Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Implementation of Thermal-Triggered Binary-Ternary Switchable Memory Performance in Zn/polysulfide/organic Complex-Based Memorizers by Finely Modulating the S62- Relaxation.

Polysulfide-based multilevel memorizers are promising as novel memorizers, in which the occurrence of Sn2- relaxation is key for their multilevel memory. However, the effects of crystal packing and the side group of organic ligands on Sn2- relaxation are still ambiguous. In this work, ionic [Zn(S6)2·Zn2(Bipy)2SO4 (1), Zn(S6)2·Zn(Pmbipy)3 (2)] and neutral [ZnS6(Ombipy) (3), ZnS6(Phen)2 (4)] Zn/polysulfide/organic complexes with different packing modes and structures of organic ligands have been synthesized and were fabricated as memory devices. In both ionic and neutral Zn complexes, the S62- relaxation will be blocked by steric hindrances due to the packing of counter-cations and hydrogen-bond restrictions. Consequently, only the binary memory performances can be seen in FTO/1/Ag, FTO/2/Ag, and FTO/4/Ag, which originate from the more condensed packing of conjugated ligands upon electrical stimulus. Interestingly, FTO/3/Ag illustrates the unique thermally triggered reversible binary-ternary switchable memory performance. In detail, after introducing a methyl group on the 6'-position of bipyridine in ZnS6(Ombipy) (3), the ring-to-chain relaxation of S62- anions at room temperature will be inhibited, but it can happen at a higher temperature of 120 °C, which has been verified by elongated S-S lengths and the strengthened C-H···S hydrogen bond upon heating. The rules drawn in this work will provide a useful guide for the design of stimulus-responsive memorizers that can be applied in special industries such as automobile, oil, and gas industries.

Molecular rotators anchored on a rod-like anionic coordination polymer adhered by charge-assisted hydrogen bonds.

On the basis of variable-temperature single-crystal X-ray diffraction, variable-temperature/frequency dielectric analysis, variable-temperature solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, here we present a new model of crystalline supramolecular rotor (i-PrNHMe2)[CdBr3], where a conformationally flexible near-spherical (i-PrNHMe2)+ cation functions as a rotator and a rod-like anionic coordination polymer {[CdBr3]-}∞ acts as the stator, and the adhesion of them is realized by charge-assisted hydrogen bonds.

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity.

The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRABACh (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors.

Thermal-Responsive Polyoxometalate-Metalloviologen Hybrid: Reversible Intermolecular Three-Component Reaction and Temperature-Regulated Resistive Switching Behaviors.

The development of new-type memristors with special performance is of great interest. Herein, an inorganic-organic hybrid crystalline polyoxometalate (POM) with usual dynamic structures is reported and used as active material for fabricating memristor with unique temperature-regulated resistive switching behaviors. The hybrid POM not only exhibits tunable thermochromic properties, but also thermal-induced reversible aggregation and disaggregation reactions, leading to reversible structural transformations in SCSC fashion. Further, the memory device using the hybrid POM as active layer exhibits uncommon performance, which can keep resistive switching silent in the low temperature range of 30-150 °C, but show nonvolatile memory behavior in the high temperature range of 150-270 °C. Particularly, the silent and working states at three special temperatures (30, 150 and 270 °C) can be monitored by chromism. The correlation between structure and resistive switching property of the material has been discussed. The work demonstrates that crystalline inorganic-organic hybrid POMs are promising materials for making memristors with superior performance.

Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain.

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.

An Insula-Central Amygdala Circuit for Guiding Tastant-Reinforced Choice Behavior.

For animals to survive, they must reliably predict during foraging which substances are suitable for consumption. Despite extensive study, the neural circuit mechanisms underlying such adaptive behavior remain poorly understood. Here, using a tastant (sucrose/quinine)-reinforced "go/no-go" task in male and female mice, we examined the anatomical and functional connectivity of the circuit linking the insular cortex (IC) to the central amygdala (CeA) and the role of this circuit in the establishment of appropriate behavioral responses. Using anatomic tracing approaches combined with optogenetics-assisted circuit mapping, we found that the gustatory region of the IC sends direct excitatory projections to the lateral division of the CeA (CeL), making monosynaptic excitatory connections with distinct populations of CeL neurons. Specific inhibition of neurotransmitter release from the CeL-projecting IC neurons prevented mice from acquiring the "no-go" response, and impaired the "go" responses in the go/no-go task. Furthermore, selective activation of the IC-CeL pathway with optogenetics drove unconditioned lick suppression in thirsty animals, induced aversive responses, and was sufficient to instruct conditioned action suppression in response to a cue predicting the optogenetic activation. These results indicate that activities in the IC-CeL circuit are critical for establishing taste-reinforced behavioral responses, including avoidance responses to an aversive tastant, and are sufficient to drive learning of anticipatory avoidance. Our findings suggest that the IC-CeL circuit plays an important role in guiding appropriate choices during foraging.SIGNIFICANCE STATEMENT An animal's ability to predict which substances are suitable for consumption and then produce an appropriate action to those substances is critical for survival. Here we found that activity in the circuit that links the insular cortex (IC) to the central amygdala (CeA) is necessary for establishing appropriate behavioral responses to taste-predicting cues. This neural circuit seems to be particularly tuned to avoid an unpleasant tastant, and is also sufficient to drive learning of such avoidance responses. These results suggest that the IC-CeA circuit is critical for generating appropriate behavioral responses during foraging when facing different choices.

A Central Extended Amygdala Circuit That Modulates Anxiety.

Both the amygdala and the bed nucleus of the stria terminalis (BNST) have been implicated in maladaptive anxiety characteristics of anxiety disorders. However, the underlying circuit and cellular mechanisms have remained elusive. Here we show that mice with Erbb4 gene deficiency in somatostatin-expressing (SOM+) neurons exhibit heightened anxiety as measured in the elevated plus maze test and the open field test, two assays commonly used to assess anxiety-related behaviors in rodents. Using a combination of electrophysiological, molecular, genetic, and pharmacological techniques, we demonstrate that the abnormal anxiety in the mutant mice is caused by enhanced excitatory synaptic inputs onto SOM+ neurons in the central amygdala (CeA), and the resulting reduction in inhibition onto downstream SOM+ neurons in the BNST. Notably, our results indicate that an increase in dynorphin signaling in SOM+ CeA neurons mediates the paradoxical reduction in inhibition onto SOM+ BNST neurons, and that the consequent enhanced activity of SOM+ BNST neurons is both necessary for and sufficient to drive the elevated anxiety. Finally, we show that the elevated anxiety and the associated synaptic dysfunctions and increased dynorphin signaling in the CeA-BNST circuit of the Erbb4 mutant mice can be recapitulated by stress in wild-type mice. Together, our results unravel previously unknown circuit and cellular processes in the central extended amygdala that can cause maladaptive anxiety.SIGNIFICANCE STATEMENT The central extended amygdala has been implicated in anxiety-related behaviors, but the underlying mechanisms are unclear. Here we found that somatostatin-expressing neurons in the central amygdala (CeA) controls anxiety through modulation of the stria terminalis, a process that is mediated by an increase in dynorphin signaling in the CeA. Our results reveal circuit and cellular dysfunctions that may account for maladaptive anxiety.

Heterometallic Organic Frameworks Built from Trinuclear Indium and Cuprous Halide Clusters: Ligand-Oriented Assemblies and Iodine Adsorption Behavior.

Two novel heterometallic organic frameworks built from trinuclear indium and cuprous halide clusters, [(In3O)2(Cu2I2)3(ina)12(H2O)6](NO3)2·7DMA·10H2O (1) and [NH2(CH3)2][In3(OH)2(H2O)2(ina)8(Cu4I4)2]·5DMA·8H2O (2), where Hina = isonicotinic acid, have been successfully constructed with the orientation of the ina ligand. 1 shows a fascinating highly porous honeycomb-like 3D cationic framework with a trigonal-bipyramid-type cage based on a planar [In3O(CO2)6]+ trimer and a rhombohedral Cu2I2 cluster. Comparably, 2 displays a 3D negative network with irregular hexagonal channels constructed from a [In3(OH)2(CO2)8]- trimer and a cubane-like Cu4I4 cluster. Especially, 1 displays a reversible I2 adsorption/release performance with high adsorption capacity, whose mechanism has been disclosed by theoretical simulation. Also, the green/red emission of 2 stems from iodocuprate centers with quenched indium-centered emission.

Encapsulating Halometallates into 3-D Lanthanide-Viologen Frameworks: Controllable Emissions, Reversible Thermochromism, Photocurrent Responses, and Electrical Bistability Behaviors.

The encapsulation of guests into metal-organic frameworks (MOF) is an efficient strategy to generate novel multifunctional materials with enhanced properties. Herein, four halometallate@MOF composites with formulas of {(Pb2I4Br3)[(Pr(bpdo)4(H2O)2]·(H2O)}n (1), {[Pb3I10(H2O)2][Y2(bpdo)5(OH)2]·4(H2O)}n (2), {(Bi2I9)[(Pr(bpdo)3(H2O)]}n (3), {(Bi4I18)[(La(bpdo)4(H2O)2]2}n (4) (bpdo = 4,4'-bipyridine N,N'-dioxide) were prepared. In these composites, lanthanide-viologen MOF act as matrices, whose cavities were penetrated by halometallates. Consequently, the insertion of electron-rich halometallates into electron-deficient lanthanide-viologen matrices leads to the presence of strong room temperature charge transfer (CT) interactions. Importantly, these composites exhibit enhanced photo/thermal stabilities, controllable white emissions, reversible thermochromisms, and good photocurrent response performances. Specially, the memory devices based on these composites illustrate reversible electrical bistability behaviors, which can be assigned to ohmic and space-charge-limited conduction (SCLC) mechanisms. This kind of composite can be utilized as a multifunctional platform with enhanced stability.

Primary Auditory Cortex is Required for Anticipatory Motor Response.

The ability of the brain to predict future events based on the pattern of recent sensory experience is critical for guiding animal's behavior. Neocortical circuits for ongoing processing of sensory stimuli are extensively studied, but their contributions to the anticipation of upcoming sensory stimuli remain less understood. We, therefore, used in vivo cellular imaging and fiber photometry to record mouse primary auditory cortex to elucidate its role in processing anticipated stimulation. We found neuronal ensembles in layers 2/3, 4, and 5 which were activated in relationship to anticipated sound events following rhythmic stimulation. These neuronal activities correlated with the occurrence of anticipatory motor responses in an auditory learning task. Optogenetic manipulation experiments revealed an essential role of such neuronal activities in producing the anticipatory behavior. These results strongly suggest that the neural circuits of primary sensory cortex are critical for coding predictive information and transforming it into anticipatory motor behavior.

Decarboxylative Trifluoromethylating Reagent [Cu(O2 CCF3 )(phen)] and Difluorocarbene Precursor [Cu(phen)2 ][O2 CCF2 Cl].

This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O2 CCF3 )] (1; phen=1,10-phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)2 ][O2 CCF2 Cl] (2). Treatment of copper tert-butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air-stable complexes 1 and 2, respectively, which were characterized by X-ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH3 CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)2 ]+ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter (ρ)=+0.56±0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest-to-excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three-center transition state.

Anti-Microbial Effect of AgBr-NP@CTMAB on Streptococcus Mutans and Assessment of Surface Roughness Hardness and Flexural Strength of PMMA.

Purpose: To investigate the inhibition of Streptococcus mutans (S.mutans) and its biofilm by AgBr-nanoparticles (NP) @CTMAB (cetyltrimethyl-ammonium bromide) and evaluate the changes in Polymethyl methacrylate (PMMA)'s surface roughness (Ra), microhardness, and flexural strength during prolonged immersion in AgBr-NP@CTMAB for application in the denture cleaning industry. Patients and Methods: The antibacterial activity of AgBr-NP@CTMAB against S.mutans was measured colony formation assay, OD600 and laser confocal microscopy. Changes in the specimens' values for surface roughness, microhardness, and flexural strength (MPa) were measured after immersion solutions for 180 or 360 days. Results: The AgBr-NP@CTMAB solution exhibited a robust antibacterial effect on planktonic S. mutans, with a minimum bactericidal concentration of 5 µg/mL. The 10 µg/mL AgBr-NP@CTMAB solution efficiently inhibited S. mutans biofilm formation. (2) No significant difference in surface roughness after immersion in AgBr-NP@CTMAB (10 µg/mL and 20 µg/mL) comparing with distilled water (P > 0.05) and Polident had significantly higher than distilled water (P < 0.05). There was a significant decrease in the surface hardness of the PMMA specimens that were immersed in the Polident compared with those in distilled water (P < 0.05). While, no significant differences in surface hardness after immersion in the AgBr-NP@CTMAB (P > 0.05). The result of flexural strength suggested that there was no statistically significant difference (P < 0.05) between AgBr-NP@CTMAB as well as Polident and water. Conclusion: AgBrNP@CTMAB can efficiently inhibit the growth of plankton S.mutans and biofilm formation, without affecting the flexural strength, microhardness, or surface roughness of PMMA. Therefore, AgBrNP@CTMAB holds promise as a new denture cleaning agent.

Exploring the Function of (+)-Naltrexone Precursors: Their Activity as TLR4 Antagonists and Potential in Treating Morphine Addiction.

Disruptions in the toll-like receptor 4 (TLR4) signaling pathway are linked to chronic inflammation, neuropathic pain, and drug addiction. (+)-Naltrexone, an opioid-derived TLR4 antagonist with a (+)-isomer configuration, does not interact with classical opioid receptors and has moderate blood-brain barrier permeability. Herein, we developed a concise 10-step synthesis for (+)-naltrexone and explored its precursors, (+)-14-hydroxycodeinone (1) and (+)-14-hydroxymorphinone (3). These precursors exhibited TLR4 antagonistic activities 100 times stronger than (+)-naltrexone, particularly inhibiting the TLR4-TRIF pathway. In vivo studies showed that these precursors effectively reduced behavioral effects of morphine, like sensitization and conditioned place preference by suppressing microglial activation and TNF-α expression in the medial prefrontal cortex and ventral tegmental area. Additionally, 3 displayed a longer half-life and higher oral bioavailability than 1. Overall, this research optimized (+)-naltrexone synthesis and identified its precursors as potent TLR4 antagonists, offering potential treatments for morphine addiction.

Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain.

Chronic pain often develops severe mood changes such as depression. However, how chronic pain leads to depression remains elusive and the mechanisms determining individuals' responses to depression are largely unexplored. Here we found that depression-like behaviors could only be observed in 67.9% of mice with chronic neuropathic pain, leaving 32.1% of mice with depression resilience. We determined that the spike discharges of the ventral tegmental area (VTA)-projecting lateral habenula (LHb) glutamatergic (Glu) neurons were sequentially increased in sham, resilient and susceptible mice, which consequently inhibited VTA dopaminergic (DA) neurons through a LHbGlu-VTAGABA-VTADA circuit. Furthermore, the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner. Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain. Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

Time-restricted feeding is an intervention against excessive dark-phase sleepiness induced by obesogenic diet.

High-fat diet (HFD)-induced obesity is a growing epidemic and major health concern. While excessive daytime sleepiness (EDS) is a common symptom of HFD-induced obesity, preliminary findings suggest that reduced wakefulness could be improved with time-restricted feeding (TRF). At present, however, the underlying neural mechanisms remain largely unknown. The paraventricular thalamic nucleus (PVT) plays a role in maintaining wakefulness. We found that chronic HFD impaired the activity of PVT neurons. Notably, inactivation of the PVT was sufficient to reduce and fragment wakefulness during the active phase in lean mice, similar to the sleep-wake alterations observed in obese mice with HFD-induced obesity. On the other hand, enhancing PVT neuronal activity consolidated wakefulness in mice with HFD-induced obesity. We observed that the fragmented wakefulness could be eliminated and reversed by TRF. Furthermore, TRF prevented the HFD-induced disruptions on synaptic transmission in the PVT, in a feeding duration-dependent manner. Collectively, our findings demonstrate that ad libitum access to a HFD results in inactivation of the PVT, which is critical to impaired nocturnal wakefulness and increased sleep, while TRF can prevent and reverse diet-induced PVT dysfunction and excessive sleepiness. We establish a link between TRF and neural activity, through which TRF can potentially serve as a lifestyle intervention against diet/obesity-related EDS.

Neurocircuitry of Predatory Hunting.

Predatory hunting is an important type of innate behavior evolutionarily conserved across the animal kingdom. It is typically composed of a set of sequential actions, including prey search, pursuit, attack, and consumption. This behavior is subject to control by the nervous system. Early studies used toads as a model to probe the neuroethology of hunting, which led to the proposal of a sensory-triggered release mechanism for hunting actions. More recent studies have used genetically-trackable zebrafish and rodents and have made breakthrough discoveries in the neuroethology and neurocircuits underlying this behavior. Here, we review the sophisticated neurocircuitry involved in hunting and summarize the detailed mechanism for the circuitry to encode various aspects of hunting neuroethology, including sensory processing, sensorimotor transformation, motivation, and sequential encoding of hunting actions. We also discuss the overlapping brain circuits for hunting and feeding and point out the limitations of current studies. We propose that hunting is an ideal behavioral paradigm in which to study the neuroethology of motivated behaviors, which may shed new light on epidemic disorders, including binge-eating, obesity, and obsessive-compulsive disorders.

Simultaneously elevating the resistive switching level and ambient-air-stability of 3D perovskite (TAZ-H)PbBr3-based memory device by encapsulating into polyvinylpyrrolidone.

The study about simultaneously enhancing the resistive switching level and ambient-air-stability of perovskite-based memorizers will promote its commercialization. Here, a new 3D perovskite (TAZ-H)PbBr3 (TAZ-H+ = protonated thiazole) has been fabricated as FTO/(TAZ-H)PbBr3/Ag device, which only exhibits binary memory performance with the high tolerant temperature of 170 °C. After encapsulating by polyvinylpyrrolidone (PVP), the (TAZ-H)PbBr3@PVP composite-based device can demonstrate ternary resistive switching behavior with considerable ON2/ON1/OFF ratio (105.9: 103.9:1) and high ternary yield (68 %). Specially, this device presents good ambient-air stability at RH 80 % and thermal tolerance of 100 °C. The binary resistive switching mechanism can be ascribed to the halogen ion migration induced by bromine defects in the (PbBr3)nn- framework. But the ternary resistive switching phenomenon in the (TAZ-H)PbBr3@PVP-based device could be depicted as the carrier transport from filled traps of PVP to (PbBr3)nn- framework (ON1 state) and then carriers flowing in the re-arranged (TAZ-H)nn+ chain in 3D channels (ON2 state). The PVP treatment can not only modify the grain boundary defects, but also facilitate the transport of injected carriers to the perovskite films via Pb-O coordinated bonds and inhibition of order-disorder transformation. This facial strategy for implementing ternary perovskite-based memorizers with good ambient-air-stability is quite meaningful for high-density memory in harsh environments.

Aspect Ratio Modulation of Sucralose through {002}/{011} Preferred Orientation in Antisolvent Crystallization.

The aspect ratio modulation in the alcoholysis process is highly significant for the production of high-quality sucralose. In this work, antisolvent crystallization (ASC) accompanied by preferred orientation was first adopted in the sucralose separation, based on which simultaneous modulations on aspect ratio, solubility, and stability have been realized. In detail, after the alcoholysis process in methanol, four antisolvents bearing different functional groups were used in ASC, i.e., isopentanol (IPN), isovaleraldehyde (IVD), isovaleric acid (IVA), and isobutyl propionate (IBP). To our interest, when IVA was used as the antisolvent, the highest separation efficiency (49.33%), fastest crystallizing rate (5.64%/h), lowest aspect ratio (1.55), and solubility (9.28 wt %) and good thermal stability (131.65 °C) of sucralose were achieved. Single crystal structures of sucralose using different antisolvents have been determined. Sucralose using IVA as the antisolvent exhibits the greatest molecular distortion and strongest intermolecular C-H···Cl hydrogen bonds; thus, the preferred growth along {002}/{011} directions has occurred and accounted for its lower aspect ratio, worse solubility, and better stability. The strongest methanol···IVA interactions due to the presence of a carboxyl group can accelerate the formation of the emulsion, resulting in the fastest crystallizing rate. The antisolvent screening and the discovery about relative mechanisms will provide a theoretical guide for the production of high-quality sucralose.