Biomedical subjects

T Curran

Publications and source records attributed to T Curran.

At least 37 records · Page 2Linked to original sources

PubMed1997

Effects of aging on implicit sequence learning: accounting for sequence structure and explicit knowledge.

The present research was intended to examine the sequence learning ability of elderly people-with a focus on comparing sequences with different structural characteristics and on properly assessing explicit knowledge. Experiment 1 showed that learning-related improvements in serial reaction time task performance were greater for young than elderly subjects, and elderly subjects were especially poor at learning a sequence with complex structural characteristics. Measures of recognition memory showed that neither young nor elderly subjects showed above-chance explicit knowledge of the sequences. Experiment 2 was designed to test the validity and sensitivity of the explicit recognition measures by comparing young subjects in groups given all random trials, given sequence trials with implicit instructions, or given sequence trials with explicit instructions. Experiment 2 confirmed the sensitivity of the recognition measures to explicit knowledge, so it is concluded that group effects in Exp. 1 reflect age-related differences in implicit learning.

Adult↗

PubMed1997

False recognition after a right frontal lobe infarction: memory for general and specific information.

We previously reported a case study of a man with right frontal lobe damage, BG, who showed extraordinarily high false alarm rates on remember-know recognition tests (Schacter, D. L. et al., Neuropsychologia, 1996, Vol. 34, pp. 793-808). Experiment 1 extends his high false alarm rate to yes-no recognition tests. BG typically gives false 'remember' responses on remember-know tests, and this pattern was uninfluenced when he was asked to explain the basis for his 'remember' responses (Experiments 2 and 3). When BG was given a semantic encoding task, he stopped giving 'remember'-based false alarms (Experiment 4). Signal detection analyses revealed that BG had a discrimination deficit and an abnormally liberal response bias (especially for 'remember' responses) in most conditions. Overall, BG's high false alarm rate is interpreted as reflecting an over-reliance on the general similarity between a test item and the study episode.

Aged↗

PubMed1997

The human reelin gene: isolation, sequencing, and mapping on chromosome 7.

The mouse reelin gene (Reln) encodes a novel protein that, when mutated, results in the characteristic reeler phenotype. A key component of this phenotype is the extensive disruption of the organization of many brain structures. Reelin is believed to be an extracellular protein that controls neural cell positioning during brain development. The reelin gene is conserved in many vertebrate species, including humans. To study the role of the reelin homolog in human brain development, we have isolated and characterized the human gene (RELN). Like its murine counterpart, RELN is large, encoding an mRNA of approximately 12 kb. Overlapping cDNA clones containing the entire open reading frame were isolated and sequenced, revealing that the predicted mouse and human proteins are similar in size (388 kD) and that the amino acid and nucleotide sequences are 94.2% and 87.2% identical, respectively. Northern hybridization analyses revealed that RELN is expressed in fetal and postnatal brain as well as liver. The expression of RELN in postnatal human brain was high in the cerebellum. RELN was mapped to human chromosome 7q22, based on both fluorescence in situ hybridization studies and localization within a well-positioned yeast artificial chromosome (YAC) contig. The YAC contig also contains a number of gentic markers. Together, these studies provide the sequence information and genetic tools for performing more detailed analyses of RELN in an attempt to define its role in human brain development and possibly in human disease.

Amino Acid Sequence↗

PubMed1997

Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning.

Positron emission tomography was employed to contrast the brain activation pattern in patients with obsessive-compulsive disorder (OCD) to that of matched control subjects while they performed an implicit learning task. Although patients and control subjects evidenced comparable learning, imaging data from control subjects indicated bilateral inferior striatal activation, whereas OCD patients did not activate right or left inferior striatum and instead showed bilateral medial temporal activation. The findings further implicate corticostriatal dysfunction in obsessive-compulsive disorder. Furthermore, when OCD patients are confronted with stimuli that call for recruitment of corticostriatal systems, they instead appear to access brain regions normally associated with explicit (conscious) information processing.

Adult↗

PubMed1997

Thyrotropin regulation by thyroid hormone in thyroid hormone receptor beta-deficient mice.

Thyroid hormone responsive genes can be both positively and negatively regulated by thyroid hormone. TSH is down-regulated by thyroid hormone and rises during thyroid hormone deprivation. Because both thyroid hormone receptor (TR) alpha and beta genes are expressed in the pituitary gland, it is unclear what the relative roles of TR alpha and TR beta are in TSH regulation. Experiments using over expression of artificial genes have yielded conflicting results. The TR beta knock-out mouse that lacks both TR beta1 and TR beta2 isoforms provides a model to examine the role of these receptors in TSH regulation. TR beta deficient (TR beta-/-) and wild-type (TR beta+/+) mice of the same strain were deprived of thyroid hormone by feeding them a low iodine diet containing propylthiouracil and were then treated with different doses of L-T3 and L-T4. Thyroid hormone deprivation rapidly increased the serum TSH level in both TR beta+/+ and TR beta-/- mice, reaching a similar level in the absence of thyroid hormone. In contrast, the decline of serum TSH by treatment with both L-T3 and L-T4 was severely blunted in TR beta-/- mice, and full suppression was not achieved with the maximal L-T3 dose of 25 microg/day x mouse. These data indicate that TR beta is not required for the up-regulation of TSH in thyroid hormone deficiency. However, although TR alpha alone can mediate thyroid hormone induced TSH suppression, TR beta enhances the sensitivity of TSH down-regulation and may be essential for the complete suppression of TSH.

Animals↗

PubMed1997

Striatal recruitment during an implicit sequence learning task as measured by functional magnetic resonance imaging.

Prior research has repeatedly implicated the striatum in implicit sequence learning; however, imaging findings have been inconclusive with respect to the sub-territories and laterality involved. Using functional magnetic resonance imaging (fMRI), we studied brain activation profiles associated with performance of the serial reaction time task (SRT) in 10 normal right-handed males. Behavioral results indicate that significant implicit learning occurred, uncontaminated by significant explicit knowledge. Concatenated fMRI data from the entire cohort revealed significant right-lateralized activation in both the caudate and putamen. Analysis of fMRI data from individual subjects showed inter-individual variability as to the precise territories involved, including right as well as left caudate and putamen. Interestingly, all seven subjects who manifested robust learning effects exhibited significant activation within the putamen. Moreover, among those seven subjects, the magnitude of signal intensity change within the putamen correlated significantly with the magnitude of reaction time advantage achieved. These findings demonstrate right-sided striatal activation across subjects during implicit sequence learning, but also highlight interindividual variability with respect to the laterality and striatal subterritories involved. In particular, results from individual subjects suggest that, during the SRT, the reaction time advantage garnered via implicit sequence learning might be predominantly associated with activity within the putamen.

Adult↗

PubMed1996

c-Jun stimulates origin-dependent DNA unwinding by polyomavirus large Tantigen.

The AP1 protein c-Jun has previously been shown to stimulate polyomavirus (Py) DNA replication in vivo. In order to define the mechanism, we added purified c-Jun protein to the origin-dependent and large T antigen (LT)-dependent in vitro DNA unwinding assay. c-Jun protein was found to stimulate by approximately 5-fold the unwinding of a 290 bp linear DNA fragment containing both the Py origin and the AP1 recognition sequence to which c-Jun binds. Efficient levels of stimulation were specifically observed at limiting concentrations of LT for unwinding. Under similar conditions, Py DNA replication was stimulated to a comparable extent by AP1 in a purified in vitro replication assay. Mobility shift and DNase I footprinting assays showed that c-Jun stimulates the ATP-dependent binding of LT to the origin core by approximately 7-fold. Furthermore, c-Jun was found to interact directly with LT, but not with replication protein A. The activities of c-Jun to stimulate unwinding and origin binding of LT were found to be harbored within the N-terminal region of c-Jun, which is distinct from the DNA binding domain. We speculate that certain transcription factors may possess specific DNA replication domains that function to stimulate the loading of replication factors at the origin during the initiation of DNA synthesis.

Adaptor Protein Complex 1↗

PubMed1996

Selective activation of calcium permeability by aspartate in Purkinje cells.

Glutamate and aspartate are endogenous excitatory amino acid neurotransmitters widely distributed in the mammalian central nervous system. Aspartate was shown to induce a large membrane current sensitive to N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists in Purkinje cells from mice lacking functional NMDA receptors (NR1(-/-)). This response was accompanied by high permeability to calcium. In contrast, no current was induced by aspartate in hippocampal neurons and cerebellar granule cells from NR1(-/-) mice. Several other glutamate receptor agonists failed to evoke this response. Thus, in Purkinje cells, aspartate activates a distinct response capable of contributing to synaptic plasticity through calcium permeability.

Animals↗

PubMed1996

The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice.

The DNA-binding activity of AP-1 proteins is modulated, in vitro, by a posttranslational mechanism involving reduction oxidation. This mode of regulation has been proposed to control both the transcriptional activity and the oncogenic potential of Fos and Jun. Previous studies revealed that reduction of oxidized Fos and Jun by a cellular protein, Ref-1, stimulates sequence-specific AP-1 DNA-binding activity. Ref-1, a bifunctional protein, is also capable of initiating the repair of apurinic/apyrymidinic sites in damaged DNA. The relationship between the redox and DNA repair activities of Ref-1 is intriguing; both activities have been suggested to play an important role in the cellular response to oxidative stress. To investigate the physiological function of Ref-1, we used a gene targeting strategy to generate mice lacking a functional ref-1 gene. We report here that heterozygous mutant mice develop into adulthood without any apparent abnormalities. In contrast, homozygous mutant mice, lacking a functional ref-1 gene, die during embryonic development. Detailed analysis indicates that death occurs following blastocyst formation, shortly after the time of implantation. Degeneration of the mutant embryos is clearly evident at embryonic day 5.5. These findings demonstrate that Ref-1 is essential for early embryonic development.

Animals↗

PubMed1996

Functional NMDA receptors are transiently active and support the survival of Purkinje cells in culture.

Conflicting evidence exists concerning the activity of NMDA receptors (NMDARs) in cerebellar Purkinje cells and their possible functions. To investigate the activity of NMDARS, we used whole-cell recording on immunocytochemically identified Purkinje cells in primary culture. In addition, we used mice with a disrupted NMDAR1 gene that lack functional NMDARs (NR1-/-) to assess the physiological role of NMDARs. In cultures from normal mice, NMDA-medicated currents were detected in all identified Purkinje cells at 4 d in vitro (div). After 14 d, however, NMDA responses were reduced in amplitude, whereas the responses to kainate and glutamate increased steadily in amplitude. In addition, the NMDA-induced current displayed a pronounced desensitization at these later stages; peak current declined to zero during steady application of NMDA. At 7 div, the number of surviving Purkinje cells was less in cultures treated with NMDA antagonists, and their survival was dose-dependent. Purkinje cell survival was correspondingly poorer in cultures from the NR1-/- mice than in wild-type controls, suggesting that NMDAR activity enhances the survival of Purkinje cells in vitro. The addition of moderate doses of NMDA promoted the survival of wild-type Purkinje cells in the presence of tetrodotoxin. Feeder layers of cerebellar granule cells derived from wild-type or NR1-/- mice promoted survival of Purkinje cells to a similar degree, suggesting that the NMDAR in Purkinje cells, but not in other cells, is directly involved in Purkinje cell viability. The results demonstrate that NMDARs transiently produce membrane current in Purkinje cells and may serve as one of the epigenetic factors that support the survival of Purkinje cells in vitro.

Animals↗

PubMed1996

Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function.

The diverse functions of thyroid hormone (T3) are presumed to be mediated by two genes encoding the related receptors, TRalpha and TRbeta. However, the in vivo functions of TRalpha and TRbeta are undefined. Here, we report that targeted inactivation of the mouse TRbeta gene results in goitre and elevated levels of thyroid hormone. Also, thyroid-stimulating hormone (TSH), which is released by pituitary thyrotropes and which is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-) mice. These findings suggest a unique role for TRbeta that cannot be substituted by TRalpha in the T3-dependent feedback regulation of TSH transcription. Thrb-/- mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH) that exhibits a similar endocrine disorder but which is typically caused by dominant TRbeta mutants that are transcriptional inhibitors. It is unknown whether TRalpha, TRbeta or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb-/- mice suggests that antagonism of TRbeta-mediated pathways underlies the disorder of the pituitary-thyroid axis. Interestingly, in the brain, the absence of TRbeta may not mimic the defects often associated with dominant RTH, since no overt behavioural or neuroanatomical abnormalities were detected in Thrb-/- mice. These data define in vivo functions for TRbeta and indicate that specificity in T3 signalling is conferred by distinct receptor genes.

Amino Acid Sequence↗

PubMed1996

Developmental expression of Fos-lacZ in the brains of postnatal transgenic rats.

Previously, we reported the production and characterization of fos-lacZ transgenic mice [41] and rats [19] that can be used to monitor both constitutive and evoked expression of c-fos in vivo. When we compared the sites of spontaneous fos-lacZ expression in the brains of developing transgenic fos-lacZ mice and rats, the patterns were almost identical. However, throughout the first postnatal month, the rat striatum contained a large number of Fos-lacZ-positive cells whereas only a few positive cells were seen in the mouse. By adulthood, the number of Fos-lacZ-positive cells in the rat striatum had declined dramatically to the low basal values seen in mice. To establish whether this species difference was evident in the adult striatum, rats and mice were treated with metamphetamine. This indirect D1 agonist, triggered a pronounced induction of fos-lacZ in the rat striatum while only a modest response was observed in the mouse. These data imply: (1) there are differences in dopamine-dependent stimulus-transcription coupling between the two species. (2) Maturation of dopaminergic signalling pathways may underlie the spontaneous immediate-early gene response in the developing rat striatum.

Amphetamines↗

PubMed1996

An enhanced immune response in mice lacking the transcription factor NFAT1.

Transcription factors of the NFAT family are thought to play a major role in regulating the expression of cytokine genes and other inducible genes during the immune response. The role of NFAT1 was investigated by targeted disruption of the NFAT1 gene. Unexpectedly, cells from NFAT1 -/- mice showed increased primary responses to Leishmania major and mounted increased secondary responses to ovalbumin in vitro. In an in vivo model of allergic inflammation, the accumulation of eosinophils and levels of serum immunoglobulin E were increased in NFAT1 -/- mice. These results suggest that NFAT1 exerts a negative regulatory influence on the immune response.

Amino Acid Sequence↗

PubMed1996

Phosphorylation of c-Fos at the C-terminus enhances its transforming activity.

c-Fos is phosphorylated by MAP kinase and the 90 kDa-ribosomal S6 kinase (RSK) in vitro at serines 362 and 374 (rat) which we demonstrate are major in vivo phosphorylation sites in early G1. We have constructed c-Fos mutants with these serines changed to aspartic acid residues (FosD) to mimic phosphorylation or to alanine residues (FosA) to prevent phosphorylation. Cells expressing FosD exhibited a more extensive transformed phenotype than those expressing either FosA or wild type c-Fos (FosWT). We also observed that FosA has a reduced half-life in comparison with FosD in G1. Furthermore, we observed enhanced AP-1 transactivation activity in cells expressing FosD. These results indicate that phosphorylation of c-Fos at its extreme carboxyterminus, possibly by MAP kinase and RSK, supports the proliferative response by increasing c-Fos stability and/or by increasing its transactivation activity. Under conditions in which the MAP kinase pathway is constitutively activated, c-Fos phosphorylation probably contributes to cellular transformation. The highly conserved nature of these phosphorylation sites in other c-fos family members suggests that these may also be targets of MAP kinase and RSK.

3T3 Cells↗

PubMed1996

Ubiquitinylation of transcription factors c-Jun and c-Fos using reconstituted ubiquitinylating enzymes.

Recombinant c-Jun and c-Fos were ubiquitinylated by the ubiquitin carrier enzymes E214K, E220K, or E232K in the presence of the ubiquitin-activating enzyme, E1. Addition of ubiquitin protein ligase E3 substantially enhanced the E214K-mediated ubiquitinylation of c-Jun and c-Fos. Truncated c-Jun and c-Fos mutant proteins including wbJun and wbFos were also ubiquitinylated under the same conditions, suggesting the sites of ubiquitinylation are located within the dimerization and DNA binding domains of c-Jun and c-Fos. The E3-dependent ubiquitinylation of c-Jun was inhibited upon the heterodimerization of c-Jun with c-Fos. Further addition of E220K significantly enhanced ubiquitinylation of c-Jun in the heterodimer suggesting a regulatory role of E220K. Polyubiquitinylated c-Jun, wbFos, and wbJun, but not E220K-ubiquitinylated c-Jun, were readily degraded by the ATP-dependent 26 S multicatalytic proteases. These results suggest that the temporal control of c-Jun and c-Fos may be regulated through the ubiquitinylation pathways, and the ubiquitinylation of c-Jun and c-Fos may in turn be regulated in response to the heterodimerization between them and the cooperation between E220K and E3 mediated polyubiquitinylation.

Adenosine Triphosphate↗

PubMed1996

False recognition and the right frontal lobe: a case study.

We described a patient, BG, who exhibited a striking pattern of false recognition after an infarction of the right frontal lobe. Seven experiments document the existence of the phenomenon, explore its characteristics, and demonstrate how it can be eliminated. BG showed pathologically high false alarm rates when stimuli were visual words (experiments 1 and 4), auditory words (experiment 2), environmental sounds (experiment 3), pseudowords (experiment 5), and pictures (experiment 7). His false alarms were not merely attributable to the semantic or physical similarity of studied and non-studied items (experiments 4 and 5). However, BG's false recognitions were virtually eliminated by presenting him with categorized stimuli and testing him with new stimuli from non-studied categories (experiments 6 and 7). The results suggest that BG's false alarms may be attributable to an over-reliance on memory for general characteristics of the study episode, along with impaired memory for specific items. The damaged right frontal lobe mechanisms may normally support the monitoring and/or retrieval processes that are necessary for item-specific recognition.

Aged↗

PubMed1996

Detection of the reelin breakpoint in reeler mice.

Disruption of the reelin gene by partial deletion causes the neurological phenotype known as reeler. Here we report the cloning and sequencing of the reelin breakpoint region from the Jackson reeler strain (rl). Based on this sequence, we developed a polymerase chain reaction screen that allows the identification of mutant mice prior to the appearance of the phenotype. The assay also permits discrimination of heterozygous from wild-type mice. These findings provide a strategy for the characterization of the early anatomical and physiological consequences of the reeler mutation.

Animals↗

PubMed1996

Neuroanatomical correlates of veridical and illusory recognition memory: evidence from positron emission tomography.

Memory distortions and illusions have been thoroughly documented in psychological studies, but little is known about the neuroanatomical correlates of true and false memories. Vivid but illusory memories can be induced by asking people whether they recall or recognize words that were not previously presented, but are semantically related to other previously presented words. We used positron emission tomography to compare brain regions involved in veridical recognition of printed words that were heard several minutes earlier and illusory recognition of printed words that had not been heard earlier. Veridical and illusory recognition were each associated with blood flow increases in a left medial temporal region previously implicated in episodic memory; veridical recognition was distinguished by additional blood flow increases in a left temporoparietal region previously implicated in the retention of auditory/phonological information. This study reveals similarities and differences in the way the brain processes accurate and illusory memories.

Acoustic Stimulation↗