Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.

Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.

α-MSH-catabolic enzyme prolylcarboxypeptidase in nucleus accumbens shell ameliorates stress susceptibility in mice through regulating synaptic plasticity.

Emerging evidence demonstrates the vital role of synaptic transmission and structural remodeling in major depressive disorder. Activation of melanocortin receptors facilitates stress-induced emotional behavior. Prolylcarboxypeptidase (PRCP) is a serine protease, which splits the C-terminal amino acid of α-MSH and inactivates it. In this study, we asked whether PRCP, the endogenous enzyme of melanocortin system, might play a role in stress susceptibility via regulating synaptic adaptations. Mice were subjected to chronic social defeat stress (CSDS) or subthreshold social defeat stress (SSDS). Depressive-like behavior was assessed in SIT, SPT, TST and FST. Based on to behavioral assessments, mice were divided into the susceptible (SUS) and resilient (RES) groups. After social defeat stress, drug infusion or viral expression and behavioral tests, morphological and electrophysiological analysis were conducted in PFX-fixed and fresh brain slices containing the nucleus accumbens shell (NAcsh). We showed that PRCP was downregulated in NAcsh of susceptible mice. Administration of fluoxetine (20 mg·kg-1·d-1, i.p., for 2 weeks) ameliorated the depressive-like behavior, and restored the expression levels of PRCP in NAcsh of susceptible mice. Pharmacological or genetic inhibition of PRCP in NAcsh by microinjection of N-benzyloxycarbonyl-L-prolyl-L-prolinal (ZPP) or LV-shPRCP enhanced the excitatory synaptic transmission in NAcsh, facilitating stress susceptibility via central melanocortin receptors. On the contrary, overexpression of PRCP in NAcsh by microinjection of AAV-PRCP alleviated the depressive-like behavior and reversed the enhanced excitatory synaptic transmission, abnormal dendritogenesis and spinogenesis in NAcsh induced by chronic stress. Furthermore, chronic stress increased the level of CaMKIIα, a kinase closely related to synaptic plasticity, in NAcsh. The elevated level of CaMKIIα was reversed by overexpression of PRCP in NAcsh. Pharmacological inhibition of CaMKIIα in NAcsh alleviated stress susceptibility induced by PRCP knockdown. This study has revealed the essential role of PRCP in relieving stress susceptibility through melanocortin signaling-mediated synaptic plasticity in NAcsh.

A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor-mediated activation of nucleus accumbens shell.

AIMS: Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress-induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. METHODS: Chronic social defeat stress (CSDS) was used to develop depressive-like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. RESULTS: CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu -NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. CONCLUSIONS: Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress-induced depressive-like behavior.

Pharmacokinetics, bioavailability and metabolism of scopoletin in dog by ultra-high-performance liquid chromatography combined with linear ion trap-Orbitrap tandem mass spectrometry.

A highly sensitive and selective method based on ultra-high-performance liquid chromatography combined with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) has been developed and validated for the determination of scopoletin in dog plasma. The analyte was extracted from plasma samples using acetonitrile and separated on an Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 µm) with 0.05% ammonium hydroxide and acetonitrile as mobile phase. The developed method was linear over the concentration range of 1-500 ng/mL, with a correlation coefficient >0.9988. The intra- and inter-day precisions (RSD) were <8.93% while the accuracy (RE) ranged from -6.50 to 8.12%. Extraction recovery, matrix effect and stability for dog plasma samples were within the required limits. The validated method has been successfully applied to investigate the pharmacokinetics and metabolism of scopoletin in dog plasma after intravenous (1 mg/kg) and oral (10, 25, 50 mg/kg) administration. The results revealed that (a) scopoletin showed short elimination half-life in dog; (b) its oral bioavailability was low (within the range of 5.69-7.08%); (c) scopoletin showed dose-independent pharmacokinetic profiles in dog plasma over the dose range of 10-50 mg/kg; and (d) glucuronidation was the predominant metabolic pathway in dog.

Bio-inspired annelid robot: a dielectric elastomer actuated soft robot.

Biologically inspired robots with inherent softness and body compliance increasingly attract attention in the field of robotics. Aimed at solving existing problems with soft robots, regarding actuation technology and biological principles, this paper presents a soft bio-inspired annelid robot driven by dielectric elastomer actuators (DEAs) that can advance on flat rigid surfaces. The DEA, a kind of soft functional actuator, is designed and fabricated to mimic the axial elongation and differential friction of a single annelid body segment. Several (at least three) DEAs are connected together into a movable multi-segment robot. Bristles are attached at the bottom of some DEAs to achieve differential friction for imitating the setae of annelids. The annelid robot is controlled by periodic square waves, propagating from the posterior to the anterior, which imitate the peristaltic waves of annelids. Controlled by these waves, each DEA, one-by-one from tail to head, anchors to the ground by circumferential distention and pushes the front DEAs forward by axial elongation, enabling the robot to advance. Preliminary tests demonstrate that a 3-segment robot can reach an average speed of 5.3 mm s-1 (1.871 body lengths min-1) on flat rigid surfaces and can functionally mimic the locomotion of annelids. Compared to the existing robots that imitate terrestrial annelids our annelid robot shows advantages in terms of speed and bionics.