Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice.

Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.

Longitudinal Relationship between Bullying Victimization and Non-Suicidal Self-Injury among Chinese Adolescents: The Buffering Roles of Gratitude and Parental Autonomy Support.

Drawing on the resilience-oriented socioecological framework, the current study contributes to scarce scholarship by exploring intrapersonal (i.e., gratitude) and interpersonal (i.e., parental autonomy support) factors in the longitudinal association between bullying victimization and adolescent non-suicidal self-injury (NSSI). Participants were 238 Chinese adolescents (Mage at Time 1 (T1) = 13.45 years; 106 girls and 132 boys) based on a two-wave prospective design with data spanning one year. At T1, adolescents self-rated all study variables, and at Time 2 (T2), youth again reported their NSSI. The results showed a significant main effect (b = 0.12, SE = 0.05, p = 0.04), indicating that bullying victimization was positively related to T2 NSSI one year later, even controlling for T1 NSSI. Moderation analyses further indicated that parental autonomy support buffered against the positive association between bullying victimization and T2 NSSI, but only when adolescents experienced lower levels of gratitude. Specifically, for adolescents with lower levels of gratitude, high levels of parental autonomy support, in a compensatory way, prevented adolescents from NSSI after victimization occurred (b = -0.03, SE = 0.09, p = 0.78); by contrast, for those with higher levels of gratitude, bullying victimization was not significantly related to T2 NSSI, regardless of the levels of parental autonomy support (b = 0.07, SE = 0.04, p = 0.59 for higher parental autonomy support; b = 0.01, SE = 0.07, p = 0.93 for lower parental autonomy support). These findings suggest that gratitude and parental autonomy support, manifesting in a compensatory interaction pattern, could serve as targeted agents for breaking the vicious linkage between bullying victimization and NSSI.

Differential remodeling of subthalamic projections to basal ganglia output nuclei and locomotor deficits in 6-OHDA-induced hemiparkinsonian mice.

The subthalamic nucleus (STN) controls basal ganglia outputs via the substantia nigra pars reticulata (SNr) and the globus pallidus internus (GPi). However, the synaptic properties of these projections and their roles in motor control remain unclear. We show that the STN-SNr and STN-GPi projections differ markedly in magnitude and activity-dependent plasticity despite the existence of collateral STN neurons projecting to both the SNr and GPi. Stimulation of either STN projection reduces locomotion; in contrast, inhibition of either the STN-SNr projection or collateral STN neurons facilitates locomotion. In 6-OHDA-hemiparkinsonian mice, the STN-SNr projection is dramatically attenuated, but the STN-GPi projection is robustly enhanced; apomorphine inhibition of the STN-GPi projection through D2 receptors is significantly augmented and improves locomotion. Optogenetic inhibition of either the STN-SNr or STN-GPi projection improves parkinsonian bradykinesia. These results suggest that the STN-GPi and STN-SNr projections are differentially involved in motor control in physiological and parkinsonian conditions.

Subthalamic neurons interact with nigral dopaminergic neurons to regulate movement in mice.

AIM: This study aims to address the role of the interaction between subthalamic (STN) neurons and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons in movement control. METHODS: Fiber photometry and optogenetic/chemogenetic techniques were utilized to monitor and manipulate neuronal activity, respectively. Locomotion in mice was recorded in an open field arena and on a head-fixed apparatus. A hemiparkinsonian mouse model was established by unilateral injection of 6-OHDA in the medial forebrain bundle. Whole-cell patch-clamp techniques were applied to record electrophysiological signals in STN neurons and SNc DA neurons. c-Fos-immunostaining was used to label activated neurons. A rabies virus-based retrograde tracing system was used to visualize STN neurons projecting to SNc DA neurons. RESULTS: The activity of STN neurons was enhanced upon locomotion in an open field arena and on a head-fixed apparatus, and the enhancement was significantly attenuated in parkinsonian mice. Optogenetic stimulation of STN neurons enhanced locomotion, increased activity of SNc DA neurons, meanwhile, reduced latency to movement initiation. Combining optogenetics with patch-clamp recordings, we confirmed that STN neurons innervated SNc DA neurons through glutamatergic monosynaptic connections. Moreover, STN neurons projecting to SNc DA neurons were evenly distributed in the STN. Either 6-OHDA-lesion or chemogenetic inhibition of SNc DA neurons attenuated the enhancement of locomotion by STN stimulation. CONCLUSION: SNc DA neurons not only affect the response of STN neurons to movement, but also contribute to the enhancement of movement by STN stimulation. This study demonstrates the role of STN-SNc interaction in movement control.

Internal States Influence the Representation and Modulation of Food Intake by Subthalamic Neurons.

Deep brain stimulation of the subthalamic nucleus (STN) is an effective therapy for motor deficits in Parkinson's disease (PD), but commonly causes weight gain in late-phase PD patients probably by increasing feeding motivation. It is unclear how STN neurons represent and modulate feeding behavior in different internal states. In the present study, we found that feeding caused a robust activation of STN neurons in mice (GCaMP6 signal increased by 48.4% ± 7.2%, n = 9, P = 0.0003), and the extent varied with the size, valence, and palatability of food, but not with the repetition of feeding. Interestingly, energy deprivation increased the spontaneous firing rate (8.5 ± 1.5 Hz, n = 17, versus 4.7 ± 0.7 Hz, n = 18, P = 0.03) and the depolarization-induced spikes in STN neurons, as well as enhanced the STN responses to feeding. Optogenetic experiments revealed that stimulation and inhibition of STN neurons respectively reduced (by 11% ± 6%, n = 6, P = 0.02) and enhanced (by 36% ± 15%, n = 7, P = 0.03) food intake only in the dark phase. In conclusion, our results support the hypothesis that STN neurons are activated by feeding behavior, depending on energy homeostatic status and the palatability of food, and modulation of these neurons is sufficient to regulate food intake.

Galantamine reversed early postoperative cognitive deficit via alleviating inflammation and enhancing synaptic transmission in mouse hippocampus.

Postoperative cognitive dysfunction (POCD) is commonly seen in patients undergoing major surgeries and may persist. Although neuroinflammation is one of the important contributors to the development of POCD, the mechanisms underlying POCD remain unclear. We performed stabilized tibial fracture operation in male mice. In comparison with sham mice (anesthesia only), the surgery mice exhibited cognitive deficits in a fear conditioning paradigm at postsurgery day 3-7, and increased numbers of microglia and elevated levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) without change of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Electrophysiological recordings from CA1 hippocampal neurons revealed that POCD mice exhibited impairment in AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) without alteration in the rectification property of AMPA receptors. Interestingly, daily intraperitoneal administration of galantamine, an inhibitor of acetylcholinesterase, reversed cognitive dysfunction in surgery mice and attenuated accumulation of microglia and protein levels of IL-1ß, IL-6 and TNF-α in the hippocampus. Additionally, galantamine potentiated AMPA receptor-mediated eEPSCs in the hippocampus more prominent in surgery mice than in sham mice. Therefore, enhancement of cholinergic tone in the hippocampus might be a therapeutic strategy for early POCD in terms of suppression of inflammation and normalization of excitatory synaptic transmission.

Bidirectional dopamine modulation of excitatory and inhibitory synaptic inputs to subthalamic neuron subsets containing α4ß2 or α7 nAChRs.

The subthalamic nucleus (STN) possesses microcircuits distinguished by subtypes of nicotinic acetylcholine receptors (nAChRs). Although dysfunction of the STN is well-known in Parkinson's disease, there is still little information about whether dopamine differentially modulates excitatory and inhibitory synaptic inputs to STN neurons expressing different nAChR subtypes. To address this issue, we performed brain slice patch-clamp recordings on STN neurons, while we pharmacologically manipulated dopaminergic inputs. In STN neuron subsets containing either α4ß2 or α7 nAChRs, D1 and D2 receptors respectively enhanced and inhibited spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs) and firing rates. The elevation of dopamine levels resulted in diverse regulations of synaptic transmission in these two neuron subsets, and interestingly, the dopamine regulation of sIPSCs significantly correlated with that of sEPSCs. Surprisingly, depletion of dopamine either by reserpine treatment or by unilateral 6-OHDA lesion of nigrostriatal dopaminergic neurons did not alter synaptic inputs to STN neurons, but STN neurons in the 6-OHDA-lesioned side exhibited hyperactivity. In summary, dopamine regulated both GABAergic and glutamatergic synaptic inputs to STN neuron subsets containing either α4ß2 or α7 nAChRs, forming a balancing machinery to control neuronal activity. In parkinsonian mice, postsynaptic mechanisms may exist and contribute to the hyperactivity of STN neurons.

FT-IR and 2D-IR spectroscopic studies on the effect of ions on the phase separation behavior of PVME aqueous solution.

Thermosensitive phase transition behavior of poly(vinyl methyl ether) (PVME) in an aqueous solution and the effect of inorganic ions on the coil-globule transition have been investigated by Fourier transform infrared (FT-IR) spectroscopy with attenuated total reflection (ATR) accessory. ATR-IR spectra of PVME aqueous solution indicate that in water-PVME-inorganic salts system, the phase separation temperature of PVME aqueous solution decreased with the increase of ion concentration and the increase of anion electronegativity. Meanwhile, two-dimensional infrared (2D-IR) measurements have been made to clarify the microcosmic conformational changes of PVME during the coil-globule transition. Results show that the conformation changes of main chains occur earlier than those of ether groups during heating. Furthermore, the 2D correlation spectroscopy of PVME aqueous solution during heating and the increase of concentration of potassium chloride have been studied. The features of 2D-IR spectra during heating did not change compared to the features of PVME aqueous solution during the increase of concentration of potassium chloride. This result implies that, although the addition of inorganic ions shifts the phase separation temperature, it does not alter the internal mechanism of the coil-globule transition of PVME.

Analysis with gas chromatography and mass spectrography of volatile components of Ligusticum wallichii Franch extracted by CO2 supercritical fluid extraction in combination with molecular distillation.

OBJECTIVE: To evaluate the possibility of using the technique of CO2 supercritical fluid extraction (SFE) combined with molecular distillation (MD) to extract, separate and purify the volatile components of Ligusticum wallichii Franch, a Chinese herbal medicine. METHODS: SFE was employed to extract the volatile components of Ligusticum wallichii Franch, followed by MD of the product. Analysis of the chemical constituents of the extract both before and after MD was performed with gas chromatography (GC) in conjunction with mass spectrography (MS). RESULTS: There were 45 kinds of chemical constituents in the extract of Ligusticum wallichii Franch yielded from SFE, among which 39 were left after distillation by MD. Changes also took place in the content of the constituents in the extract after distillation. CONCLUSIONS: SFE combined with MD, a technique better than simple SFE, can be used to extract, separate and purify the volatile components of Chinese herbs.