Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine.

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine.

An electroencephalographic signature predicts craving for methamphetamine.

Craving is central to methamphetamine use disorder (MUD) and both characterizes the disease and predicts relapse. However, there is currently a lack of robust and reliable biomarkers for monitoring craving and diagnosing MUD. Here, we seek to identify a neurobiological signature of craving based on individual-level functional connectivity pattern differences between healthy control and MUD subjects. We train high-density electroencephalography (EEG)-based models using data recorded during the resting state and then calculate imaginary coherence features between the band-limited time series across different brain regions of interest. Our prediction model demonstrates that eyes-open beta functional connectivity networks have significant predictive value for craving at the individual level and can also identify individuals with MUD. These findings advance the neurobiological understanding of craving through an EEG-tailored computational model of the brain connectome. Dissecting neurophysiological features provides a clinical avenue for personalized treatment of MUD.

Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: A randomized double-blind trial and TMS-EEG study.

It has been 15 years since repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) was approved by the FDA for clinical depression treatment. Yet, the underlying mechanisms for rTMS-induced depression relief are not fully elucidated. This study analyzes TMS-electroencephalogram (EEG) data from 64 healthy control (HC) subjects and 53 patients with major depressive disorder (MDD) before and after rTMS treatment. Prior to treatment, patients with MDD have lower activity in the DLPFC, the hippocampus (HPC), the orbitofrontal cortex (OFC), and DLPFC-OFC connectivity compared with HCs. Following active rTMS treatment, patients with MDD show a significant increase in the DLPFC, HPC, and OFC. Notably, the increase in HPC activity is specifically associated with amelioration of depressive symptoms but not anxiety or sleep quality. The orbitofrontal-hippocampal pathway plays a crucial role in mediating depression relief following rTMS treatment. These findings suggest potential alternative targets for brain stimulation therapy against depression (chictr.org.cn: ChiCTR2100052007).

NMDA Receptor-Dependent Synaptic Potentiation via APPL1 Signaling Is Required for the Accessibility of a Prefrontal Neuronal Assembly in Retrieving Fear Extinction.

BACKGROUND: The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive. METHODS: We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval. RESULTS: We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors. CONCLUSIONS: Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation.

Large magnetoelectric resistance in the topological Dirac semimetal α-Sn.

The spin-momentum locking of surface states in topological materials can produce a resistance that scales linearly with magnetic and electric fields. Such a bilinear magnetoelectric resistance (BMER) effect offers a new approach for information reading and field sensing applications, but the effects demonstrated so far are too weak or for low temperatures. This article reports the first observation of BMER effects in topological Dirac semimetals; the BMER responses were measured at room temperature and were substantially stronger than those reported previously. The experiments used topological Dirac semimetal α-Sn thin films grown on silicon substrates. The films showed BMER responses that are 106 times larger than previously measured at room temperature and are also larger than those previously obtained at low temperatures. These results represent a major advance toward realistic BMER applications. Significantly, the data also yield the first characterization of three-dimensional Fermi-level spin texture of topological surface states in α-Sn.

Developmental exposure of bisphenol A induces spatial memory deficits by weakening the excitatory neural circuits of CA3-CA1 and EC-CA1 in mice.

Bisphenol-A (BPA) is an environmental endocrine disruptor and impairs learning and memory. However, the direct evidence for BPA exposure affecting neural circuits has been limited. In this study, a virus tracing assay has been established to explore the brain's neural circuits. Thy1-Cre mice were used to investigate the effects of BPA on the neural projection of glutamatergic pyramidal neurons in hippocampal CA1 based on Thy1 promoter. These transgenic mice were orally exposed to BPA (0, 0.5 mg/kg/day) from postnatal day (PND) 0 to PND60 and then subjected to behavioral tests. Morris water maze(MWM)and Barnes maze's showed that the spatial memory was seriously impaired in BPA exposed Thy1-Cre mice. Virus tracing assay indicated that CA1 pyramidal neurons mainly received neural inputs from hippocampal CA3, entorhinal cortex (EC), and medial septum (MS). The analysis showed that BPA reduced the number of RV+ neurons in CA3 and EC but not MS. The immunohistochemistry experiment displayed that BPA decreased the percentage of CaMKIIRV+ cells in CA3 and EC. The results demonstrated that the synaptic connection of upstream glutamatergic neurons and CA1 pyramidal cells was weakened by BPA exposure. These point to potentially detrimental effects of BPA exposure on the excitatory neural circuit of CA3-CA1 and EC-CA1 in memory formation. Thus, our findings revealed that the decrease in excitatory neural circuits of CA3-CA1 and EC-CA1 contribute to the BPA-induced spatial memory deficits in Thy1-Cre mice.

Switching of a Magnet by Spin-Orbit Torque from a Topological Dirac Semimetal.

Recent experiments show that topological surface states (TSS) in topological insulators (TI) can be exploited to manipulate magnetic ordering in ferromagnets. In principle, TSS should also exist for other topological materials, but it remains unexplored as to whether such states can also be utilized to manipulate ferromagnets. Herein, current-induced magnetization switching enabled by TSS in a non-TI topological material, namely, a topological Dirac semimetal α-Sn, is reported. The experiments use an α-Sn/Ag/CoFeB trilayer structure. The magnetization in the CoFeB layer can be switched by a charge current at room temperature, without an external magnetic field. The data show that the switching is driven by the TSS of the α-Sn layer, rather than spin-orbit coupling in the bulk of the α-Sn layer or current-produced heating. The switching efficiency is as high as in TI systems. This shows that the topological Dirac semimetal α-Sn is as promising as TI materials in terms of spintronic applications.

Topological Hall Effect in a Topological Insulator Interfaced with a Magnetic Insulator.

A topological insulator (TI) interfaced with a magnetic insulator (MI) may host an anomalous Hall effect (AHE), a quantum AHE, and a topological Hall effect (THE). Recent studies, however, suggest that coexisting magnetic phases in TI/MI heterostructures may result in an AHE-associated response that resembles a THE but in fact is not. This Letter reports a genuine THE in a TI/MI structure that has only one magnetic phase. The structure shows a THE in the temperature range of T = 2-3 K and an AHE at T = 80-300 K. Over T = 3-80 K, the two effects coexist but show opposite temperature dependencies. Control measurements, calculations, and simulations together suggest that the observed THE originates from skyrmions, rather than the coexistence of two AHE responses. The skyrmions are formed due to a Dzyaloshinskii-Moriya interaction (DMI) at the interface; the DMI strength estimated is substantially higher than that in heavy metal-based systems.

Adaptor protein APPL1 links neuronal activity to chromatin remodeling in cultured hippocampal neurons.

Local signaling events at synapses or axon terminals are communicated to the nucleus to elicit transcriptional responses, and thereby translate information about the external environment into internal neuronal representations. This retrograde signaling is critical to dendritic growth, synapse development, and neuronal plasticity. Here, we demonstrate that neuronal activity induces retrograde translocation and nuclear accumulation of endosomal adaptor APPL1. Disrupting the interaction of APPL1 with Importin α1 abolishes nuclear accumulation of APPL1, which in turn decreases the levels of histone acetylation. We further demonstrate that retrograde translocation of APPL1 is required for the regulation of gene transcription and then maintenance of hippocampal late-phase long-term potentiation. Thus, these results illustrate an APPL1-mediated pathway that contributes to the modulation of synaptic plasticity via coupling neuronal activity with chromatin remodeling.

Changes of Magnetism in a Magnetic Insulator due to Proximity to a Topological Insulator.

We report the modification of magnetism in a magnetic insulator Y_{3}Fe_{5}O_{12} thin film by topological surface states (TSS) in an adjacent topological insulator Bi_{2}Se_{3} thin film. Ferromagnetic resonance measurements show that the TSS in Bi_{2}Se_{3} produces a perpendicular magnetic anisotropy, results in a decrease in the gyromagnetic ratio, and enhances the damping in Y_{3}Fe_{5}O_{12}. Such TSS-induced changes become more pronounced as the temperature decreases from 300 to 50 K. These results suggest a completely new approach for control of magnetism in magnetic thin films.

Pb exposure induces an imbalance of excitatory and inhibitory synaptic transmission in cultured rat hippocampal neurons.

An appropriate balance of excitatory and inhibitory synapse maintains the network stability of the central nervous system. Our recent work showed lead (Pb) exposure can inhibit synaptic transmission in cultured hippocampal neurons. However, it is not clear whether Pb exposure disrupt the balance of excitatory and inhibitory synaptic transmission. Here, primary cultured hippocampal neurons from Sprague-Dawley (SD) rats were exposed to Pb (0.2 µM, 1 µM, 5 µM, respectively) from Days in Vitro (DIV) 7 to DIV 12 for 5 days and the excitatory and inhibitory synaptic transmission was examined. Patch clamp recording results showed that distinct from exposures of 0.2 µM and 5 µM, 1 µM Pb exposure significantly increased the mIPSC frequency and decreased the mEPSC frequency, leading to a uniform inhibitory outcome. Further, the number of inhibitory presynaptic puncta was significantly increased after 1 µM Pb exposure, while the number of excitatory presynaptic terminals was decreased. In addition 1 µM Pb increased the glutamic acid decarboxylase (GAD65) expression and the surface GABAA receptor (GABAAR) clusters. This shift might potentiate the synthesis of GABA and enhance the surface distribution of postsynaptic GABAAR clusters in hippocampus neurons. Together, these data showed that Pb exposure disrupted the balance of excitatory and inhibitory synaptic transmission via abnormal GABAergic neurotransmission.

Magnetization switching using topological surface states.

Topological surface states (TSSs) in a topological insulator are expected to be able to produce a spin-orbit torque that can switch a neighboring ferromagnet. This effect may be absent if the ferromagnet is conductive because it can completely suppress the TSSs, but it should be present if the ferromagnet is insulating. This study reports TSS-induced switching in a bilayer consisting of a topological insulator Bi2Se3 and an insulating ferromagnet BaFe12O19. A charge current in Bi2Se3 can switch the magnetization in BaFe12O19 up and down. When the magnetization is switched by a field, a current in Bi2Se3 can reduce the switching field by ~4000 Oe. The switching efficiency at 3 K is 300 times higher than at room temperature; it is ~30 times higher than in Pt/BaFe12O19. These strong effects originate from the presence of more pronounced TSSs at low temperatures due to enhanced surface conductivity and reduced bulk conductivity.

Current-controlled propagation of spin waves in antiparallel, coupled domains.

Spin waves may constitute key components of low-power spintronic devices. Antiferromagnetic-type spin waves are innately high-speed, stable and dual-polarized. So far, it has remained challenging to excite and manipulate antiferromagnetic-type propagating spin waves. Here, we investigate spin waves in periodic 100-nm-wide stripe domains with alternating upward and downward magnetization in La0.67Sr0.33MnO3 thin films. In addition to ordinary low-frequency modes, a high-frequency mode around 10 GHz is observed and propagates along the stripe domains with a spin-wave dispersion different from the low-frequency mode. Based on a theoretical model that considers two oppositely oriented coupled domains, this high-frequency mode is accounted for as an effective antiferromagnetic spin-wave mode. The spin waves exhibit group velocities of 2.6 km s-1 and propagate even at zero magnetic bias field. An electric current pulse with a density of only 105 A cm-2 can controllably modify the orientation of the stripe domains, which opens up perspectives for reconfigurable magnonic devices.

Pb inhibits hippocampal synaptic transmission via cyclin-dependent kinase-5 dependent Synapsin 1 phosphorylation.

Lead (Pb) exposure impairs the nervous system, of which the injury of cognitive development is obvious. But the mechanism of Pb induced disorders of neuro-transmission remain elusive. In this study, primary hippocampal neurons were exposed to Pb at the dosage of 5 µM from days in vitro (DIV) 3 to DIV14 and the electrophysiological recordings were performed at DIV14. Sprague-Dawley (SD) rat pups were exposed to Pb from parturition to weaning indirectly from their mothers whose drinking water containing 250 ppm Pb, then directly exposed to Pb at the dosage of 250 ppm from postnatal day (PND) 21 to PND30. The results showed that Pb significantly decreased the frequency of both miniature excitatory postsynaptic current (mEPSC) and miniature inhibitory postsynaptic current (mIPSC) in cultured hippocampal neurons. Paird-pulse facilitation (PPF) recordings showed there was significant increase in Pb-exposed group. The increase of the magnitude of PPF (the ratio of second to first response amplitude) further confirmed that Pb reduced presynaptic neuro-transmission. By transmission electron microscope, it found that Pb disarranged presynaptic vesicles distribution and decreased the density of presynaptic vesicles. Moreover, it was interestingly found that phosphorylation of Synapsin1, which was phosphorylated by CDK5, has been decreased upon Pb exposure. With the treatment of R-Roscovitine (Ro), an inhibitor of CDK5, it was detected that Pb induced mEPSC and mIPSC frequency reduction have been reversed. Together, our results suggested that Pb disrupted the distribution of synaptic vesicles and impaired the neurotransmitter release, which was dependent on the phosphorylation level of Synapsin 1 via CDK5. This study will help for elucidation of environmental Pb-induced neuronal disorders.

Effect of Pb Exposure on Synaptic Scaling Through Regulation of AMPA Receptor Surface Trafficking.

Homeostatic synaptic plasticity (HSP) helps to stabilize the neuronal network activity, which is essential for optimal information coding. Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to activity blockade. Lead (Pb) is a ubiquitous environmental neuro-toxicant and can impair the input-specific Hebbian type synaptic plasticity, but whether Pb exerts effects in HSP remains unknown. We previously reported that blocking L-type calcium channel induces synaptic scaling, which stimulates the synthesis of all-trans retinoic acid (RA) and the expression of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Given Pb is a potent blocker of calcium channel, we hypothesized Pb may participate in synaptic scaling accompanied by RA synthesis and AMPA receptor trafficking. In this study, cultured hippocampal neurons were treated with Pb (1 µM 5 min, 15 min, 4 h, 24 h, and 10 µM 24 h) alone or in combination with tetrodotoxin (TTX, 1 µM, 24 h). The results showed that Pb alone, either at 1 µM or 10 µM, cannot induce synaptic scaling. But Pb participated in synaptic scaling when concurrent with TTX (10 µM Pb + 1 µM TTX, 24 h). Further results showed that surface heteromeric GluA1 and GluA2 AMPA receptors were increased in TTX+ Pb-induced synaptic scaling. In addition, RA was proved not to participate in TTX+ Pb-mediated synaptic scaling. Taken together, our work supported that TTX+ Pb could induce synaptic scaling and enhance synaptic accumulation of AMPAR GluA1 and GluA2 during synaptic up scaling. Our study would help for elucidation of the Pb-induced neuronal network instability mechanism.

Role of damping in spin Seebeck effect in yttrium iron garnet thin films.

The role of damping in the spin Seebeck effect (SSE) was studied experimentally for the first time. The experiments used Y3Fe5O12 (YIG)/Pt bilayered structures where the YIG films exhibit very similar structural and static magnetic properties but very different damping. The data show that a decrease in the damping gives rise to an increase in the SSE coefficient, which is qualitatively consistent with some of the theoretical models. This response also shows quasi-linear behavior, which was not predicted explicitly by previous studies. The data also indicate that the SSE coefficient shows no notable correlations with the enhanced damping due to spin pumping, which can be understood in the frame of two existing models.

Early developmental bisphenol-A exposure sex-independently impairs spatial memory by remodeling hippocampal dendritic architecture and synaptic transmission in rats.

Bisphenol-A (BPA, 4, 4'-isopropylidene-2-diphenol), a synthetic xenoestrogen that widely used in the production of polycarbonate plastics, has been reported to impair hippocampal development and function. Our previous study has shown that BPA exposure impairs Sprague-Dawley (SD) male hippocampal dendritic spine outgrowth. In this study, the sex-effect of chronic BPA exposure on spatial memory in SD male and female rats and the related synaptic mechanism were further investigated. We found that chronic BPA exposure impaired spatial memory in both SD male and female rats, suggesting a dysfunction of hippocampus without gender-specific effect. Further investigation indicated that BPA exposure causes significant impairment of dendrite and spine structure, manifested as decreased dendritic complexity, dendritic spine density and percentage of mushroom shaped spines in hippocampal CA1 and dentate gyrus (DG) neurons. Furthermore, a significant reduction in Arc expression was detected upon BPA exposure. Strikingly, BPA exposure significantly increased the mIPSC amplitude without altering the mEPSC amplitude or frequency, accompanied by increased GABAARß2/3 on postsynaptic membrane in cultured CA1 neurons. In summary, our study indicated that Arc, together with the increased surface GABAARß2/3, contributed to BPA induced spatial memory deficits, providing a novel molecular basis for BPA achieved brain impairment.