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At least 1,171 records · Page 65Linked to original sources
PubMed2006

A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes.

Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with numerous transcription factors and contains multiple functional domains. Currently, it is not known which transcription factor-binding domain of CBP is essential for memory storage. Using mice that carry inactivating mutations in the CREB-binding (KIX) domain of the coactivator CBP (CBPKIX/KIX mice), we show that the KIX domain is required for long-term memory storage. These results are the first to identify an in vivo function for the KIX domain of CBP in the brain, and they suggest that KIX-interacting transcription factors recruit CBP histone acetyltransferase activity during long-term memory storage. One such KIX-interacting factor is the transcription factor CREB. Using quantitative real-time RT-PCR, we find that the expression of specific CREB target genes is reduced in the hippocampi of CBPKIX/KIX mice during memory consolidation. The recruitment of the transcriptional coactivator CBP via the KIX domain thus imparts target gene-dependent selectivity to CREB-driven transcriptional regulation, thereby activating genes required for the long-term storage of hippocampus-dependent memory.

Animals↗
PubMed2006

Neuronal substrates of motor learning in the velocity storage generated during optokinetic stimulation in the squirrel monkey.

Chronic motor learning in the vestibuloocular reflex (VOR) results in changes in the gain of this reflex and in other eye movements intimately associated with VOR behavior, e.g., the velocity storage generated by optokinetic stimulation (OKN velocity storage). The aim of the present study was to identify the plastic sites responsible for the change in OKN velocity storage after chronic VOR motor learning. We studied the neuronal responses of vertical eye movement flocculus target neurons (FTNs) during the optokinetic after-nystagmus (OKAN) phase of the optokinetic response (OKR) before and after VOR motor learning. Our findings can be summarized as follows. 1) Chronic VOR motor learning changes the horizontal OKN velocity storage in parallel with changes in VOR gain, whereas the vertical OKN velocity storage is more complex, increasing with VOR gain increases, but not changing following VOR gain decreases. 2) FTNs contain an OKAN signal having opposite directional preferences after chronic high versus low gain learning, suggesting a change in the OKN velocity storage representation of FTNs. 3) Changes in the eye-velocity sensitivity of FTNs during OKAN are correlated with changes in the brain stem head-velocity sensitivity of the same neurons. And 4) these changes in eye-velocity sensitivity of FTNs during OKAN support the new behavior after high gain but not low gain learning. Thus we hypothesize that the changes observed in the OKN velocity storage behavior after chronic learning result from changes in brain stem pathways carrying head velocity and OKN velocity storage information, and that a parallel pathway to vertical FTNs changes its OKN velocity storage representation following low, but not high, gain VOR motor learning.

Adaptation, Physiological↗
PubMed2000

Plasticity of the superior olivary complex.

The superior olivary complex (SOC) is part of the auditory brainstem of the vertebrate brain. Residing ventrally in the rhombencephalon, it receives sensory signals from both cochleae through multisynaptic pathways. Neurons of the SOC are also a target of bilateral descending projections. Ascending and descending efferents of the SOC affect the processing of auditory signals on both sides of the brainstem and in both organs of Corti. The pattern of connectivity indicates that the SOC fulfills functions of binaural signal integration serving sound localization. But whereas many of these connectional features are shared with the inferior colliculus (with the important exception of a projection to the inner ear), cellular and molecular investigations have shown that cells residing in SOC are unique in several respects. Unlike those of other auditory brainstem nuclei, they specifically express molecules known to be involved in development, plasticity, and learning (e.g., GAP-43 mRNA, specific subunits of integrin). Moreover, neurons of the SOC in adult mammals respond to various kinds of hearing impairment with the expression of plasticity-related substances (e.g., GAP-43, c-Jun, c-Fos, cytoskeletal elements), indicative of a restructuring of auditory connectivity. These observations suggest that the SOC is pivotal in the developmental and adaptive tuning of binaural processing in young and adult vertebrates.

Animals↗
PubMed1995

Distinct adhesive properties of ciliary and choroid neurons from the avian ciliary ganglion.

The avian ciliary ganglion (CG) contains two populations of neurons: ciliary neurons, which innervate striated muscle, and choroid neurons, which innervate vascular smooth muscle. We used cell size (ciliary cells are larger) and somatostatin immunoreactivity (which is restricted to choroid cells) as markers to compare the adhesive properties of these two neuronal types. Similar numbers of freshly dissociated embryonic chick ciliary and choroid neurons adhered to laminin (laminin 1) and polylysine, consistent with the fact that each population comprises about half of the ganglionic neurons. In contrast, severalfold more ciliary neurons than choroid neurons adhered to a recombinant fragment of a synapsespecific basal lamina protein, s-laminin/laminin beta 2. Moreover, severalfold more ciliary neurons than choroid neurons adhered to a plastic surface when assayed by the method of Needels et al. in serum-free medium. Adhesion to s-laminin and plastic appears to be mediated by different cell surface components, as adhesion to recombinant s-laminin is inhibited by the tripeptide, LRE, and by Ca2+ ions, but not by heparin, whereas adhesion to plastic is LRE and Ca2+ insensitive but heparin sensitive. Both adhesive differences are apparent at embryonic day 8, soon after the ciliary and choroid neurons have begun to form synapses. Thus, two sets of neurons in the CG that send axons through different nerves and innervate different targets also show distinct adhesive behaviors.

Animals↗
PubMed1998

Output-to-input approach to neural plasticity in vestibular pathways.

Some thoughts on current interpretations of available data regarding vestibular compensation at functional, network, and neural levels are presented. Basic concepts related to neural plasticity (or elasticity) underlying motor learning and regeneration also are discussed briefly. Modifiability in vestibular pathways, at both the functional and structural levels, after peripheral and central axotomy, and subsequent to transient or permanent chemical target removal, is presented as an experimental ground to explain similarities and differences between regenerative, compensatory, and adaptive mechanisms in the mammal central nervous system.

Abducens Nerve↗
PubMed2005

LY303511 (2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one) acts via phosphatidylinositol 3-kinase-independent pathways to inhibit cell proliferation via mammalian target of rapamycin (mTOR)- and non-mTOR-dependent mechanisms.

Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates cell growth and proliferation in part via the activation of p70 S6 kinase (S6K). Rapamycin is an antineo-plastic agent that, in complex with FKBP12, is a specific inhibitor of mTOR through interaction with its FKBP12-rapamycin binding domain, thereby causing G(1) cell cycle arrest. However, cancer cells often develop resistance to rapamycin, and alternative inhibitors of mTOR are desired. 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) blocks mTOR kinase activity, but it also inhibits phosphatidylinositol 3-kinase (PI3K), an enzyme that regulates cellular functions other than proliferation. We hypothesized that a close structural analog, 2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one (LY303511) might inhibit mTOR-dependent cell proliferation without unwanted effects on PI3K. In human lung epithelial adenocarcinoma (A549) cells, LY303511, like rapamycin, inhibited mTOR-dependent phosphorylation of S6K, but not PI3K-dependent phosphorylation of Akt. LY303511 blocked proliferation in A549 as well as in primary pulmonary artery smooth muscle cells, without causing apoptosis. In contrast to rapamycin, LY303511 reduced G(2)/M progression as well as G(2)/M-specific cyclins in A549 cells. Consistent with an additional mTOR-independent kinase target, LY303511 inhibited casein kinase 2 activity, a known regulator of G(1) and G(2)/M progression. In addition to its antiproliferative effect in vitro, LY303511 inhibited the growth of human prostate adenocarcinoma tumor implants in athymic mice. Given its inhibition of cell proliferation via mTOR-dependent and independent mechanisms, LY303511 has therapeutic potential with antineoplastic actions that are independent of PI3K inhibition.

Animals↗
PubMed2006

Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.

Alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)), we studied the role of alphaCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus-dependent spatial learning in the Morris water maze. Wild-type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild-type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning-specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, alphaCaMKII(T286A) mice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild-type controls after water-maze training. Notably, both trained and swim-control groups of alphaCaMKII(T286A) mutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal alphaCaMKII function. This result demonstrates dissociation of alphaCaMKII-independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitability per se are not perfectly correlated with learning. Our findings suggest that alphaCaMKII signaling may function to suppress learning-unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.

Action Potentials↗
PubMed1993

Binding of some metastatic tumor cell lines to fibrous elastin and elastin peptides.

Recent suggestions that tumor-cell targeting of elastin-rich tissues (e.g., lung) correlates with the presence of surface elastin receptors have been investigated. Receptors for insoluble (fibrous) elastin and for soluble elastin peptides have been implemented in these correlations. A rapid assay for binding of insoluble elastin has been devised. Two of the cell lines tested (M27 and MAT-LyLu), which metastasize to the lung, strongly bound fibrous elastin whereas a third (B16-F10) did not. None of 4 metastatic cell lines that do not target the lung (A549, 3LL, TA3, TA3-iso2) bound fibrous elastin. The ability of cell lines to interact with soluble elastin was tested by cell attachment to high-molecular-weight soluble elastin peptides adsorbed on a plastic surface. Three of 7 tested cell lines, B16-F10, M27 and TA3, attached to a soluble elastin coating. In contrast to the rapid binding of insoluble elastin particles, the cell interaction with immobilized soluble elastin peptides was delayed, suggesting that induction of receptors for soluble elastin and/or modification of the elastin coat was occurring. Thus, all 3 tested cell lines where metastases target the lung, namely, MAT-LyLu, B16-F10 and M-27, show soluble- or insoluble-elastin interactions, whereas, of 4 cell lines not targeting lungs, only one, TA3, reacts with soluble elastin.

Adenocarcinoma↗
PubMed2006

Transfusion and transplantation of cryopreserved cells and tissues.

The modern era of cryomedicine began in 1949 in London and developed world-wide in the second half of the 20th century based on the first report of a novel method of cryopreservation of sperm and erythrocytes using glycerol that was reported in 1949 and 1950 by Polge and Smith. In 1951 at Hradec Kralove, Czech. Klen initiated a "tissue bank" using his unique freeze-drying system. In 1964, the initial meeting of the Society for Cryobiology was organized by its first president. B. J. Luyet in Washington, DC. Cryobiology including cryopreservation and cryosurgery, contributed immense advances for clinical medicine. Cryomedicine will realize the goals of the New Millennium medicine: regeneration, plasticity, and minimally invasive therapy. I explained the first one, regeneration in this paper in detail. Cryomedicine involved subzero-temperatures to freeze the biological objects either for preservation or for destruction. Cryopreservation involves the cooling of the target biological materials to below the temperature of solidification by consumption of energy, through continuously supplying inert cryogens to attain the necessary cryo-temperatures by Joule-Thompson's effect. Therefore biological materials for cryopreservation should be carefully selected and once frozen purposefully kept in the frozen state to be used later to regenerate human cells, tissues and organs, and also to relaize "plasticity". Recently, lyophilization of human cells and tissues came back to the main street of cryopreservation to provide low cost economical and ecological banking of cells and tissues as a hope of the New Millennium. The first attempt of that was made by Prof. Dr. Rudolf Klen and his colleagues.Finally, physicians and related scientists who are going to be interested in cryomedicine should not worry about "freezing and thawing" as being time consuming and labor intensive, otherwise they will not share in the crucial benefits of cryomedicine.

Blood Transfusion↗
PubMed2006

Pediatric traumatic brain injury: quo vadis?

In this review, five questions serve as the framework to discuss the importance of age-related differences in the pathophysiology and therapy of traumatic brain injury (TBI). The following questions are included: (1) Is diffuse cerebral swelling an important feature of pediatric TBI and what is its etiology? (2) Is the developing brain more vulnerable than the adult brain to apoptotic neuronal death after TBI and, if so, what are the clinical implications? (3) If the developing brain has enhanced plasticity versus the adult brain, why are outcomes so poor in infants and young children with severe TBI? (4) What contributes to the poor outcomes in the special case of inflicted childhood neurotrauma and how do we limit it? (5) Should both therapeutic targets and treatments of pediatric TBI be unique? Strong support is presented for the existence of unique biochemical, molecular, cellular and physiological facets of TBI in infants and children versus adults. Unique therapeutic targets and enhanced therapeutic opportunities, both in the acute phase after injury and in rehabilitation and regeneration, are suggested.

Aging↗
PubMed2001

Acute stress and dexamethasone rapidly increase hippocampal somatostatin synthesis and release from the dentate gyrus hilus.

Somatostatin is a neuropeptide whose facilitatory action in the generation of long-term potentiation (LTP) in the hippocampal dentate gyrus has been associated with memory processes. Since stress and memory seem to share some neural pathways, we studied somatostatin release from dentate gyrus hilar cells of the hippocampus in unanesthetized free-moving rats subjected to stress or dexamethasone treatments. In parallel, the number of dentate gyrus hilar cells expressing somatostatin mRNA was quantified by nonradioactive in situ hybridization in these two experimental conditions. Rats were stereotaxically implanted with a push-pull cannula in the dentate gyrus hilar region. Animals were perfused 1 week later in basal or stress (30 min immobilization stress) conditions. The other group was intraperitoneally injected with the synthetic glucocorticoid dexamethasone (3 mg/kg b.w.). Samples were collected every 15 min for somatostatin radioimmunoassay. In parallel, in other groups of animals undergoing the same treatments, brains were removed for in situ hybridization studies with an oligonucleotide labeled with digoxigenin that recognizes somatostatin-14. The results showed that stress induced a significant increase in somatostatin release from dentate gyrus hilar cells 30-45 min after immobilization stress application. Dexamethasone-injected animals exhibited a similar response 45 min after drug administration. In situ hybridization analysis revealed that the two treatments significantly increased the number of cells expressing somatostatin mRNA in the hilar region. In conclusion, somatostatin interneurons of the hippocampal hilar region appear to be a novel stress stimulus target. Their rapid reactivity, expressed as modifications of both somatostatin release and number of cells expressing somatostatin mRNA, provides an interesting model of neuronal plasticity.

Acute Disease↗
PubMed1991

Altered growth regulation of rat kidney proximal tubule epithelial cells transformed in vitro by SV40 viral DNA: fibroblast growth factors (heparin-binding growth factors) are potent inducers of anchorage-independent growth.

The majority of renal cancers are thought to arise from the proximal tubule epithelium, but little is known about their etiology. In this investigation, we have established an in vitro model to study the transformation of these target cells using rat kidney proximal tubule epithelial cells (RPTE) transformed in defined medium with SV40-viral DNA. Selection by passaging cells onto plastic surfaces yielded a population of cells (SV-RPTE) that expressed keratin and vimentin along with SV40 large-T antigen. The cells were morphologically transformed and lost their differentiated character as determined by several RPTE markers. SV-RPTE cells grew in soft agar in serum-supplemented medium containing insulin, epidermal growth factor, and cholera toxin, but were unable to grow when serum and growth factors were not combined. Acidic and basic fibroblast growth factors (aFGF and bFGF) were unique since they were the only single factor that induced anchorage-independent growth in the presence of serum alone. Transforming growth factor-beta 1 (TGF-beta 1) was a potent inhibitor of anchorage-independent growth, but the inhibition was partially overcome by a combination of growth factors. The growth factor responses of SV-RPTE in monolayer cultures differed from those in soft agar; the cells were more sensitive to growth stimulation by insulin and insulin-like growth factor, neither of which stimulated anchorage-independent growth. SV-RPTE cells in monolayer cultures had also lost the sensitivity to growth inhibition by TGF-beta 1 characteristic of normal RPTE. The RPTE transformation model described here will be very useful for investigating the molecular basis and etiology of renal cancers. Furthermore, the data suggest that maintenance of the transformed phenotype by aFGF and bFGF and loss of negative growth regulation by TGF-beta 1 could play a role in renal carcinogenesis.

Animals↗
PubMed2003

Role of calcineurin in activity-dependent pattern formation in the dorsal lateral geniculate nucleus of the ferret.

In the retinogeniculate pathway of the ferret, in addition to the separation of the inputs from the two eyes to form eye-specific layers, there is also an anatomical segregation of the terminal arbors of on-center retinal ganglion cells from the terminal arbors of off-center retinal ganglion cell axons to form on/off sublaminae. Sublamination normally occurs during postnatal weeks 3-4 and requires the activity of retinal afferents, N-methyl-D-aspartate receptors, nitric oxide synthase, and a target of nitric oxide, cyclic guanosine monophosphate. Calcineurin is a calcium/calmodulin dependent serine, threonine protein phosphatase suggested to mediate NMDA-receptor dependent synaptic plasticity in the hippocampus. We have examined whether calcineurin plays a role during on/off sublamination in the dorsal lateral geniculate nucleus (dLGN) of the ferret. Immunohistochemistry showed that calcineurin expression is transiently up-regulated in dLGN cells and neuropil during the period of on/off sublamination. A functional role for calcineurin during sublamination was investigated by blocking the enzyme locally via intracranial infusion of FK506. Treatment with FK506 during postnatal weeks 3-4 disrupted the appearance of sublaminae. These results suggest that calcineurin may play a role during this process of activity-dependent pattern formation in the visual pathway.

Afferent Pathways↗
PubMed1995

Changes in cortical nicotinic acetylcholine receptor numbers following unilateral destruction of pyramidal neurones by intrastriatal volkensin injection.

Experimental lesions using the retrogradely transported toxic lectin, volkensin, were used in conjunction with quantitative autoradiography to investigate the cellular localization of nicotinic and adenosine A1 receptors. Lesions were produced by unilateral intrastriatal injection of volkensin, ricin (another toxic lectin but not transported in the central nervous system), quinolinate, and unilateral intrathalamic injection of ibotenate. Volkensin injection significantly reduced the number and mean cell size of large, infragranular pyramidal neurones in cortical areas Fr1/Fr2 (close to the midline) and more laterally in Par1/Par2. Selective destruction of these cells was accompanied by significant increases in the binding of [3H] nicotine in cortical areas contralateral to the lesion. A small but significant reduction in the binding of [3H] 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) to adenosine A1 receptors was observed only in deep layers of Fr1/Fr2 on the side ipsilateral to the lesion. No other toxin consistently changed the binding of either ligand in control animal groups with the exception of [3H] nicotine where small reductions were observed in the middle layers of one thalamic injection group. These data indicate differential plasticity of nicotinic receptors compared with other receptors studied previously using this paradigm. In the light of these findings, nicotinic receptors are discussed as targets for pharmacological manipulation of the activity of pyramidal neurones.

Animals↗
PubMed2026

Defining and managing high-risk acute myeloid leukemia (AML) in 2026.

Acute myeloid leukemia (AML) remains a highly heterogeneous malignancy in which outcomes are particularly poor for patients classified as having high-risk disease. Traditionally, high-risk AML has been defined by adverse baseline genetic features, including complex cytogenetics, TP53 alterations, and mutations associated with secondary or therapy-related disease. However, this static, genetics-centered definition is increasingly insufficient in the modern therapeutic era. Emerging evidence supports a more dynamic and context-dependent model in which risk is shaped not only by molecular architecture but also by treatment intensity, patient fitness, measurable residual disease (MRD), and evolving resistance mechanisms. Advances in genomic profiling have refined risk stratification frameworks, including ELN 2022 for intensively treated patients and the ELN 2024 classification for those receiving less-intensive therapies. In parallel, MRD has emerged as a powerful biomarker that reclassifies patients during treatment, identifying those with persistent, therapy-resistant disease despite morphologic remission. Biologically, high-risk AML is driven by the interplay of clonal evolution, epigenetic plasticity, leukemic stem cell persistence, and protective microenvironmental and immune interactions, all of which contribute to relapse. Therapeutically, the landscape has expanded to include targeted agents, venetoclax-based combinations, and transplantation strategies, yet outcomes remain limited in key high-risk subsets, particularly TP53-mutated disease and post-venetoclax relapse. Accordingly, current strategies emphasize rational combination therapies, MRD-guided treatment adaptation, and approaches targeting both leukemic cells and their supportive niches. In 2026, high-risk AML is best understood as a dynamic, treatment-context-dependent state. Improving outcomes will require integration of precision diagnostics, biologically informed therapy, and adaptive strategies designed to anticipate and overcome resistance.

Humans↗
PubMed1998

Pharmacology of pain processing systems.

Integration of nociceptive signaling comprises peripheral, spinal, and supraspinal sites of the nervous system. Various excitatory or inhibitory neurotransmitter and--modulator systems participate in pain processing and modulation. Chronic pain states are associated with functional and structural alterations of nociceptive pathways. The numerous dynamic changes in the pharmacologically distinct systems offer novel targets for selective pharmacotherapy.

Analgesics↗
PubMed2006

Exposure to music in the perinatal period enhances learning performance and alters BDNF/TrkB signaling in mice as adults.

Music has been suggested to have a beneficial effect on various types of performance in humans. However, the physiological and molecular mechanism of this effect remains unclear. We examined the effect of music exposure during the perinatal period on learning behavior in adult mice, and measured the levels of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), which play critical roles in synaptic plasticity. In addition, we measured the levels of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and mitogen-activated protein kinase (MAPK), downstream targets of two main pathways in BDNF/TrkB signaling. Music-exposed mice completed a maze learning task with fewer errors than the white noise-exposed mice and had lower levels of BDNF and higher levels of TrkB and PDK1 in the cortex. MAPK levels were unchanged. Furthermore, TrkB and PDK1 protein levels in the cortex showed a significant negative correlation with the number of errors on the maze. These results suggest that perinatal exposure of mice to music has an influence on BDNF/TrkB signaling and its intracellular signaling pathway targets, including PDK1, and thus may induce improved learning and memory functions.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2005

RNA reigns in neurons.

A workshop entitled "RNA Control of Neuronal Function" was recently held in Kfar Blum, Israel. The main topics discussed at the meeting included neuronal RNA targeting mechanisms and the contributing codes and components, translational control mechanisms in dendrites and axons, and the relevance of these mechanisms for neuronal development, plasticity, and dysfunction.

Animals↗