The investigation of the effects of topiramate on the hypothalamic levels of fat mass/obesity-associated protein and neuropeptide Y in obese female rats

Objective: The aim of the present study is to investigate the effects of topiramate on the fat mass/obesity-associated protein (FTO) and on the neuropeptide Y (NPY) level in the hypothalamus depending on the recently increased prevalence of obesity.

Method: In this study, twenty-four female rats were divided into four equal groups: Non-obese control, obese control, non-obese topiramate, and obese topiramate. Obese groups were fed with a 40% high-fat diet. At the end of the 9th week, the drug treatment started and the subjects were treated with topiramate once a day for 6 weeks. All animals underwent cardiac perfusion under high-dose anesthesia on the 15th week. Tissues were analyzed using biochemical, histological, and stereological methods.

Results: In terms of neuron number in the arcuate nucleus area, a significant difference was observed among all groups (P?<?0.01). The neuron number of the non-obese topiramate group was found to be significantly higher than that of the non-obese control group (P?<?0.01). In the examination of the ventromedial nucleus of the entire group, it was observed that the neuron number of the non-obese control group was significantly lower than those of the other groups (P?<?0.01). A significant increase in the NPY levels of the obese groups compared to the groups treated with topiramate was observed. Furthermore, the amount of the FTO protein increased in obese rats, while FTO and NPY levels decreased in the groups treated with topiramate.

Discussion: In conclusion, the mechanism of the effect of topiramate to create a state of obesity is thought to involve the decrease in the levels of NPY and FTO.     

A Prechop Technique Using a Reverse Chopper

Purpose: To describe a manual prechop technique for splitting the nucleus of the lens using a recently developed reverse chopper. Methods: During the process, the reverse chopper and the Nagahara chopper are placed diagonally in the peripheral area of the nucleus of the lens after capsulorhexis. The reverse chopper and the Nagahara chopper then are pushed horizontally toward each other so they meet at the center of the lens to split the nucleus of lens into 2 parts. Results: In all cases, the reverse chopper was effective during the prechop procedure for hard nuclei, the nucleus of the lens remained in situ during the chopping process, and the reverse chopper did not retract the suspensory ligament in patients in whom the ligament was fragile. During the prechop procedure, no capsule breakage occurred, and the time and energy required for effective phacoemulsification were reduced significantly. Conclusions: The prechop technique using the reverse chopper can be applied for cases with grade III–V nuclei, overripe nuclei, and fragile suspensory ligaments. The procedure is simple, and the learning curve is not steep.     

Complex negative emotions induced by electrical stimulation of the human hypothalamus

BackgroundStimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated.ObjectiveTo examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions.MethodsWe examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG).ResultsRecordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and structural connectivity.ConclusionThis patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus and its connected structures ought to be seen as causally important for human affective experience.     

19 F MRSI of capecitabine in the liver at 7 T using broadband transmit–receive antennas and dual‐band RF pulses

Capecitabine (Cap) is an often prescribed chemotherapeutic agent, successfully used to cure some patients from cancer or reduce tumor burden for palliative care. However, the efficacy of the drug is limited, it is not known in advance who will respond to the drug and it can come with severe toxicity. ¹⁹ F Magnetic Resonance Spectroscopy (MRS) and Magnetic Resonance Spectroscopic Imaging (MRSI) have been used to non‐invasively study Cap metabolism in vivo to find a marker for personalized treatment. In vivo detection, however, is hampered by low concentrations and the use of radiofrequency (RF) surface coils limiting spatial coverage. In this work, the use of a 7T MR system with radiative multi‐channel transmit–receive antennas was investigated with the aim of maximizing the sensitivity and spatial coverage of ¹⁹ F detection protocols. The antennas were broadband optimized to facilitate both the ¹H (298 MHz) and ¹⁹ F (280 MHz) frequencies for accurate shimming, imaging and signal combination. B₁⁺ simulations, phantom and noise measurements showed that more than 90% of the theoretical maximum sensitivity could be obtained when using B₁⁺ and B₁^? information provided at the ¹H frequency for the optimization of B₁⁺ and B₁^? at the ¹⁹ F frequency. Furthermore, to overcome the limits in maximum available RF power, whilst ensuring simultaneous excitation of all detectable conversion products of Cap, a dual‐band RF pulse was designed and evaluated. Finally, ¹⁹ F MRS(I) measurements were performed to detect ¹⁹ F metabolites in vitro and in vivo. In two patients, at 10 h (patient 1) and 1 h (patient 2) after Cap intake, ¹⁹ F metabolites were detected in the liver and the surrounding organs, illustrating the potential of the set‐up for in vivo detection of metabolic rates and drug distribution in the body. Copyright © 2015 John Wiley & Sons, Ltd.     

Prenatal stress‐related alterations in synaptic transmission and 5‐HT7 receptor‐mediated effects in the rat dorsal raphe nucleus are ameliorated by the 5‐HT7 receptor antagonist SB 269970

Early life adversity exerts a detrimental influence on developing brain neuronal networks and its consequences may include mental health disorders. In rats, prenatal stress may lead to anxiety and depressive‐like behavior in the offspring. Several lines of evidence implicated an involvement of prenatal stress in alterations of the brain serotonergic system functions, but the effects of prenatal stress on its core, the dorsal raphe nucleus (DRN), still remain incompletely understood. The present study was aimed at finding whether prenatal stress induces modifications in the glutamatergic and GABAergic inputs to DRN projection cells and whether it affects DRN 5‐HT₇ receptors, which modulate activity of these synapses. Prenatal stress resulted in an increase in basal frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and in a decrease in basal frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from putative projection neurons in DRN slices ex vivo. While there were no changes in the excitability of DRN projection neurons, the 5‐HT₇ receptor‐mediated reduction in the sEPSC frequency and rise in the sIPSC frequency, seen in control rats, were largely absent in slices obtained from prenatally stressed rats. Repeated administration of SB 269970, a 5‐HT₇ receptor antagonist, resulted in a reversal of prenatal stress‐induced alterations in 5‐HT₇ receptor‐mediated effects on the sEPSC/sIPSC frequency. Moreover, the treatment reversed prenatal stress‐induced alterations in basal excitatory transmission and partially reversed the effect of stress on basal inhibitory transmission in the DRN.     

咬合创伤对三叉神经脊束核敏化作用的研究

目的　研究咬合创伤时前速激肽原A(PPTA)及c fosmRNA在三叉神经脊束核尾侧亚核 (VC)的表达变化 ,探讨咬合创伤对口面部初级传入中枢兴奋性的影响。方法　高出咬合面1 5mm的嵌体粘固于 18只杂种犬右侧上颌第一、二磨牙咬合面的Ⅰ类洞型内 ,造成对颌牙的创伤。粘固嵌体后 3、7、14、30、6 0d时取双侧VC ,用反转录 聚合酶链式反应 (RT PCR)检测PPTA及c fosmRNA的表达并与无咬合创伤的对照组犬比较。结果　①对照犬VC内有极少量PPTA和c fosmRNA的表达。②戴嵌体后 3d起 ,所有实验犬创伤侧VC内PPTAmRNA表达开始上调 ,14d时表达水平最高并持续至 30d ,其后开始下降。 3～ 30d内实验组创伤侧PPTAmRNA表达水平显著高于对照组。③ 3d和 7d时创伤侧VC内有明确的c fosmRNA表达增强 ,其余时间段未检测到c fosmRNA。④创伤咬合侧PPTA及c fosmRNA表达明显强于对侧。结论　咬合创伤时VC内PPTA及c fosmRNA表达水平明显上调 ;咬合创伤使口面部初级传入中枢兴奋性增强并可能与咬合创伤性口面痛相关     

Anterior thalamic nuclei deep brain stimulation inhibits mossy fiber sprouting via 3′,5′-cyclic adenosine monophosphate/protein kinase A signaling pathway in a chronic epileptic monkey model

BackgroundAnterior thalamic nuclei (ATN) deep brain stimulation (DBS) is an effective method of controlling epilepsy, especially temporal lobe epilepsy. Mossy fiber sprouting (MFS) plays an indispensable role in the pathogenesis and progression of epilepsy, but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown. This study aimed to investigate the effect of ATN-DBS on MFS, as well as potential signaling pathways by a kainic acid (KA)-induced epileptic model.MethodsTwenty-four rhesus monkeys were randomly assigned to control, epilepsy (EP), EP-sham-DBS, and EP-DBS groups. KA was injected to establish the chronic epileptic model. The left ATN was implanted with a DBS lead and stimulated for 8 weeks. Enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus. One-way analysis of variance, followed by the Tukey post hoc correction, was used to analyze the statistical significance of differences among multiple groups.ResultsATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy. The number of ectopic granule cells was reduced in monkeys that received ATN stimulation (P < 0.0001). Levels of 3′,5′-cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the hippocampus, together with Akt phosphorylation, were noticeably reduced in monkeys that received ATN stimulation (P = 0.0030 and P = 0.0001, respectively). ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions (all P < 0.0001).ConclusionATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells, which may be associated with the reduced MFS in chronic epilepsy. The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.     

Ultrasonic characterization of whole cells and isolated nuclei

High frequency ultrasound imaging (20 to 60 MHz) is increasingly being used in small animal imaging, molecular imaging and for the detection of structural changes during cell and tissue death. Ultrasonic tissue characterization techniques were used to measure the speed of sound, attenuation coefficient and integrated backscatter coefficient for (a) acute myeloid leukemia cells and corresponding isolated nuclei, (b) human epithelial kidney cells and corresponding isolated nuclei, (c) multinucleated human epithelial kidney cells and d) human breast cancer cells. The speed of sound for cells varied from 1522 to 1535 m/s, while values for nuclei were lower, ranging from 1493 to 1514 m/s. The attenuation coefficient slopes ranged from 0.0798 to 0.1073 dB mm(-1) MHz(-1) for cells and 0.0408 to 0.0530 dB mm(-1) MHz(-1) for nuclei. Integrated backscatter coefficient values for cells and isolated nuclei showed much greater variation and increased from 1.71 x 10(-4) Sr(-1) mm(-1) for the smallest nuclei to 26.47 x 10(-4) Sr(-1) mm(-1) for the cells with the largest nuclei. The findings suggest that integrated backscatter coefficient values, but not attenuation or speed of sound, are correlated with the size of the nuclei.     

Production of reflex cough by brainstem respiratory networks

Delineation of neural mechanisms involved in reflex cough is essential for understanding its many physiological and clinical complexities, and the development of more desirable antitussive agents. Brainstem networks that generate and modulate the breathing pattern are also involved in producing the motor patterns during reflex cough. Neurones of the ventrolateral medulla respiratory pattern generator mutually interact with neural networks in the pons, medulla and cerebellum to form a larger dynamic network. This paper discusses evidence from our laboratory and others supporting the involvement of the nucleus tractus solitarii, midline raphe nuclei and lateral tegmental field in the medulla, and the pontine respiratory group and cerebellum in the production of reflex cough. Gaps in our knowledge are identified to stimulate further research on this complicated issue.