The neurophysiological mechanisms of medial prefrontal-perirhinal cortex circuit mediating temporal order memory decline in early stage of AD rats.

The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.

An intelligent workflow for sub-nanoscale 3D reconstruction of intact synapses from serial section electron tomography.

BACKGROUND: As an extension of electron tomography (ET), serial section electron tomography (serial section ET) aims to align the tomographic images of multiple thick tissue sections together, to break through the volume limitation of the single section and preserve the sub-nanoscale voxel size. It could be applied to reconstruct the intact synapse, which expands about one micrometer and contains nanoscale vesicles. However, there are several drawbacks of the existing serial section ET methods. First, locating and imaging regions of interest (ROIs) in serial sections during the shooting process is time-consuming. Second, the alignment of ET volumes is difficult due to the missing information caused by section cutting and imaging. Here we report a workflow to simplify the acquisition of ROIs in serial sections, automatically align the volume of serial section ET, and semi-automatically reconstruct the target synaptic structure. RESULTS: We propose an intelligent workflow to reconstruct the intact synapse with sub-nanometer voxel size. Our workflow includes rapid localization of ROIs in serial sections, automatic alignment, restoration, assembly of serial ET volumes, and semi-automatic target structure segmentation. For the localization and acquisition of ROIs in serial sections, we use affine transformations to calculate their approximate position based on their relative location in orderly placed sections. For the alignment of consecutive ET volumes with significantly distinct appearances, we use multi-scale image feature matching and the elastic with belief propagation (BP-Elastic) algorithm to align them from coarse to fine. For the restoration of the missing information in ET, we first estimate the number of lost images based on the pixel changes of adjacent volumes after alignment. Then, we present a missing information generation network that is appropriate for small-sample of ET volume using pre-training interpolation network and distillation learning. And we use it to generate the missing information to achieve the whole volume reconstruction. For the reconstruction of synaptic ultrastructures, we use a 3D neural network to obtain them quickly. In summary, our workflow can quickly locate and acquire ROIs in serial sections, automatically align, restore, assemble serial sections, and obtain the complete segmentation result of the target structure with minimal manual manipulation. Multiple intact synapses in wild-type rat were reconstructed at a voxel size of 0.664 nm/voxel to demonstrate the effectiveness of our workflow. CONCLUSIONS: Our workflow contributes to obtaining intact synaptic structures at the sub-nanometer scale through serial section ET, which contains rapid ROI locating, automatic alignment, volume reconstruction, and semi-automatic synapse reconstruction. We have open-sourced the relevant code in our workflow, so it is easy to apply it to other labs and obtain complete 3D ultrastructures which size is similar to intact synapses with sub-nanometer voxel size.

TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration.

While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75NTR, a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75NTR. In addition, TrkB-agoAbs elicit much longer TrkB activation, reduced TrkB internalization and less intracellular degradation, compared with BDNF. More importantly, some of these TrkB-agoAbs bind TrkB epitopes distinct from that by BDNF, and work cooperatively with endogenous BDNF. Unlike BDNF, the TrkB-agoAbs exhibit a half-life of days/weeks and diffused readily in nerve tissues. We tested one of TrkB-agoAbs further and showed that it enhanced motoneuron survival in the spinal-root avulsion model for motoneuron degeneration in vivo. Thus, TrkB-agoAbs are promising drug candidates for the treatment of neural injury.

Differences in Non-suicidal Self-injury Behaviors between Unipolar Depression and Bipolar Depression in Adolescent Outpatients.

OBJECTIVE: Non-suicidal self-injury (NSSI) has a higher prevalence in adolescents with depressive disorders than in community adolescents. This study examined the differences in NSSI behaviors between adolescents with unipolar depression (UD) and those with bipolar depression (BD). METHODS: Adolescents with UD or BD were recruited from 20 general or psychiatric hospitals across China. The methods, frequency, and function of NSSI were assessed by Functional Assessment of Self-Mutilation. The Beck Suicide Ideation Scale was used to evaluate adolescents' suicidal ideation, and the 10-item Kessler Psychological Distress Scale to estimate the anxiety and depression symptoms. RESULTS: The UD group had higher levels of depression (19.16 vs.17.37, F=15.23, P<0.001) and anxiety symptoms (17.73 vs.16.70, F=5.00, P=0.026) than the BD group. Adolescents with BD had a longer course of NSSI than those with UD (2.00 vs.1.00 year, Z=-3.39, P=0.001). There were no statistical differences in the frequency and the number of methods of NSSI between the UD and BD groups. Depression (r=0.408, P<0.01) and anxiety (r=0.391, P<0.01) were significantly and positively related to NSSI frequency. CONCLUSION: Adolescents with BD had a longer course of NSSI than those with UD. More importantly, NSSI frequency were positively and strongly correlated with depression and anxiety symptoms, indicating the importance of adequate treatment of depression and anxiety in preventing and intervening adolescents' NSSI behaviors.

Weakly supervised learning analysis of Aß plaque distribution in the whole rat brain.

Alzheimer's disease (AD) is a great challenge for the world and hardly to be cured, partly because of the lack of animal models that fully mimic pathological progress. Recently, a rat model exhibiting the most pathological symptoms of AD has been reported. However, high-resolution imaging and accurate quantification of beta-amyloid (Aß) plaques in the whole rat brain have not been fulfilled due to substantial technical challenges. In this paper, a high-efficiency data analysis pipeline is proposed to quantify Aß plaques in whole rat brain through several terabytes of image data acquired by a high-speed volumetric imaging approach we have developed previously. A novel segmentation framework applying a high-performance weakly supervised learning method which can dramatically reduce the human labeling consumption is described in this study. The effectiveness of our segmentation framework is validated with different metrics. The segmented Aß plaques were mapped to a standard rat brain atlas for quantitative analysis of the Aß distribution in each brain area. This pipeline may also be applied to the segmentation and accurate quantification of other non-specific morphology objects.

An App knock-in rat model for Alzheimer's disease exhibiting Aß and tau pathologies, neuronal death and cognitive impairments.

A major obstacle in Alzheimer's disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized Aß sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of Aß plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.

Gold(III) N-heterocyclic carbene complexes mediated synthesis of ß-enaminones from 1,3-dicarbonyl compounds and aliphatic amines.

A series of gold(III) N-heterocyclic carbene complexes [1-(R(1))-3-(R(2))imidazol-2-ylidene]AuBr(3) [R(1) = i-Pr, R(2) = CH(2)Ph (1c); R(1) = mesityl, R(2) = CH(2)Ph (2c); R(1) = i-Pr, R(2) = CH(2)COt-Bu (3c), and R(1) = t-Bu, R(2) = CH(2)COt-Bu (4c)] act as effective precatalysts in the synthesis of ß-enaminones from 1,3-dicarbonyl compounds and primary amines under ambient conditions. Specifically the 1c-4c complexes efficiently catalyzed the condensation of a variety of cyclic as well as acyclic 1,3-dicarbonyl compounds, namely, acetyl acetone, benzoylacetone, 2-acetylcyclopentanone, and ethyl-2-oxocyclopentanecarboxylate with primary aliphatic amines, viz., methylamine, ethylamine, n-propylamine, i-propylamine, and n-butylamine, yielding ß-enamines at room temperature. Interestingly enough, the more electrophilic gold(III) 1c-4c complexes exhibited superior activity in comparison to the gold(I) counterparts 1b-4b. A comparison along a representative 4a-c series further underscored the importance of gold in the reaction as both the gold(I) 4b and gold(III) 4c complexes were more effective than the silver analogue 4a. The density functional theory (DFT) study revealed that the strong σ-donating nature of the N-heterocyclic carbene ligand results in a strong C(carbene)-Au(III) interaction in the 1c-4c complexes.

Silicon-Carbon bond cleavage reactions of Ansa tungstenocene compounds: the [Me2Si] bridge as a site for metallocene functionalization.

[Me(2)Si(Cp(Me(2)))(2)]W(H)Cl is obtained via reaction of WCl(6) with a mixture of [Me(2)Si(Cp(Me(2)))(2)]Li(2) and NaBH(4), from which the dichloride [Me(2)Si(Cp(Me(2)))(2)]WCl(2) is obtained via treatment with CHCl(3). [Me(2)Si(Cp(Me(2)))(2)]WCl(2) provides a means to access other ansa tungstenocene compounds, such as [Me(2)Si(Cp(Me(2)))(2)]WH(2), [Me(2)Si(Cp(Me(2)))(2)]WMe(2), and [Me(2)Si(Cp(Me(2)))(2)]WCO. Of most interest, the reactions of [Me(2)Si(Cp(Me(2)))(2)]W(H)Cl with organolithium reagents do not yield simple ansa tungstenocene derivatives. Specifically, the reactions of [Me(2)Si(Cp(Me(2)))(2)]W(H)Cl with MeLi, Bu(n)Li, or PhLi result in the formation of mixed-ring tungstenocene compounds resulting from C-Si cleavage and functionalization of the ansa bridge, namely (Cp(Me(2)))(eta(5),kappa(1)-C(5)H(2)Me(2)SiMe(2)CH(2))WH, (Cp(Me(2)))[eta(5),kappa(1)-C(5)H(2)Me(2)Si(Me)(Bu(n))CH(2)]WH, and (Cp(Me(2)))[eta(5),kappa(1)-C(5)H(2)Me(2)SiMe(2)(C(6)H(4))]WH, respectively. In contrast to the C-Si cleavage achieved by MeLi, Bu(n)Li, and PhLi, the ansa bridge of [Me(2)Si(Cp(Me(2)))(2)]W(H)Cl is inert to Bu(t)Li and the product obtained is the fulvene ("tuck-in") complex [Me(2)Si(Cp(Me(2)))(eta(6)-C(5)MeH(2)CH(2))]WH derived from dehydrohalogenation.

2-Mercapto-1-t-butylimidazolyl as a Bridging Ligand: Synthesis and Structural Characterization of Nickel and Palladium Paddlewheel Complexes.

Nickel and palladium paddlewheel complexes that feature 2-mercapto-1-t-butylimidazolyl (mim(Bu(t) )) bridging ligands, namely Ni(2)[mim (Bu(t) )](4) and Pd(2)[mim (Bu(t) )](4), have been synthesized and structurally characterized by X-ray diffraction. Since the mim (Bu(t) ) ligand bridges in an asymmetric manner via a sulfur and nitrogen donor, paddlewheel compounds of the type M(2)[mim (Bu(t) )](4) may exist as isomers that are distinguished by the relative orientations of the ligands. In this regard, the (4,0)-Ni(2)[mim (Bu(t) )](4) and trans-(2,2)-Ni(2)[mim (Bu(t) )](4) isomers have been isolated for the nickel system, while the (4,0)-Pd(2)[mim (Bu(t) )](4) and (3,1)-Pd(2)[mim (Bu(t) )](4) isomers have been isolated for the palladium system.

Extracellular Juxtamembrane Motif Critical for TrkB Preformed Dimer and Activation.

Receptor tyrosine kinases are believed to be activated through ligand-induced dimerization. We now demonstrate that in cultured neurons, a substantial amount of endogenous TrkB, the receptor for brain-derived neurotrophic factor (BDNF), exists as an inactive preformed dimer, and the application of BDNF activates the pre-existing dimer. Deletion of the extracellular juxtamembrane motif (EJM) of TrkB increased the amount of preformed dimer, suggesting an inhibitory role of EJM on dimer formation. Further, binding of an agonistic antibody (MM12) specific to human TrkB-EJM activated the full-length TrkB and unexpectedly also truncated TrkB lacking ECD (TrkBdelECD365), suggesting that TrkB is activated by attenuating the inhibitory effect of EJM through MM12 binding-induced conformational changes. Finally, in cells co-expressing rat and human TrkB, MM12 could only activate TrkB human-human dimer but not TrkB human-rat TrkB dimer, indicating that MM12 binding to two TrkB monomers is required for activation. Our results support a model that TrkB preforms as an inactive dimer and BDNF induces TrkB conformation changes leading to its activation.

Reactivity of the Ni-->B dative sigma-bond in the nickel boratrane compounds [kappa4-B(mimBut)3]NiX (X=Cl, OAc, NCS, N3): synthesis of a series of B-functionalized tris(2-mercapto-1-tert-butylimidazolyl)borato complexes, [YTmBut)]NiZ.

The nickel boratrane complexes [kappa4-B(mimBut))3]Ni(kappa1-OAc), [kappa4-B(mimBut)3]NiNCS and [kappa4-B(mimBut)3]NiN3 are obtained via metathesis of the chloride ligand of [kappa4-B(mimBut)3]NiCl with TlOAc, KSCN and NaN3, respectively; the Ni-->B bond in these complexes is a site of reactivity, thereby providing a means of synthesizing nickel complexes that feature B-functionalized tris(mercaptoimidazolyl)borate derivatives, [YTmBut]NiZ.

Optical effects of S-oxidation and M(n+) binding in meso-thienyl dipyrrin systems and of stepwise bromination of 4,4-difluoro-8-(2,5-dibromo-3-thienyl)-4-bora-3a,4a-diaza-s-indacene.

We report 16 novel species and 8 molecular structures in studying how meso-thienyl-substituted dipyrrole oxidation, bromination, and metal ion binding impart optical changes, as monitored by UV-vis absorption/emission spectroscopy. Treatment of 4,4-difluoro-8-(3-benzothienyl)-4-bora-3a,4a-diaza-s-indacene (varphi(F) = 0.19) with m-CPBA gives selective S-dioxidation (varphi(F) = 0.006). Results of titrations of transition metal- and "scorpionate"-like dipyrrin species varied under room temperature treatment of m-CPBA. Ni-(thienyl-dipyrrin)(n) (n = 2) degraded significantly in the presence of m-CPBA, whereas related species (M = Cu, Fe, Co; n = 2, 3) were inert. meso-Thienyl group properties were revealed through the use of 3,4,4-triphenyl-8-(thienyl)-4-bora-3a,4a-diaza-s-indacene; Cu(2+) addition resulted in smooth absorption decreases which were modeled to support 1:1 substrate:M(2+) binding; for Hg(2+) 1:2 substrate:M(2+) binding was found. Treatment of 4,4-difluoro-8-(2,5-dibromo-3-thienyl)-4-bora-3a,4a-diaza-s-indacene with Br(2) gave red-shifted UV-vis absorption band features that grow with increasing dipyrrin bromination. Structures of the di- and tetra-substituted bromination products were obtained.

Magnesium boosts the memory restorative effect of environmental enrichment in Alzheimer's disease mice.

BACKGROUND: Environmental enrichment (EE) has been shown to enhance cognitive function in mouse models of Alzheimer's disease (AD). Magnesium-L-threonate (MgT) is a compound with a newly discovered effect to rescue learning and memory function in aging and AD mice. AIM: To study the additive therapeutic effect of EE combined with MgT (EM) and the potential mechanism underlying the effects. MATERIALS AND METHODS: APP/PS1 mice were treated with EE, MgT, or combination of EE and MgT (EM) and compared for restored memory function. RESULTS: EM was more effective in improving cognition and spatial memory than either treatment alone in either long-term (12 months, started at 3 months old, which was before disease manifestation) or short-term (3 months, started at 6 months old, which was after disease manifestation) treatment. The behavioral improvement has coincided with rescue of synaptic contacts in the hippocampal region of the AD mouse brain. Immunoblots also showed that EM but neither single treatment rescued the activity reduction in CaMKII and CREB, two important downstream molecules in the N-methyl-D-aspartate receptor (NMDAR) pathway. CONCLUSION: Environmental enrichment and MgT may synergistically improve recognition and spatial memory by reducing synaptic loss and restoring the NMDAR signaling pathway in AD mice, which suggests that combination of EE and MgT may be a novel therapeutic strategy for AD.

MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation.

Magnetic manipulation of cell activity offers advantages over optical manipulation but an ideal tool remains elusive. The MagR protein was found through its interaction with cryptochrome (Cry) and the protein in solution appeared to respond to magnetic stimulation (MS). After we initiated an investigation on the specific role of MagR in cellular response to MS, a subsequent study claimed that MagR expression alone could achieve cellular activation by MS. Here we report that despite systematically testing different ways of measuring intracellular calcium and different MS protocols, it was not possible to detect any cellular or neuronal responses to MS in MagR-expressing HEK cells or primary neurons from the dorsal root ganglion and the hippocampus. By contrast, in neurons co-expressing MagR and channelrhodopin, optical but not MS increased calcium influx in hippocampal neurons. Our results indicate that MagR alone is not sufficient to confer cellular magnetic responses.

Palladium complexes with Pd-->B dative bonds: analysis of the bonding in the palladaboratrane compound [kappa4-B(mimBut)3]Pd(PMe3).

The dinuclear complex {[mu-kappa(1),kappa(3)-B(mim(Bu(t)))(3)]Pd}(2), which features a Pd-->B dative bond, may be obtained by the reaction of [Tm(Bu(t))]K with Pd(OAc)(2); treatment of {[mu-kappa(1),kappa(3)-B(mim(Bu(t)))(3)]Pd}(2) with PMe(3) affords the mononuclear boratrane derivative [kappa(4)-B(mim(Bu(t)))(3)]Pd(PMe(3)), for which a molecular orbital analysis indicates that the palladium center possesses a d(8) configuration.

Synthesis and structural characterization of tris(2-seleno-1-mesitylimidazolyl) hydroborato complexes: a new type of strongly electron donating tripodal selenium ligand.

A new tripodal ligand that features three selenium donors, namely the tris(2-seleno-1-mesitylimidazolyl)hydroborato ligand, [Tse(Mes)], has been constructed via the reaction of KBH(4) with 1-mesitylimidazole-2-selone; comparison of the IR spectroscopic data of [Tse(Mes)]Re(CO)(3) with those of a variety of related LRe(CO)(3) complexes demonstrates that the [Tse(Mes)] ligand is more strongly electron donating than Cp, Cp*, [Tp], [Tp(Me(2))] and [Tm(Mes)] ligands.

A three dimensional porous metal-organic framework [Fe4L6.(DMF)3.(H2O)10] constructed from neutral discrete Fe4L6 pyramids [H2L = 1,3-benzodihydroxamix acid].

A 3-D porous zeolite-like metal-organic framework surviving guest removal is assembled from a well-defined tetrahedral Fe(4)L(6) cavity by the cooperativity of hydrogen bonds and [small pi]-[small pi] stacking.