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Biomedical subjects

J D Newman

Publications and source records attributed to J D Newman.

At least 19 recordsLinked to original sources

Effects of separation and novelty on distress vocalizations and cortisol in the common marmoset (Callithrix jacchus).

In socially-bonding species, separation from familiar attachment figures is widely known to stimulate a physiological and behavioral stress response. This study investigated the hormonal and vocal responses of adult common marmosets to separation from familiar group members and to 24 hr of cohabitation with an unfamiliar opposite-sex conspecific. All subjects were removed from their home cages and placed into a novel environment for 20 min. In one group, marmosets were exposed to an unfamiliar, opposite-sex partner in the novel environment and remained paired with this partner for the 24 hr test period. In three other groups, marmosets experienced the novel environment alone and subsequently were returned to their original social- or single-housing condition, or kept separate from their social groups for a 24 h period. Blood samples were collected the day before, and at 30 min, 90 min, and at 24 h after separation. Cortisol responses were differentially affected by the length of separation and the presence of unfamiliar conspecifics. Brief separation followed by the return to the social group had minimal effect on plasma cortisol levels. All marmosets produced high levels of separation calls in the novel environment, but there was no apparent relationship between calling and cortisol levels. The lack of a temporal relationship between the production of distress vocalizations and serum cortisol has previously been noted in squirrel monkey and rhesus monkey infant separation studies; the behavioral and physiological responses to separation appear to be similarly dissociated in the marmoset. Further, the characteristics of a separation environment can differentially affect the hormonal response by adult marmosets without differentially affecting their behavioral response.

Animals

Vasopressin in the forebrain of common marmosets (Callithrix jacchus): studies with in situ hybridization, immunocytochemistry and receptor autoradiography.

The distribution of vasopressin (AVP) producing cells, their projections and AVP receptors was examined in the brain of common marmosets (Callithrix jacchus) using in situ hybridization, immunocytochemistry and receptor autoradiography. Clusters of cells labeled for AVP mRNA or stained for AVP immunoreactivity (AVP-ir) were found in the paraventricular (PVN), supraoptic (SON) and suprachiasmatic nuclei (SCN) of the hypothalamus. Scattered AVP producing cells were also found in the lateral hypothalamus and the bed nucleus of the stria terminalis (BST). Neither AVP mRNA-labeled nor AVP-ir cells were detected in the amygdala. Although AVP-ir fibers were evident outside of the hypothalamic-neurohypophyseal tract, a plexus of fibers in the lateral septum, as observed in the rat brain, was not detected. Receptor autoradiography using 125I-linear-AVP revealed specific binding for AVP receptors in the nucleus accumbens, diagonal band, lateral septum, the BST, SCN, PVN, amygdala, anterodorsal and ventromedial nucleus of the hypothalamus, indicating sites for central AVP action in the marmoset brain. Together, these data provide a comprehensive picture of AVP pathways in the marmoset brain, demonstrating differences from rodents in the distribution of cell bodies, fibers and receptors.

Animals

Neonatal ablations of the amygdala and inferior temporal cortex alter the vocal response to social separation in rhesus macaques.

Rhesus macaques that had received bilateral ablations to either the amygdala or area TE in inferior temporal cortex in the 1st week of life were briefly separated from familiar conspecifics at 10-14.5 months of age in order to assess the vocal response to this mild challenge. Sound spectrograms were subjected to quantitative analysis and compared with calls from normal, age-matched controls subjected to the same testing conditions. Animals with TE damage called at a higher rate than animals in the other two groups. TE subjects also produced more coos than controls. Males with TE lesions produced noisy calls at a higher rate than males of the other two groups. Females did not differ between groups in this measure. Analysis of the detailed acoustic structure of the 'coo' indicated significant differences in a measure of slope of the fundamental frequency (rate of frequency change over time) between amygdalectomized animals and those of the other 2 groups. The amygdalectomized monkeys produced calls with lower slope values, giving the calls a less inflected quality both in sonagrams and to the listener. These findings suggest an important role for the amygdala and inferior temporal cortex in regulating the vocal response to social separation during development.

Amygdala

Social context affects phee call production by nonreproductive common marmosets (Callithrix jacchus).

Common marmosets produce two variants of their long call (phee call) in different situations. Intergroup calls are produced in territorial situations, and intragroup separation calls are produced by marmosets isolated from group members. Marmoset groups frequently include postpubertal, nonreproductive members; their roles in the spontaneous production of territorial vocalizations is unclear. This study analyzed the production of home cage phee calls by nonreproductive, postpubertal marmosets while they were housed in their natal groups and after pairing with an opposite-sex conspecific. Additionally, the production of the separation phee call variant was assessed in both social conditions. The results indicated that the marmosets rarely produced home cage, or territorial, phee calls while they were natally housed. In contrast, both males and females produced the territorial phee call at a much higher rate as early as 4 days after pairing. Agematched females remaining in their natal groups throughout the study produced home cage phee calls infrequently. Most marmosets produced separation phee calls at a high rate after separation from either their natal group or a partner, suggesting that the makeup of a social group has little effect on an animal's motivation to reunite with conspecifics. These results suggest that the social environment has an important influence on the production of territorial phee calls.

Animals

Vasopressin and oxytocin immunoreactive neurons and fibers in the forebrain of male and female common marmosets (Callithrix jacchus).

Vasopressin (AVP) and oxytocin (OT) immunoreactive (ir) neurons and fibers were examined in the forebrain of male and female common marmosets (Callithrix jacchus). As expected from previous studies of cell distribution in the rodent and primate brain, AVP-ir cells were most evident in the paraventricularis, supraopticus, and suprachiasmaticus of the hypothalamus. AVP-ir cells were also widely distributed in the lateral hypothalamus and the bed nucleus of the stria terminalis. A sexually dimorphic pattern of AVP-ir cells was found in the bed nucleus of the stria terminalis, in which males had more AVP-ir cells than females. OT-ir cells were found in the paraventricularis and supraopticus of the hypothalamus as well as in the bed nucleus of the stria terminalis and the medial amygdala. Male and female marmosets did not differ in the distribution of OT-ir cells. Fibers for both AVP and OT were evident outside of the hypothalamic-neurohypophyseal tract, but a plexus of AVP-ir fibers in the lateral septum or lateral habenular nucleus, as seen in the rat brain, could not be detected for either peptide.

Animals

Effects of administration regime on the psychotomimetic properties of d-amphetamine in the squirrel monkey (Saimiri sciureus).

Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and can induce abnormal behaviour patterns in monkeys that resemble the psychotic symptoms observed in man. The purpose of the present study was to identify a drug administration regime that in squirrel monkeys reliably could induce such behaviours in order to use this as a model of schizophrenia. The behavioural effects of acute, subchronic and continuous administration of d-amphetamine were determined in male and female squirrel monkeys during short term separation from the colony and in the home cage. It was found that abnormal behaviours developed in both male and female subjects and that they were most evident in the home cage. The number of subjects responding was highest during continuous infusion followed by subchronic treatment. The study indicated that prolonged administration of high doses of d-amphetamine is necessary for the development of abnormal behaviours. These findings suggest that animal models of schizophrenia based on d-amphetamine should be based on chronic administration or continuous infusion of d-amphetamine instead of acute injections.

Animals

An ethologically based, stimulus and gender-sensitive nonhuman primate model for anxiety.

1. Adult male and female squirrel monkeys were tested for behavioral responses to 5 min. social separation (alone in test room) followed by 30-sec. exposure to 2 humans wearing a leather capture glove. 2. Trials were preceded by intramuscular injection of an anticholinergic drug, benactyzine hydrochloride, in doses of 0.0, 0.6, 1.0, 2.0, and 3.0 mg/kg. 3. Measured behaviors were number and type of vocalization and locomotor activity (duration in sec) in each of the two testing conditions. 4. A dose-response relationship for bark/yap vocalizations during the 30-sec trials was established, with 1.0 mg/kg being the most effective dose. 5. Males and females differed in the number of barks/yaps produced during 30-sec. trials at every drug dose. 6. The present testing paradigm provides the basis for efficiently determining the extent of gender differences in dose/response relationships for drugs of possible therapeutic value in the treatment of anxiety-related behavioral disorders.

Animals

Infection of soybean and pea nodules by Rhizobium spp. purine auxotrophs in the presence of 5-aminoimidazole-4-carboxamide riboside.

Purine auxotrophs of various Rhizobium species are symbiotically defective, usually unable to initiate or complete the infection process. Earlier studies demonstrated that, in the Rhizobium etli-bean symbiosis, infection by purine auxotrophs is partially restored by supplementation of the plant medium with 5-amino-imidazole-4-carboxamide (AICA) riboside, the unphosphorylated form of the purine biosynthetic intermediate AICAR. The addition of purine to the root environment does not have this effect. In this study, purine auxotrophs of Rhizobium fredii HH303 and Rhizobium leguminosarum 128C56 (bv. viciae) were examined. Nutritional and genetic characterization indicated that each mutant was blocked in purine biosynthesis prior to the production of AICAR. R. fredii HH303 and R. leguminosarum 128C56 appeared to be deficient in AICA riboside transport and/or conversion into AICAR, and the auxotrophs derived from them grew very poorly with AICA riboside as a purine source. All of the auxotrophs elicited poorly developed, uninfected nodules on their appropriate hosts. On peas, addition of AICA riboside or purine to the root environment led to enhanced nodulation; however, infection threads were observed only in the presence of AICA riboside. On soybeans, only AICA riboside was effective in enhancing nodulation and promoting infection. Although AICA riboside supplementation of the auxotrophs led to infection thread development on both hosts, the numbers of bacteria recovered from the nodules were still 2 or more orders of magnitude lower than in fully developed nodules populated by wild-type bacteria. The ability to AICA riboside to promote infection by purine auxotrophs, despite serving as a very poor purine source for these strains, supports the hypothesis that AICAR plays a role in infection other than merely promoting bacterial growth.

Aminoimidazole Carboxamide

Enhanced insulin-receptor tyrosine kinase activity associated with chromosomal translocation (1;19) in a pre-B-cell leukemia line.

The gene for the insulin receptor has been assigned to chromosome 19 near the breakpoint of the translocation t(1;19) which occurs in 25% of pre-B-cell leukemias. Insulin receptors in a pre-B-cell leukemia cell line (ACV) with t(1;19) were found to have 2-fold higher affinity for insulin, 5-fold higher basal and insulin-stimulated beta sub-unit autophosphorylation, and 2-fold higher basal and 4-fold higher insulin-stimulated beta sub-unit kinase activity on the synthetic peptide poly(Glu,Tyr), compared to receptors in a B-cell line (ADD) with normal karyotype from the same patient. ACV cells had a novel 13-kb receptor mRNA species and expressed a DNA polymorphism localized to the tyrosine kinase domain of the receptor gene. These findings suggest that t(1;19) in the ACV cell may result in rearrangement of the insulin receptor gene and translation of a receptor with enhanced tyrosine kinase activity.

Blotting, Northern

Cu/Zn superoxide dismutase mRNA and enzyme activity, and susceptibility to lipid peroxidation, increases with aging in murine brains.

To protect against reactive oxygen species, prokaryotic and eukaryotic cells have developed an antioxidant defence mechanism where O2- is converted to H2O2 by superoxide dismutase (Sod), and in a second step, H2O2 is converted to H2O by catalase (Cat) and/or glutathione peroxidase (Gpx). If Sod levels are increased without a concomitant Gpx increase, then the intermediate H2O2 accumulates. This intermediate could undergo the Fenton's reaction, generating hydroxyl radicals which may lead to lipid peroxidation in cells. In this study, we investigate the expression of Sod1, Gpx1 and susceptibility to lipid peroxidation during the aging process in mouse brains. We demonstrate that the mRNA levels and enzyme activity of Sod1 are higher in brains from adult mice compared to neonatal mice. Furthermore, we show that a linear increase in Sod1 mRNA and enzyme activity occurs with aging (1-100 weeks). On the contrary, we find that the mRNA and enzyme activity for Gpx1 does not increase with aging in mouse brains. In addition, our results demonstrate that the susceptibility of murine brains to lipid peroxidation increases with aging. The data in this study are consistent with the notion that reactive oxygen species may contribute to the aging process in mammalian brains. These results are discussed in relation to the normal aging process in mammals, and to the premature aging and mental retardation in Down syndrome.

Aging

Modulation of vocal and nonvocal behavior in adult squirrel monkeys by selective MAO-A and MAO-B inhibition.

The acute effects of monoamine oxidase inhibitors L-deprenyl (0.5-5.0 mg/kg), clorgyline (1.0-10.0 mg/kg), and milacemide (100-400 mg/kg) on the behavior of adult male squirrel monkeys were examined during brief social separations beginning 60 min after subcutaneous drug administration. All three drugs selectively reduced the rate of calling during social separation at doses which did not affect time spent in locomotion, nor the frequency of vigilance-checking. Deprenyl and milacemide, but not clorgyline, produced concurrent decreases in locomotion at the higher doses tested. At threshold doses, clorgyline, but not deprenyl or milacemide, increased call duration and decreased call peak frequency compared to vehicle control values. Plasma levels of MHPG were decreased by an optimal dose of clorgyline but not by deprenyl or milacemide, indicating that substrate specificity was maintained at the drug doses employed. We conclude that different MAO substrates mediate different aspects of vocal and nonvocal behavior in adult male squirrel monkeys.

Acetamides

Biosensors for process control.

Biosensors have been extensively studied during the last 20 years, and a myriad of laboratory biosensors have been developed. Improvements are required in biosensor design and performance before they become widely accepted in industrial process monitoring. However, as the biotechnology industry expands, biosensors may become more acceptable because, despite their limitations, they are the only devices capable of delivering the information required.

Biosensing Techniques

Gender differences in reactivity of adult squirrel monkeys to short-term environmental challenges.

Evidence is presented to show that individual adult squirrel monkeys show gender-specific reactivity profiles to threatening stimuli under laboratory conditions, and that a putative anxiogenic drug, benactyzine hydrochloride, enhances the vocal response to threatening stimuli, but otherwise preserves the relative importance of the stimuli to both males and females. These data support the conclusion that screening of putative anxiolytic drugs in a primate model can be accomplished using efficient, ethologically based testing procedures in the laboratory.

Aggression

Insulin receptor expression in Burkitt lymphoma cell lines.

The specific binding of insulin to 7 different Burkitt lymphoma cell lines containing chromosomal translocations t(8;14), t(8;2) and t(8;22) was markedly decreased when compared to binding to lymphoblastoid cells of normal karyotype derived from Burkitt lymphoma patients or the human IM-9 lymphoblastoid line. The number of insulin-binding sites on intact Burkitt cells was decreased by greater than 90% compared to lymphoblastoid cells, with no change in affinity. This decrease in binding was paralleled by reduced amounts of insulin receptor alpha (Mr 130,000) and beta (Mr 95,000) subunits detected by cell-surface-labelling and insulin receptor mRNA transcripts, indicating that transcription of receptor mRNA is decreased in Burkitt cells compared to lymphoblastoid cells and/or that receptor mRNA is less stable. Burkitt cells displayed negligible insulin-stimulated beta subunit auto-phosphorylation, which could reflect either their decreased number of receptors or a defect in signal transduction. Structural analysis also revealed that the Burkitt cells had an increase in a precursor form (Mr 210,000) of the receptor, suggesting that decreased expression of the receptor may be associated with defective processing. Four Burkitt cell lines with t(8;14) also had reductions of 45-100% in expression of class-1 major histocompatibility (MHC) antigens. The expression of insulin receptors in both Burkitt and lymphoblastoid cells correlated with the expression of class-1 MHC antigens. There was also an inverse correlation between the expression of c-myc and both insulin receptors and class-1 MHC antigens. As the insulin receptor is absent on resting B cells and is induced after cell activation, the decrease in receptor expression on Burkitt cells may reflect their less activated phenotype compared to lymphoblastoid cells.

Burkitt Lymphoma

Induction of the insulin receptor and other differentiation markers by sodium butyrate in the Burkitt lymphoma cell, Raji.

The very low expression of insulin receptors in the Burkitt lymphoma cell Raji was increased 2-fold, 6-fold and 10-fold after 1, 2 and 3 days, respectively, by incubation with the differentiation inducer sodium butyrate. Insulin receptor number was increased without a change in receptor affinity, in association with an increase in the receptor alpha and beta subunits detected after cell-surface labelling and immunoprecipitation. Expression of cell-surface class I and II human leukocyte antigens, the intercellular adhesion molecule-1 and the CD38 leukocyte antigen was also increased, consistent with B cell differentiation. Butyrate effects were not unspecific, as the binding of tumour necrosis factor and growth hormone and the expression of the B cell markers CD20, B5 and CD21 was not increased. The low expression of insulin receptors on Raji cells is therefore a reflection of the less differentiated state of these cells compared to lymphoblastoid cells.

Antigens, Differentiation, B-Lymphocyte

CRH and alpha-helical-CRH modulate behavioral measures of arousal in monkeys.

Several neuropeptides involved in the control of pituitary-adrenal activation have also been shown to have behavioral effects which may be mediated by actions on brain mechanisms independent of pituitary release. The behavioral effects of intraventricular administration of CRH and the synthetic peptide antagonist alpha-helical-CRH were assessed in socially separated squirrel monkeys. Treated monkeys were presented with a sequence of behavioral challenges including undisturbed social separation, presentation of a mirror image, and presentation of a "predator" stimulus. The test sequence was repeated at several time intervals after administration of the peptides. CRH produced dose-related increases in several species-typical measures of arousal including motor activity, vigilance-checking, and marking. Pretreatment with alpha-helical-CRH prevented the increased motor activity but not the marking behavior associated with CRH. When administered alone, alpha-helical-CRH increased vigilance-checking. In addition, alpha-helical-CRH increased aggressive behaviors exhibited at the mirror stimulus. The data provide further support for a central role for CRH in the mediation of both activational and inhibitory behavioral responses to stressful stimuli. These data also suggest both antagonistic and partial agonist effects for alpha-helical-CRH.

Animals