Search

The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson's disease (PD). In addition to motor symptoms, some PD patients may experience non-motor symptoms, including cognitive and memory deficits. A possible explanation for their manifestation is a disturbed pattern of dopamine release in brain regions involved in learning and memory, such as the hippocampus. Therefore, investigating neuropathological alterations in dopamine release prior to neurodegeneration is imperative. This study aimed to characterize evoked hippocampal dopamine release and assess the impact of the neurotoxin MPP + using a genetically encoded dopamine sensor and gene expression analysis. Additionally, considering the potential neuroprotective attributes demonstrated by apoptosis signal-regulating kinase 1 ( Ask1 ) in various animal-disease-like models, the study also aimed to determine whether Ask1 knockdown restores MPP + -altered dopamine release in acute hippocampal slices. We applied variations of low- and high-frequency stimulation to evoke dopamine release within different hippocampal regions and discovered that acute application of MPP + reduced the amount of dopamine released and hindered the recovery of dopamine release after repeated stimulation. In addition, we observed that Ask1 deficiency attenuated the detrimental effects of MPP + on the recovery of dopamine release after repeated stimulation. RNA sequencing analysis indicated that genes associated with the synaptic pathways are involved in response to MPP + exposure. Notably, Ask1 deficiency was found to downregulate the expression of Slc5a7 , a gene encoding a sodium-dependent high-affinity choline transporter that regulates acetylcholine levels. Respective follow-up experiments indicated that Slc5a7 plays a role in Ask1 deficiency-mediated protection against MPP + neurotoxicity. In addition, increasing acetylcholine levels using an acetylcholinesterase inhibitor could exacerbate the toxicity of MPP + . In conclusion, our data imply that the modulation of the dopamine-acetylcholine balance may be a crucial mechanism of action underlying the neuroprotective effects of Ask1 deficiency in PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zhao, Li, Zhuang, Yan, Gao and Behnisch.)

Structural supercapacitors (SSCs) are multifunctional energy storage composites (MESCs) that combine the mechanical properties of fiber-reinforced polymers and the electrochemical performance of supercapacitors to reduce the overall mass in lightweight applications with electrical energy consumption. These novel MESCs have huge potentials, and their properties have improved dramatically since their introduction in the early 2000's. However, the current properties of SSCs are not sufficient for complete energy supply of electrically driven devices. To overcome this drawback, the aim of the current study is to identify key areas for enhancement of the multifunctional performance of SSCs. Critical modification paths for the SSC constituents are systematically analyzed. Special focus is given to the improvement of carbon fiber-based electrodes, the selection of structural electrolytes and the implementation of separators for the development of more efficient SSCs. Finally, current SSCs are compared in terms of their multifunctionality including material combinations and modifications.

The hippocampal formation, particularly the CA2 subregion, is critical for social memory formation and memory processing, relying on synaptic plasticity-a fundamental mechanism by which synapses strengthen. Given the role of the ubiquitin-proteasome system (UPS) in various nervous system processes, including learning and memory, we were particularly interested in exploring the involvement of RING-type ubiquitin E3 ligases, such as UHRF2 (NIRF), in social behavior and synaptic plasticity. Our results revealed altered social behavior in mice with systemic Uhrf2 knockout, including changes in nest building, tube dominance, and the three-chamber social novelty test. In Uhrf2 knockout mice, the entorhinal cortex-CA2 circuit showed significant reductions in synaptic plasticity during paired-pulse facilitation and long-term potentiation, while the inability to evoke synaptic plasticity in the Schaffer-collateral CA2 synapses remained unaffected. These changes in synaptic plasticity correlated with significant changes in gene expression including genes related to vesicle trafficking and transcriptional regulation. The effects of Uhrf2 knockout on synaptic plasticity and the observed gene expression changes highlight UHRF2 as a regulator of learning and memory processes at both the cellular and systemic levels. Targeting E3 ubiquitin ligases, such as UHRF2, may hold therapeutic potential for memory-related disorders, warranting further investigation.

NRSF/REST (neuron-restrictive silencer element, also known as repressor element 1-silencing transcription factor), plays a key role in neuronal homeostasis as a transcriptional repressor of neuronal genes. NRSF/REST relates to cognitive preservation and longevity of humans, but its specific functions in age-dependent and Alzheimer's disease (AD)-related memory deficits remain unclear. Here, we show that conditional NRSF/REST knockout either in the dorsal telencephalon or specially in neurons induced an age-dependently diminished retrieval performance in spatial or fear conditioning memory tasks and altered hippocampal synaptic transmission and activity-dependent synaptic plasticity. The NRSF/REST deficient mice were also characterized by an increase of activated glial cells, complement C3 protein and the transcription factor C/EBPβ in the cortex and hippocampus. Reduction of NRSF/REST by conditional depletion upregulated the activation of astrocytes in APP/PS1 mice, and increased the C3-positive glial cells, but did not alter the Aβ loads and memory retrieval performances of 6- and 12-month-old APP/PS1 mice. Simultaneously, overexpression of NRSF/REST improved cognitive abilities of aged wild type, but not in AD mice. These findings demonstrated that NRSF/REST is essential for the preservation of memory performance and activity-dependent synaptic plasticity during aging and takes potential roles in the onset of age-related memory impairments. However, while altering the glial activation, NRSF/REST deficiency does not interfere with the Aβ deposits and the electrophysiological and cognitive AD-like pathologies., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Parkinson's disease (PD) is a neurodegenerative disease that affects both motor and non-motor functions. Although motor impairment is a prominent clinical sign of PD, additional neurological symptoms may also occur, particularly in the preclinical and prodromal stages. Among these symptoms, social cognitive impairment is common and detrimental. This article aims to review non-motor symptoms in PD patients, focusing on social cognitive deficits. It also examines the specific characteristics of the CA2 region and its involvement in social behavior, highlighting recent advances and perspectives. Additionally, this review provides critical insights into and analysis of research conducted in rodents and humans, which may help improve the understanding of the current status of putative therapeutic strategies for social cognitive dysfunction in PD and potential avenues related to the function of the hippocampal CA2 region.

Freeze Foams are cellular, ceramic structures with hierarchical pore structures that are manufactured using the direct foaming process. By tailoring their morphology and strength, these foam structures are able to cover a wide range of application. Earlier works identified that pore-forming influencing factors (water and air content, suspension temperature, as well as pressure reduction rate) dictate the constitution on a macroscopic and microscopic scale. Therefore, the ability to manufacture foams whose properties align with the component requirements would be an important step in advancing towards a widespread application of these promising materials. With this goal in mind, the correlation between the pore-forming influencing factors and the resulting mechanical properties was quantified. Foams with independently adjustable porosities were produced at the micro and macro scales and evaluated according to their material failure behavior under compressive loads. As a result, foams with determined macroporosities between 38 and 62%, microporosities between 25 and 42%, and compression strengths between 1 and 7 MPa with different material failure characteristics were manufactured and systematically investigated.

Freeze foaming is a method to manufacture cellular ceramic scaffolds with a hierarchical porous structure. These so-called freeze foams are predestined for the use as bone replacement material because of their internal bone-like structure and biocompatibility. On the one hand, they consist of macrostructural foam cells which are formed by the expansion of gas inside the starting suspension. On the other hand, a porous microstructure inside the foam struts is formed during freezing and subsequent freeze drying of the foamed suspension. The aim of this work is to investigate for the first time the formation of macrostructure and microstructure separately depending on the composition of the suspension and the pressure reduction rate, by means of appropriate characterization methods for the different pore size ranges. Moreover, the foaming behavior itself was characterized by in-situ radiographical and computed tomography (CT) evaluation. As a result, it could be shown that it is possible to tune the macro- and microstructure separately with porosities of 49-74% related to the foam cells and 10-37% inside the struts.

Haploinsufficiency in SYNGAP1 is implicated in intellectual disability (ID) and autism spectrum disorder (ASD) and affects the maturation of dendritic spines. The abnormal spine development has been suggested to cause a disbalance of excitatory and inhibitory (E/I) neurotransmission at distinct developmental periods. In addition, E/I imbalances in Syngap1 +/- mice might be due to abnormalities in K + -Cl - co-transporter function (NKCC1, KCC2), in a maner similar to the murine models of Fragile-X and Rett syndromes. To study whether an altered intracellular chloride ion concentration represents an underlying mechanism of modified function of GABAergic synapses in Dentate Gyrus Granule Cells of Syngap1 +/- recordings were performed at different developmental stages of the mice. We observed depolarised neurons at P14-15 as illustrated by decreased Cl - reversal potential in Syngap1 +/- mice. The KCC2 expression was decreased compared to Wild-type (WT) mice at P14-15. The GSK-3β inhibitor, 6-bromoindirubin-3'-oxime (6BIO) that crosses the blood-brain barrier, was tested to restore the function of GABAergic synapses. We discovered that the intraperitoneal administration of 6BIO during the critical period or young adolescents [P30 to P80 (4-week to 10-week)] normalised an altered E/I balance, the deficits of synaptic plasticity, and behavioural performance like social novelty, anxiety, and memory of the Syngap1 +/- mice. In summary, altered GABAergic function in Syngap1 +/- mice is due to reduced KCC2 expression leading to an increase in the intracellular chloride concentration that can be counteracted by the 6BIO, which restored cognitive, emotional, and social symptoms by pharmacological intervention, particularly in adulthood., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years because of its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the nonselective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic AChR activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the threshold for the subsequent induction of persistent long-term potentiation (LTP) of synaptic transmission at EC-CA2 and the plasticity-resistant SC-CA2 pathways. The effects of such a cholinergic-dependent synaptic depression on subsequent LTP at EC-CA2 and SC-CA2 synapses have not been previously explored. Collectively, the results demonstrate that CA2 synaptic learning rules are regulated in a metaplastic manner, whereby modifications triggered by prior cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the reinforcement of LTP at EC inputs to CA2 following the priming stimulus coexists with concurrent sustained CCh-LTD at the SC-CA2 pathway and is dynamically scaled by modulation of SC-CA2 synaptic transmission. SIGNIFICANCE STATEMENT The release of the neuromodulator acetylcholine is critically involved in processes of hippocampus-dependent memory formation. Cholinergic afferents originating in the medial septum and diagonal bands of Broca terminating in the hippocampal area CA2 might play an important role in the modulation of area-specific synaptic plasticity. Our findings demonstrate that cholinergic receptor activation induces an LTD of synaptic transmission at entorhinal cortical- and Schaffer collateral-CA2 synapses. This cholinergic activation-mediated LTD displays a bidirectional metaplastic switch to LTP on a future timescale. This suggests that such bidirectional synaptic modifications triggered by the dynamic modulation of tonic cholinergic receptor activation may support the formation of CA2-dependent memories given the increased hippocampal cholinergic tone during active wakefulness observed in exploratory behavior., (Copyright © 2021 the authors.)

Membrane lipids and their metabolism have key functions in neurotransmission. Here we provide a quantitative lipid inventory of mouse and rat synaptic junctions. To this end, we developed a multiomics extraction and analysis workflow to probe the interplay of proteins and lipids in synaptic signal transduction from the same sample. Based on this workflow, we generate hypotheses about novel mechanisms underlying complex changes in synaptic connectivity elicited by environmental stimuli. As a proof of principle, this approach reveals that in mice exposed to an enriched environment, reduced endocannabinoid synthesis and signaling is linked to increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in a subset of Cannabinoid-receptor 1 positive synapses. This mechanism regulates synaptic strength in an input-specific manner. Thus, we establish a compartment-specific multiomics workflow that is suitable to extract information from complex lipid and protein networks involved in synaptic function and plasticity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Generative hybridization enables the efficient production of lightweight structures by combining classic manufacturing processes with additive manufacturing technologies. This type of functionalization process allows components with high geometric complexity and high mechanical properties to be produced efficiently in small series without the need for additional molds. In this study, hybrid specimens were generated by additively depositing PA6 (polyamide 6) via fused layer modeling (FLM) onto continuous woven fiber GF/PA6 (glass fiber/polyamide 6) flat preforms. Specifically, the effects of surface pre-treatment and process-induced surface interactions were investigated using optical microscopy for contact angle measurements as well as laser profilometry and thermal analytics. The bonding characteristic at the interface was evaluated via quasi-static tensile pull-off tests. Results indicate that both the bond strength and corresponding failure type vary with pre-treatment settings and process parameters during generative hybridization. It is shown that both the base substrate temperature and the FLM nozzle distance have a significant influence on the adhesive tensile strength. In particular, it can be seen that surface activation by plasma can significantly improve the specific adhesion in generative hybridization.

Continuous carbon fibre-reinforced thermoplastic composites have convincing anisotropic properties, which can be used to strengthen structural components in a local, variable and efficient way. In this study, an additive manufacturing (AM) process is introduced to fabricate in situ consolidated continuous fibre-reinforced polycarbonate. Specimens with three different nozzle temperatures were in situ consolidated and tested in a three-point bending test. Computed tomography (CT) is used for a detailed analysis of the local material structure and resulting material porosity, thus the results can be put into context with process parameters. In addition, a highly curved test structure was fabricated that demonstrates the limits of the process and dependent fibre strand folding behaviours. These experimental investigations present the potential and the challenges of additive manufacturing-based in situ consolidated continuous fibre-reinforced polycarbonate.

Background: The transcriptional repressor positive regulatory domain I-binding factor 1 (PRDM1) is expressed in adult mouse dorsal root ganglion and regulates the formation and function of peripheral sensory neurons. The authors hypothesized that PRDM1 in the dorsal root ganglion may contribute to peripheral nerve injury-induced nociception regulation and that its mechanism may involve Kv4.3 channel transcriptional repression., Methods: Nociception was induced in C57BL/6 mice by applying chronic constriction injury, complete Freund's adjuvant, or capsaicin plantar injection. Nociceptive response was evaluated by mechanical allodynia, thermal hyperalgesia, cold hyperalgesia, or gait analysis. The role of PRDM1 was evaluated by injection of Prdm1 knockdown and overexpression adeno-associated viruses. The interaction of PRDM1 at the Kv4.3 (Kcnd3) promoter was evaluated by chromatin immunoprecipitation assay. Excitability of dorsal root ganglion neurons was evaluated by whole cell patch clamp recordings, and calcium signaling in spinal dorsal horn neurons was evaluated by in vivo two-photon imaging., Results: Peripheral nerve injury increased PRDM1 expression in the dorsal root ganglion, which reduced the activity of the Kv4.3 promoter and repressed Kv4.3 channel expression (injured vs. uninjured; all P < 0.001). Knockdown of PRDM1 rescued Kv4.3 expression, reduced the high excitability of injured dorsal root ganglion neurons, and alleviated peripheral nerve injury-induced nociception (short hairpin RNA vs. Scram; all P < 0.05). In contrast, PRDM1 overexpression in naive mouse dorsal root ganglion neurons diminished Kv4.3 channel expression and induced hyperalgesia (PRDM1 overexpression vs. control, mean ± SD; n = 13; all P < 0.0001) as evaluated by mechanical allodynia (0.6 ± 0.3 vs. 1.2 ± 0.2 g), thermal hyperalgesia (5.2 ± 1.3 vs. 9.8 ± 1.7 s), and cold hyperalgesia (3.4 ± 0.5 vs. 5.3 ± 0.6 s). Finally, PRDM1 downregulation in naive mice reduced the calcium signaling response of spinal dorsal horn neurons to thermal stimulation., Conclusions: PRDM1 contributes to peripheral nerve injury-induced nociception by repressing Kv4.3 channel expression in injured dorsal root ganglion neurons., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2'-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D 1 and D 2 receptors and GABA A receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.