Cross-and-Diagonal Networks: An Indirect Self-Attention Mechanism for Image Classification.

In recent years, computer vision has witnessed remarkable advancements in image classification, specifically in the domains of fully convolutional neural networks (FCNs) and self-attention mechanisms. Nevertheless, both approaches exhibit certain limitations. FCNs tend to prioritize local information, potentially overlooking crucial global contexts, whereas self-attention mechanisms are computationally intensive despite their adaptability. In order to surmount these challenges, this paper proposes cross-and-diagonal networks (CDNet), innovative network architecture that adeptly captures global information in images while preserving local details in a more computationally efficient manner. CDNet achieves this by establishing long-range relationships between pixels within an image, enabling the indirect acquisition of contextual information. This inventive indirect self-attention mechanism significantly enhances the network's capacity. In CDNet, a new attention mechanism named "cross and diagonal attention" is proposed. This mechanism adopts an indirect approach by integrating two distinct components, cross attention and diagonal attention. By computing attention in different directions, specifically vertical and diagonal, CDNet effectively establishes remote dependencies among pixels, resulting in improved performance in image classification tasks. Experimental results highlight several advantages of CDNet. Firstly, it introduces an indirect self-attention mechanism that can be effortlessly integrated as a module into any convolutional neural network (CNN). Additionally, the computational cost of the self-attention mechanism has been effectively reduced, resulting in improved overall computational efficiency. Lastly, CDNet attains state-of-the-art performance on three benchmark datasets for similar types of image classification networks. In essence, CDNet addresses the constraints of conventional approaches and provides an efficient and effective solution for capturing global context in image classification tasks.

Chronic Pb exposure impairs learning and memory abilities by inhibiting excitatory projection neuro-circuit of the hippocampus in mice.

Lead (Pb) is an environmental neurotoxic metal. Chronic Pb exposure causes behavioral changes in humans and rodents, such as dysfunctional learning and memory. Nevertheless, it is not clear whether Pb exposure disrupts the neural circuit. Thus, here we aim at investigating the effects the chronic Pb exposure on neural-behavioral and neural circuits in mice from prenatal to postnatal day (PND) 63. Pregnant mice and their male offspring were treated with Pb (150 ppm) until postnatal day 63. In this study, several behavior tests and Golgi-Cox staining methods were used to assess spatial memory ability and synaptogenesis. Virus-based tracing systems and immunohistochemistry assays were used to test the relevance of chronic Pb exposure with disrupted neural circuits. The behavioral experiments and Golgi-Cox staining results showed that Pb exposure impaired spatial memory and spine density in mice. The virus tracing results revealed that the Entorhinal cortex (EC) neurons could be directly projected to Cornuammonis 1 (CA1) and Dentate gyrus (DG), forming a critical circuit inhibited, in either a direct or indirect way, by Pb invasion. In addition, excitatory neural input from EC（labeled with CaMKII）to CA1 and DG was significantly attenuated by Pb exposure. In conclusion, our data indicated that Pb significantly impaired the excitatory connections from EC to the hippocampus (CA1 and DG), providing a novel neuro-circuitry basis for Pb neurotoxicity.

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.

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.

Phytohormone Abscisic Acid Improves Spatial Memory and Synaptogenesis Involving NDR1/2 Kinase in Rats.

The abscisic acid (ABA) is a phytohormone involved in plant growth, development and environmental stress response. Recent study showed ABA can also be detected in other organisms, including mammals. And it has been reported that ABA can improve learning and memory in rats. In this study, we attempted to investigate the effects of ABA on the alternation of dendritic spine morphology of pyramidal neurons in developmental rats, which may underlie the learning and memory function. Behavior tests showed that ABA significantly improved spatial memory performance. Meanwhile, Golgi-Cox staining assay showed that ABA significantly increased the spine density and the percentage of mushroom-like spines in pyramidal neurons of hippocampus, indicating that ABA increased dendritic spine formation and maturation, which may contribute to the improvement of spatial memory. Furthermore, ABA administration increased the protein expression of NDR1/2 kinase, as well as mRNA levels of NDR2 and its substrate Rabin8. In addition, NDR1/2 shRNA prohibited the ABA-induced increases in the expression of NDR1/2 and spine density. Together, our study indicated that ABA could improve learning and memory in rats and the effect are possibly through the regulation of synaptogenesis, which is mediated via NDR1/2 kinase pathway.

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.

Kiwifruit Alleviates Learning and Memory Deficits Induced by Pb through Antioxidation and Inhibition of Microglia Activation In Vitro and In Vivo.

Lead (Pb) exposure, in particular during early postnatal life, increases susceptibility to cognitive dysfunction and neurodegenerative outcomes. The detrimental effect of Pb exposure is basically due to an increasing ROS production which overcomes the antioxidant systems and finally leads to cognitive dysfunction. Kiwifruit is rich in the antioxidants like vitamin C and polyphenols. This study aims to investigate the effects and mechanism of kiwifruit to alleviate learning and memory deficits induced by Pb exposure. Sprague-Dawley (SD) rat pups acquired Pb indirectly through their mothers during lactation period and after postnatal day 21 (PND21) directly acquired Pb by themselves. Five kinds of kiwifruits were collected in this study and the amounts of vitamin C and polyphenols in them were measured and the antioxidation effects were determined. Among them, Qinmei kiwifruit (Qm) showed the strongest antioxidation effects in vitro. In vivo, Qm significantly repaired Pb-induced learning and memory deficits and dendritic spine loss. In addition, Pb compromised the enzymatic activity and transcriptional levels of SOD and GSH-Px and decreased the microglial activation, which, to some extent, could be reversed by Qm kiwifruit administration. The results suggest that kiwifruit could alleviate Pb-induced cognitive deficits possibly through antioxidative stress and microglia inactivation. Consequently, kiwifruit could be potentially regarded as the functional food favorable in the prevention and treatment of Pb intoxication.

ß-Asarone Rescues Pb-Induced Impairments of Spatial Memory and Synaptogenesis in Rats.

Chronic lead (Pb) exposure causes cognitive deficits. This study aimed to explore the neuroprotective effect and mechanism of ß-asarone, an active component from Chinese Herbs Acorus tatarinowii Schott, to alleviate impairments of spatial memory and synaptogenesis in Pb-exposed rats. Both Sprague-Dawley developmental rat pups and adult rats were used in the study. Developmental rat pups were exposed to Pb throughout the lactation period and ß-asarone (10, 40mg kg-1, respectively) was given intraperitoneally from postnatal day 14 to 21. Also, the adult rats were exposed to Pb from embryo stage to 11 weeks old and ß-asarone (2.5, 10, 40mg kg-1, respectively) was given from 9 to 11 weeks old. The level of ß-asarone in brain tissue was measured by High Performance Liquid Chromatography. The Morris water maze test and Golgi-Cox staining method were used to assess spatial memory ability and synaptogenesis. The protein expression of NR2B subunit of NMDA receptor, Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and Wnt family member 7A (Wnt7a) in hippocampus, as well as mRNA expression of Arc/Arg3.1 and Wnt7a, was also explored. We found that ß-asarone could pass through the blood brain barrier quickly. And ß-asarone effectively attenuated Pb-induced reduction of spine density in hippocampal CA1 and dentate gyrus areas in a dose-dependent manner both in developmental and adult rats, meanwhile the Pb-induced impairments of learning and memory were partially rescued. In addition, ß-asarone effectively up-regulated the protein expression of NR2B, Arc and Wnt7a, as well as the mRNA levels of Arc/Arg3.1 and Wnt7a, which had been suppressed by Pb exposure. The results suggest the neuroprotective properties of ß-asarone against Pb-induced memory impairments, and the effect is possibly through the regulation of synaptogenesis, which is mediated via Arc/Arg3.1 and Wnt pathway.