Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is ...desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.
Protein cages are attractive building blocks to build high order materials such as 3D cage lattices, which offer accurately ordered bio-templates. However, controlling the size or valency of these ...cage-to-cage assemblies is extremely difficult due to highly multivalent and symmetric cage structures. Here, various high order cage assemblies with homogeneous sizes and geometries are constructed by developing an anisotropic ferritin cage with limitedly exposed binding modules, leucine zipper. The anisotropic ferritin is produced as expressed in cells without the need of complex
cage fabrication by careful subunit manipulation. Ferritin cages with limitedly exposed zippers are assembled around a core ferritin with fully exposed opposing zippers, generating homogeneous high order structures, whereas two fully exposed ferritins are assembled into heterogeneous cage aggregates. Diverse fully exposed core cages are prepared by varying the zipper-ferritin fusion geometries and even by using larger cage structures. With these core cages and the anisotropic ferritin, a range of high order cage assemblies with diverse ferritin valencies (3 to over 12) and sizes (over 40 nm) are created. Cell surface binding and internalization of cage structures are greatly varied by assembly sizes, where high order ferritins are clearly more effective than monomeric ferritin.
Most antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve therapeutic onset. ...This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here we show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibition of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Furthermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. Our results indicate that compounds that target mossy cell activity would be attractive candidates for the development of new antidepressant medications.
An early diagnosis of Alzheimer's disease is crucial as treatment efficacy is limited to the early stages. However, the current diagnostic methods are limited to mid or later stages of disease ...development owing to the limitations of clinical examinations and amyloid plaque imaging. Therefore, this study aimed to identify molecular signatures including blood plasma extracellular vesicle biomarker proteins associated with Alzheimer's disease to aid early‐stage diagnosis. The hippocampus, cortex, and blood plasma extracellular vesicles of 3‐ and 6‐month‐old 5xFAD mice were analyzed using quantitative proteomics. Subsequent bioinformatics and biochemical analyses were performed to compare the molecular signatures between wild type and 5xFAD mice across different brain regions and age groups to elucidate disease pathology. There was a unique signature of significantly altered proteins in the hippocampal and cortical proteomes of 3‐ and 6‐month‐old mice. The plasma extracellular vesicle proteomes exhibited distinct informatic features compared with the other proteomes. Furthermore, the regulation of several canonical pathways (including phosphatidylinositol 3‐kinase/protein kinase B signaling) differed between the hippocampus and cortex. Twelve potential biomarkers for the detection of early‐stage Alzheimer's disease were identified and validated using plasma extracellular vesicles from stage‐divided patients. Finally, integrin α‐IIb, creatine kinase M‐type, filamin C, glutamine γ‐glutamyltransferase 2, and lysosomal α‐mannosidase were selected as distinguishing biomarkers for healthy individuals and early‐stage Alzheimer's disease patients using machine learning modeling with approximately 79% accuracy. Our study identified novel early‐stage molecular signatures associated with the progression of Alzheimer's disease, thereby providing novel insights into its pathogenesis.
In this study, multi‐proteomic analyses revealed molecular signatures that can aid the elucidation of AD pathology. Moreover, our study identified candidate blood plasma EV biomarkers for the diagnosis of early‐stage AD, which included A2M, CKM, FLNA, ITGA2B, ORM2, PLTP, HP, QSOX1, TGM2, FLNC, HSP70, and MAN2B1.
Human ferritins are emerging platforms for non‐toxic protein‐based drug delivery, owing to their intrinsic or acquirable targeting abilities to cancer cells and hollow cage structures for drug ...loading. However, reliable strategies for high‐level drug encapsulation within ferritin cavities and prompt cellular drug release are still lacking. Ferritin nanocages were developed with partially opened hydrophobic channels, which provide stable routes for spontaneous and highly accumulated loading of FeII‐conjugated drugs as well as pH‐responsive rapid drug release at endoplasmic pH. Multiple cancer‐related compounds, such as doxorubicin, curcumin, and quercetin, were actively and heavily loaded onto the prepared nicked ferritin. Drugs on these minimally modified ferritins were effectively delivered inside cancer cells with high toxicity.
Spontaneous and high‐level uptake of diverse drugs onto a ferritin nanocage was achieved by fractionally opening hydrophobic channels of ferritin. Drug–FeII complexes were actively and stably accumulated in this nicked ferritin and delivered inside cells by the cell targeting ability of ferritin in a pH‐responsive manner.
Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic ...stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.
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•Traumatic stress exposure debilitates contextual discrimination•Dentate gyrus MCs are suppressed in response to traumatic stress•MC inhibition is causally linked to impaired contextual discrimination•MCs coordinate context-specific granule cell ensembles for proper pattern separation
Jeong et al. provide the cell type-specific mechanism in the DG that underlies contextual fear generalization resulting from traumatic stress and reveal a potential therapeutic target for cognitive symptoms of PTSD.
Human ferritin has been heavily investigated as a protein‐based drug deliver agent, due to its unique hollow cage structure for drug loading and an intrinsic tumor targeting function. However, facile ...strategies for high‐level drug loading and controlled release have not been established, which hampered the use of ferritin as an in vivo delivery platform. We examined active drug uptake and release patterns of various flopped ferritin variants, which use fourfold channels as a route for drug uptake. A flopped channel pore structure was adjusted by diverse mutations around the helix‐connecting loop of the channel. Active loading and release of anti‐cancer drug doxorubicin for these ferritin variants were quantitatively monitored. Drug‐loading ability and spontaneous release degree were both enhanced by channel flopping and a pore size increase. The results could lay a stepping stone for further understanding of drug loading via fourfold ferritin channels.
Characterization of active drug uptake processes with fourfold channel flopped ferritin variants: Active drug loading and release properties of flopped ferritins were closely monitored to investigate the effects of fourfold channel structures for this attractive drug‐loading method of cage protein drug delivery vesicles.
With increasing coffee production and consumption, the amount of coffee by-product is also increasing. Therefore, there is growing worldwide interest in using these by-products as a renewable energy ...source. In this study, hydrothermal carbonization was conducted with subcritical water to improve the fuel characteristics of spent coffee grounds. The water content was varied, with the mass ratio between the dry sample and water set to 1:1.5 and 1:4. The reaction temperature was increased by 10 °C from 180 to 250 °C. The fuel and thermal characteristics of the reaction products were investigated through mass and energy yields, elemental, proximate, and heating value analysis. In analysis results, as the reaction temperature increased, carbon and fixed carbon content increased, and oxygen and volatile matter content decreased, resulting in an increase in calorific value. Thermogravimetric analysis, derivative thermogravimetry, and Fourier transform infrared spectroscopy were also conducted on the reaction products. To investigate their storage characteristics, chemical oxygen demand analysis was conducted. The results showed that with increasing reaction temperature, the fixed carbon content and heating value increased; also, the fuel characteristics became similar to those of coal. In addition, the reaction products became more hydrophobic as the reaction temperature increased.
Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory ...impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARβ) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.
Organic printable dielectric layers are required for next‐generation electronic circuits, particularly those used as gate insulators (GIs) in organic field‐effect transistors (OFETs). Herein, ...optimized electrohydrodynamic (EHD) jet printing with an electrostatic force‐assisted mode is suggested for the fabrication of polyvinyl alcohol (PVA)‐based dielectric patterns after careful consideration of the ink system. The PVA molecules maintain good solubility in polar solvents, even when a crosslinking agent is added, which enables a continuous PVA jet stream with a width smaller than the diameter of the nozzle to be stably obtained. Subsequent EHD printing produces uniform PVA patterns with a smooth surface morphology suitable for the crystal growth of overlying organic semiconductors. The addition of a crosslinking agent in PVA results in direct GI patterns that exhibit superior insulating properties with high dielectric strength as compared with PVA without crosslinking agents. The OFETs with PVA‐based GIs prepared with EHD printing show stable operation with low gate leakage currents. In addition, the feasibility of EHD‐printed PVA layers is demonstrated for application as GIs in organic complementary logic gates.
Electrohydrodynamic (EHD) printing produces uniform polyvinyl alcohol (PVA)‐based gate insulators (GIs), even after adding optimized crosslinking agent (PMF). PMF effectively cross links the printed GIs that show high dielectric strength. Fully covering the patterned gate electrodes with printed GIs enables to fabricate integrated devices, including complementary inverters, and NAND/NOR logic gates, showing good switching performances.
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