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Biomedical subjects

J R Alberts

Publications and source records attributed to J R Alberts.

At least 19 recordsLinked to original sources

Co-amplification of a novel gene, NAG, with the N-myc gene in neuroblastoma.

Substantial evidence implicates amplification of the N-myc gene with aggressive tumor growth and poor outcome in neuroblastoma. However some evidence suggests that this gene alone is not the sole determinant of outcome in N-myc amplified tumors. We have searched for genes that co-amplify with N-myc in neuroblastoma by means of two-dimensional analysis of genomic restriction digests. Using this approach, we have identified and cloned a novel genomic fragment which is co-amplified with N-myc in neuroblastomas. This fragment was mapped in close vicinity to N-myc on chromosome arm 2p24. It was amplified in 5/8 N-myc amplified neuroblastoma cell lines and in 9/13 N-myc amplified tumors. Using a PCR-based approach we isolated a 4.5 kb c-DNA sequence that is partly contained in the genomic fragment. The open reading frame of the cDNA encodes a predicted protein of 1353 amino acids (aa). The homology of the predicted protein, which we designated NAG (neuroblastoma amplified gene), to a C. elegans protein of as yet unknown function, and its ubiquitous expression suggest that NAG may serve an essential function. By Northern blot analysis we showed that amplification of the cloned gene correlates with over-expression in neuroblastoma cell lines. Amplification and consequent over-expression of NAG may, therefore, contribute to the phenotype of a subset of neuroblastomas.

Chromosome Mapping

Ontogenetic adaptation and learning: a developmental constraint in learning for a thermal reinforcer.

Hoffman, Flory, and Alberts (1999) demonstrated that 1-, 5-, and 11-day-old rats in a cool environment (25 degrees C) acquired an operant head-turning response when rewarded with a 20-s warming of the platform on which they lay. In the current experiment 5- and 11-day-old rats in a hot environment (40 degrees C) acquired the head-turning response when rewarded with a 20-s cooling of the platform on which they lay, but 1-day-olds did not. The concept of ontogenetic adaptation helps us interpret these results: Neonatal thermotaxis constrains the 1-day-olds from learning a novel operant response for a cool reinforcer in a hot environment. Because the thermotaxis wanes from birth, it is not as strong in 5- and 11-day-old pups that are thus able to learn the operant for a cool reinforcer.

Adaptation, Physiological

Neonatal thermotaxis improves reversal of a thermally reinforced operant response.

One-, 5-, and 11-day-old rats in a cool environment (25 degrees C) acquired an operant response when rewarded with a 20-s-long warming of the platform (from 25 to 36 degrees C) on which they lay. In Experiment 1, the head-turning response was learned by pups at all ages. When the contingency was reversed so that pups were reinforced for turning to the side opposite that correct during training, the original response extinguished for 1-day-olds, but not for 5- or 11-day-olds. In Experiment 2, the rewarded side was randomly selected for each trial. One-day-olds perseverated in turning to the side correct on that trial while the reinforcer remained on, but 5- and 11-day-old rat pups did not. We conclude that 1-day-old pups were more responsive to the change in experimental contingency in Experiment 1 due to this thermotaxic behavior.

Age Factors

Oxytocin is elevated in plasma of 10-day-old rats following gastric distension.

In adult rats, oxytocin (OT) has been shown to reduce the intake of both food and fluids, and oxytocinergic cells are activated by gastric distension and administration of the intestinal peptide cholecystokinin (CCK-8). These and other findings indicate that OT can play a role in inhibiting ingestion under some conditions. A previous study has shown, however, that oxytocinergic cells are unresponsive to CCK-8 in 2-day-old rats. We report here that OT is elevated in the plasma of 10-day-old rats after induction of gastric distension with both mother's milk and saline. These results indicate that the vagal-hypothalamic axis becomes mature between 2- and 10-days of age in infant rats.

Animals

Acute, early thermal experience alters weaning onset in rats.

We hypothesized that first ingestion of solid food (weaning onset) would be accelerated in young rats with advanced thermoregulatory development. To manipulate the pups' thermoregulatory development, we exposed rat pups, but not their dams, to a Cold (10 degrees C), Moderate (21 degrees C), or Warm (31 degrees C) ambience for 2 h/day from postnatal Day 2-14, expecting that early exposure to cooler temperatures would accelerate development of thermoregulatory capabilities and thus accelerate nest egression as well as onset of feeding. Contrary to expectation, cold exposure was associated with a profile of developmental delays in both growth and maturation. Pups in the Cold condition began feeding later than pups with Moderate or Warm thermal experiences. We then evaluated thermoregulatory status (mechanisms for heat production and temperature conservation) on Day 15-16 (just prior to weaning onset). Thermogenesis, measured by oxygen consumption, was unaltered by the thermal manipulation. In contrast, pelage development (insulation) was altered. Pups in the Warm condition had greater fur density and an increased frequency of longer hairs relative to pups in the Cold condition. Although the developmental response to early cold exposure was in the direction opposite to our predictions, the hypothesized relation of thermoregulatory development to weaning onset was supported: Thermoregulatory status correlated with weaning onset.

Aging

Perinatal stimulation facilitates suckling onset in newborn rats.

The fetus' experience of birth derives from a sequence of stimulation provided by the mother's labor contractions, her licking and handling, and the contrasting environmental conditions of the uterus and outside world. In the present investigation, Day 21 fetal rats were externalized from the dam's body; subjects in one uterine horn were compressed by simulated uterine contractions while control subjects in the opposite horn were not compressed. All pups were Cesarean-delivered, stroked, and exposed to a thermal environment simulating either room (21 degrees C), nest (33 degrees C), or intrauterine (36 degrees C) temperature. After 1-hr exposure to the experimental temperature, all pups were maintained at 33 degrees C and tested for their suckling response to an anesthetized dam. When newborns were tested at 120 min postpartum, simulated contractions increased the probability of nipple attachment in pups exposed to 21 degrees C relative to noncompressed littermates maintained at the same temperature. Atypically warm postpartum conditions (nestlike or intrauterine) obviated the effects of compression by increasing suckling above the levels seen in noncompressed newborns exposed to the cool condition. Thus, compressions facilitate the achievement of suckling under thermal conditions resembling those typically encountered by the newborn rat.

Animals

Self-organized huddles of rat pups modeled by simple rules of individual behavior.

Starting at infancy and continuing throughout adult life, huddling is a major component of the behavioral repertoire of Norway rats (Rattus norvegicus). Huddling behavior maintains the cohesion of litters throughout early life, and in adulthood, it remains a consistent feature of social behavior of R. norvegicus. During infancy, rats have severely limited sensorimotor capabilities, and yet they are capable of aggregating and display a form of group regulatory behavior that conserves metabolic effort and augments body temperature regulation. The functions of huddling are generally understood as group adaptations, which are beyond the capabilities of the individual infant rat. We show, however, that huddling as aggregative or cohesive behavior can emerge as a self-organizing process from autonomous individuals following simple sensorimotor rules. In our model, two sets of sensorimotor parameters characterize the topotaxic responses and the dynamics of contact in 7-day-old rats. The first set of parameters are conditional probabilities of activity and inactivity given prior activity or inactivity and the second set are preferences for objects in the infant rat's environment. We found that the behavior of the model and of actual rat pups compare very favorably, demonstrating that the aggregative feature of huddling can emerge from the local sensorimotor interactions of individuals, and that complex group regulatory behaviors in infant rats may also emerge from self-organizing processes. We discuss the model and the underlying approach as a paradigm for investigating the dynamics of social interactions, group behavior, and developmental change.

Animals

Instrumental learning for a thermal reinforcer in 1-day-old rats.

One-day-old rats in a cool environment (25 degrees C) quickly acquired an instrumental response when rewarded with a 20-s warming of the platform (from 25 degrees C to 36 degrees C) on which they lay. The instrumental response, turning the head to one side, was learned within 30 min after the thermal contingency began and extinguished when the contingency was reversed. This experiment demonstrates rapid operant learning by neonates in a task that does not contain a Pavlovian stimulus-reinforcer contingency. The novel experimental method has wide applicability in psychology and neuroscience.

Animals

Postsuckling behavioral arousal in weanling rats (Rattus norvegicus).

Twenty-day-old litters and their dams were observed in seminatural habitats consisting of a nest compartment and adjacent open field that contained powdered rat chow. It was found that pups displayed marked bursts of activity after suckling. Independent feeding reliably followed nursing bout termination (Experiment 1). Nipple withdrawal, with or without milk transfer, induced behavioral arousal whereas withdrawal of thermotactile and conspecific odor cues did not (Experiments 2-3). Increased thermogenesis was observed following milk transfer (Experiment 4). Finally, preweanling pups (10- to 12-day-olds) also displayed postsuckling arousal within the confines of the nest; full locomotor expression of this arousal was not evident until weaning age (Experiment 5). It was concluded that postsuckling arousal in weanlings functions to stimulate activities performed away from the nest and suckling, propelling pups into the field where feeding begins.

Animals

Environmental temperature modulates onset of independent feeding: warmer is sooner.

Individual dams and their litters were observed from Days 14-22 in a seminatural environment consisting of a nestbox attached to a larger, open field in which powdered chow was available. Ambient temperature in the field was either warm (30 degrees C), moderate (21 degrees C), or cold (10 degrees C); nest temperature was always moderate. Behavior was monitored 12 hr/day by time-lapse video recording. The pups' egressions into the field and onset of independent feeding were temperature-related: Weaning was earliest in the warmth and increasingly late with decreasing ambient temperature. Among subjects in the cold condition, there was a positive correlation between duration in the field and duration feeding. Pup growth was unaffected by the temperature regimes. Environmental temperature has emerged as a determinant for early nest egressions and weaning onset.

Animals

Perinatal stimulation and adaptation of the neonate.

The present report describes psychobiological studies of behavior around the time of birth. An adaptive, ecological perspective is presented in which stimulation of the fetus and newborn is purported to instigate adaptive postpartum behavior. Studies describing the perinatal sensory environment are reviewed, with a consideration of emergent sensory function of the fetus. It is asserted that afferent input associated with parturition perturbs the fetus and neonate, producing a general arousal state that facilitates breathing, suckling, and early learning. The view developed herein is that perinatal sensory input induces and canalizes the newborn's behavior, thereby regulating adaptive postpartum function. Deviations in afferent input may alter ontogenetic trajectories and compromise developmental outcome by reducing availability of conditions necessary for adequate postpartum adaptation.

Adaptation, Psychological

Simulated uterine contractions facilitate fetal and newborn respiratory behavior in rats.

We tested the hypothesis that sensory and nonsensory factors associated with birth stimulate respiratory behavior in the fetal and newborn rat. Late gestation (Day 21) rat fetuses were externalized from the uterus with intact umbilical connections to the dam and exposed to stimuli normally associated with labor and delivery. Onset and maintenance of respiratory movements were monitored. In the first experiment, rat fetuses were exposed to either: (i) simulated uterine contractions; (ii) cooling (26 degrees C); (iii) umbilical cord occlusion; or (iv) air heated to intrauterine temperature (37.5 degrees C). Subjects were videotaped for 1 h, and respiratory movements counted during tape review. Fetuses in each group showed some respiratory behavior although compression significantly elevated respiratory rate compared to other experimental conditions. All subjects in each group were respiring after 1 h, except for pups that received umbilical cord occlusion. The 100% attrition rate of the cord occlusion-alone group was reversed by combining cord occlusion with compression, or with compression and cooling, but not by combining cord occlusion with cooling. Simulated birth pups (i.e., those exposed to compression, cooling and umbilical cord occlusion) and normal, vaginally delivered pups breathed at identical rates and showed a similar pattern of postpartum breathing. These results suggest that mechanical stimulation of the fetus associated with uterine contractions plays a critical role in the maintenance of continuous respiration at birth. Possible mechanisms for the facilitative effects of compression on perinatal breathing are discussed.

Animals

Differential influence of adult and juvenile conspecifics on feeding by weanling rats (Rattus norvegicus): a size-related explanation.

Weanling Sprague Dawley rat pups (Rattus norvegicus) selected between 2 safe palatable diets in concordance with the preferences of either an adult or a juvenile conspecific model (Experiment 1). Nevertheless, weanlings chose to feed more in the vicinity of an adult than in the vicinity of a juvenile, thus fulfilling the prediction of an adaptive feeding strategy (Experiment 2). The weanlings' bias for feeding in the vicinity of an adult was eliminated by increasing the magnitude of pup stimulus to 3 pups (Experiment 3). Thus, weanlings do not possess a specialization rendering them more sensitive to adults than to pups as models for diet selection. By responding to stimulus magnitude, weanlings are more likely to feed with adult conspecifics, choose foods used by them, and derive the benefits correlated with the adults' successful feeding habits.

Animals

Proximal control of fetal rat behavior.

We examined the influence of the amniotic sac on spontaneous movement in late gestation fetal rats. Using techniques for in vivo observation of fetal behavior, Day 21 rat fetuses were exteriorized from the uterus, with umbilical connections to the dam intact, and videotaped for 15 min either: (a) through the intact amniotic membranes, or (b) following removal of the membranes. Analysis of fetal behavior categories replicated the findings of previous investigators: Movements of the head, forelimbs, and rearlimbs were significantly increased by sac removal, as was the total frequency of behavior categories and the simultaneous occurrence of different behavior categories. Frame-by-frame analysis of videotaped behavior revealed that amniotic sac removal increased the frequency of movement bouts without altering the overall amount of time that fetuses spent moving. Movement bout durations ranged from 50 msec to 70 s. The average duration of movement bouts was significantly reduced for fetuses lacking the amniotic sac as compared to fetuses within the sac, as was the overall distribution of movement bout durations. Frequency distributions of movement bout durations and interbout interval (IBIs) revealed that sac removal significantly increased the occurrence of short (1-2 s) movement bouts and reduced the frequency of protracted movement bouts and interbout intervals (> 10-s duration). Taken together, these findings indicate that the quantitative dimensions of fetal rat movements are influenced by proximal features of the uterine environment. During prenatal life, the amniotic sac appears to sustain movement, possibly by providing proprioceptive feedback or physical support to the fetus, or by regulating the chemical milieu.

Animals

Learning as adaptation of the infant.

The present report advocates an adaptive, ecological approach to the study of learning in infants. Concepts of developmental niche and ontogenetic adaptation are applied to early mammalian development. Within this conceptual framework, it is asserted that learning cannot be fully understood separately from a behaving body; that learning is a dimension of behavior and physiology. The role of learning in the development of ingestive behavior, especially suckling and the transition to solid food, is used to illustrate the potential of studying learning in development. These considerations are offered as examples of an alternative approach to the empirical study of learning by infants. The approach advocated herein can be applied to clinical issues: developmental adaptations evolved in contexts that differ from our modern environments. Exposure to contexts or contingencies that are evolutionarily unexpected may inadvertently create pathology.

Adaptation, Physiological

Anatomy and forebrain projections of the olfactory and vomeronasal organs in axolotls (Ambystoma mexicanum).

We examined the anatomy of the nasal cavity and forebrain in the axolotl (Ambystoma mexicanum) to determine whether the olfactory and vomeronasal systems are present in this neotenic aquatic salamander. The current study was motivated by two considerations: (a) little is known of the anatomy of the vomeronasal system in aquatic vertebrates, and (b) the presence of both olfactory and vomeronasal systems in larval amphibians has broad implications for the evaluation of these systems in vertebrates. From cresyl-violet-stained sections of snouts we determined that the nasal cavity of axolotls is much like that of terrestrial salamanders. The main chamber of the nasal cavity contains an olfactory epithelium, which is confined to grooves between longitudinal ridges of connective tissue covered in a nonsensory epithelium which lacks goblet cells. Using transmission electron microscopy, we found morphologically distinct olfactory receptor cells: many receptor cells terminate in microvillar dendrites, and fewer terminate in motile cilia with the 9 + 2 microtubule array typical of vertebrate olfactory receptor cells. The ciliated and microvillar cells occur in clusters with little intermingling. Horseradish peroxidase labeling revealed that axons of the olfactory receptor cells terminate in large glomeruli in the main olfactory bulb at the rostral end of the telencephalon. Lateral to the main chamber of the nasal cavity is a diverticulum that is entirely lined with a vomeronasal epithelium containing basal cells, microvillar receptor cells, sustentacular cells that lack specialized processes on the apical surface, and large ciliated cells that may function to move fluid across the vomeronasal epithelium. Unlike the olfactory epithelium, the vomeronasal epithelium lacks Bowman's glands. Using horseradish peroxidase, we determined that the axons of the vomeronasal receptor cells project to the accessory olfactory bulb, a distinct structure dorsal and caudal to the main olfactory bulb. The presence of both olfactory and vomeronasal systems in axolotls and other neotenic salamanders implies that both systems are pleiomorphic in larval amphibians; we therefore suggest that the vomeronasal system may not have originated as an adaptation to terrestrial life.

Ambystoma mexicanum