Geraniol enhances inhibitory inputs to the paraventricular thalamic nucleus and induces sedation in mice.

BACKGROUND: Plant extracts with sedative effects have a long history of clinical use for treating insomnia and epilepsy. Geraniol (GE), a plant-derived acyclic monoterpene, reduces locomotion and prolongs barbiturate-induced anesthesia in rats. However, the mechanisms of GE in sedation remain elusive. PURPOSE: This study aimed to investigate the mechanisms of GE in sedation in mice. METHODS: GE was administered systemically by nebulization and intraperitoneal injection. Open field tests, acute seizure tests, and electroencephalogram (EEG) recordings were performed to examine the sedative effects of GE in mice. The time of loss of the righting reflex and return of the righting reflex were recorded in anesthesia experiments to examine the effect of GE on anesthesia. In vitro c-Fos staining and in vivo fiber photometry recordings were performed to detect the activity change of the paraventricular thalamic nucleus (PVT). Microinjection of GE into PVT and related behavioral tests were performed to confirm that PVT was a critical target for GE. Whole-cell recordings were performed to dissect the effects of GE on PVT neurons via GABAA receptors. Molecular docking was performed to examine the interaction between GE and GABAA receptor subunits. RESULTS: We found that GE reduced locomotion, relieved acute seizures, altered the EEG, and facilitated general anesthesia in mice. Next, we found that GE decreased c-Fos expression and suppressed the calcium activity in PVT. Microinjection of GE into PVT reduced locomotion and facilitated anesthesia. Furthermore, electrophysiology results showed that GE induced dramatic membrane hyperpolarization and suppressed the activity of PVT neurons, mainly by prolonging spontaneous inhibitory postsynaptic currents and inducing tonic inhibitory currents. Molecular docking results indicated that the ß3 subunit might be a potential target for GE. CONCLUSION: By combined using behavioral tests, immunohistochemistry, calcium recording, and electrophysiology, we systematically revealed that GE inhibits PVT and induces sedation in mice. Essential oils have long been considered part of traditional medicine, and they are playing a critical role in aromatherapy. Since GE has a comparatively ideal safety property and multiple delivery methods, GE has great application potential in aromatherapy. Our study also provides a potential candidate for further development of sedatives and anaesthetics.

Modulation of itch and pain signals processing in ventrobasal thalamus by thalamic reticular nucleus.

Thalamic reticular nucleus (TRN) is known to be crucial for dynamically modulating sensory processing. Recently, the functional role of TRN in itch and pain sensation processing has drawn much attention. We found that ventrobasal thalamus (VB) neurons exhibited scratching behavior-related and nociceptive behavior-related neuronal activity changes, and most of VB neurons responsive to pruritic stimulus were also activated by nociceptive stimulus. Inhibition of VB could relieve itch-induced scratching behaviors and pathological pain without affecting basal nociceptive thresholds, and activation of VB could facilitate scratching behaviors. Tracing and electrophysiology recording results showed that VB mainly received inhibitory inputs from ventral TRN. Furthermore, optogenetic activation of TRN-VB projections suppressed scratching behaviors, and ablation of TRN enhanced scratching behaviors. In addition, activation of TRN-VB projections relieved the pathological pain without affecting basal nociceptive thresholds. Thus, our study indicates that TRN modulates itch and pain signals processing via TRN-VB inhibitory projections.

PBN-PVT projections modulate negative affective states in mice.

Long-lasting negative affections dampen enthusiasm for life, and dealing with negative affective states is essential for individual survival. The parabrachial nucleus (PBN) and thalamic paraventricular nucleus (PVT) are critical for modulating affective states in mice. However, the functional roles of PBN-PVT projections in modulating affective states remain elusive. Here, we show that PBN neurons send dense projection fibers to the PVT and form direct excitatory synapses with PVT neurons. Activation of the PBN-PVT pathway induces robust behaviors associated with negative affective states without affecting nociceptive behaviors. Inhibition of the PBN-PVT pathway reduces aversion-like and fear-like behaviors. Furthermore, the PVT neurons innervated by the PBN are activated by aversive stimulation, and activation of PBN-PVT projections enhances the neuronal activity of PVT neurons in response to the aversive stimulus. Consistently, activation of PVT neurons that received PBN-PVT projections induces anxiety-like behaviors. Thus, our study indicates that PBN-PVT projections modulate negative affective states in mice.

Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions.

It is well known that affective and pleasant touch promotes individual well-being and facilitates affiliative social communication, although the neural circuit that mediates this process is largely unknown. Here, we show that social-touch-like tactile stimulation (ST) enhances firing of oxytocin neurons in the mouse paraventricular hypothalamus (PVH) and promotes social interactions and positively reinforcing place preference. These results link pleasant somatosensory stimulation to increased social interactions and positive affective valence. We further show that tachykinin 1 (Tac1+) neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) send monosynaptic excitatory projections to PVH oxytocin neurons. Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing. Together, these results identify a dipeptidergic pathway from l/vlPAG Tac1+ neurons to PVH oxytocin neurons, through which pleasant sensory experience promotes social behavior.

Norepinephrine modulates wakefulness via α1 adrenoceptors in paraventricular thalamic nucleus.

Norepinephrine (NE) neurons in the locus coeruleus (LC) play key roles in modulating sleep and wakefulness. Recent studies have revealed that the paraventricular thalamic nucleus (PVT) is a critical wakefulness-controlling nucleus in mice. However, the effects of NE on PVT neurons remain largely unknown. Here, we investigated the mechanisms of NE modulating wakefulness in the PVT by using viral tracing, behavioral tests, slice electrophysiology, and optogenetics techniques. We found that the PVT-projecting LC neurons had few collateral projections to other brain nuclei. Behavioral tests showed that specific activation of the LC-PVT projections or microinjection of NE into the PVT accelerated emergence from general anesthesia and enhanced locomotion activity. Moreover, brain slice recording results indicated that NE increased the activity of the PVT neurons mainly by increasing the frequency of spontaneous excitatory postsynaptic currents via α1 adrenoceptors. Thus, our results demonstrate that NE modulates wakefulness via α1 adrenoceptors in the PVT.

Temporal changes in Egr-1 and c-fos expression in rat models of myocardial ischemia.

BACKGROUND: The pathological diagnosis of sudden cardiac death caused by myocardial ischemia is a difficult problem. Relevant evidence shows that the expression of Egr-1 and c-fos undergo changes in the early stage of myocardial ischemia, but the detailed temporal variation of them is not clear. Therefore, the aim of this study was to observe the temporal changes in mRNA and protein expression of Egr-1 and c-fos in ischemic myocardium in rats. METHODS: Sixty-six Sprague-Dawley rats were divided into the control group, the early myocardial ischemia (EMI) group, the sham operated group and the allergy group. The EMI rats were further divided into eight subgroups according to the different time points (30 min and 1, 2, 4, 8, 12, 24, and 48 h) after modeling. The mRNA and protein of Egr-1 and c-fos of each group were detected by real-time quantitative polymerase chain reaction and immunohistochemistry, respectively. RESULTS: In the EMI group, Egr-1 mRNA in ischemic myocardium rose 30 min after ischemia and peaked at 2 h; the plateau was maintained up to 8 h after ischemia, and then returned to the baseline level at 12 h. The c-fos mRNA in ischemic myocardium demonstrated a consistent changing curve with that of Egr-1. The mRNA of Egr-1 and c-fos showed no significant changes in the control group, the sham operated group and the allergy group. Immunohistochemistry showed that Egr-1 protein in the myocardial ischemic area was slightly positive 30 min after ischemia, and then strongly positive at 4 and 8 h, decreased at 12 h, and was negative at 24 h. The changing trends of c-fos protein were almost the same as that of Egr-1. Immunohistochemistry of Egr-1 and c-fos protein were all negative in the control group, the sham operated group and the allergy group. CONCLUSIONS: The mRNA and protein expression of Egr-1 and c-fos presented rapid and temporal changes after myocardial ischemia, and this may be helpful in distinguishing sudden death induced by myocardial ischemia from that of allergy.

Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs.

Spinal gastrin-releasing peptide receptor-expressing (GRPR+) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR+ neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR+ neurons. We found that spinal galanin+ GABAergic neurons form inhibitory synapses with GRPR+ neurons in the spinal cord and play an important role in gating the GRPR+ neuron-dependent itch signaling pathway. Spinal GRPR+ neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR+ neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs could play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR+ neurons.

Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation.

Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.

Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus.

Serotonergic neurons play key roles in various biological processes. However, circuit mechanisms underlying tight control of serotonergic neurons remain largely unknown. Here, we systematically investigated the organization of long-range synaptic inputs to serotonergic neurons and GABAergic neurons in the dorsal raphe nucleus (DRN) of mice with a combination of viral tracing, slice electrophysiological, and optogenetic techniques. We found that DRN serotonergic neurons and GABAergic neurons receive largely comparable synaptic inputs from six major upstream brain areas. Upon further analysis of the fine functional circuit structures, we found both bilateral and ipsilateral patterns of topographic connectivity in the DRN for the axons from different inputs. Moreover, the upstream brain areas were found to bidirectionally control the activity of DRN serotonergic neurons by recruiting feedforward inhibition or via a push-pull mechanism. Our study provides a framework for further deciphering the functional roles of long-range circuits controlling the activity of serotonergic neurons in the DRN.

[Methods of detector response function establishment in X-ray fluorescence spectra analysis].

During the measurement and analysis process of X-ray fluorescence spectra, it is very helpful to improve the analyze speed, accuracy and automaticity of X-ray fluorescence spectra analysis by establishing detector response function(DRF), which represents the shape of full energy peak and can provide former basic data for subsequent X-ray analysis technique. For the theory and model of semiconductor DRF in X-ray energy spectrum measurements, methods of three typical detector response function model establishment, key parameters of full energy peak standard deviation and Fano factor calculation, etc. are discussed, and meanwhile, the summarization and contrast of existing studies are shown in this paper. Finally, the suggestion for modeling methods of DRF in X-ray fluorescence spectra measurements is provided.

[Effect of jingui shenqi pill on pituitary adrenocorticotropic hormone gene expression in shen-yang deficiency rats].

OBJECTIVE: To explore the effect of Jingui Shenqi pill (JGSQP) with various concentrations at different time points on pituitary adrencorticotropic hormone (ACTH) gene expression level in Shen-Yang deficiency rats. METHODS: The Shen-Yang deficiency rats were randomly divided into the model control group and the high, medium and low dosage of JGSQP groups. Reverse transcriptase polymerase chain reaction was used to observe the effect of JGSQP on the ACTH mRNA of pituitary tissue in rats treated at different time points (10 d, 20 d, 30 d). RESULTS: As compared with that in the model group, the ACTH gene expression level was significantly higher in the high dose JGSQP group (P < 0.05), and the increment in the medium dosage group was significantly higher in comparing with that in the high and low dosage groups (P < 0.05 or P < 0.01). CONCLUSION: Through up-regulation on ACTH gene expression is possibly one of the mechanisms of JGSQP in treating Shen-Yang deficiency.