Nicotinic α4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits

Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine’s (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHβE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHβE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4β2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4β2 nAChR-mediated transmission.     

Low Ambient Temperature and Intracerebral Hemorrhage: The INTERACT2 Study

Background

Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale.

Methods

INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH (<6h of onset) and elevated systolic blood pressure (SBP, 150–220 mmHg) assigned to intensive (target SBP <140 mmHg) or guideline-recommended (SBP <180 mmHg) BP treatment. We linked individual level hourly temperature to baseline data of 1997 participants, and performed case-crossover analyses using a distributed lag non-linear model with 24h lag period to assess the association of ambient temperature and risk of ICH. Results were presented as overall cumulative odds ratios (ORs) and 95% CI.

Results

Low ambient temperature (≤10°C) was associated with increased risks of ICH: overall cumulative OR was 1.37 (0.99–1.91) for 10°C, 1.92 (1.31–2.81) for 0°C, 3.13 (1.89–5.19) for -10°C, and 5.76 (2.30–14.42) for -20°C, as compared with a reference temperature of 20°C.There was no clear relation of low temperature beyond three hours after exposure. Results were consistent in sensitivity analyses.

Conclusions

Exposure to low ambient temperature within several hours increases the risk of ICH.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00716079","term_id":"NCT00716079"}}NCT00716079     

An abundant and novel protein of 22 kDa (SM22) is widely distributed in smooth muscles. Purification from bovine aorta.

Using a rabbit polyclonal-antibody preparation directed against the chicken gizzard protein, we demonstrated by immunoblotting the presence of the 22 kDa protein (SM22) in a variety of chicken smooth-muscle-containing organs, including uterus, intestine, gizzard, oesophagus and aorta. Protein SM22 was present in only trace amounts in brain, liver and heart, and could not be detected in chicken breast muscle. The antibody preparation did not cross-react with extracts of bovine aorta. However, the presence of SM22 as a major component in bovine aorta and pig carotid was demonstrated by its co-migration with the purified chicken gizzard protein on one- and two-dimensional polyacrylamide electrophoretic gels. Its molar abundance relative to actin was estimated to be 0.9:6.0 and 1.4:6.0 for bovine aorta and pig carotid respectively. Like the chicken gizzard protein, it separates on pH-gradient electrophoresis into at least three variants, alpha, beta and gamma, with similar apparent Mr. Purification of the aorta SM22 showed it to have a similar amino acid composition to the chicken gizzard protein. We conclude that SM22 is widely distributed and an abundant and unique protein component of smooth-muscle tissues of birds and mammals.     

Spatial frequency difference thresholds depend on stimulus area

Spatial frequency difference thresholds were estimated for vertical, high contrast 5.0 cpd sinewave gratings that had been multiplied by a two dimensional Gaussian window function of contrast. A range of different elliptical window configurations were tested that varied in their relative height and width. Spatial frequency acuity improved as the area of the target was increased. The data are compatible with a model of spatial frequency discrimination that is based on statistical averaging of spatial intervals interpolated between local retinal signs.     

Aspergillus fumigatus chsE: A Gene Related to CHS3 of Saccharomyces cerevisiae and Important for Hyphal Growth and Conidiophore Development but Not Pathogenicity

The Aspergillus fumigatus chsE (AfchsE) gene was isolated from an A. fumigatus DNA library on the basis of hybridization to a segment of Saccharomyces cerevisiae CHS3 (ScCHS3). The amino acid sequence derived from AfchsE is 28% identical with ScCHS3 and 80% identical with the product of Aspergillus nidulans chsD (AnchsD). A mutant strain constructed by disruption of AfchsE has reduced levels of mycelial chitin, periodic swellings along the length of hyphae, and a block in conidiation that can be partially restored by growth in osmotic stabilizer. This phenotype is different from that reported for an AnchsD mutant, in which germinating conidia and hyphal tips undergo lysis and the colonial growth rate is significantly reduced. Despite the defects associated with the AfchsE- strain, its virulence was not significantly reduced when compared with the wild-type parental strain in a mouse model of pulmonary aspergillosis.     

Spatial frequency discrimination for sinewave gratings with random, bandpass frequency modulation: evidence for averaging in spatial acuity

Spatial frequency difference thresholds for vertical, high contrast sinewave gratings were estimated at 1.25, 2.5, 5.0 and 10.0 cyc deg-1. Within an experiment two independent manipulations of the stimulus were employed: (1) the number of cycles of the sinewave grating was varied over a range of 2.0 to 15.0 cycles; and (2) a stationary, random frequency modulation was imposed on the sinewave. The probability density function of the frequency modulation was a Gaussian whose dispersion coefficient was varied, in different experiments, in the range of 0 to 10% of the frequency of the parent sinewave. Both of these experimental variables were found to affect the precision with which spatial frequency discrimination could be performed. The Weber fraction increased both as the number of cycles present was decreased and as the dispersion coefficient of the modulating function was increased. These two effects were independent. The data support previous psychophysical findings that spatial frequency discrimination involves averaging over the total area of the stimulus and are compatible with spatial primitive models of spatial contrast vision. The data are not compatible with those of Hirsch and Hylton (J. opt. Soc. Am. 72, 1367-1374) which suggest that spatial interval discrimination occurs solely by operation of foveal mechanisms.