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M Gallagher

Publications and source records attributed to M Gallagher.

At least 55 records · Page 3Linked to original sources
PubMed1999

Functions of the amygdala and related forebrain areas in attention and cognition.

This paper will concentrate on two features of the systems described by Alheid and Heimer that have influenced research in our laboratory in recent years. In the first part, we describe our findings on a representational function of the amygdaloid basolateral complex that appears to depend on its interconnections with the prefrontal cortex. In the second part, we describe progress assessing the function of magnocellular corticopetal neurons within the basal forebrain and the strong input to this system from the central amygdaloid group. These lines of behavioral research have revealed that sub-systems in the basal forebrain and amygdala serve adaptive functions beyond the domains of motivation and emotion to include attention and cognition.

Amygdala↗
PubMed1999

Thalamic and basal forebrain cholinergic connections of the rat posterior parietal cortex.

The thalamic connectivity and basal forebrain cholinergic input to the posterior parietal cortex (PPC) of Long-Evans rats was examined using combined retrograde tracing and immunocytochemical methods. As in previous studies, the PPC could be distinguished by its input from the lateral posterior, lateral dorsal, and posterior nuclei of the thalamus, but not the lateral geniculate nucleus or ventrobasal complex. These nuclei were also observed to receive reciprocal projections from the ipsilateral PPC. Cholinergic neurons innervating the PPC were primarily localized to the substantia innominata/nucleus basalis region. The implications of these data for possible functions of the cholinergic input to PPC are discussed.

Animals↗
PubMed1999

Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning.

Orbitofrontal cortex (OFC) is part of a network of structures involved in adaptive behavior and decision making. Interconnections between OFC and basolateral amygdala (ABL) may be critical for encoding the motivational significance of stimuli used to guide behavior. Indeed, much research indicates that neurons in OFC and ABL fire selectively to cues based on their associative significance. In the current study recordings were made in each region within a behavioral paradigm that allowed comparison of the development of associative encoding over the course of learning. In each recording session, rats were presented with novel odors that were informative about the outcome of making a response and had to learn to withhold a response after sampling an odor that signaled a negative outcome. In some cases, reversal training was performed in the same session as the initial learning. Ninety-six of the 328 neurons recorded in OFC and 60 of the 229 neurons recorded in ABL exhibited selective activity during evaluation of the odor cues after learning had occurred. A substantial proportion of those neurons in ABL developed selective activity very early in training, and many reversed selectivity rapidly after reversal. In contrast, those neurons in OFC rarely exhibited selective activity during odor evaluation before the rats reached the criterion for learning, and far fewer reversed selectivity after reversal. The findings support a model in which ABL encodes the motivational significance of cues and OFC uses this information in the selection and execution of an appropriate behavioral strategy.

Action Potentials↗
PubMed1999

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats.

The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus.

Aging↗
PubMed1999

Establishment and characterization of adenoviral E1A immortalized cell lines derived from the rat suprachiasmatic nucleus.

Primary cultured cells from the presumptive anlage of the rat suprachiasmatic nucleus (SCN) were immortalized by infection with a retroviral vector encoding the adenovirus 12S E1A gene. After drug selection, the resulting neural cell lines (SCN1.4 and SCN2.2) displayed (a) extended growth potential without evidence of transformed or tumorigenic properties, (b) expression of E1A protein within all cell nuclei, and (c) heterogeneous cell types in various stages of differentiation. A large proportion of the SCN1.4 and SCN2.2 cells were characterized by gliallike morphologies, but showed limited expression of corresponding cell type-specific antigens. In addition, both lines exhibited a stable population of cells with neuronlike characteristics. When treated so as to enhance differentiation, these cells were often distinguished by fine, long processes and immunocytochemical expression of neuronal markers and peptides found within SCN neurons in situ. Observations on SCN neuropeptide immunostaining, content, release, and mRNA expression followed a concordant pattern in which somatostatin and vasopressin cells were the most and least common peptidergic phenotypes in both lines, respectively. Since these results indicate that constituents of E1A-immortalized lines derived from the primordial SCN can differentiate into cells with phenotypes resembling parental peptidergic neurons, it will be critical to explore next whether these lines also retain the distinctive function of the SCN to generate circadian rhythms. Cloning of immortalized cell types could subsequently yield useful tools for studying the development of SCN glial and peptidergic cell types and delineating their distinct roles in mammalian circadian time-keeping.

Adenovirus E1A Proteins↗
PubMed1999

Hippocampal lesions interfere with Pavlovian negative occasion setting.

Rats were trained with either a serial feature positive (L-->T1+ T-) or a serial feature negative (L-->T1-, T1+) discrimination, intermixed with training on another, nonconditional discrimination (T2+, N-), using a Pavlovian appetitive conditioning preparation with multiple response measures. Among rats trained with the serial feature positive discrimination, neurotoxic lesions of the hippocampus produced a transient impairment in the acquisition of that discrimination, but did not affect acquisition of the nonconditional discrimination. In contrast, among rats that received serial feature negative discrimination training, hippocampal lesions produced enduring deficits in the acquisition of both discriminations. The results of transfer tests indicated that both lesioned and control rats used a conditional learning strategy (occasion setting) to solve the feature positive and feature negative discriminations. Furthermore, lesioned rats, especially those that received training with the feature negative discrimination, displayed increasingly higher levels of general activity as training progressed. The results suggest that hippocampal lesions particularly interfere with inhibitory learning (negative occasion setting) about both explicit and contextual cues.

Animals↗
PubMed1999

Amygdala circuitry in attentional and representational processes.

The amygdala has long been implicated in the display of emotional behavior and emotional information processing, especially in the context of aversive events. In this review, we discuss recent evidence that links the amygdala to several aspects of food-motivated associative learning, including functions often characterized as attention, reinforcement and representation. Each of these functions depends on the operation of separate amygdalar subsystems, through their connections with other brain systems. Notably, very different processing systems seem to be mediated by the central nucleus and basolateral amygdala, subregions of the amygdala that differ in their anatomy and in their connectivity. The basolateral amygdala is involved in the acquisition and representation of reinforcement value, apparently through its connections with ventral striatal dopamine systems and with the orbitofrontal cortex. The dentral nucleus, however, contributes heavily to attentional function in conditioning, by way of its influence on basal forebrain cholinergic systems and on the dorsolateral striatum.

Journal Article↗
PubMed1999

Living donor liver transplantation in critically ill children.

From December 1993, St Christopher's Hospital for Children, Philadelphia, PA, USA has provided living donors the opportunity to donate a portion of their liver to children who are critically ill. This report evaluates the results of living donor liver transplants (LDLT) in critically ill children. We retrospectively reviewed the first 22 LDLT at our institution and compared the patient and graft survival of the nine critically ill children with the 13 stable children. Twenty-two LDLT have been performed at our institution between December 1993 and October 1997. Nine of 22 transplants [United Network for Organ Sharing (UNOS) Status I] were performed in children who were critically ill. Thirteen of the LDLT (UNOS Status II and III) were performed on stable children either in the hospital or admitted electively from home. The median weight and age at the time of transplant were 7 kg (range 4.6-54.5 kg) and 16 months (range 3 months-12 yr), respectively, and there was no statistical difference between the two groups. In critically ill children the 1-yr allograft and patient survival was 66% and 89%, respectively, exceeding the published results from UNOS for patients on life support (59.5% graft and 69.7% patient survival at 1 yr). One-yr allograft and patient survival in the stable children was 92.3% and 100%, respectively. All living donors are alive and well with normal liver function. In conclusion, our results show that LDLT is a viable approach for transplantation in critically ill children with liver failure and should be offered to potential donors.

Biliary Atresia↗
PubMed1999

Disconnection of the amygdala central nucleus and substantia innominata/nucleus basalis disrupts increments in conditioned stimulus processing in rats.

Rats with a neurotoxic lesion of the amygdala central nucleus (CN) in one hemisphere and a 192 immunoglobulin G (192IgG)-saporin lesion of cholinergic neurons in the contralateral substantia innominata/nucleus basalis (SI/nBM) failed to show the enhanced attentional processing of a conditioned stimulus (CS) observed in sham-operated rats when that CS's predictive value was altered. Performance of these asymmetrically lesioned rats was poorer than that of rats with a unilateral lesion of either structure or with a symmetrical lesion of both structures in the same hemisphere. These results implicate connections between the CN and SI/nBM in the incremental attentional processing of CSs, extending previous research that has shown similar effects of bilateral lesions of either the CN or the SI/nBM.

Amygdala↗
PubMed1999

Impairments in conditioned stimulus processing and conditioned responding after combined selective removal of hippocampal and neocortical cholinergic input.

Previous studies indicated that changes in attentional processing of conditioned stimuli (CSs) are regulated by the basal forebrain (BF) cholinergic system. In those studies, destruction of BF innervation of the neocortex interfered with enhancements in CS processing, and destruction of BF innervation of the hippocampus prevented reductions in CS processing. In the current experiments, the performance of rats with 192 IgG-saporin lesions of both hippocampal and neocortical cholinergic input was examined. These combined lesions disrupted both enhancements and reductions in CS processing. Lesioned rats also showed more general impairments in conditioned responding. These results indicate that, although the neural systems for increasing and decreasing attentional processing may be largely independent, combined loss of hippocampal and neocortical cholinergic input may produce behavioral impairments that are not apparent after either lesion alone.

Animals↗
PubMed1999

Blocking can occur without losses in attention in rats with selective removal of hippocampal cholinergic input.

Prior studies showed that 192 IgG-saporin lesions of cholinergic input to the hippocampus disrupted reductions in processing of uninformative stimuli. In 2 experiments in this study, the performance of rats with these lesions was examined in blocking procedures. In both lesioned and normal rats, previous pairing of one conditioned stimulus (CS) with food blocked conditioning of a 2nd CS when a compound of both CSs was paired with food. However, in subsequent savings tests, lesioned rats showed faster learning than did normal rats when the blocked CS was established as a signal for either reinforcement or nonreinforcement. Thus, the reduced attention to the blocked CS found in normal but not lesioned rats was not essential for the occurrence of blocking. Although rats with selective removal of hippocampal cholinergic input may be unable to reduce attention to redundant stimuli, other mechanisms of stimulus selection remain available to them.

Animals↗
PubMed1999

Pyrimidine nucleotide-evoked inhibition of cyclic AMP accumulation in equine epithelial cells.

Uridine triphosphate (UTP) evoked inhibition of adrenaline-evoked cAMP accumulation in cultured equine epithelial cells (EC50, 1.8 +/- 0.2 microM) and this effect was mimicked by 5-Br-UTP (EC50, 6.6 +/- 1.8 microM) and uridine diphosphate (UDP; EC50, 96 +/- 26 microM). This inhibitory action of UTP was abolished by pre-treating cells with pertussis toxin (10 ng ml-1, 24 h). UTP (EC50, 2.3 +/- 0.3 microM) and 5-Br-UTP (EC50, 29.4 +/- 9.4 microM) also increased intracellular free calcium ([Ca2+]i) whilst UDP did not; the two effects are thus differentially sensitive to these pyrimidine nucleotides. ATP evoked cAMP accumulation in control cells and this response was unaffected by pertussis toxin. There is, therefore, no indication that ATP activates the pertussis toxin-sensitive inhibitory pathway. The UTP-evoked inhibition of cAMP accumulation was abolished by isobutylmethylxanthine (IBMX, 5 mM) and so the negative control over cAMP levels appears to be mediated by receptors that are selectively activated by pyrimidine nucleotides and permit control over phosphodiesterase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A).

PURPOSE: Raf-1 is a protein kinase that plays a broad role in oncogenic signaling and acts as a downstream effector of Ras in the mitogen-activated protein kinase pathway. The present study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-raf-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treated patients was studied using a reverse transcriptase polymerase chain reaction assay. PATIENTS AND METHODS: Patients with refractory malignancies received ISIS 5132 as a 2-hour intravenous infusion three times weekly for 3 consecutive weeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-1 mRNA analysis were collected at baseline and on days 3, 5, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter. RESULTS: Thirty-one patients received ISIS 5132 at one of nine dose levels ranging from 0.5 mg/kg to 6.0 mg/kg. Clinical toxicities included fever and fatigue, but these were not dose limiting. A clinically defined MTD was not reached. The harmonic mean half-life of ISIS 5132 was 59.8 minutes (range, 35.5 to 107.3 minutes). The area under the concentration-time curve increased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (range, 1.21 to 2.41 mL/kg/min). Two patients experienced prolonged stable disease lasting more than 7 months, which was associated with persistent reduction in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expression were identified at time points after the baseline value (P <.05) at doses >/= 2.5 mg/kg. CONCLUSION: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.

Adult↗
PubMed1999

Heme oxygenase-2 is neuroprotective in cerebral ischemia.

Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast, stroke damage is not significantly altered in HO1(-/-) mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-d-aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.

Animals↗
PubMed1999

c-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A).

Abnormally regulated signaling through proliferative signal transduction pathways characterizes many of the common solid tumors. The best described of these involves potentially oncogenic proteins of the Ras family, which activate Raf proteins in the early steps of the mitogen-activated protein kinase cascade. ISIS 5132, a phosphorothioate antisense oligodexoynucleotide directed to the 3' untranslated region of the c-raf-1 mRNA, inhibits the growth of human tumor cell lines in vitro and in vivo in association with specific down-regulation of target message expression. Using a semiquantitative reverse transcription-PCR assay, we analyzed changes in c-raf-1 mRNA expression in peripheral blood mononuclear cells collected from patients with advanced cancers treated with ISIS 5132 as part of a clinical trial. Specimens were collected for analysis pretreatment and on days 3, 5, 8, and 15 of the first cycle and on day 1 of each subsequent cycle. We observed significant reductions of c-raf-1 expression from baseline by day 3 in 13 of 14 patients (P = 0.002). The time course and depletion of c-raf-1 message in peripheral blood mononuclear cells paralleled the clinical benefit in two patients. These findings demonstrate that ISIS 5132 specifically reduces target gene expression in treated patients and that peripheral blood mononuclear cells are suitable tissues for biomarker studies in future trials.

Aged↗
PubMed1998

Removal of cholinergic input to rat posterior parietal cortex disrupts incremental processing of conditioned stimuli.

Recent research suggests that the basal forebrain cholinergic neurons innervating the cortex play a role in attentional functions in both primates and rodents. Among the cortical targets of these projections in primates is the posterior parietal cortex (PPC), a region shown to be critically involved in the regulation of attention. Recent anatomical studies have defined a cortical region in the rat that may be homologous to the PPC of primates. In the present study, cholinergic innervation of the PPC was depleted by intracortical infusion of the immunotoxin 192 IgG-saporin. Control and lesioned rats were then tested in two associative learning paradigms designed to increase attentional processing of conditioned stimuli (CSs). In one experiment, attention was manipulated by shifting a predictive relation between a light CS and another CS to a less predictive relation. Unlike control rats, lesioned rats failed to increase attention when the predictive relation was modified. In a second experiment, attentional processing of a tone CS was increased when its introduction during training coincided with a change in the value of the unconditioned stimulus, a phenomenon referred to as unblocking. Unlike control rats, lesioned rats failed to exhibit unblocking. In both paradigms, lesioned rats conditioned normally when the training procedures did not encourage increased attentional processing. These findings, across different behavioral paradigms and stimulus modalities, provide converging evidence that intact cholinergic innervation of the PPC is important for changes in attention that can increase the processing of certain cues.

Acetylcholinesterase↗
PubMed1998

Hippocampal lesions enhance configural learning by reducing proactive interference.

Rats were trained on an operant conditional discrimination in which an ambiguous stimulus (X) indicated both the occasions on which responding in the presence of a second cue (A) would be reinforced and the occasions on which responding in the presence of a third cue (B) would not be reinforced (X --> A+, A-, X --> B-, B+). Both rats with neurotoxic lesions of the hippocampus and control rats learned this discrimination more rapidly when the training trials were widely spaced (mean intertrial interval of 8 min) than when they were massed (mean intertrial interval of 1 min). With spaced practice, lesioned and control rats learned this discrimination equally well. But when the training trials were massed, lesioned rats learned more rapidly than controls. At the end of training, performance of all rats was tested at three different intertrial intervals, 0.5 min, 1 min, and 8 min. The control rats trained with 8-min intertrial intervals showed deficits in discrimination performance when the test intertrial interval was 0.5 min or 1 min. An analysis of sequential effects indicated that a major source of this performance deficit was the control rats' failure to withhold responding on nonreinforced trials when those trials were immediately preceded by reinforced trials within 0.5 min or 1 min. In contrast, performance of lesioned rats was not affected by either the test intertrial interval or by the nature of preceding trials. Thus, with short intertrial intervals, hippocampal lesions may have improved learning or performance on a given trial by reducing proactive interference from the previous trial.

Animals↗