support for continued use of looking-time and touchscreens in orangutan research. The final manuscript assessed the contrast sensitivity function (CSF). Orangutans were trained to select vertical or horizontal lines, and then the CSF threshold was estimated by increasing the spatial frequency and decreasing the contrast of the stimuli. Orangutan CSF was similar in shape and position on the frequency scale to those of humans and macaques, but overall sensitivity was lower. We propose that this was due to testing conditions and low motivation. Across these three manuscripts orangutans demonstrated overall vision and looking behaviour that was similar to humans, however with high variability likely due to competing interests, low motivation, and individual differences

The Effect of Oral Tactile Sensitivity on Texture Discrimination and Mastication

Texture perception is one of the most important factors in food acceptance. Individual differences between consumers for perception and oral processing techniques makes research on related topics difficult to find overall effects. It is thought that individual differences in texture perception could be caused by oral sensitivity or mastication behavior. The first hypothesis is that the variation in texture perception across populations is dependent on oral tactile sensitivity and masticatory performance. To address this hypothesis, the study was aimed to measure tactile acuity with a battery of tests and quantitate the relationship to masticatory performance. In general, sensitivity and masticatory performance in the younger age groups was superior to that of older adults (p \u3c 0.0001). A positive linear trend was also found between bite force sensitivity and masticatory performance with younger participants, a trend not found in older participants. No significant relationship between age groups for bite force sensitivity and masticatory performance was found, suggesting that age-related declines in bite force sensitivity are not a significant cause of altered masticatory performance. The second hypothesis is that as oral sensitivity decreases so will a participant’s ability to discriminate texture differences, since there will be less feedback from the oral cavity. We noted that oral sensitivity was not a significant factor when looking at differences in discrimination ability between high and low sensitivity groups. However, the study found that multiple masticatory behaviors were being modulated by oral sensitivity, including overall chewing patterns used (p \u3c 0.0001). More specifically, those in the high sensitivity group used more stochastic chewing movements, while those in the low sensitivity group were found to use crescent and crossed-shaped chewing cycles. It was also noted that in the high sensitivity group the jaw moved further distances (p \u3c 0.0001) in all phases (opening and closing) and moved at a higher velocity when opening (p \u3c 0.0001) but not when closing, when compared to the low sensitivity group. These results help bolster evidence that sensitivity and masticatory performance are related and, as previously reported, both decline as people age (Calhoun, Gibson, Hartley, Minton, & Hokanson, 1992)