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Sleep-promoting functions of the hypothalamic median preoptic nucleus: inhibition of arousal systems. McGinty D,Gong H,Suntsova N,Alam Md N,Methippara M,Guzman-Marin R,Szymusiak R Archives italiennes de biologie Recent work supports the hypotheses developed by von Economo and Nauta and elaborated by Sallanon et al. that the POA contains a sleep-promoting output that opposes wake-promoting neuronal groups in the PH. The POA gives rise to descending pathways that terminate within wake-promoting populations in pLH, PH and midbrain. Current evidence suggests that this output originates in POA sleep-active GABAergic neurons. This output also seems to convey the signals of homeostatic drive. Disynaptic projections from the SCN to both MnPN and VLPO were recently identified. These may regulate the circadian control of sleep propensity. The hypothesis that the descending projections from POA sleep-active neurons to sites of arousal-related neurons originates in GABAergic neurons must be confirmed. Also to be further clarified is the anatomical distribution of putative sleep-active GABAergic neurons within the POA. Segregated groups have been found in the MnPN and VLPO, but unit recording studies of sleep-active neurons, lesion studies and local neurochemical application studies all indicate that sleep-active neurons may be found diffusely in the POA and adjacent areas. The MnPN has been shown previously to be involved in water balance and blood pressure regulation and to be responsive to hyperthermia. Our studies suggest that this nucleus also contains sleep-active, putative sleep-promoting neurons. However, interactions between sleep control and physiological variables must be considered. In particular, the details of neuronal basis of the coupling of warm-sensitive neurons in MnPN to the POA hypnogenic output has not been explored. It is also worth noting that both the VLPO and MnPN lie close to the ventricular and subarachnoid surface and are punctuated by radial arterioles. The possibility that the sleep-regulatory functions of these sites is coupled to physiological signals conveyed through epithelial cells has been suggested for the actions of PGD2 but has yet to be explored in detail for other putative hypnogens.
gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. Lancel M,Langebartels A The Journal of pharmacology and experimental therapeutics Many hypnotics, such as benzodiazepines, are agonistic modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. Such compounds increase the ability to fall and stay asleep, but inhibit rapid-eye movement (REM) sleep and deep non-REM sleep. However, tolerance to their hypnotic action may develop rapidly. Previous findings in rats and humans demonstrate that the gamma-aminobutyric acid(A) agonist 4, 5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) promotes deep non-REM sleep and increases non-REM sleep continuity. To investigate the effects of repeated administration, we assessed sleep in rats before, during, and after chronic dosing of THIP (3 mg/kg, once daily for 5 days; n = 9) or of placebo (n = 8). The substances were administered i.p. at the onset of darkness. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 h after injection. During baseline recording, the placebo and the THIP group exhibited similar sleep patterns. After the first THIP injection, rats displayed more non-REM sleep, longer non-REM episodes, and higher levels of slow wave activity in the EEG within non-REM sleep than the placebo group rats. The effects were sustained during all treatment days. REM sleep was not affected. After drug withdrawal, the sleep patterns of the THIP and the placebo group were practically identical again. These observations suggest that THIP does not rapidly produce tolerance toward its sleep effects and abrupt drug withdrawal may not be associated with sleep disturbances. These findings confirm and extend the existing information suggesting that THIP may be promising for treatment of insomnia.
Ultrasonic neuromodulation. Naor Omer,Krupa Steve,Shoham Shy Journal of neural engineering Ultrasonic waves can be non-invasively steered and focused into mm-scale regions across the human body and brain, and their application in generating controlled artificial modulation of neuronal activity could therefore potentially have profound implications for neural science and engineering. Ultrasonic neuro-modulation phenomena were experimentally observed and studied for nearly a century, with recent discoveries on direct neural excitation and suppression sparking a new wave of investigations in models ranging from rodents to humans. In this paper we review the physics, engineering and scientific aspects of ultrasonic fields, their control in both space and time, and their effect on neuronal activity, including a survey of both the field's foundational history and of recent findings. We describe key constraints encountered in this field, as well as key engineering systems developed to surmount them. In closing, the state of the art is discussed, with an emphasis on emerging research and clinical directions. 10.1088/1741-2560/13/3/031003
A review of low-intensity focused ultrasound pulsation. Bystritsky Alexander,Korb Alex S,Douglas Pamela K,Cohen Mark S,Melega William P,Mulgaonkar Amit P,DeSalles Antonio,Min Byoung-Kyong,Yoo Seung-Schik Brain stimulation With the recent approval by the Food and Drug Administration (FDA) of Deep Brain Stimulation (DBS) for Parkinson's Disease, dystonia and obsessive compulsive disorder (OCD), vagus nerve stimulation (VNS) for epilepsy and depression, and repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression, neuromodulation has become increasingly relevant to clinical research. However, these techniques have significant drawbacks (eg, lack of special specificity and depth for the rTMS, and invasiveness and cumbersome maintenance for DBS). This article reviews the background, rationale, and pilot studies to date, using a new brain stimulation method-low-intensity focused ultrasound pulsation (LIFUP). The ability of ultrasound to be focused noninvasively through the skull anywhere within the brain, together with concurrent imaging (ie, functional magnetic resonance imaging [fMRI]) techniques, may create a role for research and clinical use of LIFUP. This technique is still in preclinical testing and needs to be assessed thoroughly before being advanced to clinical trials. In this study, we review over 50 years of research data on the use of focused ultrasound (FUS) in neuronal tissue and live brain, and propose novel applications of this noninvasive neuromodulation method. 10.1016/j.brs.2011.03.007
Effect of operative trauma and multiple propofol anesthesia on neurodevelopment and cognitive function in developmental rats. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences To investigate the effect of multiple propofol anesthesia and operative trauma on neuroinflammation and cognitive function in development rats and its mechanism. A total of 104 13-day-old neonatal Sprague-Dawley rats were randomly divided into 4 groups with 26 rats in each group: control group was treated with saline q.d for propofol group was treated with propofol q.d for surgery group received abdominal surgery under local anesthesia and then treated with saline q.d for surgery with propofol group received propofol anesthesia plus abdominal surgery under local anesthesia with ropivacaine at d1, then treated with propofol q.d for At d2 of experiment, 13 rats from each group were sacrificed and brain tissue samples were taken, the concentration of TNF-α in hippocampus was detected with ELISA, the expression of caspase-3 and c-fos in hippocampal tissue was determined with immunohistochemical method, the number of apoptotic neurons in hippocampus was examined with TUNEL assay. Morris water maze test was used to examine the cognitive function of the rest rats at the age of 60 d, and the TNF-α concentration, caspase-3, c-fos expressions and the number of apoptotic neurons in hippocampus were also detected. Compared with control group, TNF-α concentration, caspase-3, c-fos expression and the neuroapoptosis in hippocampus increased significantly in other three groups (all <0.05). Compared with surgery group, propofol group and surgery with propofol group showed increased TNF-α level, caspase-3 and c-fos expressions and apoptotic cell numbers (all <0.05), but there was no significant difference between last two groups (all >0.05). Morris water maze test showed that there were no significant differences in swimming speed, escape latency, target quadrant residence time and crossing times among groups (all >0.05). TNF-α level, expressions of caspase-3 and c-fos and apoptotic cell numbers in hippocampus had no significant differences among the 4 adult rats groups (all >0.05). Abdominal surgery and multiple propofol treatment can induce neuroinflammation and neuroapoptosis in hippocampus of neonatal rats, however, which may not cause adverse effects on neurodevelopment and cognitive function when they grown up. 10.3724/zdxbyxb-2021-0004
Brain activity complexity has a nonlinear relation to the level of propofol sedation. Boncompte Gonzalo,Medel Vicente,Cortínez Luis I,Ossandón Tomás British journal of anaesthesia BACKGROUND:Brain activity complexity is a promising correlate of states of consciousness. Previous studies have shown higher complexity for awake compared with deep anaesthesia states. However, little attention has been paid to complexity in intermediate states of sedation. METHODS:We analysed the Lempel-Ziv complexity of EEG signals from subjects undergoing moderate propofol sedation, from an open access database, and related it to behavioural performance as a continuous marker of the level of sedation and to plasma propofol concentrations. We explored its relation to spectral properties, to propofol susceptibility, and its topographical distribution. RESULTS:Subjects who retained behavioural performance despite propofol sedation showed increased brain activity complexity compared with baseline (M=13.9%, 95% confidence interval=7.5-20.3). This was not the case for subjects who lost behavioural performance. The increase was most prominent in frontal electrodes, and correlated with behavioural performance and propofol susceptibility. This effect was positively correlated with high-frequency activity. However, abolishing specific frequency ranges (e.g. alpha or gamma) did not reduce the propofol-induced increase in Lempel-Ziv complexity. CONCLUSIONS:Brain activity complexity can increase in response to propofol, particularly during low-dose sedation. Propofol-mediated Lempel-Ziv complexity increase was independent of frequency-specific spectral power manipulations, and most prominent in frontal areas. Taken together, these results advance our understanding of brain activity complexity and anaesthetics. They do not support models of consciousness that propose a direct relation between brain activity complexity and states of consciousness. 10.1016/j.bja.2021.04.023
The effect of anesthetic dose on the motor response induced by low-intensity pulsed ultrasound stimulation. Yuan Yi,Wang Xingran,Yan Jiaqing,Li Xiaoli BMC neuroscience BACKGROUND:Low-intensity pulsed ultrasound stimulation (LIPUS) has been proven to be a noninvasive method with high spatial resolution and deep penetration. Previous studies have qualitatively demonstrated that the electromyographic response caused by LIPUS in the mouse motor cortex is affected by the anesthetic state of the mice. However, the quantitative relationship between motor response and anesthetic dose remains unclear. RESULTS:Experimental results show that the success rate decreases stepwise as the isoflurane concentration/mouse weight ratio increases (ratios: [0.004%/g, 0.01%/g], success rate: ~ 90%; [0.012%/g, 0.014%/g], ~ 40%; [0.016%/g, 0.018%/g], ~ 7%; 0.024%/g, 0). The latency and duration of EMG increase significantly when the ratio is more than 0.016%/g. Compared with that at ratios from 0.004 to 0.016%/g, normalized EMG amplitude decreases significantly at ratios of 0.018%/g and 0.020%/g. CONCLUSIONS:Quantitative calculations indicate that the anesthetic dose has a significant regulatory effect on the motor response of mice during LIPUS. Our results have guiding significance for the selection of the anesthetic dose for LIPUS in mouse motor cortex experiments. 10.1186/s12868-018-0476-2
The Effect of Low-Intensity Transcranial Ultrasound Stimulation on Neural Oscillation and Hemodynamics in the Mouse Visual Cortex Depends on Anesthesia Level and Ultrasound Intensity. Yuan Yi,Zhang Kaiqing,Zhang Yiyao,Yan Jiaqing,Wang Zhijie,Wang Xingrang,Liu Mengyang,Li Xiaoli IEEE transactions on bio-medical engineering OBJECTIVE:Low-intensity transcranial ultrasound stimulation (TUS) can induce motor responses, neural oscillation and hemodynamic responses. Early studies demonstrated that the motor responses evoked by TUS critically depend on anesthesia levels and ultrasound intensity. However, the neural mechanism of how anesthesia levels and ultrasound intensity influence on brain responses during TUS has never been explored yet. To investigate this question, we applied different anesthesia levels and ultrasound intensities on the visual cortex of mouse and observed neural oscillation change and hemodynamic responses during TUS. METHODS:low-intensity ultrasound was delivered to mouse visual cortex under different anesthesia levels, and simultaneous recordings for local field potentials (LFPs) and hemodynamic responses were carried out to measure and analyze the changes quantitatively. RESULTS:(i) The change of mean amplitude and mean relative power of sharp wave-ripple (SPW-R) in LFPs induced by TUS decreased as the anesthesia level increased (from awake to 1.5% isoflurane). (ii) The hemodynamic response level induced by TUS decreased as the anesthesia level increased (from awake to1.5% isoflurane). (iii) The coupling strength between neural activities and hemodynamic responses was dependent on anesthesia level. (iv) The neural activities and hemodynamic responses increase as a function of ultrasound intensity. CONCLUSION:These results support that the neural activities and hemodynamic response of the mouse visual cortex induced by TUS are related to the anesthesia level and ultrasound intensity. SIGNIFICANCE:This finding suggests that careful maintenance of anesthesia level and ultrasound intensity is required to acquire accurate LFP and hemodynamic data from samples with TUS. 10.1109/TBME.2021.3050797
Pharmaco-fUS: Quantification of pharmacologically-induced dynamic changes in brain perfusion and connectivity by functional ultrasound imaging in awake mice. Rabut Claire,Ferrier Jérémy,Bertolo Adrien,Osmanski Bruno,Mousset Xavier,Pezet Sophie,Deffieux Thomas,Lenkei Zsolt,Tanter Mickaël NeuroImage There is a critical need for reliable quantitative biomarkers to assess functional brain alterations in mouse models of neuropsychiatric diseases, but current imaging methods measuring drug effects through the neurovascular coupling, face issues including poor sensitivity, drug-induced changes in global brain perfusion and the effects of anesthesia. Here we demonstrate the proof-of-concept of a minimally-invasive fUS imaging approach to detect the acute cholinergic modulatory effects of Scopolamine (ScoP) on functional brain connectivity in awake and behaving mice, through the intact skull. A machine-learning algorithm constructed an ad-hoc pharmacological score from the ScoP-induced changes in connectivity patterns of five mice. The discrimination model shows important ScoP-induced increase of the hippocampo-cortical connectivity. The pharmacological score led to robust discrimination of ScoP treatment from baseline in an independent dataset and showed, in another independent group, dose-dependent specific effects of central cholinergic modulation of functional connectivity, independent from global brain perfusion changes. In conclusion, we introduce pharmaco-fUS as a simple, robust, specific and sensitive modality to monitor drug effects on perfusion and functional connectivity in the awake mouse brain. 10.1016/j.neuroimage.2020.117231