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PubMed2026

Co-targeting Deregulated WNT and MAPK Signaling Pathways Limits Phenotypic Reprogramming of Intestinal Stem Cell Progeny in KRAS-Hyperactivated Colorectal Cancer.

In their recent article, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer growth is driven by a reprogramming of Lgr5+ intestinal stem cell (ISC) progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related ISCs and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insights into genomic patterns of colorectal cancer and targeted therapy strategies.

Colorectal Neoplasms↗
PubMed2005

Functional neuroimaging in motor recovery after stroke.

Neuroimaging techniques provide information on the neural substrates underlying functional recovery after stroke, the number one cause of long-term disability. Despite the methodological difficulties, they promise to offer insight into the mechanisms by which therapeutic interventions can modulate human cortical plasticity. This information should lead to the development of new, targeted interventions to maximize recovery.

Functional Laterality↗
PubMed2001

TrkA-expressing trigeminal sensory neurons display both neurochemical and structural plasticity despite a loss of p75NTR function: responses to normal and elevated levels of nerve growth factor.

In neural crest-derived sensory ganglia, approximately half of the neuronal population expresses the transmembrane trkA receptor that is required for neuronal binding of target-derived nerve growth factor (NGF). These same neurons also express the p75 neurotrophin receptor (NTR) that increases the affinity of trkA for NGF. Depleting p75NTR expression reduces both the survival of trkA-positive sensory neurons and their afferent innervation of peripheral targets. In this investigation, we assessed the neurochemical and structural plasticity of trigeminal sensory neurons in p75NTR-deficient mice in response to either normal or elevated levels of NGF during postnatal development and into adulthood. Although p75NTR-deficient mice have 30% fewer trigeminal neurons, levels of trkA mRNA expression are modestly elevated in these mutant mice as compared to control mice. The density of central afferent axons and local levels of NGF are, however, comparable between mutant and control animals. Thus, despite the survival of fewer trigeminal neurons, neither ganglionic levels of trkA mRNA expression nor the density of central afferent projections are depleted in p75NTR-deficient mice. In response to elevated levels of NGF protein, transgenic mice with and without p75NTR expression display both increased levels of trkA mRNA expression and a greater density of trigeminal central afferent axons as compared to control mice. These data further reveal that an absence of p75NTR function in trigeminal sensory neurons does not diminish their capacity for NGF-dependent plasticity, namely trkA mRNA expression and collateral growth of central afferent axons.

Animals↗
PubMed1989

Critical review on quantitative autoradiography of D1 and D2 dopaminergic receptors in the striatum of the mammalian brain: differential localization and plastic changes after pharmacological manipulation and dopaminergic input disruption.

Major technical progress in the development of computer-based image analysis systems has made possible the entry of autoradiographic and immunohistochemical techniques into a new era where quantification via densitometry and morphometry has become easily accessible. In this context, quantitative biochemical data can be adapted to anatomical and histological resolution. This adaptation is most efficient in the neuroscience fields because of the huge importance of cellular communication via neuronal networks in the nervous system. Therefore, any experimental approach to the brain which considers the brain as a 'black box' appears now as very crude. In fact, subtle heterogeneity in the distribution of biochemical markers can now be demonstrated, as illustrated here by the use of quantitative autoradiography of D1 and D2 dopaminergic receptors in the striatum of the mammalian brain. Also, local adaptive changes resulting from chronic blockade of the dopaminergic input can be detected after repeated treatments with dopaminergic antagonists selective for D1 or D2 receptors or with surgical lesioning of the dopaminergic nigrostriatal pathway. The resulting plastic changes are unevenly distributed throughout the striatal target organ and vary according to the mode of suppressing the dopaminergic flow: direct destruction of the dopaminergic pathway or selective pharmacological manipulation without physical elimination of the dopaminergic cells themselves. All these results are discussed and reviewed in light of the most recent reports in this field.

Animals↗
PubMed2026

A minimal three-arm oral regimen for healthspan: mechanistic alignment with transcriptomic signals from a large parental-lifespan GWAS.

A large genome-wide association study of parental lifespan was reported in 2019. A later transcriptome-wide association study (TWAS) based on those summary statistics identified a set of transcriptional programs associated with longer genetically predicted survival, including increased brain NAD + salvage, especially NMNAT2, reduced glucose-stimulated insulin secretion, a shift toward synaptic pruning with less broad plasticity, and a glial pattern characterized by relatively greater microglial and lower astrocytic signatures, with only weak pan-tissue senescence signals. Building on those directional findings, this short communication proposes a minimal three-arm oral regimen with unequal evidentiary weight: first, the Cheung Glutamatergic Regimen, consisting of low-dose dextromethorphan potentiated by a CYP2D6 inhibitor together with piracetam and L-glutamine, as an exploratory adjunct aimed at preserving residual functional connectivity; second, daily nicotinamide mononucleotide and N-acetylcysteine with pulsed senolytics for NAD + salvage and senescence modulation; and third, GLP-1 receptor agonism for metabolic reprogramming. The NAD+/senescence arm is the primary mechanistic anchor, GLP-1 receptor agonism provides secondary metabolic support, and the glutamatergic arm is exploratory. Each arm targets a separate node within the pruning-plasticity-metabolic triad. The regimen is fully oral, uses conservative dosing, and draws on prior therapeutic or human-exposure data, although the proposed combination has no established safety profile. Although direct combination data are lacking and the foundational TWAS remains a preprint, the components show plausible but uneven mechanistic alignment with the TWAS signals and may justify carefully designed, safety-focused pilot evaluation.

GLP-1↗
PubMed1996

Presynaptic calcium current modulation by a metabotropic glutamate receptor.

Metabotropic glutamate receptors (mGluRs) regulate transmitter release at mammalian central synapses. However, because of the difficulty of recording from mammalian presynaptic terminals, the mechanism underlying mGluR-mediated presynaptic inhibition is not known. Here, simultaneous recordings from a giant presynaptic terminal, the calyx of Held, and its postsynaptic target in the medial nucleus of the trapezoid body were obtained in rat brainstem slices. Agonists of mGluRs suppressed a high voltage-activated P/Q-type calcium conductance in the presynaptic terminal, thereby inhibiting transmitter release at this glutamatergic synapse. Because several forms of presynaptic modulation and plasticity are mediated by mGluRs, this identification of a target ion channel is a first step toward elucidation of their molecular mechanism.

Aminobutyrates↗
PubMed2005

Altered long-term synaptic plasticity and kainate-induced Ca2+ transients in the substantia gelatinosa neurons in GLU(K6)-deficient mice.

Functional kainate receptors are expressed in the spinal cord substantia gelatinosa region, and their activation contributes to bi-directional regulation of excitatory synaptic transmission at primary afferent synapses with spinal cord substantia gelatinosa neurons. However, no study has reported a role(s) for kainate receptor subtypes in long-term synaptic plasticity phenomena in this region. Using gene-targeted mice lacking glutamate receptor 5 (GLU(K5)) or GLU(K6) subunit, we here show that GLU(K6) subunit, but not GLU(K5) subunit, is involved in the induction of long-term potentiation of excitatory postsynaptic potentials, evoked by two different protocols: (1) high-frequency primary afferent stimulation (100 Hz, 3 s) and (2) low-frequency spike-timing stimulation (1 Hz, 200 pulses). In addition, GLU(K6) subunit plays an important role in the expression of kainate-induced Ca2+ transients in the substantia gelatinosa. On the other hand, genetic deletion of GLU(K5) or GLU(K6) subunit does not prevent the induction of long-term depression. These results indicate that unique expression of kainate receptors subunits is important in regulating spinal synaptic plasticity and thereby processing of sensory information, including pain.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2003

Regulation of cpg15 by signaling pathways that mediate synaptic plasticity.

Transcriptional activation is a key link between neuronal activity and long-term synaptic plasticity. Little is known about genes responding to this activation whose products directly effect functional and structural changes at the synapse. cpg15 is an activity-regulated gene encoding a membrane-bound ligand that regulates dendritic and axonal arbor growth and synaptic maturation. We report that cpg15 is an immediate-early gene induced by Ca(2+) influx through NMDA receptors and L-type voltage-sensitive calcium channels. Activity-dependent cpg15 expression requires convergent activation of the CaM kinase and MAP kinase pathways. Although activation of PKA is not required for activity-dependent expression, cpg15 is induced by cAMP in active neurons. CREB binds the cpg15 promoter in vivo and partially regulates its activity-dependent expression. cpg15 is an effector gene that is a target for signal transduction pathways that mediate synaptic plasticity and thus may take part in an activity-regulated transcriptional program that directs long-term changes in synaptic connections.

Animals↗
PubMed2007

Molecular mechanisms mediating pathological plasticity in Huntington's disease and Alzheimer's disease.

Neurodegenerative diseases such as Huntington's disease and Alzheimer's disease, although very different in etiology, share common degenerative processes. These include neuronal dysfunction, decreased neural connectivity, and disruption of cellular plasticity. Understanding the molecular mechanisms underlying the neural plasticity deficits in these devastating conditions may lead the way toward new therapeutic targets, both disease-specific and more generalized, which can ameliorate degenerative cognitive deficits. Furthermore, investigations of 'pathological plasticity' in these diseases lend insight into normal brain function. This review will present evidence for altered plasticity in Huntington's and Alzheimer's diseases, relate these findings to symptomatology, and review possible causes and commonalities.

Alzheimer Disease↗
PubMed1995

Changes of liver-resident NK cells during liver regeneration in rats.

To determine the role of NK cells in regulation of tissue growth, the phenotype and function of liver-resident NK cells were studied after 70% partial hepatectomy in rats. The process of liver regeneration was generally completed by day 14. In contrast, the number of liver-resident NK cells (NKR-P1bright) was restored as early as day 3 after partial hepatectomy. However, spontaneous functions of liver-resident NK cells, including killing of YAC-1 and P815 targets, Ab-dependent cellular cytotoxicity, and redirected killing via NKR-P1, were continuously suppressed throughout the entire period of liver regeneration (from 3 h to 14 days). Augmentation of NK cytotoxicity against P815 targets and induction of NK cell adherence to plastic following 24 h of IL-2 stimulation showed a similar pattern of suppression. However, IL-2-induced augmentation of YAC-1 killing, proliferation and generation of adherent NK cells, and LAK activity in 5- to 7-day cultures were found to be suppressed only during the first 24 h and increased between days 2 and 7 after hepatectomy. Sorted NK cells (> or = NKR-P1bright) from liver-resident mononuclear leukocytes 24 h after partial hepatectomy showed the same pattern of suppression as unsorted mononuclear leukocytes. In contrast to liver-resident NK cells, no significant changes were detected in peripheral blood or spleen NK cells of rats following partial hepatectomy. Of particular interest, in normal liver, hepatocytes were resistant to NK lysis, while resident NK cells were cytotoxic for various NK-sensitive targets. In contrast, during the early period of liver regeneration, when hepatocytes were sensitive to lysis by liver-resident NK cells of normal rats, NK cells obtained from regenerating liver tissues were unable to mediate cytotoxicity. At the final phase of liver regeneration (days 7-14 after hepatectomy), both resistance of hepatocytes to killing by NK cells and cytotoxicity of liver-resident lymphocytes against hepatocytes from regenerating liver were simultaneously restored. In vivo depletion of NK cells by injection of rats with anti-NKR-P1 mAb resulted in a significant augmentation of liver regeneration subsequent to partial hepatectomy. Our data suggest that liver-resident NK cells may be involved in regulation of the extent of liver regeneration.

Animals↗
PubMed2005

Quantitative morphology and postsynaptic targets of thalamocortical axons in critical period and adult ferret visual cortex.

Thalamocortical axons segregate into ocular dominance columns several weeks before the onset of critical period plasticity in ferret visual cortex, a stage characterized by anatomical changes in thalamic input as a consequence of abnormal visual stimulation. In search of possible anatomical correlates of this plasticity, we examined, at electron microscope resolution, the morphology and the synapsing and target selection properties of thalamic axons in ferret visual cortex during and after the critical period. Adult thalamocortical terminals visualized by anterograde tract-tracing display significantly larger cross-section areas than terminals at postnatal day (P) 35, P40, and P49 critical period ages. They are also significantly larger than nonthalamocortical terminals, which attain an adult-like size distribution by P40. The synaptic zones of adult thalamocortical terminals are significantly larger than those of critical period terminals. Perforated and invaginated synapses are encountered frequently on thalamic axons in both adulthood and the P40-49 age group. This result contradicts the view that synaptic perforations and spinules are indicative of a capacity for plasticity. It also suggests that at least some morphological features of thalamic terminals attain maturity on a developmental schedule that is independent of critical period plasticity. Connectivity properties of labeled axons, however, suggest an active role for thalamocortical axons in the critical period. In P40, P49, and adult brains, 23%, 17%, and 9%, respectively, of all thalamocortical synapses contact GABAergic interneurons, suggesting that thalamic input is more strongly involved in driving inhibitory circuits in young ages. Furthermore, thalamocortical axons in P35-49 brains form about 60% more synapses per axon length than in adult brains, suggesting that stabilization of thalamic synapses at the end of the critical period may be accompanied by a reduction of synaptic contacts, as well as a reorganization of postsynaptic circuit selectivity.

Age Factors↗
PubMed2004

Molecular determinants mediating effects of acute stress on hippocampus-dependent synaptic plasticity and learning.

The understanding of the molecular events underlying the neuroendocrine and behavioral sequelae of the response to stress has advanced rapidly over recent years. The hippocampus is a target of stress hormones, and we are beginning to dissect the molecular players in the modulation of synaptic plasticity and learning and memory involving this region of the brain. Given the wealth of data obtained from electrophysiological and behavioral experiments and in view of the importance to use identical experimental protocols in order to correlate the results obtained under both experimental conditions, this review focuses primarily on those contributions, which combine both approaches. From these studies it is evident that a single stressful event elicits responses in the hippocampus with different time-spans ranging from rapid changes in glutamatergic neurotransmission (i.e., N-methyl-d-aspartate receptor signaling), activation of second messenger cascades by corticotropin-releasing factor to long-lasting transcriptional changes of acetylcholinesterase. The relative contribution of these molecular targets to the stress response, the relation to hippocampal synaptic plasticity and memory formation, and the possible interaction of the underlying processes are discussed.

Acute Disease↗
PubMed1999

Memory suppressor genes: enhancing the relationship between synaptic plasticity and memory storage.

Memory suppressor genes encode proteins that act as inhibitory constraints to impede memory storage. The study of memory suppressor genes is important not only for understanding the link between synaptic plasticity and learning but also for identifying potential targets for future pharmaceuticals to treat memory disorders. This article first reviews the evidence for proteins that impede memory storage from work in invertebrates and then explores recent evidence for the existence of memory suppressor genes in vertebrates in the context of hippocampus-dependent forms of memory. In Aplysia, memory suppressor gene products act at each step in long-term facilitation: in the cytoplasm to regulate kinase activity, in the nucleus to alter the activity of transcriptional regulatory proteins, and on the cell surface to modulate cell-cell interactions. Studies of genetically modified Drosophila have provided behavioral evidence for the existence of memory suppressor genes. One of the best candidates for a neuronal mechanism underlying learning is long-term potentiation (LTP), which has been extensively studied in the mammalian hippocampus. Recent work has identified a number of putative memory suppressor gene products that act in the hippocampus at the levels of LTP induction, regulation of intracellular signaling cascades, and transcriptional control. Using these gene products as tools to study enhancements rather than deficits in LTP and learning may generate more precise information about the relationship between synaptic plasticity and behavioral learning. The study of mammalian memory suppressor genes may provide insights into alleviating the learning and memory deficits that accompany both normal aging and a variety of human disorders.

Animals↗
PubMed2004

Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression.

Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic (but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium- or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Animals↗
PubMed1994

Short-term plasticity in turtle dorsal horn neurons mediated by L-type Ca2+ channels.

Windup--the gradual increase of the response--of dorsal horn neurons to repeated activation of primary afferents is an elementary form of short-term plasticity that may mediate central sensitization to pain. In deep dorsal horn neurons of the turtle spinal cord in vitro we report windup of the response to repeated depolarizing current pulses as well as to repeated stimulation of the ipsilateral dorsal root. We found both forms of windup to be mediated by a depolarizing potential produced by increasing activation of postsynaptic L-type Ca2+ channels. These results suggest a central role for intrinsic postsynaptic properties in nociceptive plasticity and for L-type Ca2+ channels as a promising target for therapeutic intervention.

Action Potentials↗
PubMed1981

Killing of tumor cells in vitro by macrophages from mice given injections of squalene-treated cell wall skeleton of Nocardia rubra.

Peritoneal exudate cells (PEC) harvested from mice after i.p. injection of squalene-treated cell wall skeleton of Nocardia rubra (N. rubra-CWS) demonstrated vigorous cytolytic activity in vitro toward tumor target cells. Fractionation of these PEC by adherence to plastic dishes showed that the cytolytic activity in PEC was associated with an adherent phagocytic cell. Induction of the cytolytic adherent PEC required an optimal dose of 50 micrograms N. rubra-CWS and i.p. injection. Cytolytic activity of N. rubra-CWS-induced adherent PEC was maximal after 5 days and fell steadily thereafter. Susceptible tumor targets included cells syngeneic, allogeneic, and xenogeneic to the effector cell source. In contrast, nonneoplastic xenogeneic cells were not affected by N. rubra-CWS-induced adherent PEC. The effector cells were not found in the spleen or peripheral lymph nodes. In addition, the cytolytic activity of N. rubra-CWS-induced adherent PEC was completely inhibited by treatment with antimacrophage serum and complement or carrageenan. Treatment with monoclonal anti-Thy 1.2 antibody and complement, however, did not affect the cytolytic activity of the adherent PEC. These features make it likely that N. rubra-CWS-induced cytolytic effector cells are macrophages.

Animals↗
PubMed2004

Sensory processing and functional reorganization of sensory transmission under pathological conditions in the spinal dorsal horn.

The superficial dorsal horn, particularly substantia gelatinosa (SG) in the spinal cord, receives inputs from small-diameter primary afferents that predominantly convey noxious sensation. This sensory information via the high-threshold Adelta and C afferents is modified and integrated in SG, and consequently regulates the outputs of projection neurons located in lamina I and laminae IV-V. Recent studies using slice and in vivo patch-clamp recordings indicate that the sensory inputs to SG are functionally reorganized during post-natal development. Even in the mature state, the synaptic connectivity and receptor expression in SG can be altered easily following peripheral tissue damage. In addition, the descending pain inhibitory system to SG is also modified under certain pathological conditions. Considering that the pain system is phylogenetically primitive, it is, therefore, not surprising that the system easily exhibits a plastic change in response to inflammation or nerve damage. Because such plastic changes in the neuronal circuit or receptor expression in SG are now generally accepted to be one of the explanations for the induction of pathological pain, SG is thought to be a primary therapeutic target for chronic pain. We review here recent results demonstrating plastic changes in SG under pathological conditions.

Animals↗
PubMed2005

[Prevalence for isolated systolic hypertension and analysis on its relative factors in 1002 cases >or= 80 year old persons].

OBJECTIVE: To study and analysis prevalence and incidence of target organ injury and the relative factors for isolated systolic hypertension (ISH) in Beijing. METHODS: 1002 cases aged 80 to 99 years were investigated in 28 cadre retirement centers in Beijing. Blood pressure was taken for three times with mercurial sphygmomanometer in every person, the mean values were recorded and the relative material was gathered according to questionnaire after the health education. Physical examination form of outpatient department and inpatient case history in fixed hospital were analyzed. RESULTS: In 1002 very old persons, there were 673 hypertensive patients (67.2%) and 455 ISH (45.4%). Among all hypertensive patients, the rate of ISH was 67.6% and double hypertension was 32.4%. Awareness rate was 87.90% and 97.71%, taking antihypertensive drug rate was 77.58% and 80.73%, control rate was 58.68% and 62.84% in ISH and in double hypertension group, respectively, which were no significant differences between the two groups. There was no significant difference in morbidities of cardiac heart disease, myocardial infarction and chronic renal insufficiency between the two groups. The incidences of heart failure, cerebrovascular disease, disability and dementia were 4.62% and 8.72%, 41.54% and 55.50%, 10.55% and 16.06%, 8.57% and 12.84% in ISH and double hypertension group, respectively, which were significant differences between the two groups (P < 0.01). The susceptible age period for ISH was 70 to 79 years in this study. CONCLUSION: ISH is more common in hypertensive patients in very old persons at 28 cadre retirement centers in Beijing. Morbidity of heart failure, cerebrovascular disease, disability and dementia were higher in double hypertension group compared with those in ISH group. The results showed that increase of both systolic and diastolic blood pressure was more dangerous than that of systolic pressure only for very old persons. The improvement of small arterial plastic and the control of blood pressure to target level (< 140/90 mm Hg) in very old hypertensive patients are very important for decreasing the incidence of target organ injury and increasing their life quality and late survival rate.

Aged, 80 and over↗