High‐sensitivity cerebral perfusion mapping in mice by kbGRASE‐FAIR at 9.4 T

The combination of flow‐sensitive alternating inversion recovery (FAIR) and single‐shot k‐space‐banded gradient‐ and spin‐echo (kbGRASE) is proposed here to measure perfusion in the mouse brain with high sensitivity and stability. Signal‐to‐noise ratio (SNR) analysis showed that kbGRASE‐FAIR boosts image and temporal SNRs by 2.01 ± 0.08 and 2.50 ± 0.07 times, respectively, when compared with standard single‐shot echo planar imaging (EPI)‐FAIR implemented in our experimental systems, although the practically achievable spatial resolution was slightly reduced. The effects of varying physiological parameters on the precision and reproducibility of cerebral blood flow (CBF) measurements were studied following changes in anesthesia regime, capnia and body temperature. The functional MRI time courses with kbGRASE‐FAIR showed a more stable response to 5% CO₂ than did those with EPI‐FAIR. The results establish kbGRASE‐FAIR as a practical and robust protocol for quantitative CBF measurements in mice at 9.4 T. Copyright © 2010 John Wiley & Sons, Ltd.     

Effect of 2 weeks of endurance training on uncoupling protein 3 content in untrained human subjects

Aim: The mitochondrial uncoupling protein‐3 (UCP3) is able to lower the proton gradient across the inner mitochondrial membrane, thereby uncoupling substrate oxidation from ATP production and dissipating energy as heat. What the effect of endurance training on UCP3 is, is still controversial. Endurance‐trained athletes are characterized by lower levels of UCP3, but longitudinal studies in rodents reported no effect of endurance training on muscular UCP3 levels. Here, we examined the effect of a 2‐week training programme on skeletal muscle UCP3 protein content in untrained human subjects, and hypothesized that UCP3 will be reduced after the training programme. Methods: Nine untrained men [age: 23.3 ± 3.2 years; BMI: 22.6 ± 2.6 kg m^?2; maximal power output (W_max): 3.8 ± 0.6 W kg^?1 body weight] trained for 2 weeks. Before and at least 72 h after the training period, muscle biopsies were taken for determination of UCP3 protein content. Results: UCP3 protein content tended to be lower after the training programme [95 ± 10 vs. 109 ± 12 arbitrary units (AU), P = 0.08]. Cytochrome c content tended to increase with 33% in response to endurance training (52 ± 6 vs. 39 ± 6 AU, P = 0.08). The ratio UCP3 relative to cytochrome c tended to decrease significantly upon endurance training (2.0 ± 0.4 vs. 3.2 ± 0.6 AU, P = 0.01). Conclusion: A short‐term (2‐week) endurance training programme decreased UCP3 protein levels and significantly reduced the ratio of UCP3 to cytochrome c.     

Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats

Clozapine, an atypical antipsychotic agent important for the treatment of schizophrenia, has marked inhibitory effects on sympathetic outflow to the thermoregulatory cutaneous circulation. In rabbits clozapine reverses ear pinna vasoconstriction induced either by administration of MDMA (3,4-methylenedioxymethamphetamine, ecstasy) or by exposing the animal to a cold environment. In rats, both these procedures are known to increase sympathetic activation of interscapular brown adipose tissue (iBAT) thermogenesis, important for heat production in the rat. In the present study in conscious rats we determined whether clozapine reduces iBAT thermogenesis induced by MDMA and by exposure to cold. We designed our study so that we could also determine effects of clozapine on the acute (stress-induced) increases in iBAT thermogenesis initiated by the process of s.c. injection. MDMA increased iBAT temperature (+1.7+/-0.2 degrees C after 90 min, P<0.01, n=14 measurements from seven rats each studied on two occasions). Clozapine acutely reversed the MDMA-elicited increase in iBAT temperature (-1.3+/-0.2 degrees C 60 min after clozapine treatment following MDMA versus +0.3+/-0.2 degrees C for 60 min after vehicle treatment following MDMA, P<0.01, n=7). Clozapine also reduced stress-induced increases in iBAT temperature, as well as increases elicited by exposing rats to a cold (5 degrees C) environment. Results, taken together with our previous findings, suggest that MDMA activates the sympathetic thermoregulatory outputs (including the output to iBAT) that defend body temperature against cold exposure and that increase body temperature in response to environmental stress. Clozapine's marked inhibition of iBAT thermogenesis may provide a clue to its marked tendency to cause obesity when used to treat humans with mental disorders including schizophrenia. Our demonstration in rats that clozapine decreases sympathetically-mediated increases in iBAT temperature elicited by MDMA adds to the likelihood that clozapine and clozapine-like agents might be therapeutically effective in life threatening hyperthermia induced by MDMA in humans.     

Sex-associated differences in cold-induced UCP1 synthesis in rodent brown adipose tissue

 The effects of acute and chronic acclimation to cold on uncoupling protein 1 (UCP1) levels, as well as on GDP-binding to mitochondria, cytochrome c oxidase activity and mitochondrial protein concentration in brown adipose tissue (BAT) of intact male and female rats have been analyzed. Results reveal that females rats are more sensitive to cold because their threshold temperature for the thermogenic response is set at a higher value (around 22°C) than that of males (around 18°C), hence leading to differences in BAT UCP1 levels between the sexes at different environmental temperatures. In vitro experiments showed that steroid hormones, β-estradiol, estrone and progesterone, can reduce norepinephrine-induced UCP1 synthesis in brown adipocytes differentiated in primary culture. Thus the different sex-associated response of cold-induced thermogenesis in rats does not appear to be explained by a direct action of sex steroids upon the adipocyte, implying that other factors in the thermogenic regulatory system must be involved. Received: 23 March 1998 / Received after revision: 20 May 1998 / Accepted: 21 May 1998     

Temperature modulated histamine-itch in lesional and nonlesional skin in atopic eczema – a combined psychophysical and neuroimaging study

Background:  Itch is the major symptom of many allergic diseases; yet it is still difficult to measure objectively. The aim of this study was to use an evaluated itch stimulus model in lesional (LS) and nonlesional (NLS) atopic eczema (AE) skin and to characterize cerebral responses using functional magnetic resonance imaging (fMRI). Methods:  Thermal modulation was performed on a histamine stimulus in randomized order on LS or NLS in rapid alternating order from 32°C (warm) to 25°C (cold). Subjective itch ratings were recorded. Additionally, fMRI measurements were used to analyze the cerebral processing (n = 13). Healthy skin (HS) of age‐matched volunteers served as control (n = 9). Results:  Mean VAS itch intensity was significantly (P < 0.0001) higher during the relative cold [55.2 ± 8.3% (LS); 48.6 ± 8.2% (NLS)] compared to the relative warm blocks [36.0 ± 7.3% (LS); 33.7 ± 7.6% (NLS)]. Compared to HS, the itch response was delayed in LS and NLS. Itch intensity was perceived highest in LS, followed by NLS and HS.
For NLS, fMRI revealed at the beginning of the itch provocation a cerebral deactivation pattern in itch processing structures (thalamus, prefrontal, cingulate, insular, somatosensory and motor cortex). During the course of stimulation, the cerebral deactivation was reduced with time and instead an activation of the basal ganglia occurred. In contrast LS showed an activation instead of deactivation pattern already at the beginning of the stimulation in the above mentioned structures. Conclusions:  Moderate short‐term temperature modulation led to a reproducible, significant enhancement of histamine‐induced itch with the strongest effect in LS.
The differences in itch perception and itch kinetics between healthy volunteers and NLS in patients point towards an ongoing central inhibitory activity patients with AE, especially at the beginning of the itch provocation.     

The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine

Body temperature regulation involves a homeostatic balance between heat production and dissipation. Sympathetic agents such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can disrupt this balance and as a result produce an often life-threatening hyperthermia. The hyperthermia induced by MDMA appears to result from the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-thyroid/adrenal axis. Norepinephrine release mediated by MDMA creates a double-edged sword of heat generation through activation of uncoupling protein (UCP3) along with ₁- and ₃-adrenoreceptors and loss of heat dissipation through SNS-mediated vasoconstriction. This review examines cellular mechanisms involved in MDMA-induced thermogenesis from UCP activation to vasoconstriction and how these mechanisms are related to other thermogenic conditions and potential treatment modalities.     

Calculation methods for ventricular diffusion-weighted imaging thermometry: phantom and volunteer studies

A method for the measurement of temperature in the lateral ventricle using diffusion‐weighted imaging (DWI) has been proposed recently. This method uses predetermined arbitrary thresholds, but a more objective method of calculation would be useful. We therefore compared four different calculation methods, two of which were newly created and did not require predetermined thresholds. A rectangular polyethylene terephthalate bottle (8 × 10 × 28 cm³) was filled with heated water (35.0–38.8 °C) and used as a water phantom. The DWI data of 23 healthy subjects (aged 26–75 years; mean ± standard deviation, 50.13 ± 19.1 years) were used for this study. The temperature was calculated using the following equation: T(°C) = 2256.74/ln(4.39221/D) ? 273.15, where D is the diffusion coefficient. The mean ventricular temperature was calculated by four methods: two thresholding methods and two histogram curve‐fitting methods. As a reference, we used the temperature measured at the tympanic membrane, which is known to be approximately 1 °C lower than the brain temperature. The averaged differences in temperature between mercury thermometry and classical predetermined thresholding methods for the water phantom were 0.10 ± 0.42 and 0.05 ± 0.41 °C, respectively. The histogram curve‐fitting methods, however, yielded temperatures a little lower (averaged differences of ?0.24 ± 0.32 and ?0.14 ± 0.31 °C, respectively) than mercury thermometry. There was very little difference in temperature between tympanic thermometry and classical predetermined thresholding methods (+0.01 and ?0.07 °C, respectively). In humans, however, the histogram curve‐fitting methods yielded temperatures approximately 1 °C higher (+1.04 °C and +1.36 °C, respectively), suggesting that temperatures measured in this way more closely approximate the true brain temperature. The histogram curve‐fitting methods were more objective and better matched the estimated brain temperature than did classical predetermined thresholding methods, although the standard deviation was wider in the former methods. Copyright © 2011 John Wiley & Sons, Ltd.     

Elevated core and muscle temperature to levels comparable to exercise do not increase heat shock protein content of skeletal muscle of physically active men

Aim: Exercise‐associated hyperthermia is routinely cited as the signal responsible for inducing an increased production of heat shock proteins (HSPs) following exercise. This hypothesis, however, has not been tested in human skeletal muscle. The aim of the present study was to therefore investigate the role of increased muscle and core temperature in contributing to the exercise‐induced production of the major HSP families in human skeletal muscle. Methods: Seven physically active males underwent a passive heating protocol of 1 h duration during which the temperature of the core and vastus lateralis muscle were increased to similar levels to those typically occurring during moderately demanding aerobic exercise protocols. One limb was immersed in a tank containing water maintained at approximately 45 °C whilst the contra‐lateral limb remained outside the tank and was not exposed to heat stress. Muscle biopsies were obtained from the vastus lateralis of both legs immediately prior to and at 48 h and 7 days post‐heating. Results: The heating protocol induced significant increases (P < 0.05) in rectal (1.5 ± 0.2 °C) and muscle temperature of the heated leg (3.6 ± 0.5 °C). Muscle temperature of the non‐heated limb showed no significant change (P > 0.05) following heating (pre: 36.1 ± 0.5, post: 35.7 ± 0.2 °C). Heating failed to induce a significant increase (P > 0.05) in muscle content of HSP70, HSC70, HSP60, HSP27, αB‐crystallin, MnSOD protein content or in the activity of superoxide dismutase and catalase. Conclusions: These data demonstrate that increases in both systemic and local muscle temperature per se do not appear to mediate the exercise‐induced production of HSPs in human skeletal muscle and suggest that non‐heat stress factors associated with contractile activity are of more importance in mediating this response.     

Reliability of MRSI brain temperature mapping at 1.5 and 3 T

MRSI permits the non‐invasive mapping of brain temperature in vivo, but information regarding its reliability is lacking. We obtained MRSI data from 31 healthy male volunteers [age range, 22–40 years; mean ± standard deviation (SD), 30.5 ± 5.0 years]. Eleven subjects (age range, 23–40 years; mean ± SD, 30.5 ± 5.2 years) were invited to receive four point‐resolved spectroscopy MRSI scans on each of 3 days in both 1.5‐T (TR/TE = 1000/144 ms) and 3‐T (TR/TE = 1700/144 ms) clinical scanners; a further 20 subjects (age range, 22–40 years; mean ± SD, 30.5 ± 4.9 years) were scanned on a single occasion at 3 T. Data were fitted in the time domain to determine the water–N‐acetylaspartate chemical shift difference, from which the temperature was estimated. Temperature data were analysed using a linear mixed effects model to determine variance components and systematic temperature changes during the scanning sessions. To characterise the effects of instrumental drift on apparent MRSI brain temperature, a temperature‐controlled phantom was constructed and scanned on multiple occasions. Components of apparent in vivo temperature variability at 1.5 T/3 T caused by inter‐subject (0.18/0.17 °C), inter‐session (0.18/0.15 °C) and within‐session (0.36/0.14 °C) effects, as well as voxel‐to‐voxel variation (0.59/0.54 °C), were determined. There was a brain cooling effect during in vivo MRSI of 0.10 °C [95% confidence interval (CI): –0.110, –0.094 °C; p < 0.001] and 0.051 °C (95% CI: –0.054, –0.048 °C; p < 0.001) per scan at 1.5 T and 3 T, respectively, whereas phantom measurements revealed minimal drift in apparent MRSI temperature relative to fibre‐optic temperature measurements. The mean brain temperature at 3 T was weakly associated with aural (R = 0.55, p = 0.002) and oral (R = 0.62, p < 0.001) measurements of head temperature. In conclusion, the variability associated with MRSI brain temperature mapping was quantified. Repeatability was somewhat higher at 3 T than at 1.5 T, although subtle spatial and temporal variations in apparent temperature were demonstrated at both field strengths. Such data should assist in the efficient design of future clinical studies. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

Age-dependent brain temperature decline assessed by diffusion-weighted imaging thermometry

Brain metabolism declines with age, but cerebral blood flow (CBF) is less age dependent. We therefore hypothesized that the brain temperature would decline with age, and measured the temperatures of the lateral ventricles in healthy volunteers. Diffusion‐weighted imaging (DWI) data from 45 healthy volunteers [mean (± standard deviation) age, 30.6 ± 8.66 years; range, 19–56 years] were used for this study. The temperature of water molecules is directly related to the diffusion coefficient, so that the temperature of cerebrospinal fluid can be measured using DWI. Temperature was calculated using the equation, T ( °C) = 2256.74/ln(4.39221/D) – 273.15, where D is the diffusion coefficient. The lateral ventricles were manually extracted by an experienced neuroradiologist on b₀ images. The mean ventricular temperature was determined from the distribution function of the temperature of all selected voxels. The mean lateral ventricular temperature in healthy volunteers showed a linear decrease with age (correlation coefficient R² = 0.8879; p < 0.01), presumably caused by an asynchronous decline in brain metabolism and CBF. DWI‐based thermometry demonstrates that ventricular temperature declines with the normal aging process. Further study is warranted to define the relationships between temperature, metabolism and circulation. Copyright © 2011 John Wiley & Sons, Ltd.     

Growth hormone and prolactin responses during partial and whole body warm‐water immersions

Aim: To elucidate the role of core and skin thermoreceptors in the release of growth hormone (GH) and prolactin (PRL), a sequence of two experiments using whole‐body (head‐out) and partial (one forearm) hot water immersions was performed. Methods: Experiment 1: Nine healthy men were exposed to head‐out and partial water immersions (25 min, 38–39 °C). Results: Head‐out immersion increased the core temperature (38.0 ± 0.1 vs. 36.7 ± 0.1 °C, P < 0.001) and plasma concentration of the hormones (GH, 16.1 ± 4.5 vs. 1.2 ± 0.4 ng mL^?1, P < 0.01; PRL, 9.1 ± 1.0 vs. 6.4 ± 0.4 ng mL^?1, P < 0.05). During the partial immersion the core temperature was slightly elevated (36.8 ± 0.1 vs. 36.6 ± 0.1, P < 0.001), the concentration of GH increased (4.8 ± 1.7 vs. 0.6 ± 0.3, P < 0.05), while plasma PRL decreased (7.6 ± 0.8, 6.0 ± 0.6, 5.2 ± 0.6, P < 0.01). Experiment 2: Seven volunteers immersed one forearm once in 39 °C and once in 38 °C water. The measurements were performed in 5‐min intervals. The GH concentration increased gradually from the beginning of the immersions (min 10; 39 °C: 1.9 ± 1.0 vs. 0.6 ± 0.3 ng mL^?1, P < 0.01; 38 °C: 0.19 ± 0.03 vs. 0.14 ± 0.03, P < 0.05) and peaked after their completion (39 °C: +10 min, 3.7 ± 2.0, P < 0.001; 38 °C: +15 min, 0.86 ± 0.61, P < 0.01). The core temperature was unchanged until min 15 of the 39 °C bath. Thereafter, it increased about 0.15 °C above the baseline (P < 0.01). Immersion in 38 °C water did not induce core temperature changes. Conclusions: Peripheral thermoreceptors are involved in GH release when the body is exposed to elevated environmental temperature while a substantial elevation of core temperature is a precondition of PRL release.     

The Effect of Sevoflurane Inhalation on Gabaergic Neurons Activation: Observation on the GAD67‐GFP Knock‐In Mouse

The mechanisms underlying volatile anesthesia agents are not well elucidated. Emerging researches have focused on the participation of γ‐aminobutyric acid (GABA) neurons but there still lacks morphological evidence. To elucidate the possible activation of GABAergic neurons by sevoflurane inhalation in morphology, Fos (as neuronal activity marker) and GABA neurons double labeling were observed on the brain of glutamic acid decarboxylase (GAD) 67‐GFP knock‐in mice after sevoflurane inhalation. Twenty GAD67‐GFP knock‐in mice were divided into three groups: S1 group: incomplete anesthesia state induced by sevoflurane; S2 group: complete anesthesia state induced by sevoflurane; control(C) group. Sevoflurane induced a significant increase of Fos expression in the dorsomedial hypothalamic nucleus (DM), periaqueductal grey (PAG), hippocampus (CA1, DG), paraventricular thalamic nucleus (PV), lateral septal nucleus (LS), and cingulate cortex (Cg1 and Cg2) in S1 group compared to C group, and increase of Fos expression in S2 group compared to S1 group. In S2 group, Fos was only expressed in the medial amygdaloid nucleus (MeA), Edinger–Westphal (E–W) nucleus, arcuate hypothalamic nucleus (Arc) and the ventral part of paraventricular hypothalamic nucleus (PaV). Double immunofluroscent staining indicated that in LS, almost all Fos werepresent in GABAergic neurons. In CA1, DG, DM, cg1, cg2, and PAG, Fos was expressed as well, but only few were present in GABAergic neurons. Fos expression was very high in thalamus, but no coexistence were found as noGABAergic neuron was detected in this area. Our results provided morphological evidence that GABAergic transmission in specific brain areas may participate in the sevoflurane‐induced anesthesia. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

Brain temperature by Biosensor Imaging of Redundant Deviation in Shifts (BIRDS): comparison between TmDOTP5−and TmDOTMA−

Chemical shifts of complexes between paramagnetic lanthanide ions and macrocyclic chelates are sensitive to physiological variations (of temperature and/or pH). Here we demonstrate utility of a complex between thulium ion (Tm³⁺) and the macrocyclic chelate 1,4,7,10‐tetramethyl 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetate (or DOTMA^4?) for absolute temperature mapping in rat brain. The feasibility of TmDOTMA^? is compared with that of another Tm³⁺‐containing biosensor which is based on the macrocyclic chelate 1,4,7,10‐tetraazacyclododecane‐ 1,4,7,10‐tetrakis(methylene phosphonate) (or DOTP^8?). In general, the in vitro and in vivo results suggest that Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from these agents (but exclude water) can provide temperature maps with good accuracy. While TmDOTP^5? emanates three major distinct proton resonances which are differentially sensitive to temperature and pH, TmDOTMA^? has a dominant pH‐insensitive proton resonance from a ? CH₃ group to allow higher signal‐to‐noise ratio (SNR) temperature assessment. Temperature (and pH) sensitivities of these resonances are practically identical at low (4.0T) and high (11.7T) magnetic fields and at nominal repetition times only marginal SNR loss is expected at the lower field. Since these resonances have extremely short relaxation times, high‐speed chemical shift imaging (CSI) is needed to detect them. Repeated in vivo CSI scans with BIRDS demonstrate excellent measurement stability. Overall, results with TmDOTP^5? and TmDOTMA^? suggest that BIRDS can be reliably applied, either at low or high magnetic fields, for functional studies in rodents. Copyright © 2009 John Wiley & Sons, Ltd.     

Transit time mapping in the mouse brain using time‐encoded pCASL

The cerebral blood flow (CBF) is a potential biomarker for neurological disease. However, the arterial transit time (ATT) of the labeled blood is known to potentially affect CBF quantification. Furthermore, ATT could be an interesting biomarker in itself, as it may reflect underlying macro‐ and microvascular pathologies. Currently, no optimized magnetic resonance imaging (MRI) sequence exists to measure ATT in mice. Recently, time‐encoded labeling schemes have been implemented in rats and humans, enabling ATT mapping with higher signal‐to‐noise ratio (SNR) and shorter scan time than multi‐delay arterial spin labeling (ASL). In this study, we show that time‐encoded pseudo‐continuous arterial spin labeling (te‐pCASL) also enables transit time measurements in mice. As an optimal design that takes the fast blood flow in mice into account, time encoding with 11 sub‐boli of 50 ms is proposed to accurately probe the inflow of labeled blood. For perfusion imaging, a separate, traditional pCASL scan was employed. From the six studied brain regions, the hippocampus showed the shortest ATT (169 ± 11 ms) and the auditory/visual cortex showed the longest (284 ± 16 ms). Furthermore, ATT was found to be preserved in old wild‐type mice. In a mouse with an induced carotid artery occlusion, prolongation of ATT was shown. In conclusion, this study shows the successful implementation of te‐pCASL in mice, making it possible, for the first time, to measure ATT in mice in a time‐efficient manner.     

MRS thermometry calibration at 3 T: effects of protein,ionic concentration and magnetic field strength

MRS thermometry has been utilized to measure temperature changes in the brain, which may aid in the diagnosis of brain trauma and tumours. However, the temperature calibration of the technique has been shown to be sensitive to non‐temperature‐based factors, which may provide unique information on the tissue microenvironment if the mechanisms can be further understood. The focus of this study was to investigate the effects of varied protein content on the calibration of MRS thermometry at 3 T, which has not been thoroughly explored in the literature. The effects of ionic concentration and magnetic field strength were also considered. Temperature reference materials were controlled by water circulation and freezing organic fixed‐point compounds (diphenyl ether and ethylene carbonate) stable to within 0.2 °C. The temperature was measured throughout the scan time with a fluoro‐optic probe, with an uncertainty of 0.16 °C. The probe was calibrated at the National Physical Laboratory (NPL) with traceability to the International Temperature Scale 1990 (ITS‐90). MRS thermometry measures were based on single‐voxel spectroscopy chemical shift differences between water and N‐acetylaspartate (NAA), Δ_(H20‐NAA), using a Philips Achieva 3 T scanner. Six different phantom solutions with varying protein or ionic concentration, simulating potential tissue differences, were investigated within a temperature range of 21–42 °C. Results were compared with a similar study performed at 1.5 T to observe the effect of field strengths. Temperature calibration curves were plotted to convert Δ_(H20‐NAA) to apparent temperature. The apparent temperature changed by ?0.2 °C/% of bovine serum albumin (BSA) and a trend of 0.5 °C/50 mM ionic concentration was observed. Differences in the calibration coefficients for the 10% BSA solution were seen in this study at 3 T compared with a study at 1.5 T. MRS thermometry may be utilized to measure temperature and the tissue microenvironment, which could provide unique unexplored information for brain abnormalities and other pathologies. Copyright © 2015 John Wiley & Sons, Ltd.     

When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: effects of pretreatment with 5-HT1A and dopamine D2 antagonists

When given in a warm environment MDMA (3,4-methylenedioxymethamphetamine, ecstasy) causes hyperthermia by increasing interscapular brown adipose tissue (iBAT) heat production and decreasing heat loss via cutaneous vasoconstriction. When given in a cold environment, however, MDMA causes hypothermia by an unknown mechanism. This paper addresses these mechanisms and in addition examines whether antagonists at 5-HT(1A) and D(2) receptors reduce the hypothermic action of MDMA. Male Sprague-Dawley rats instrumented with a Doppler probe for measuring tail blood flow, and probes for measuring core and iBAT temperatures, were placed in a temperature-controlled chamber. The chamber temperature was reduced to 10 degrees C and vehicle (0.5 ml Ringer), the 5-HT(1A) antagonist WAY 100635 (0.5 mg/kg), the D(2) antagonist spiperone (20 mug/kg), or the combination of Way 100635 and spiperone were injected s.c. Thirty minutes later the antagonists were injected again along with MDMA (10 mg/kg) or vehicle. MDMA reduced core body temperature by preventing cold-elicited iBAT thermogenesis and by transiently reversing cold-elicited cutaneous vasoconstriction. Pretreatment with WAY 100635 prevented MDMA induced increases in tail blood flow, and briefly attenuated MDMA's effects on iBAT and core temperature. While spiperone alone failed to affect any of the parameters, the combination of spiperone and WAY 100635 decreased MDMA-mediated hypothermia by attenuating both the effects on tail blood flow and iBAT thermogenesis. MDMA's prevention of cold-induced iBAT thermogenesis appears to have a central origin as it rapidly reverses cold-induced increases in iBAT sympathetic nerve discharge in anesthetized rats. Our results demonstrate that MDMA in a cold environment reduces core body temperature by inhibiting iBAT thermogenesis and tail artery vasoconstriction and suggest that mechanisms by which this occurs include the activation of 5-HT1A and dopamine D2 receptors.     

Orexin-a regulates body temperature in coordination with control of arousal state

Orexin-a regulates body temperature in coordination with control of arousal state     

Simultaneous CBF and BOLD mapping of high frequency acupuncture induced brain activity

This study mapped brain activity elicited by high frequency electroacupuncture by simultaneously using blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) contrasts. Forty subjects participated in the study, in which twenty ones were imaged during electrical acupoint stimulation (EAS) to the left LI4 acupoint at a maximal intensity without pain, and the others were with a minimal-EAS at a just detectible intensity. Both BOLD and CBF data were acquired simultaneously during alternating blocks of rest and stimulation. The results showed that the minimal-EAS mostly induced the activities in somatosensory region, including those in inferior parietal lobule, SII, insula, and thalamus. On the other hand, EAS activated more including also posterior middle cingulate cortex (pMCC), and deactivated superior temporal gyrus. Moreover, deactivation was found in posterior cingulated cortex (PCC), precuneus from BOLD and in culmen of cerebellum, caudate from CBF. The comparison between EAS and minimal-EAS revealed deactivation in the default mode network in both BOLD and CBF signals, activation in thalamus, insula, and caudal anterior cingulate cortex (ACC) in the CBF signal alone, and deactivation in putamen, rostral ACC and parahippocampal gyrus in the BOLD signal alone. This study provides, for the first time, simultaneous CBF and BOLD responses to high frequency EAS at the LI4 acupoint, revealing concordant and complementary insights into the neural effects of EAS, including modulation of subcortical structures and limbic system.     

Bioinspired All‐Polyester Diblock Copolymers Made from Poly(pentadecalactone) and Poly(2‐(2‐hydroxyethoxy)benzoate): Synthesis and Polymer Film Properties

The bioinspired diblock copolymers poly(pentadecalactone)‐block‐poly(2‐(2‐hydroxyethoxy)benzoate) (PPDL‐block‐P2HEB) are synthesized from pentadecalactone and dihydro‐5H‐1,4‐benzodioxepin‐5‐one (2,3‐DHB). No transesterification between the blocks is observed. In a sequential approach, PPDL obtained by ring‐opening polymerization (ROP) is used to initiate 2,3‐DHB. Here, the molar mass M_n of the P2HEB block is limited. In a modular approach, end‐functionalized PPDL and P2HEB are obtained separately by ROP with functional initiators, and connected by 1,3‐dipolar Huisgen reaction (“click‐chemistry”). Block copolymer compositions from 85:15 mass percent to 28:72 mass percent (PPDL:P2HEB) are synthesized, with M_n of from about 30 000–50 000 g mol^?1. The structure of the block copolymer is confirmed by proton NMR, Fourier‐transform infrared spectroscopy, and gel permeation chromatography. Morphological studies by atomic force microscopy (AFM) further confirms the block copolymer structure, while quantitative nanomechanical AFM measurements reveal that the Derjaguin–Muller–Toporov moduli of the block copolymers range between 17.2 ± 1.8 and 62.3 ± 5.7 MPa, i.e., between the values of the parent P2HEB and PPDL homopolymers (7.6 ± 1.4 and 801 ± 42 MPa, respectively). Differential scanning calorimetry shows that the thermal properties of the homopolymers are retained by each of the copolymer blocks (melting temperature 90 °C, glass transition temperature 36 °C).     

Stimulation‐induced transient changes in neuronal activity,blood flow and N‐acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS‐BOLD study

Brain activation studies in humans have shown the dynamic nature of neuronal N‐acetylaspartate (NAA) and N‐acetylaspartylglutamate (NAAG) based on changes in their MRS signals in response to stimulation. These studies demonstrated that upon visual stimulation there was a focal increase in cerebral blood flow (CBF) and a decrease in NAA or in the total of NAA and NAAG signals in the visual cortex, and that these changes were reversed upon cessation of stimulation. In the present study we have developed an animal model in order to explore the relationships between brain stimulation, neuronal activity, CBF and NAA. We use “designer receptor exclusively activated by designer drugs” (DREADDs) technology for site‐specific neural activation, a local field potential electrophysiological method for measurement of changes in the rate of neuronal activity, functional MRS for measurement of changes in NAA and a blood oxygenation level‐dependent (BOLD) MR technique for evaluating changes in CBF. We show that stimulation of the rat prefrontal cortex using DREADDs results in the following: (i) an increase in level of neuronal activity; (ii) an increase in BOLD and (iii) a decrease in the NAA signal. These findings show for the first time the tightly coupled relationships between stimulation, neuron activity, CBF and NAA dynamics in brain, and also provide the first demonstration of the novel inverse stimulation–NAA phenomenon in an animal model.