Retinoids: A group of tetraterpenes, with four terpene units joined head-to-tail. Biologically active members of this class are used clinically in the treatment of severe cystic ACNE; PSORIASIS; and other disorders of keratinization.Ligands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)Tretinoin: An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE).Receptors, Retinoic Acid: Proteins in the nucleus or cytoplasm that specifically bind RETINOIC ACID or RETINOL and trigger changes in the behavior of cells. Retinoic acid receptors, like steroid receptors, are ligand-activated transcription regulators. Several types have been recognized.Vitamin A: Retinol and derivatives of retinol that play an essential role in metabolic functioning of the retina, the growth of and differentiation of epithelial tissue, the growth of bone, reproduction, and the immune response. Dietary vitamin A is derived from a variety of CAROTENOIDS found in plants. It is enriched in the liver, egg yolks, and the fat component of dairy products.Acitretin: An oral retinoid effective in the treatment of psoriasis. It is the major metabolite of ETRETINATE with the advantage of a much shorter half-life when compared with etretinate.Isotretinoin: A topical dermatologic agent that is used in the treatment of ACNE VULGARIS and several other skin diseases. The drug has teratogenic and other adverse effects.Retinoid X Receptors: A subtype of RETINOIC ACID RECEPTORS that are specific for 9-cis-retinoic acid which function as nuclear TRANSCRIPTION FACTORS that regulate multiple signaling pathways.Retinol-Binding Proteins: Proteins which bind with RETINOL. The retinol-binding protein found in plasma has an alpha-1 mobility on electrophoresis and a molecular weight of about 21 kDa. The retinol-protein complex (MW=80-90 kDa) circulates in plasma in the form of a protein-protein complex with prealbumin. The retinol-binding protein found in tissue has a molecular weight of 14 kDa and carries retinol as a non-covalently-bound ligand.Keratolytic Agents: Agents that soften, separate, and cause desquamation of the cornified epithelium or horny layer of skin. They are used to expose mycelia of infecting fungi or to treat corns, warts, and certain other skin diseases.Etretinate: An oral retinoid used in the treatment of keratotic genodermatosis, lichen planus, and psoriasis. Beneficial effects have also been claimed in the prophylaxis of epithelial neoplasia. The compound may be teratogenic.Retinaldehyde: A carotenoid constituent of visual pigments. It is the oxidized form of retinol which functions as the active component of the visual cycle. It is bound to the protein opsin forming the complex rhodopsin. When stimulated by visible light, the retinal component of the rhodopsin complex undergoes isomerization at the 11-position of the double bond to the cis-form; this is reversed in "dark" reactions to return to the native trans-configuration.Tetrahydronaphthalenes: Partially saturated 1,2,3,4-tetrahydronaphthalene compounds.CD40 Ligand: A membrane glycoprotein and differentiation antigen expressed on the surface of T-cells that binds to CD40 ANTIGENS on B-LYMPHOCYTES and induces their proliferation. Mutation of the gene for CD40 ligand is a cause of HYPER-IGM IMMUNODEFICIENCY SYNDROME, TYPE 1.Benzoates: Derivatives of BENZOIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxybenzene structure.Fenretinide: A synthetic retinoid that is used orally as a chemopreventive against prostate cancer and in women at risk of developing contralateral breast cancer. It is also effective as an antineoplastic agent.Retinol-Binding Proteins, Cellular: A subclass of retinol-binding proteins that take part in the intracellular storage and transport of RETINOL. They are both functionally and structurally distinct from PLASMA RETINOL-BINDING PROTEINS.Fas Ligand Protein: A transmembrane protein belonging to the tumor necrosis factor superfamily that was originally discovered on cells of the lymphoid-myeloid lineage, including activated T-LYMPHOCYTES and NATURAL KILLER CELLS. It plays an important role in immune homeostasis and cell-mediated toxicity by binding to the FAS RECEPTOR and triggering APOPTOSIS.beta-Carotene 15,15'-Monooxygenase: A monooxygenase that catalyzes the conversion of BETA-CAROTENE into two molecules of RETINAL. It was formerly characterized as EC 1.13.11.21 and EC 1.18.3.1.Vitamin A Deficiency: A nutritional condition produced by a deficiency of VITAMIN A in the diet, characterized by NIGHT BLINDNESS and other ocular manifestations such as dryness of the conjunctiva and later of the cornea (XEROPHTHALMIA). Vitamin A deficiency is a very common problem worldwide, particularly in developing countries as a consequence of famine or shortages of vitamin A-rich foods. In the United States it is found among the urban poor, the elderly, alcoholics, and patients with malabsorption. (From Cecil Textbook of Medicine, 19th ed, p1179)Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Nicotinic Acids: 2-, 3-, or 4-Pyridinecarboxylic acids. Pyridine derivatives substituted with a carboxy group at the 2-, 3-, or 4-position. The 3-carboxy derivative (NIACIN) is active as a vitamin.Retinal Dehydrogenase: A metalloflavoprotein enzyme involved the metabolism of VITAMIN A, this enzyme catalyzes the oxidation of RETINAL to RETINOIC ACID, using both NAD+ and FAD coenzymes. It also acts on both the 11-trans- and 13-cis-forms of RETINAL.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Dermatologic Agents: Drugs used to treat or prevent skin disorders or for the routine care of skin.Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.RANK Ligand: A transmembrane protein belonging to the tumor necrosis factor superfamily that specifically binds RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B and OSTEOPROTEGERIN. It plays an important role in regulating OSTEOCLAST differentiation and activation.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Anticarcinogenic Agents: Agents that reduce the frequency or rate of spontaneous or induced tumors independently of the mechanism involved.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Kinetics: The rate dynamics in chemical or physical systems.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Isomerism: The phenomenon whereby certain chemical compounds have structures that are different although the compounds possess the same elemental composition. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)beta Carotene: A carotenoid that is a precursor of VITAMIN A. It is administered to reduce the severity of photosensitivity reactions in patients with erythropoietic protoporphyria (PORPHYRIA, ERYTHROPOIETIC). (From Reynolds JEF(Ed): Martindale: The Extra Pharmacopoeia (electronic version). Micromedex, Inc, Engewood, CO, 1995.)Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Receptors, Cytoplasmic and Nuclear: Intracellular receptors that can be found in the cytoplasm or in the nucleus. They bind to extracellular signaling molecules that migrate through or are transported across the CELL MEMBRANE. Many members of this class of receptors occur in the cytoplasm and are transported to the CELL NUCLEUS upon ligand-binding where they signal via DNA-binding and transcription regulation. Also included in this category are receptors found on INTRACELLULAR MEMBRANES that act via mechanisms similar to CELL SURFACE RECEPTORS.Retinol-Binding Proteins, Plasma: Retinol binding proteins that circulate in the PLASMA. They are members of the lipocalin family of proteins and play a role in the transport of RETINOL from the LIVER to the peripheral tissues. The proteins are usually found in association with TRANSTHYRETIN.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.CD30 Ligand: A membrane-bound tumor necrosis family member found primarily on activated T-LYMPHOCYTES that binds specifically to CD30 ANTIGEN. It may play a role in INFLAMMATION and immune regulation.Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells.TNF-Related Apoptosis-Inducing Ligand: A transmembrane-protein belonging to the TNF family of intercellular signaling proteins. It is a widely expressed ligand that activates APOPTOSIS by binding to TNF-RELATED APOPTOSIS-INDUCING LIGAND RECEPTORS. The membrane-bound form of the protein can be cleaved by specific CYSTEINE ENDOPEPTIDASES to form a soluble ligand form.Acne Vulgaris: A chronic disorder of the pilosebaceous apparatus associated with an increase in sebum secretion. It is characterized by open comedones (blackheads), closed comedones (whiteheads), and pustular nodules. The cause is unknown, but heredity and age are predisposing factors.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Carotenoids: The general name for a group of fat-soluble pigments found in green, yellow, and leafy vegetables, and yellow fruits. They are aliphatic hydrocarbons consisting of a polyisoprene backbone.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).Hypervitaminosis A: A symptom complex resulting from ingesting excessive amounts of VITAMIN A.Retinoid X Receptor alpha: A nuclear transcription factor. Heterodimerization with PPAR GAMMA is important in regulation of GLUCOSE metabolism and CELL GROWTH PROCESSES.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.Retinol O-Fatty-Acyltransferase: An enzyme that catalyzes the acyl group transfer of acyl COENZYME A to RETINOL to generate COENZYME A and a retinyl ester.Mice, Inbred C57BLChromatography, High Pressure Liquid: Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Dibenzazepines: Compounds with two BENZENE rings fused to AZEPINES.cis-trans-Isomerases: Enzymes that catalyze the rearrangement of geometry about double bonds. EC 5.2.OX40 Ligand: A membrane-bound tumor necrosis family member that is expressed on activated antigen-presenting cells such as B-LYMPHOCYTES and MACROPHAGES. It signals T-LYMPHOCYTES by binding the OX40 RECEPTOR.Receptors, Cell Surface: Cell surface proteins that bind signalling molecules external to the cell with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell (From Alberts, Molecular Biology of the Cell, 2nd ed, pp693-5). Cell surface receptors, unlike enzymes, do not chemically alter their ligands.Cell Line, Tumor: A cell line derived from cultured tumor cells.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Chromans: Benzopyrans saturated in the 2 and 3 positions.Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer.Transcriptional Activation: Processes that stimulate the GENETIC TRANSCRIPTION of a gene or set of genes.Recombinant Fusion Proteins: Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
  • This receptor and its heterodimeric partner retinoid X receptor α (RXRα) form a DNA-binding complex that regulates transcription of adipocyte-specific genes ( 7 - 11 ). (pnas.org)
  • Moreover, given the protective role of Nurr1, this study also investigated how Nurr1 could be pharmacologically targeted via bexarotene, a ligand of Nurr1's heterodimerization partner retinoid X receptor (RXR). (scilifelab.se)
  • Studies of these mutants revealed that trimethylation of Lys 347 of RARα facilitated its interactions with cofactors p300/CREB-binding protein-associated factor and receptor-interacting protein 140 as well as its heterodimeric partner retinoid X receptor, suggesting that site-specific hydrophobicity at Lys 347 enhanced molecular interaction of RARα with its modulators. (mcponline.org)
  • The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999. (wikipedia.org)
  • Dynamics and ligand-induced solvent accessibility changes in human retinoid X receptor homodimer determined by hydrogen deuterium exchange and mass spectrometry. (semanticscholar.org)
  • The crystal structure of the human retinoid-X receptor RXR-alpha ligand-binding domain reveals a previously undiscovered fold of an antiparallel alpha-helical sandwich, packed as dimeric units. (nih.gov)
  • Selective RXR ligands, referred to as rexinoids, are already used or are being developed for cancer therapy and have promise for the treatment of metabolic diseases. (rcsb.org)
  • This volume explores the latest synthetic procedures for producing receptor-specific retinoids and rexinoids, molecular biology methods, and new technologies to demonstrate the therapeutic activities of molecules. (springer.com)
  • Carotenoids as possible interphotoreceptor retinoid-binding protein (IRBP) ligands: a surface plasmon resonance (SPR) based study. (semanticscholar.org)
  • here, we consider the potential role of interphotoreceptor retinoid-binding protein (IRBP) in this process. (semanticscholar.org)
  • It has been proposed that the interphotoreceptor retinoid-binding protein (IRBP) is essential for this intercellular exchange, and that it serves to prevent the potentially cytotoxic effects of retinoids. (jneurosci.org)
  • One of the more unique members of this family is the interphotoreceptor retinoid-binding protein (IRBP), a large glycoprotein (M r ∼140 kDa) synthesized by the visual cells and extruded into the interphotoreceptor matrix (IPM) of the vertebrate retina. (jneurosci.org)
  • Cutting-edge and comprehensive, Retinoid and Rexinoid Signaling: Methods and Protocols is a valuable resources for graduate students, postdoctoral fellows, and principal investigators who are interested in further exploring the signaling mechanisms of these molecules in their specific preclinical models. (springer.com)
  • In some cases, pharmacologic doses of retinoids can overcome these cancer specific defects in retinoid signaling. (springer.com)
  • Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. (scilifelab.se)
  • Coyle KM, Sultan M, Thomas M, Kashani AV, Marcato P (2013) Retinoid Signaling in Cancer and its Promise for Therapy. (omicsonline.org)
  • Here, we will review the RA signaling pathway in normal and malignant hematopoiesis, and will discuss the advantages and the limitations related to retinoid therapy in acute myeloid leukemia. (mdpi.com)
  • The goal of this work was to test the hypothesis that activation of retinoid acid (RA) signaling in the central nervous system (CNS) would be neuroprotective in ALS. (frontiersin.org)
  • To demonstrate RARβ's neuroprotective role in vitro , we found that activation of retinoid signaling through the RARβ receptor significantly increased survival of primary motor neurons in response to oxidative stress. (frontiersin.org)
  • Together, these data suggest that that activation of retinoid signaling may be an adaptive, protective response to cell damage in ALS. (frontiersin.org)
  • Since altered retinoid signaling has been implicated in experimental myopia, we explored the role of this pathway in the lrp2 mutant phenotype. (arvojournals.org)
  • Retinoid signaling is required for the establishment of a ZPA and for the expression of Hoxb-8, a mediator of ZPA formation. (mpg.de)
  • We show that neurons deficient in nuclear retinoid signaling are responsive to odors and form correct odorant receptor-specific axonal projections to target neurons in the olfactory bulb of the brain. (jneurosci.org)
  • In addition, we find that nuclear retinoid signaling is required for the expression of a retinoic acid-degrading enzyme, Cyp26B1, in a small fraction of mature neurons. (jneurosci.org)
  • Olfactory sensory neurons (OSNs) in the olfactory epithelium and their synaptic target structures, the glomeruli of the olfactory bulb, provide a useful system to determine the role of retinoid signaling during formation, refinement, maintenance, and/or regeneration of an axonal projection map in mammals. (jneurosci.org)
  • We provide evidence that RARE-dependent transcription and local homeostatic control of retinoids is required for the maintenance of a population of functional neurons with established projections and that inhibition of retinoid signaling results in postnatal and adult neurodegeneration. (jneurosci.org)
  • Ligand-dependent transcriptional activation of RARs is a multistep process that ends with the formation of a multimeric co-activator complex on regulated promoters (1,2). (novusbio.com)
  • When ligand is bound, the receptor undergoes conformational changes, leading to a decrease in the interaction with corepressors and an increase in interactions with co-activators such as SRC-1 and GRIP-1, which then leads to transcriptional activation. (creative-biogene.com)
  • Modifying effects of 1'-acetoxychavicol acetate (ACA) and the novel synthetic retinoids Re-80, Am-580 and Am-55P in a two-stage carcinogenesis model in female rats. (curehunter.com)
  • Prospects include modulation of the epigenetic status of ATRA-insensitive AML cells, agents that influence intracellular signalling events that are provoked by ATRA, and the use of novel synthetic retinoids. (hindawi.com)
  • Consistent with the finding that anti-retinoid X receptor (RXR) could supershift the NR1-nuclear protein complex, DNA affinity chromatography with NR1 oligonucleotides enriched the nuclear orphan receptor RXR from the hepatic nuclear extracts of phenobarbital-treated mice. (asm.org)
  • The VDR-RXR conformation (which was more ligand-sensitive) gained through EB1089 a higher affinity (7-fold) for DNA binding and a more sensitive (9-fold) activation of an IP9-type VDRE than of a DR3-type VDRE, whereas with the natural hormone VD, no VDRE-type preference could be observed. (aspetjournals.org)
  • This indicates that promoter selectivity of VDR ligands is based on their property to selectively increase affinity for VDREs and very sensitively stabilize VDR conformations in VDR-RXR-VDRE complexes. (aspetjournals.org)
  • Vitamin A and its derivatives (retinoids) play an essential role in the development and maintenance of various tissues throughout the body. (jneurosci.org)
  • Vitamin D Receptor (VDR) and Retinoid X Receptor (RXR) a. are ligand-inducible transcription factors. (bl.uk)
  • Authoritative and cutting-edge, Retinoids: Methods and Protocols seeks to aid beginning and experienced researchers from widely varied fields in the search to uncover even more vital aspects of vitamin A's impact on the human body. (springer.com)
  • However, the pleiotropic effects of vitamin A derivatives have made it difficult to determine whether retinoid signals act directly or indirectly on OSNs and/or their progenitors. (jneurosci.org)
  • These and other results suggest that RPE cells modulate emmetropization in part by controlling homeostasis of periocular retinoids, and dysregulation contributes high myopia. (arvojournals.org)
  • Considering this role of RXR, it is obvious that the relative activities of retinoids at RAR and RXR may have profound effects on their overall biological effects. (aspetjournals.org)
  • To determine whether 22( R )-OHC and CDCA bind to similar structural features of FXR, site-directed mutagenesis was performed in the FXR ligand binding domain. (aspetjournals.org)
  • Vision in all vertebrates is dependent on an exchange of retinoids between the retinal pigment epithelium and the visual photoreceptors. (jneurosci.org)