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Adenosine A Receptor mRNA Expression by Neurons and Glia in the Auditory Forebrain.
Hackett TA
(2018) Anat Rec (Hoboken) 301: 1882-1905
MeSH Terms: Animals, Auditory Cortex, Female, Gene Expression, Geniculate Bodies, Male, Mice, Mice, Inbred C57BL, Neuroglia, Neurons, Prosencephalon, RNA, Messenger, Receptor, Adenosine A1
Show Abstract · Added March 3, 2020
In the brain, purines such as ATP and adenosine can function as neurotransmitters and co-transmitters, or serve as signals in neuron-glial interactions. In thalamocortical (TC) projections to sensory cortex, adenosine functions as a negative regulator of glutamate release via activation of the presynaptic adenosine A1 receptor (A R). In the auditory forebrain, restriction of A R-adenosine signaling in medial geniculate (MG) neurons is sufficient to extend LTP, LTD, and tonotopic map plasticity in adult mice for months beyond the critical period. Interfering with adenosine signaling in primary auditory cortex (A1) does not contribute to these forms of plasticity, suggesting regional differences in the roles of A R-mediated adenosine signaling in the forebrain. To advance understanding of the circuitry, in situ hybridization was used to localize neuronal and glial cell types in the auditory forebrain that express A R transcripts (Adora1), based on co-expression with cell-specific markers for neuronal and glial subtypes. In A1, Adora1 transcripts were concentrated in L3/4 and L6 of glutamatergic neurons. Subpopulations of GABAergic neurons, astrocytes, oligodendrocytes, and microglia expressed lower levels of Adora1. In MG, Adora1 was expressed by glutamatergic neurons in all divisions, and subpopulations of all glial classes. The collective findings imply that A R-mediated signaling broadly extends to all subdivisions of auditory cortex and MG. Selective expression by neuronal and glial subpopulations suggests that experimental manipulations of A R-adenosine signaling could impact several cell types, depending on their location. Strategies to target Adora1 in specific cell types can be developed from the data generated here. Anat Rec, 301:1882-1905, 2018. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
© 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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MeSH Terms
Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain.
Fujiyama T, Miyashita S, Tsuneoka Y, Kanemaru K, Kakizaki M, Kanno S, Ishikawa Y, Yamashita M, Owa T, Nagaoka M, Kawaguchi Y, Yanagawa Y, Magnuson MA, Muratani M, Shibuya A, Nabeshima YI, Yanagisawa M, Funato H, Hoshino M
(2018) Cell Rep 24: 79-94
MeSH Terms: Animals, Cell Lineage, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Gonads, Hypothalamus, Male, Mice, Inbred C57BL, Mice, Knockout, Prosencephalon, Sex Differentiation, Sexual Behavior, Animal, Transcription Factors
Show Abstract · Added July 27, 2018
The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.
Muller CL, Anacker AM, Rogers TD, Goeden N, Keller EH, Forsberg CG, Kerr TM, Wender C, Anderson GM, Stanwood GD, Blakely RD, Bonnin A, Veenstra-VanderWeele J
(2017) Neuropsychopharmacology 42: 427-436
MeSH Terms: Animals, Female, Genotype, Maternal-Fetal Exchange, Mice, Inbred Strains, Mice, Transgenic, Placenta, Pregnancy, Prosencephalon, Rhombencephalon, Serotonin, Serotonin Plasma Membrane Transport Proteins, Thalamus
Show Abstract · Added August 31, 2018
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.
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Differential impact of genetically modulated choline transporter expression on the release of endogenous versus newly synthesized acetylcholine.
Iwamoto H, Calcutt MW, Blakely RD
(2016) Neurochem Int 98: 138-45
MeSH Terms: Acetylcholine, Animals, Animals, Genetically Modified, Choline, Gene Expression, Genotype, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Potassium, Prosencephalon, Synaptic Transmission
Show Abstract · Added February 3, 2017
The efficient import of choline into cholinergic nerve terminals by the presynaptic, high-affinity choline transporter (CHT, SLC5A7) dictates the capacity for acetylcholine (ACh) synthesis and release. Tissue levels of ACh are significantly reduced in mice heterozygous for a loss of function mutation in Slc5a7 (HET, CHT(+/-)), but significantly elevated in overexpressing, Slc5a7 BAC-transgenic mice (BAC). Since the readily-releasable pool of ACh is thought to constitute a small fraction of the total ACh pool, these genotype-dependent changes raised the question as to whether CHT expression or activity might preferentially influence the size of reserve pool ACh vesicles. In the current study, we approached this question by evaluating CHT genotype effects on the release of ACh from suprafused mouse forebrain slices. We treated slices from HET, BAC or wildtype (WT) controls with elevated K(+) and monitored release of both newly synthesized and storage pools of ACh. Newly synthesized ACh produced following uptake of [(3)H]choline was quantified by scintillation spectrometry whereas release of endogenous ACh storage pools was quantified by an HPLC-MS approach, from the same samples. Whereas endogenous ACh release scaled with CHT gene dosage, preloaded [(3)H]ACh release displayed no significant genotype dependence. Our findings suggest that CHT protein levels preferentially impact the capacity for ACh release afforded by mobilization of reserve pool vesicles.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.
Mingote S, Chuhma N, Kusnoor SV, Field B, Deutch AY, Rayport S
(2015) J Neurosci 35: 16259-71
MeSH Terms: Animals, Channelrhodopsins, DNA-Binding Proteins, Dopamine Plasma Membrane Transport Proteins, Dopaminergic Neurons, Excitatory Postsynaptic Potentials, Female, Glutamic Acid, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Neural Pathways, Neurotransmitter Agents, Phosphopyruvate Hydratase, Prosencephalon, Transduction, Genetic, Tyrosine 3-Monooxygenase, Ventral Tegmental Area
Show Abstract · Added February 22, 2016
UNLABELLED - In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome.
SIGNIFICANCE STATEMENT - Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are capable of glutamate cotransmission. With conditional expression of channelrhodopsin in dopamine neurons, we systematically explored dopamine neuron connections in the forebrain and identified regionally specific dopamine neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from dopamine neurons will help to determine the function of dopamine neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of dopamine neuron signals.
Copyright © 2015 the authors 0270-6474/15/3516259-13$15.00/0.
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20 MeSH Terms
Transcriptional maturation of the mouse auditory forebrain.
Hackett TA, Guo Y, Clause A, Hackett NJ, Garbett K, Zhang P, Polley DB, Mirnics K
(2015) BMC Genomics 16: 606
MeSH Terms: Animals, Animals, Newborn, Auditory Cortex, Cluster Analysis, Databases, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Male, Mice, Prosencephalon, Sequence Analysis, RNA
Show Abstract · Added February 22, 2016
BACKGROUND - The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well.
RESULTS - The main findings were: (1) Global gene expression patterns were tightly clustered by postnatal age and brain region; (2) comparing A1 and MG, the total numbers of differentially expressed genes were comparable from P7 to P21, then dropped to nearly half by adulthood; (3) comparing successive age groups, the greatest numbers of differentially expressed genes were found between P7 and P14 in both regions, followed by a steady decline in numbers with age; (4) maturational trajectories in expression levels varied at the single gene level (increasing, decreasing, static, other); (5) between regions, the profiles of single genes were often asymmetric; (6) GSEA revealed that genesets related to neural activity and plasticity were typically upregulated from P7 to adult, while those related to structure tended to be downregulated; (7) GSEA and pathways analysis of selected functional networks were not predictive of expression patterns in the auditory forebrain for all genes, reflecting regional specificity at the single gene level.
CONCLUSIONS - Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age. Maturational changes are evident at the global through single gene levels. Transcriptome profiles in A1 and MG are distinct at all ages, and differ from other brain regions. The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.
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13 MeSH Terms
Quantitative proteomics analysis of CaMKII phosphorylation and the CaMKII interactome in the mouse forebrain.
Baucum AJ, Shonesy BC, Rose KL, Colbran RJ
(2015) ACS Chem Neurosci 6: 615-31
MeSH Terms: Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Membrane, Cytosol, Gene Knock-In Techniques, HEK293 Cells, Holoenzymes, Humans, Immunoprecipitation, Male, Mass Spectrometry, Mice, Transgenic, Phosphorylation, Prosencephalon, Proteomics, Recombinant Proteins, Sf9 Cells, Spodoptera, Synapses
Show Abstract · Added February 15, 2016
Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) autophosphorylation at Thr286 and Thr305/Thr306 regulates kinase activity and modulates subcellular targeting and is critical for normal synaptic plasticity and learning and memory. Here, a mass spectrometry-based approach was used to identify Ca(2+)-dependent and -independent in vitro autophosphorylation sites in recombinant CaMKIIα and CaMKIIβ. CaMKII holoenzymes were then immunoprecipitated from subcellular fractions of forebrains isolated from either wild-type (WT) mice or mice with a Thr286 to Ala knock-in mutation of CaMKIIα (T286A-KI mice) and analyzed using the same approach in order to characterize in vivo phosphorylation sites in both CaMKII isoforms and identify CaMKII-associated proteins (CaMKAPs). A total of six and seven autophosphorylation sites in CaMKIIα and CaMKIIβ, respectively, were detected in WT mice. Thr286-phosphorylated CaMKIIα and Thr287-phosphorylated CaMKIIβ were selectively enriched in WT Triton-insoluble (synaptic) fractions compared to Triton-soluble (membrane) and cytosolic fractions. In contrast, Thr306-phosphorylated CaMKIIα and Ser315- and Thr320/Thr321-phosphorylated CaMKIIβ were selectively enriched in WT cytosolic fractions. The T286A-KI mutation significantly reduced levels of phosphorylation of CaMKIIα at Ser275 across all subcellular fractions and of cytosolic CaMKIIβ at Ser315 and Thr320/Thr321. Significantly more CaMKAPs coprecipitated with WT CaMKII holoenzymes in the synaptic fraction compared to that in the membrane fraction, with functions including scaffolding, microtubule organization, actin organization, ribosomal function, vesicle trafficking, and others. The T286A-KI mutation altered the interactions of multiple CaMKAPs with CaMKII, including several proteins linked to autism spectrum disorders. These data identify CaMKII isoform phosphorylation sites and a network of synaptic protein interactions that are sensitive to the abrogation of Thr286 autophosphorylation of CaMKIIα, likely contributing to the diverse synaptic and behavioral deficits of T286A-KI mice.
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19 MeSH Terms
Identification and characterization of ML352: a novel, noncompetitive inhibitor of the presynaptic choline transporter.
Ennis EA, Wright J, Retzlaff CL, McManus OB, Lin Z, Huang X, Wu M, Li M, Daniels JS, Lindsley CW, Hopkins CR, Blakely RD
(2015) ACS Chem Neurosci 6: 417-27
MeSH Terms: Animals, Benzamides, Choline, Dose-Response Relationship, Drug, Enzyme Inhibitors, Gene Expression Regulation, HEK293 Cells, Hemicholinium 3, Humans, Isoxazoles, Male, Membrane Potentials, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Models, Biological, Mutation, Neural Inhibition, Prosencephalon, Protein Binding, Rats, Rats, Sprague-Dawley, Synaptosomes
Show Abstract · Added February 12, 2015
The high-affinity choline transporter (CHT) is the rate-limiting determinant of acetylcholine (ACh) synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. To expand CHT pharmacology, we pursued a high-throughput screen for novel CHT-targeted small molecules based on the electrogenic properties of transporter-mediated choline transport. In this effort, we identified five novel, structural classes of CHT-specific inhibitors. Chemical diversification and functional analysis of one of these classes identified ML352 as a high-affinity (Ki = 92 nM) and selective CHT inhibitor. At concentrations that fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase (AChE) or cholineacetyltransferase (ChAT) and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and synaptosomes and reduced the apparent density of hemicholinium-3 (HC-3) binding sites in membrane assays, suggesting allosteric transporter interactions. Pharmacokinetic studies revealed limited in vitro metabolism and significant CNS penetration, with features predicting rapid clearance. ML352 represents a novel, potent, and specific tool for the manipulation of CHT, providing a possible platform for the development of cholinergic imaging and therapeutic agents.
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23 MeSH Terms
Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory.
Wieczorek L, Majumdar D, Wills TA, Hu L, Winder DG, Webb DJ, Muglia LJ
(2012) Transl Psychiatry 2: e126
MeSH Terms: Adenylyl Cyclases, Animals, Calcium, Crosses, Genetic, Fear, Gene-Environment Interaction, Hippocampus, Long-Term Potentiation, Membrane Glycoproteins, Mental Recall, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins, Neurogenesis, Neuronal Plasticity, Prosencephalon, Synapses
Show Abstract · Added May 19, 2014
Ca(2+)-stimulated adenylyl cyclase (AC) 1 and 8 are two genes that have been shown to play critical roles in fear memory. AC1 and AC8 couple neuronal activity and intracellular Ca(2+) increases to the production of cyclic adenosine monophosphate and are localized synaptically, suggesting that Ca(2+)-stimulated ACs may modulate synaptic plasticity. Here, we first established that Ca(2+)-stimulated ACs modulate protein markers of synaptic activity at baseline and after learning. Primary hippocampal cell cultures showed that AC1/AC8 double-knockout (DKO) mice have reduced SV2, a synaptic vesicle protein, abundance along their dendritic processes, and this reduction can be rescued through lentivirus delivery of AC8 to the DKO cells. Additionally, phospho-synapsin, a protein implicated in the regulation of neurotransmitter release at the synapse, is decreased in vivo 1 h after conditioned fear (CF) training in DKO mice. Importantly, additional experiments showed that long-term potentiation deficits present in DKO mice are rescued by acutely replacing AC8 in the forebrain, further supporting the idea that Ca(2+)-stimulated AC activity is a crucial modulator of synaptic plasticity. Previous studies have demonstrated that memory is continually modulated by gene-environment interactions. The last set of experiments evaluated the effects of knocking out AC1 and AC8 genes on experience-dependent changes in CF memory. We showed that the strength of CF memory in wild-type mice is determined by previous environment, minimal or enriched, whereas memory in DKO mice is unaffected. Thus, overall these results show that AC1 and AC8 modulate markers of synaptic activity and help integrate environmental information to modulate fear memory.
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18 MeSH Terms
Substrate-selective and calcium-independent activation of CaMKII by α-actinin.
Jalan-Sakrikar N, Bartlett RK, Baucum AJ, Colbran RJ
(2012) J Biol Chem 287: 15275-83
MeSH Terms: Actinin, Actins, Amino Acid Sequence, Animals, Binding Sites, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Enzyme Activation, HEK293 Cells, Humans, Immunoblotting, Mice, Microscopy, Fluorescence, Models, Molecular, Molecular Sequence Data, Mutation, Phosphorylation, Prosencephalon, Protein Binding, Protein Structure, Tertiary, Receptors, N-Methyl-D-Aspartate, Sequence Homology, Amino Acid, Serine, Substrate Specificity, Threonine
Show Abstract · Added December 5, 2013
Protein-protein interactions are thought to modulate the efficiency and specificity of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) signaling in specific subcellular compartments. Here we show that the F-actin-binding protein α-actinin targets CaMKIIα to F-actin in cells by binding to the CaMKII regulatory domain, mimicking CaM. The interaction with α-actinin is blocked by CaMKII autophosphorylation at Thr-306, but not by autophosphorylation at Thr-305, whereas autophosphorylation at either site blocks Ca(2+)/CaM binding. The binding of α-actinin to CaMKII is Ca(2+)-independent and activates the phosphorylation of a subset of substrates in vitro. In intact cells, α-actinin selectively stabilizes CaMKII association with GluN2B-containing glutamate receptors and enhances phosphorylation of Ser-1303 in GluN2B, but inhibits CaMKII phosphorylation of Ser-831 in glutamate receptor GluA1 subunits by competing for activation by Ca(2+)/CaM. These data show that Ca(2+)-independent binding of α-actinin to CaMKII differentially modulates the phosphorylation of physiological targets that play key roles in long-term synaptic plasticity.
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25 MeSH Terms