Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval.

Stressful life events induce abnormalities in emotional and cognitive behaviour. The endogenous opioid system plays an essential role in stress adaptation and coping strategies. In particular, the µ-opioid receptor (µR), one of the major opioid receptors, strongly influences memory processing in that alterations in µR signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether µR signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective µR depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal µR signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal µRs were significantly activated during acute stress. Blockage of hippocampal µRs, non-selective deletion of µRs or selective deletion of µRs on GABAergic neurons (µRGABA) reversed EP-stress-induced impairment of memory retrieval, with no effect on the elevation of serum corticosterone after stress. Electrophysiological results demonstrated that stress depressed hippocampal GABAergic synaptic transmission to CA1 pyramidal neurons, thereby leading to excitation/inhibition (E/I) imbalance in a µRGABA-dependent manner. Pharmaceutically enhancing hippocampal GABAA receptor-mediated inhibitory currents in stressed mice restored their memory retrieval, whereas inhibiting those currents in the unstressed mice mimicked the stress-induced impairment of memory retrieval. Our findings reveal a novel pathway in which endogenous opioids recruited by acute stress predominantly activate µRGABA to depress GABAergic inhibitory effects on CA1 pyramidal neurons, which subsequently alters the E/I balance in the hippocampus and results in impairment of memory retrieval.

Dopamine inhibits high-frequency stimulation-induced long-term potentiation of intrinsic excitability in CA1 hippocampal pyramidal neurons.

The efficiency of neural circuits is modified by changes not only in synaptic strength, but also in intrinsic excitability of neurons. In CA1 hippocampal pyramidal neurons, bidirectional changes in the intrinsic excitability are often presented after induction of synaptic long-term potentiation or depression. This plasticity of intrinsic excitability has been identified as a cellular correlate of learning. Besides, behavioral learning often involves action of reinforcement or rewarding mediated by dopamine (DA). Here, we examined how DA influences the intrinsic plasticity of CA1 hippocampal pyramidal neurons when high-frequency stimulation (HFS) was applied to Schaffer collaterals. The results showed that DA inhibits the decrease in rheobase and increase in mean firing rate of pyramidal neurons induced by HFS, and that this inhibition was abolished by the D1-like receptor antagonist SCH23390 but not by the D2-like receptor antagonist sulpiride. The results suggest that DA inhibits the potentiation of excitability induced by presynaptic HFS, and that this inhibition depends on the activation of D1-like receptors.

[High-frequency stimulation on cell soma induces potentiation of intrinsic excitability in VTA dopaminergic neurons].

Ventral tegmental area (VTA) is an important relay station of signal transmission in the reward system. The plasticity of VTA dopaminergic neurons directly influences actions of other regions of the reward system. Studies concerning the plasticity of VTA dopaminergic neurons focus mainly on synaptic plasticity, while much less attention has been given to the plasticity of intrinsic excitability of the neurons. The aim of the present study was to investigate the effect of high-frequency stimulation (HFS) on the plasticity of excitability of VTA neuron. Whole-cell patch-clamping was performed on VTA dopaminergic neurons in midbrain slices bathed with PTX, AP-5 and CNQX, and HFS was introduced to cell soma. The result showed that, after HFS induction the pharmacologically isolated neurons showed increased input resistance and firing frequency, as well as decreased rheobase. Meanwhile, the steady-state whole-cell current decreased, and the hyperpolarization-activated current (I(h)) decreased. These results suggest that HFS on soma induces a long-term potentiation of excitability in VTA dopaminergic neurons, and the underlying mechanism involves the changes of membrane current.

[Repeated morphine pretreatment reduces glutamatergic synaptic potentiation in the nucleus accumbens induced by acute morphine exposure].

Repeated exposure to morphine leads to the addiction, which influences its clinical application seriously. The glutamatergic projection from prefrontal cortex (PFC) to the nucleus accumbens (NAc) plays an important role in rewarding effects. It is still unknown whether morphine exposure changes PFC-NAc synaptic transmission. To address this question, in vivo field excitatory postsynaptic potentials (fEPSPs) induced by electric stimulating PFC-NAc projection fibers were recorded to evaluate the effect of acute morphine exposure (10 mg/kg, s.c.) on glutamatergic synaptic transmission in NAc shell of repeated saline/morphine pretreated rats. It was showed that acute morphine exposure enhanced fEPSP amplitude and reduced paired-pulse ratio (PPR) in saline pretreated rats, which could be reversed by following naloxone injection (1 mg/kg, i.p.), an opiate receptor antagonist. However, repeated morphine pretreatment significantly inhibited both the enhancement of fEPSP amplitude and reduction of PPR induced by acute morphine exposure. Those results indicate that the initial morphine exposure enhances PFC-NAc synaptic transmission by pre-synaptic mechanisms, whereas morphine pretreatment occludes this effect.

[The influence of L-glutamate and carbachol on burst firing of dopaminergic neurons in ventral tegmental area].

Burst firing of dopaminergic neurons in ventral tegmental area (VTA) induces a large transient increase in synaptic dopamine (DA) release and thus is considered the reward-related signal. But the mechanisms of burst generation of dopaminergic neuron still remain unclear. This experiment investigated the burst firing of VTA dopaminergic neurons in rat midbrain slices perfused with carbachol and L-glutamate individually or simultaneously to understand the neurotransmitter mechanism underlying burst generation. The results showed that bath application of carbachol (10 µmol/L) and pulse application of L-glutamate (3 mmol/L) both induced burst firing in dopaminergic neuron. Co-application of carbachol and L-glutamate induced burst firing in VTA dopaminergic cells which couldn't be induced to burst by the two chemicals separately. The result indicates that carbachol and L-glutamate co-regulate burst firing of dopaminergic neuron.

[The modulation of 4-aminopyridine sensitive potassium channel to bifurcation scenario of the spontaneous neural firing rhythms].

Neuronal firing is crucial to the information processing in the nervous system. In order to make a further study of bifurcation scenarios, experiments were performed on neural pacemakers formed at the injured site of rat sciatic nerve subjected to chronic ligatures. We chose the conductance of voltage-dependent potassium ion channels as conditional parameter, and the extracellular calcium concentration as bifurcation parameter, to give a demonstration of how the firing pattern of neural pacemaker responses to dual parameter adjusting. Among 28 preparations observed, 21 were insensitive to dual parameter adjusting since no change of bifurcation scenario structure was detected. On the contrary, the residual 7 preparations showed dramatic bifurcation scenario shifting corresponding to different dual parameter configuration. Briefly, when concentration of 4-aminopyridine (4-AP), a voltage-dependent potassium ion channels blocker, was kept at different level and extracellular Ca2+ concentration was decreased gradually, different bifurcation scenarios of firing patterns were exhibited in an identical neural pacemaker. The two-parameter bifurcation scenarios of experimental neural pacemaker with different parameter configuration were also different. The results show that neural firing pattern is different when the parameter configuration is different, and the bifurcation scenario is a fundamental framework to identify the transitions between firing patterns.

Acute Stress Facilitates LTD Induction at Glutamatergic Synapses in the Hippocampal CA1 Region by Activating µ-Opioid Receptors on GABAergic Neurons.

Acute stress impairs recall memory through the facilitation of long-term depression (LTD) of hippocampal synaptic transmission. The endogenous opioid system (EOS) plays essential roles in stress-related emotional and physiological responses. Specifically, behavioral studies have shown that the impairment of memory retrieval induced by stressful events involves the activation of opioid receptors. However, it is unclear whether signaling mediated by µ-opioid receptors (µRs), one of the three major opioid receptors, participates in acute stress-related hippocampal LTD facilitation. Here, we examined the effects of a single elevated platform (EP) stress exposure on excitatory synaptic transmission and plasticity at the Schaffer collateral-commissural (SC) to CA1 synapses by recording electrically evoked field excitatory postsynaptic potentials and population spikes of hippocampal pyramidal neurons in anesthetized adult mice. EP stress exposure attenuated GABAergic feedforward and feedback inhibition of CA1 pyramidal neurons and facilitated low-frequency stimulation (LFS)-induced long-term depression (LTD) at SC-CA1 glutamatergic synapses. These effects were reproduced by exogenously activating µRs in unstressed mice. The specific deletion of µRs on GABAergic neurons (µRGABA) not only prevented the EP stress-induced memory impairment but also reversed the EP stress-induced attenuation of GABAergic inhibition and facilitation of LFS-LTD. Our results suggest that acute stress endogenously activates µRGABA to attenuate hippocampal GABAergic signaling, thereby facilitating LTD induction at excitatory synapses and eliciting memory impairments.

Improvement of therapeutic effects of mesenchymal stem cells in myocardial infarction through genetic suppression of microRNA-142.

Transplanted mesenchymal stem cells (MSCs) have been shown to contribute to myocardial repair after myocardial infarction (MI), primarily through production and secretion some growth factors and cytokines related to cell survival and regeneration. Further improvement of the therapeutic potential of MSCs appears to be an attractive strategy for MI treatment. CXC chemokine receptor (CXCR) 7 is the receptor for stromal cell-derived factor-1 (SDF-1), an important chemokine that is essential for tissue repair and angiogenesis. SDF-1/CXCR7 axis plays a critical role in the mobilization, recruitment and function of MSCs during tissue regeneration. Here, we depleted miR-142 that targets CXCR7 in MSCs cells through expression of antisense of miR-142, resulting in enhanced expression of CXCR7 in these miR-142-depleted MSCs (md-MSCs). In vitro, presence of md-MSCs reduced hypoxia-induced cardiac muscle cell apoptosis in a more pronounced manner than MSCs. In vivo, compared to transplantation of MSCs, transplantation of md-MSCs further enhanced cardiac re-vascularization and further improved cardiac functions after MI in mice. Together, our data suggest that depletion of miR-142 in MSCs may improve their therapeutic effects on MI.

Ischemia-modified albumin in type 2 diabetic patients with and without peripheral arterial disease.

OBJECTIVE: To determine whether there is an association between serum ischemia-modified albumin and the risk factor profile in type 2 diabetic patients with peripheral arterial disease and to identify the risk markers for peripheral arterial disease. METHODS: Participants included 290 patients (35.2% women) with type 2 diabetes. The ankle-brachial pressure index was measured using a standard protocol, and peripheral arterial disease was defined as an ankle-brachial index <0.90 or >1.3. The basal ischemia-modified albumin levels and clinical parameters were measured and analyzed. The risk factors for peripheral arterial disease were examined by multiple logistic analyses. RESULTS: Age, systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, urine albumin, homocysteine, and ischemia-modified albumin were significantly higher in patients with peripheral arterial disease than in disease-free patients (p<0.05), while ankle-brachial index was lower in the former group (p<0.05). Ischemia-modified albumin was positively associated with HbA1c and homocysteine levels (r = 0.220, p = 0.030; r = 0.446, p = 0.044, respectively), while no correlation was found with ankle-brachial index. Multiple logistic analyses indicated that HbA1c, systolic blood pressure, homocysteine and ischemia-modified albumin were independent risk factors for peripheral arterial disease in the diabetic subjects. CONCLUSION: The baseline ischemia-modified albumin levels were significantly higher and positively associated with HbA1c and homocysteine levels in type 2 diabetic patients with peripheral arterial disease. Ischemia-modified albumin was a risk marker for peripheral arterial disease. Taken together, these results might be helpful for monitoring diabetic peripheral arterial disease.

Role of ischemia-modified albumin and total homocysteine in estimating symptomatic lacunar infarction in type 2 diabetic patients.

OBJECTIVE: To investigate whether ischemia-modified albumin (IMA) is reliable for early diagnosing symptomatic lacunar infarction (SLI) in type 2 diabetics. DESIGN AND METHODS: Ninety-seven consecutive diabetic patients, 47 with SLI, and 45 healthy controls were enrolled. Serum IMA and plasma total homocysteine (tHcy) were measured on an autoanalyzer and evaluated in distinguishing SLI. RESULTS: Serum IMA levels were 97.35 ± 5.25 U/L in the healthy control group, 103.26 ± 7.43 U/L in the non-SLI group, and 139.84 ± 20.00 U/L in the SLI group. Plasma tHcy levels were 8.08 ± 1.82 µmol/L, 11.31 ± 3.03 µmol/L, and 13.10 ± 3.67 µmol/L, respectively. The differences in IMA and tHcy levels were statistically significant for all groups (p<0.05). Receiver operating characteristic curve analyses revealed the areas under curve were 0.866 for IMA and 0.352 for tHcy. CONCLUSION: This study indicates that IMA was significantly elevated in the acute phase of SLI and more sensitive than tHcy in distinguishing SLI.

Ischemia-modified albumin in type 2 diabetic patients with and without peripheral arterial disease

OBJECTIVE: To determine whether there is an association between serum ischemia-modified albumin and the risk factor profile in type 2 diabetic patients with peripheral arterial disease and to identify the risk markers for peripheral arterial disease. METHODS: Participants included 290 patients (35.2 percent women) with type 2 diabetes. The ankle-brachial pressure index was measured using a standard protocol, and peripheral arterial disease was defined as an ankle-brachial index <0.90 or >1.3. The basal ischemia-modified albumin levels and clinical parameters were measured and analyzed. The risk factors for peripheral arterial disease were examined by multiple logistic analyses. RESULTS: Age, systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, urine albumin, homocysteine, and ischemia-modified albumin were significantly higher in patients with peripheral arterial disease than in disease-free patients (p<0.05), while ankle-brachial index was lower in the former group (p<0.05). Ischemia-modified albumin was positively associated with HbA1c and homocysteine levels (r = 0.220, p = 0.030; r = 0.446, p = 0.044, respectively), while no correlation was found with ankle-brachial index. Multiple logistic analyses indicated that HbA1c, systolic blood pressure, homocysteine and ischemia-modified albumin were independent risk factors for peripheral arterial disease in the diabetic subjects. CONCLUSION: The baseline ischemia-modified albumin levels were significantly higher and positively associated with HbA1c and homocysteine levels in type 2 diabetic patients with peripheral arterial disease. Ischemia-modified albumin was a risk marker for peripheral arterial disease. Taken together, these results might be helpful for monitoring diabetic peripheral arterial disease.