The effects of posterior parietal and posterior temporal cortical lesions on multimodal spatial and nonspatial competencies in rats.

The functional consequences of posterior parietal (PPC) and posterior temporal (Te2/3) cortical lesions on rat spatial and nonspatial multimodal learning, and memory were assessed using three behavioral paradigms. In the first, a stimulus-elicited object-place recognition task, PPC-lesioned animals were found to habituate to repeated presentation and dishabituate to changes in the visual and auditory properties of the objects but they fail to respond to changes in their location. The Te2/3-lesioned animals recognized changes in spatial location, but not changes in auditory or visual characteristics of the objects. Sham controls recognized both. In water maze-based auditory and visual place object conditional learning tasks, Te2/3 and Sham controls learned both discriminations, whereas the performance of PPC animals was significantly retarded. In the third paradigm, all three groups learned the visual discriminations. Although PPC-lesioned animals subsequently demonstrated recognition of the amodal property of duration in a visual/auditory cross-modal transfer (CMT) test, they were unable to do so on two CMT tasks involving the property of space. In all three tests, the Sham controls consistently displayed CMT and the Te2/3-lesioned animals did not. The present study extends the description of somewhat distinctive roles played by two association cortical regions (PPC and Te2/3) in the perceptual/cognitive functioning, particularly with respect to auditory stimuli and correspondences between auditory and visual events.

The influences of rearing environment and neonatal choline dietary supplementation on spatial learning and memory in adult rats.

The facilitative effects of early environmental enrichment and perinatal choline chloride dietary supplementation on adult rat spatial learning and memory were examined using delayed match-to-place (DMTP) and delayed spatial win-shift (DSWSh) discrimination tasks. Animals were either maintained in a standard lighted colony (LR) or were given supplementary exposure to a complex environment (CR) for 2-h daily from 20 to 90 days of age. In each case, half the animals were exposed to the choline supplementation both prenatally (through the diet of pregnant rats) and postnatally (subcutaneous injection) for 24 days. In the first experiment, all 90-day-old rats were given trials in which they first found a hidden platform in a Morris water maze (MWM) in a particular location (acquisition trial), and then were required to remember that position 10 min later (test trial). Both environmental enrichment and early diet had significant impacts on performance. CR animals, given neonatal choline pretreatment, found the platform on test trials significantly faster than any of the other groups. CR animals exposed to the control saline diet showed better retention than did the LR animals given the early choline diet, which in turn, were superior to animals given neither environmental enrichment nor choline. All animals were subsequently tested in the same paradigm immediately following atropine sulfate injections. The atropine eliminated the difference between the four groups of animals on test trials. In a second experiment, both CR, and neonatal choline treatment facilitated performance on a DSWSh radial arm maze (RAM) task previously found to be sensitive to hippocampal and/or medial prefrontal lesions. Performance differences between groups were facilitated by the anticholinesterase drug, tacrine and attenuated by the cholinergic antagonist, Atropine. The present study extends the descriptions of long-term functional enhancements produced by perinatal choline supplementation and environmental enrichment and to relate these effects to common modifications to targets of cholinergic basal forebrain systems.

The influences of sex, rearing environment, and neonatal choline dietary supplementation on spatial and nonspatial learning and memory in adult rats.

The potential facilitative effects of early environmental enrichment and perinatal choline chloride dietary supplementation on male and female adult rats' learning and memory were examined using a "stimulus-elicited investigative," and a social/observational learning-cued spatial memory paradigm. Male and female animals were either maintained in a standard lighted colony (SC) or were given supplementary exposure to a complex environment (EC) for 2 hr daily from 24-90 days of age. In each case, half of the animals were exposed to the choline supplementation both prenatally and postnatally for 24 days. In one paradigm, the 90-day-old EC rats were found to be significantly more responsive than SC rats to each change in the spatial relationships of objects contained in an open field. Neither sex nor early diet of the animals were much of a factor in the investigative behavior observed. In the second paradigm, the effects of the perinatal choline diet did interact with those of sex and postnatal environment to alter the impact of social/observational experience on the acquisition and memory of place in the water maze. The choline-treated EC males were the most influenced by their experience seeing a demonstrator swim to a platform location. The present study provides some further insight into the scope of the long-term functional enhancements produced by perinatal choline supplementation and EC in male and female animals and relates these effects to common modifications to targets of cholinergic basal forebrain systems.

The effects of neonatal choline dietary supplementation on adult spatial and configural learning and memory in rats.

The facilitative effects of pre- and early postnatal choline chloride dietary supplementation on adult rat spatial and nonspatial learning and memory were examined using a delayed match-to-place and a transverse-patterning discrimination task. Animals were exposed to the choline supplementation both prenatally (through the diet of pregnant rats) and postnatally (subcutaneous injection) for 24 days. In the first experiment, 90-day-old rats were given pairs of trials in which they first found a hidden platform in a Morris water maze in a particular location (acquisition trials), and then were required to remember that position 10 min later (test trials). Those animals given neonatal choline pretreatment found the platform on test trials significantly faster than did animals in a saline-treated control group. All animals were subsequently tested in the same paradigm following atropine sulfate injections. The atropine eliminated the difference between experimental and control animals on test trials. In a second experiment, neonatally treated choline rats performed significantly better than controls in acquiring a visual transverse patterning discrimination task previously found to be sensitive to hippocampal and/or frontal damage. The present study extends the description of long-term functional enhancement produced by perinatal choline supplementation to include the ability to use and remember visual configural associations, working spatial memory, and to relate these effects to modifications in cholinergic basal forebrain systems.

Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP) protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP or the presentation of LPS/LBP complexes to CD14.

Cellular responses to LPS, the major lipid component of the outer membrane of Gram-negative bacteria, are enhanced markedly by the LPS-binding protein (LBP), a plasma protein that transfers LPS to the cell surface CD14 present on cells of the myeloid lineage. LBP has been shown previously to potentiate the host response to LPS. However, experiments performed in mice with a disruption of the LBP gene have yielded discordant results. Whereas one study showed that LBP knockout mice were resistant to endotoxemia, another study did not confirm an important role for LBP in the response of mice challenged in vivo with low doses of LPS. Consequently, we generated rat mAbs to murine LBP to investigate further the contribution of LBP in experimental endotoxemia. Three classes of mAbs were obtained. Class 1 mAbs blocked the binding of LPS to LBP; class 2 mAbs blocked the binding of LPS/LBP complexes to CD14; class 3 mAbs bound LBP but did not suppress LBP activity. In vivo, class 1 and class 2 mAbs suppressed LPS-induced TNF production and protected mice from lethal endotoxemia. These results show that the neutralization of LBP accomplished by blocking either the binding of LPS to LBP or the binding of LPS/LBP complexes to CD14 protects the host from LPS-induced toxicity, confirming that LBP is a critical component of innate immunity.

Influences on infant speech processing: toward a new synthesis.

To comprehend and produce language, we must be able to recognize the sound patterns of our language and the rules for how these sounds "map on" to meaning. Human infants are born with a remarkable array of perceptual sensitivities that allow them to detect the basic properties that are common to the world's languages. During the first year of life, these sensitivities undergo modification reflecting an exquisite tuning to just that phonological information that is needed to map sound to meaning in the native language. We review this transition from language-general to language-specific perceptual sensitivity that occurs during the first year of life and consider whether the changes propel the child into word learning. To account for the broad-based initial sensitivities and subsequent reorganizations, we offer an integrated transactional framework based on the notion of a specialized perceptual-motor system that has evolved to serve human speech, but which functions in concert with other developing abilities. In so doing, we highlight the links between infant speech perception, babbling, and word learning.

A cocktail of three monoclonal antibodies significantly increases the sensitivity of an enzyme immunoassay for human granulocyte-macrophage colony-stimulating factor.

A sensitive and specific two-site ELISA was developed for human granulocyte-macrophage colony-stimulating factor (huGM-CSF) based on monoclonal antibodies (mAbs) which have been selected for high affinities and different epitope specificities. Using a cocktail of three mAbs, both for coating and, in their labeled form, for detection, a major increase in sensitivity was achieved (20-fold) compared to a two-site assay employing two different mAbs (one for coating and one for detection). The assay is as sensitive as the most sensitive biological assays. Recombinant mammalian cell expressed and natural huGM-CSF can be reliably detected down to 100 pg/ml (7 pmol/l). In contrast to conventional bioassays, the ELISA is highly specific for huGM-CSF and does not detect other human lymphokines. Results from quantification of recombinant and natural huGM-CSF in ELISA and bioassay correlate.

An examination of the intramodal and intermodal behavioral consequences of long-term vibrissae removal in rats.

An assessment was made of the effects of long-term tactile restriction by bilateral removal of the mystacial vibrissae from an early age on the subsequent somatosensory capacities of rats (i.e., the intramodal consequences) as well as its effects on visual and spatial capacities (i.e., the intermodal consequences). Rearing environment (enriched vs. normal) and method of vibrissae removal (cauterization of follicles vs. plucking) were examined to determine specific factors that m might influence the effect of vibrissae removal. Early, long-term tactile restriction had significant intramodal and intermodal consequences. Dewhiskered rats showed attenuated orientation to tactile stimuli presented to their mystacial pads and enriched-reared rats whose vibrissae follicles had been cauterized showed increased orientation to visual stimuli. Manipulation of early somatosensory signals had no impact on the development of certain spatial and precise manipulatory skills. These data provide limited evidence for theories of modality interdependence and yield basic information concerning the role of the mystacial vibrissae in the behavior of the rat.

The effect of early experience on water maze spatial learning and memory in rats.

In the first of two experiments on spatial competence, groups of light-reared (LR) and dark-reared (DR) rats were compared using a "latent learning" variation of the Morris Water Maze task. On their initial test, the LR rats benefited more than DR rats did from viewing the room/pool from a platform in the correct location. Further, visually experienced rats remember the location of the platform more than DR rats when retested one month later. In a second experiment, in which a proximal cue as well as location was varied from trial to trial. LR rats again proved to be more competent than their DR counterparts. This second task also revealed significant benefits related to stimulation history in the case of a third group of animals raised in enriched or complex environment (CR) conditions. The results are discussed in terms of the nature of the impact of early experience on the ability to acquire and remember spatial concepts.

Development of defensive burying in Rattus norvegicus: experience and defensive responses.

Rats (Rattus norvegicus) deprived of the opportunity to interact with particulate matter until they were young adults engaged in defensive burying after they were shocked by a wire-wrapped dowel in a test chamber that held bedding material. Interacting with a particulate substrate during development is not necessary for the expression of defensive burying in adulthood. However, interacting with a particulate substrate early in the rats' lives did have a substantial effect on the emergence and maintenance of burying behavior. Defensive burying developed at a later age and declined at an earlier age in rats maintained on wire mesh from birth until testing than it did in rats raised until weaning on bedding and housed on mesh thereafter. Because defensive burying is a complex, flexible, yet reliable response sequence that cannot be performed without the appropriate substrate, it has considerable potential as a model for the study of the development of species-specific defense responses.

Parallel perceptual/cognitive functions in humans and rats: space and time.

The nature of the evidence on the role played by early stimulation history in perceptual development related to an appreciation of intermodal attributes involving space and time is reviewed. In conjunction with this analysis, an examination was undertaken of the effect of early visual deprivation on the ability of dark- (DR) and light-reared (LR) rats to learn discriminations involving location of sounds or lights and to abstract the intersensory correspondence involved from the initial modality-specific training. Visually inexperienced DR rats were somewhat slower to acquire a discrimination involving the location of visual events under some stimulus/response arrangements. More importantly, such animals were not as effective as their visually experienced LR counterparts in demonstrating cross-modal transfer (CMT) to signals in a new modality. The present study also revealed that CMT involving location of signals was less salient than CMT of duration information in rats regardless of their rearing condition. Finally, findings are discussed more generally, providing contextual information that bears on issues related to parallel cognitive functions in rats and human neonates and on the role of early visual experience in the ontogeny of intersensory perceptual competence in mammals.

Effects of superior colliculus lesions on rats' orienting and detection of neglected visual cues.

Superior colliculus lesions generally result in a deficit in visual orienting described as sensory neglect. This observation was confirmed in this study: Rats with lesions did not orient to some stimuli that intact rats readily oriented to. However, rats with lesions did orient to stimuli that the intact rats treated as more salient. Also, when the less salient stimuli signaled aversive stimulation, the rats with lesions detected these stimuli. These findings suggest that superior colliculus lesions do not affect the detection of visual stimuli that have been neglected.

Effects of intertrial reinforcers on rats' timing behavior.

Two experiments were conducted to assess the effects of non-contingent intertrial interval (ITI) reinforcers on rats' discrimination of duration. In the first experiment, rats' discrimination of a 2 vs. 8 s of light was significantly disrupted when reinforcers were presented in the ITI. Disruption was not different on short (2 s) and long (8 s) trials. The second experiment showed that this disruptive effect was not specific to trials preceded by ITI reinforcers; responding on empty ITI trials run in the same session as ITI-reinforcer trials was also disrupted. This disruption however was not as great as on the ITI-reinforcer trials. The results of these experiments show that ITI reinforcers affect timing discriminations in much the same way they affect classical conditioning and delayed matching to sample. However, detailed examination of the results suggests that the deleterious effects of ITI reinforcers in these different paradigms might be produced by different rather than the same mechanism. The results also support the conclusion that pre-trial reinforcement "priming" produces disruption rather than facilitation in complex tasks.

Fine specificity and cross-reactivity of monoclonal antibodies to cyclosporine.

More than 180 monoclonal antibodies (McAbs) to the cyclic undecapeptide cyclosporine (Cs) have been prepared. Several immunization protocols and antibody screening processes were compared. Two main groups of McAbs recognizing different "sides" of the Cs molecule could be differentiated. The antibodies belonged to the IgG and IgA classes and showed high affinity for Cs (up to 10(-10) -10(-11) mol/l). Based on their ability to discriminate Cs-derivatives modified singly at each of the 11 residues of the Cs molecule, the antigenic recognition pattern of different McAbs was studied at the level of individual residues. Closely related recognition patterns were found in each of the two main McAb groups. The apparent size of the Cs antigenic sites recognized by different McAbs varied from four to ten residues and did not correlate with antibody affinity.

Joint inflammation in mice induced by a MT4+ Lyt-2- T cell clone. Characteristics and the induction of flare-up reactions.

Joint inflammations were induced in mice by cloned MT4+ Lyt-2- T cells specific for methylated bovine serum albumin. This was done either by intra-articular or by i.v. administration of the cloned T cells, together with local injection of the antigen. Local rechallenge with methylated bovine serum albumin several weeks after waning of the joint inflammation caused a flare-up reaction. The inflammations were quantified by a 99mTc-uptake method and examined histologically. The arthritis induced by the cloned T cells showed aspects of a delayed type hypersensitivity reaction characterized by an intense infiltrate which resembles the inflammation in the human rheumatoid joint. The data presented show that joint inflammations can be induced by T cells only and that, after waning, reexposition to the original antigen can induce a flare-up reaction. The data suggest a central role of T cells in the induction and the exacerbations observed in rheumatoid arthritis.

Intersensory coordination and the effects of early sensory deprivation.

The effect of early visual deprivation on the ability of dark- (DR) and light-reared (LR) rats to learn temporal discriminations involving sounds and lights and to abstract the intersensory correspondence involving duration from initial modality-specific training was examined in this study. While visually inexperienced DR rats were somewhat less successful in acquiring an initial discrimination involving visual events and responding to a rule reversal per se, they were as effective as their visually experienced LR counterparts in demonstrating cross-modal transfer (CMT) to signals in a new modality. The results revealed by the investigation are discussed in terms of the consequences and lack of consequences of the manipulation of early visual experience on the ontogeny of intersensory perceptual development in mammals.

Potential of monoclonal antibodies to improve therapeutic monitoring of cyclosporine.

We show that monitoring of cyclosporine by immunoassay could be improved by using monoclonal antibodies (MAbs) of restricted specificity instead of polyclonal antisera that recognize both unmodified cyclosporine and its metabolites. MAbs with high affinity for cyclosporine have been prepared and characterized. We tested their ability to discriminate between native cyclosporine and its metabolites in indirect solid-phase enzyme immunoassay with a set of cyclosporine metabolites modified at residues 1, 4, 6, and 9 (corresponding to the six known sites of metabolism of cyclosporine). All the metabolites tested were detected by MAb1 at least 15- to 1000-fold less well than unmodified cyclosporine. A second MAb recognized unmodified cyclosporine and most of its metabolites equally well. Both MAbs retained their activity when coupled to alkaline phosphatase and could therefore be used in a direct solid-phase enzyme immunoassay.