Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats.

Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a "two-hit" stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.

Reduced motor cortex GABABR function following chronic alcohol exposure.

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors.

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia.

Ataxia, characterized by uncoordinated movement, is often found in patients with cerebellar hemorrhage (CH), leading to long-term disability without effective management. Microglia are among the first responders to CNS insult. Yet the role and mechanism of microglia in cerebellar injury and ataxia after CH are still unknown. Using Ki20227, an inhibitor for colony-stimulating factor 1 receptor which mediates the signaling responsible for the survival of microglia, we determined the impact of microglial depletion on cerebellar injury and ataxia in a murine model of CH. Microglial depletion reduced cerebellar lesion volume and alleviated gait abnormality, motor incoordination, and locomotor dysfunction after CH. Suppression of CH-initiated microglial activation with minocycline ameliorated cerebellum infiltration of monocytes/macrophages, as well as production of proinflammatory cytokines and chemokine C-C motif ligand-2 (CCL-2) that recruits monocytes/macrophages. Furthermore, both minocycline and bindarit, a CCL-2 inhibitor, prevented apoptosis and electrophysiological dysfunction of Purkinje cells, the principal neurons and sole outputs of the cerebellar cortex, and consequently improved ataxia-like motor abnormalities. Our findings suggest a detrimental role of microglia in neuroinflammation and ataxic motor symptoms after CH, and pave a new path to understand the neuroimmune mechanism underlying CH-induced cerebellar ataxia.

[Analysis of adverse reactions of Xianling Gubao preparation based on real world SRS data].

From January 1, 2004 to July 21, 2016 a total of 2 796 cases of adverse drug reaction/adverse event(ADR/AE) after the use of Xianling Gubao Capsules/Tablets were reported by National Adverse Drug Reaction Monitoring Center. The following results were obtained by analyzing the reports of 2 796 cases of adverse drug reactions/adverse drug events after the use of Xianling Gubao Capsules/Tablets. A total of 75 patients, accounting for 2.68% of the total ADR/AE time, had severe ADR/AE events. Among them, 30 patients were aged 65 and above, accounting for 40.00% of the total number of severe ADR/AE patients. All the patients with ADR/AE were aged 45-64 years, which totaled 1 346 cases and took up 48.14% of the total patients with ADR/AE. All of ADR/AE cases and severe ADR/AE cases were orally given Xianling Gubao Capsules/Tablets. Females accounted for 52.50% and 76.00%, respectively, and the proportion of females was significantly higher than that of males. Among patients with a medical history of ADR/AE, severe ADR/AE was higher than the average, accounting for about 1.33%. The proportion of cases orally given 1-3 tablets of Xianling Gubao Capsules/Tablets in all ADR/AE cases and severe ADR/AE cases was 95.32% and 96.00%, which conformed to the usage in the package insert. All ADR/AE cases and severe ADR/AE cases orally given Xianling Gubao Capsules/Tablets twice daily occupied the highest proportions, or 77.00% and 61.00%, respectively. The proportion of severe ADR/AE cases orally given Xianling Gubao Capsules/Tablets was slightly higher than that of all ADR/AE cases in the medication frequency, which didn't conform to the usage in the package insert. All the symptoms of ADR/AE orally given Xianling Gubao Capsules showed many manifestations, and the top 10 symptoms were nausea, rash, itching, stomach dysfunction, vomiting, abdominal pain, dizziness, diarrhea, anaphylaxis, and reflux heartburn. The symptoms of severe ADR/AE after oral administration of Xianling Gubao Capsules were varied, and the top 10 symptoms were abnormal liver function, rash, suffocation, itching, dizziness, vomiting, anaphylaxis, abdominal pain, weakness, and convulsions. Abnormal liver function accounted for 44.12%. All of ADR/AE cases occurred within 2 days after oral administration of Xianling Gubao Capsules/Tablets, accounting for 54.26%. Severe ADR/AE occurred within 2 days after the use of Xianling Gubao Capsules/Tablets, accounting for 25.34%. The proportion of ADR/AE cases occurring within 15 days after oral administration of Xianling Gubao Capsules/Tablets increased again(57.33%). The overall trend contained two peaks.

Paricalcitol alleviates lipopolysaccharide-induced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation.

Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant activated microglia play a pivotal role in the pathogenesis of depression. Paricalcitol (Pari), a vitamin D2 analogue, has been demonstrated to exert anti-inflammative effects on renal and cardiovascular diseases. In this study, mice were pretreated with Pari before being induced to acute depression-like behaviors by systemic lipopolysaccharide (LPS) injection. To determine the therapeutic effects of Pari, alterations in acute body weight, sucrose preference, forced swimming and tail suspension tests were assessed. Then, alterations of pro-inflammation cytokine IL1-ß level and microglia activity in the hypothalamus, which are involved in the pathophysiology of depression, were examined. The results showed that Pari significantly alleviated systemic LPS injection induced depressive-like behaviors as shown by increased sucrose preference and decreased TST and FST immobility. Pari could specifically regulate microglia-mediated neuroinflammation process and local activity of renin-angiotensin system to exert its anti-depressant effects. This study demonstrated a potential for paricalcitol in treating depressive symptoms induced by systemic inflammation, particularly in patients with chronic hypertension.

Histamine H1 Receptor Contributes to Vestibular Compensation.

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.

Presynaptic α2-adrenoceptor modulates glutamatergic synaptic transmission in rat nucleus accumbens in vitro.

The nucleus accumbens (NAc), integrating information from the prefrontal cortex and limbic structures, plays a critical role in reward and emotion regulation. Previous studies have reported that the NAc shell receives direct noradrenergic projections, and activation of α2-adrenoceptor (α2-AR) in the NAc shell decreases the fear or anxiety level of rats. However, the underlying mechanism is still little known. Intriguingly, glutamatergic neurotransmission in the NAc shell is closely related to reward and emotion. Here, using brain slice preparations and whole-cell patch clamp recordings, we examined the effect of activation of α2-AR on glutamatergic neurotransmission in the NAc shell. Perfusing slice with α2-AR selective agonist clonidine (CLON) reduced the evoked excitatory postsynaptic currents (EPSCs) on the NAc shell neurons. This inhibitory effect on AMPA-mediated glutamatergic EPSCs was blocked by the α2-AR selective antagonist yohimbine (YOH). Notably, CLON reduced the frequency but not the amplitude of miniature EPSCs. Furthermore, CLON decreased the first EPSC amplitude but increased the paired-pulse facilitation on the NAc shell neurons, and it did not affect postsynaptic AMPA/NMDA ratio, revealing a presynaptic mechanism of α2-AR-mediated inhibition on glutamatergic transmission. In addition, the modulation on glutamatergic transmission by α2-AR was independent of presynaptic NMDA receptor. These results suggest that noradrenergic afferent inputs may suppress glutamatergic synaptic transmission via presynaptic α2-AR in the NAc shell, and actively participate in rewarding and emotional processes via the NAc.

Excitatory effect of norepinephrine on neurons in the inferior vestibular nucleus and the underlying receptor mechanism.

The central noradrenergic system, originating mainly from the locus coeruleus in the brainstem, plays an important role in many physiological functions, including arousal and attention, learning and memory, anxiety, and nociception. However, little is known about the roles of norepinephrine (NE) in somatic motor control. Therefore, using extracellular recordings on rat brainstem slices and quantitative real-time RT-PCR, we investigate the effect and mechanisms of NE on neuronal activity in the inferior vestibular nucleus (IVN), the largest nucleus in the vestibular nuclear complex, which holds an important position in integration of information signals controlling body posture. Here, we report that NE elicits an excitatory response on IVN neurons in a concentration-dependent manner. Activation of α1 - and ß2 -adrenergic receptors (ARs) induces an increase in firing rate of IVN neurons, whereas activation of α2 -ARs evokes a decrease in firing rate of IVN neurons. Therefore, the excitation induced by NE on IVN neurons is a summation of the excitatory components mediated by coactivation of α1 - and ß2 -ARs and the inhibitory component induced by α2 -ARs. Accordingly, α1 -, α2 -, and ß2 -AR mRNAs are expressed in the IVN. Although ß1 -AR mRNAs are also detected, they are not involved in the direct electrophysiological effect of NE on IVN neurons. All these results demonstrate that NE directly regulates the activity of IVN neurons via α1 -, α2 -, and ß2 -ARs and suggest that the central noradrenergic system may actively participate in IVN-mediated vestibular reflexes and postural control. © 2016 Wiley Periodicals, Inc.

Na(+) -Ca(2+) Exchanger, Leak K(+) Channel and Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Comediate the Histamine-Induced Excitation on Rat Inferior Vestibular Nucleus Neurons.

AIMS: Antihistaminergic drugs have traditionally been used to treat vestibular disorders in the clinic. As a potential central target for antihistaminergic drugs, the inferior vestibular nucleus (IVN) is the largest subnucleus of the central vestibular nuclear complex and is considered responsible for vestibular-autonomic responses and integration of vestibular, cerebellar, and multisensory signals. However, the role of histamine on the IVN, particularly the underlying mechanisms, is still not clear. METHODS: Using whole-cell patch-clamp recordings on rat brain slices, histamine-induced effect on IVN neurons and the underlying receptor and ionic mechanisms were investigated. RESULTS: We found that histamine remarkably depolarized both spontaneous firing neurons and silent neurons in IVN via both histamine H1 and histamine H2 receptors. Furthermore, Na(+) -Ca(2+) exchangers (NCXs) and background leak K(+) channels linked to H1 receptors and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to H2 receptors comediate the histamine-induced depolarization on IVN neurons. CONCLUSION: These results demonstrate the multiple ionic mechanisms underlying the excitatory modulation of histamine/central histaminergic system on IVN neurons and the related vestibular reflexes and functions. The findings also suggest potential targets for the treatment of vestibular disorders in the clinic, at the level of ionic channels in central vestibular nuclei.

[Common clinical medical combinations with Shenfu injection based on 25 704 electronic medical records].

Shenfu injection is a common clinical medicine. To explore the common clinical medical combinations with Shenfu injection the real world, 25 704 patients who used Shenfu injection were selected from the hospital information system (HIS) database established by Clinical and Basic Research Institute for Traditional Chinese Medicine of China Academy of Chinese Medical Sciences. The association rules were applied in a correlation analysis on common medical combinations with Shenfu injection in the patients. According to the findings, when Shenfu injection was combined with a single medicine in clinic, the ratio of using Omeprazole, Lidocaine or Furosemide were respectively 22.19%, 20.32%, 19.61%; when Shenfu injection was combined with two medicines, the top three medical combinations were respectively midazolam + omeprazole (11.01%), lidocaine + omeprazole (10.8%) and propofol + midazolam (10.76%); when Shenfu injection was combined with three medicines, the top three medical combinations were respectively propofol + fentany + midazolam (8.83%), remifentanil + propofol + midazolam (8.77% ) and propofol + midazolam + omeprazole (8.77%). According to the further analysis, the combination of Shenfu injection and Propofol + Fentany + Midazolam may reduce the incidence of hypotension and bradycardia during anesthesia, accelerate recovery after anesthesia and relieve the synergistic effect after anesthesia. The combination of Shenfu injection and furosemide may show the synergistic effect in treating the acute left ventricular failure by reducing the returned blood volume and increasing the myocardial contractile force and vitality. The combination of Shenfu injection and Omeprazole may play the synergistic effect in shortening the digestive tract ulcer healing time, reducing the ulcer recurrence and preventing hemorrhagic shock and stress ulcer caused by shock in treating ulcer hemorrhage.

Postsynaptic mechanisms underlying the excitatory action of histamine on medial vestibular nucleus neurons in rats.

BACKGROUND AND PURPOSE: Anti-histaminergic drugs have been widely used in the clinical treatment of vestibular disorders and most studies concentrate on their presynaptic actions. The present study investigated the postsynaptic effect of histamine on medial vestibular nucleus (MVN) neurons and the underlying mechanisms. EXPERIMENTAL APPROACH: Histamine-induced postsynaptic actions on MVN neurons and the corresponding receptor and ionic mechanisms were detected by whole-cell patch-clamp recordings on rat brain slices. The distribution of postsynaptic histamine H1, H2 and H4 receptors was mapped by double and single immunostaining. Furthermore, the expression of mRNAs for H1, H2 and H4 receptors and for subtypes of Na⁺ -Ca²âº exchangers (NCXs) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels was assessed by quantitative real-time RT-PCR. KEY RESULTS: A marked postsynaptic excitatory effect, co-mediated by histamine H1 and H2 receptors, was involved in the histamine-induced depolarization of MVN neurons. Postsynaptic H1 and H2 rather than H4 receptors were co-localized in the same MVN neurons. NCXs contributed to the inward current mediated by H1 receptors, whereas HCN channels were responsible for excitation induced by activation of H2 receptors. Moreover, NCX1 and NCX3 rather than NCX2, and HCN1 rather than HCN2-4 mRNAs, were abundantly expressed in MVN. CONCLUSION AND IMPLICATIONS: NCXs coupled to H1 receptors and HCN channels linked to H2 receptors co-mediate the strong postsynaptic excitatory action of histamine on MVN neurons. These results highlight an active role of postsynaptic mechanisms in the modulation by central histaminergic systems of vestibular functions and suggest potential targets for clinical treatment of vestibular disorders.

Histamine excites neurons of the inferior vestibular nucleus in rats by activation of H1 and H2 receptors.

By using brain slice preparations and extracellular recordings, the effect of histamine on spontaneous firing activities of neurons in the inferior vestibular nucleus (IVN), a key structure responsible for integration of vestibular, multisensory, and cerebellar inputs, in rats was investigated. Perfusing slices with histamine (1-10µM) elicited an excitatory response on IVN neurons. The responses were not blocked by low Ca(2+)/high Mg(2+) medium, indicating a direct postsynaptic effect of the amine. Furthermore, the histamine-induced excitation was partially blocked by selective histamine H1 receptor antagonist mepyramine (1µM) and H2 receptor antagonist ranitidine (1µM), respectively. Co-application of mepyramine and ranitidine nearly totally antagonized the histamine-induced excitation. Additionally, both selective H1 receptor agonist 2-pyridylethylamine (30-300µM) and H2 receptor agonist dimaprit (10-100µM) effectively mimicked the excitatory action of histamine on IVN neurons. Moreover, selective H4 antagonist JNJ7777120 (10µM) and agonist VUF8430 (30-300µM) had no effect on IVN neurons. These results demonstrate that histamine excites IVN neurons via postsynaptic H1 and H2 rather than H4 receptors, and suggest that the central histaminergic system actively modulate all four major vestibular nuclei including the IVN and may subsequently influence the vestibular nuclei-related reflexes and functions.