Nonreactive Strains Research Articles

Non-human contributions to personality neuroscience - from fish through primates. An introduction to the special issue.

The most fundamental emotional systems that show trait control are evolutionarily old and extensively conserved. Psychology in general has benefited from non-human neuroscience and from the analytical simplicity of behaviour in those with simpler nervous systems. It has been argued that integration between personality, psychopathology, and neuroscience is particularly promising if we are to understand the neurobiology of human experience. Here, we provide some general arguments for a non-human approach being at least as productive in relation to personality, psychopathology, and their interface. Some early personality theories were directly linked to psychopathology (e.g., Eysenck, Panksepp, and Cloninger). They shared a common interest in brain systems that naturally led to the use of non-human data; behavioural, neural, and pharmacological. In Eysenck's case, this also led to the selective breeding, at the Maudsley Institute, of emotionally reactive and non-reactive strains of rat as models of trait neuroticism or trait emotionality. Dimensional personality research and categorical approaches to clinical disorder then drifted apart from each other, from neuropsychology, and from non-human data. Recently, the conceptualizations of both healthy personality and psychopathology have moved towards a common hierarchical trait perspective. Indeed, the proposed two sets of trait dimensions appear similar and may even be eventually the same. We provide, here, an introduction to this special issue of Personality Neuroscience, where the authors provide overviews of detailed areas where non-human data inform human personality and its psychopathology or provide explicit models for translation to human neuroscience. Once all the papers in the issue have appeared, we will also provide a concluding summary of them.

The Defecation Index as a Measure of Emotionality: Questions Raised by HPA Axis and Prolactin Response to Stress in the Maudsley Model.

The Maudsley Reactive and Maudsley Non-Reactive strains have been selectively bred for differences in open-field defecation (OFD), a putative index of stress. We investigated whether variations in the hypothalamic-pituitary-adrenal (HPA) axis are correlated with strain differences in OFD in the Maudsley model. Exposure to the open-field test did not result in increases in ACTH in male rats of either strain and there were no strain differences in the large increases in ACTH and corticosteroid that occurred in response to intermittent footshock. Parallel studies of prolactin showed that Maudsley Reactive rats had greater response to the open-field and to footshock than Maudsley Non-Reactive rats. The lack of correlation between strain differences in OFD and reactivity of the HPA axis is consistent with the idea that HPA response to stress and OFD reflect the output of different neural systems and that individual differences in emotionality, as indexed by OFD do not influence other measures of stress-reactivity in a simple manner, if at all. The reactivity of the prolactin system to the open-field test and lack of response of ACTH to the same situation is consistent with the idea that the prolactin system is sensitive to lower levels of stress than the HPA axis, a finding at variance with the presumed extreme sensitivity of the latter system. Earlier comparisons of the HPA axis in these strains implicate local factors such as neuropeptide-Y peptide in the adrenal in attenuating the response of the adrenal cortex to ACTH and hints at the complexity of regulation of the HPA axis.

Colony morphology variation of Burkholderia pseudomallei is associated with antigenic variation and O-polysaccharide modification.

Burkholderia pseudomallei is a CDC tier 1 select agent that causes melioidosis, a severe disease in humans and animals. Persistent infections are common, and there is currently no vaccine available. Lipopolysaccharide (LPS) is a potential vaccine candidate. B. pseudomallei expresses three serologically distinct LPS types. The predominant O-polysaccharide (OPS) is an unbranched heteropolymer with repeating d-glucose and 6-deoxy-l-talose residues in which the 6-deoxy-l-talose residues are variably replaced with O-acetyl and O-methyl modifications. We observed that primary clinical B. pseudomallei isolates with mucoid and nonmucoid colony morphologies from the same sample expressed different antigenic types distinguishable using an LPS-specific monoclonal antibody (MAb). MAb-reactive (nonmucoid) and nonreactive (mucoid) strains from the same patient exhibited identical LPS banding patterns by silver staining and indistinguishable genotypes. We hypothesized that LPS antigenic variation reflected modification of the OPS moieties. Mutagenesis of three genes involved in LPS synthesis was performed in B. pseudomallei K96243. Loss of MAb reactivity was observed in both wbiA (encoding a 2-O-acetyltransferase) and wbiD (putative methyl transferase) mutants. The structural characteristics of the OPS moieties from isogenic nonmucoid strain 4095a and mucoid strain 4095c were further investigated. Utilizing nuclear magnetic resonance (NMR) spectroscopy, we found that B. pseudomallei 4095a and 4095c OPS antigens exhibited substitution patterns that differed from the prototypic OPS structure. Specifically, 4095a lacked 4-O-acetylation, while 4095c lacked both 4-O-acetylation and 2-O-methylation. Our studies indicate that B. pseudomallei OPS undergoes antigenic variation and suggest that the 9D5 MAb recognizes a conformational epitope that is influenced by both O-acetyl and O-methyl substitution patterns.

Characterization ofVP7andVP4genes of rotavirus strains: 1990–1994 and 2000–2002

A total of 90 rotavirus-positive faecal specimens collected from patients hospitalized with diarrhoea in 1990-1994 (n=77) and 2000-2002 (n=13) were investigated for VP7 and VP4 genotypes. The specimens included 21 typable and 69 non-reactive or multireactive rotavirus strains as monitored by monoclonal antibody-based serotyping ELISA. Genotyping was carried out by multiplex PCR/sequencing using primers specific for both VP7 and VP4 genes. The contribution of common genotypes (G1P[8], G2P[4], G3P[8], G4P[8]) in causing rotavirus diarrhoea was 79.2% and 92.3% in the years 1990-1994 and 2000-2002, respectively, while G9P[8] infections were detected at lower levels (1.3% and 7.7%) at both time-points. There was a predominance of G1P[8] in 1990-1994 and of G2P[4] in 2000-2002. The detection of unusual rotavirus strains (G1P[6], G1P[4], G1P[19], G2P[8], G3P[4], G4P[6]) in 19.5% of the patients indicated a significant contribution of reassortants in causing diarrhoea in western India.

Behavioral and neurochemical changes following predatory stress in mice

This article had several objectives. First it aimed at investigating the anxiogenic-like behaviors elicited by unavoidable cat exposure and/or cat odor across nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in a modified version of the free-exploration test. The second objective was to investigate possible neurochemical changes following cat exposure in Swiss mice by measuring the turnover of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in several brain regions known to be involved in the modulation of emotional processes (hippocampus, hypothalamus and striatum). Finally, the third objective was to examine the effects of anxiolytic drug treatments on the anxiogenic responses elicited by a cat odor (i.e. a feces) in Swiss mice previously exposed to a cat using the free-exploration test. Results from the strain comparison showed that mice could be divided into three distinct groups: two non-reactive strains (NZB and SJL) which were relatively insensitive to predatory exposure and/or odor; five intermediate-reactive strains (Swiss, NMRI, CBA, C3H and BALB/c) which displayed clear anxiogenic-like responses only when exposed to both cat and, subsequently, to feces; and two high reactive strains (C57BL/6 and DBA/2) which showed anxiogenic-like reactions following cat exposure, regardless of the stimulus (clay or feces) present in the free-exploration cage. Neurochemical data revealed that, while brain levels of NA, DA, 5-HT in cat exposed Swiss mice were not significantly different from those of control animals, turnover rates of these monoamines were increased in the hippocampus (NA and 5-HT), hypothalamus and striatum (DA) after cat exposure. Results from pharmacological experiments indicated that repeated administration of the 5-HT reuptake inhibitor fluoxetine (5–20 mg/kg, twice a day, for 5 days) completely abolished avoidance of the cat feces in Swiss mice previously exposed to the predator. Neither acute nor repeated administration of the classical anxiolytic diazepam was able to reduce avoidance behavior of the anxiogenic stimulus in the free-exploration test. Taken together, these findings indicate that the exposure of mice to unavoidable predatory stimuli is associated with behavioral and neurochemical changes consistent with increased anxiety.

Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice.

Natural strain differences exist in mice for behavioural traits such as emotional reactivity. The present experiments compared the behavioural profiles of nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in two models of anxiety after the administration of the benzodiazepine diazepam. The tests used were the light/dark choice task and the elevated plus-maze, two well-validated anxiolytic screening tests. In vehicle-treated animals, differences on variables designed to measure anxiety-related behaviours were observed in both tests. In the light/dark test, the strains could be divided into three distinct groups: two non-reactive strains (NZB and SJL), an intermediate-reactive group (C3H, CBA, DBA/2, NMRI, C57BL/6 and Swiss), and one highly reactive strain (BALB/c). In the elevated plus-maze, SJL, NMRI, CBA and, to a lesser extent, C3H strains of mice, consistently showed low levels of anxiety-related behaviours. Intermediate levels were seen in the Swiss and BALB/c strains, and high levels of emotional reactivity were seen in C57BL/6, DBA/2 and NZB. The strain distribution between the light/dark and the elevated plus-maze tests shows similarities and differences, suggesting that each of these experimental procedures represents a different set of behaviours. Marked differences between a number of strains of mice in their sensitivity to the anxiolytic-like action of diazepam were observed in both the light/dark and the elevated plus-maze tests. Mice of the BALB/c, Swiss and, to a lesser extent, CBA and C3H strains were responsive to diazepam in both tests, although in the case of CBA mice, effects may have been contaminated by behavioural suppression. SJL mice were largely unresponsive to the action of the benzodiazepine in both tests, whereas in C57, DBA/2, NMRI and NZB mice, diazepam produced positive effects only in the elevated plus-maze. The finding of differential strain distributions both with and without diazepam treatment in the light/dark and the elevated plus-maze tests, indicates that not all strains of mice are suitable for investigating the effects of GABA/BZ receptor ligands. This study may thus provide a useful guide for choosing the best strain of mice for studying the pharmacology of fear-related behaviours.

Capsule expression by bovine isolates of Staphylococcus aureus from Argentina: genetic and epidemiologic analyses.

Staphylococcus aureus is an important cause of bovine mastitis worldwide, and effective preventive or therapeutic modalities are lacking. Although most human S. aureus isolates produce capsular polysaccharides (CPs), few reports have described the prevalence of capsules on bovine isolates. This information is important for the rational design of a vaccine for the prevention of staphylococcal mastitis. We serotyped 195 S. aureus strains isolated between 1989 and 1997 from the milk of mastitic cows in Argentina. Only 14 (7.1%) of the strains were serotype 5, and all were recovered between 1989 and 1992. Thirteen serotype 8 strains were identified, and 12 of these were isolated between 1991 and 1994. The remaining 168 isolates were nonreactive (NR) with CP serotype 5 (CP5)- or CP8-specific antibodies. Hybridization studies performed with genomic DNA from eight NR strains revealed that only three of them carried the capsule genes. Pulsed-field gel electrophoresis (PFGE) performed with 127 of the 195 S. aureus isolates revealed that most (86%) strains belonged to one of four major PFGE groups. Although 8 of 14 CP5 isolates showed a common PFGE pattern (arbitrarily defined as A1), 31 other A1 isolates from the same time period (1989 to 1992) were not CP5 positive. In contrast, only nine PFGE type B3 isolates were recovered between 1990 and 1994, and eight of these were positive for CP8 (P < 0.0003). The results of this study underscore the variability in capsule expression by S. aureus strains isolated from different geographical regions and cast doubt on the roles of CP5 and CP8 in the pathogenesis and immunoprophylaxis of bovine mastitis in Argentina.

Identification of the perfect state of Cryptococcus neoformans from 195 clinical isolates including 84 from AIDS patients.

Filobasidiella neoformans is the teleomorphic state of Cryptococcus neoformans and it is a heterothalic. The purpose of this study was to establish the proportions of each mating types (a, alpha) from among 195 strains of C. neoformans isolated from clinical material. The culture medium used was sunflower agar. Cultures were incubated at 20-22 degrees C for 15 days and observed periodically for one month. Non-reactive strains were mated several times with different reactive strains. Under these conditions 96.8% of the strains were found to be reactors. Among both varieties of C. neoformans, mating type alpha was found to have the highest frequency of 95% in the variety neoformans and 84% in the variety gattii. These results showed a higher reactivity in comparison with other investigators. This difference could be due to the medium used or to repeated mating with different reactive tested strains.

Utility of monoclonal antibody coagglutination to identify Neisseria gonorrhoeae.

The Phadebact monoclonal gonococcus coagglutination test was evaluated with 1367 (996 anogenital and 371 pharyngeal) neisserial isolates from patients who gave positive diagnostic test results for Neisseria gonorrhoeae. The overall correlation with carbohydrate utilisation was 99.7%. The Phadebact test had a specificity of 100% (286/286) and a sensitivity of 99.7% (1077/1080). The three non-reactive strains were epidemiologically linked and were of a very unusual serovar. Unlike polyclonal antibody based tests, the monoclonal antibody test provides reliable identification of gonococci from anogenital and pharyngeal sites. Because non-reactive strains are rare, however, negative anogenital isolates from heterosexual patients should be tested biochemically. The use of two reagents comprising separate pools of monoclonal antibodies against gonococcal protein IA and IB permitted the identification of an appreciable number of double infections, which would otherwise have been missed. Genital, rectal, and pharyngeal isolates from the same patient should be identified individually.

Fimbriae from the oral anaerobe Bacteroides gingivalis: a screening of clinical isolates from various places.

Clinical isolates of Bacteroides gingivalis from several different locations were screened for the presence of fimbriae, primarily by immunological methods. About 60% of the strains tested had fimbriae as determined by agglutination with rabbit anti-fimbriae sera, and about two-thirds reacted with the anti-fimbrilin sera. The high detection rate of fimbriae implies that B. gingivalis fimbriae may play an important role in the adherence of this organism to host cells. These studies also suggest that not all strains share fimbriae cross-reactive with the fimbriae of B. gingivalis 381. The non-reactive strains may be devoid of fimbriae or may have fimbriae of different antigenic types.

The sleep lactate infusion: Arousal and the panic mechanism

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Effect of low dose ethanol on spontaneous motor activity in alcohol-preferring and -nonpreferring lines of rats.

To determine if behavioral arousal may be associated with ethanol preference, the effects of low to moderate doses of ethanol on spontaneous motor activity (SMA) were studied in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats as well as in the Maudsley Reactive (MR/N) and Nonreactive (MNR/N) strains. Alcohol-naive rats had food and water available ad lib, but food was removed 24 hr before and during activity testing. After an intraperitoneal injection of saline (5 ml) or ethanol (0.12 to 1.5 g/kg), SMA was monitored every three min for 30 min in an electronic activity monitor. The P and MR/N rats exhibited increased SMA after doses of 0.12 and 0.25 g/kg. Both the NP and MNR/N rats failed to show increased SMA at any ethanol dose. Moderate doses of ethanol, 1.0 and 1.5 g/kg, consistently depressed SMA in all lines/strains. In 24 hr-fasted rats, increased SMA occurred within 6-12 min after injection, but free-fed rats exhibited increased SMA 12-24 min after an ethanol dose of 0.25 g/kg. Free-choice drinking scores (10% ethanol (v/v) versus water) for the P, MR/N, MNR/N and NP rats were 6.6 +/- 0.5, 4.9 +/- 0.8, 2.2 +/- 0.7 and 1.4 +/- 0.3 g ethanol/kg body wt/day (mean +/- SEM), respectively. The data indicate a positive relationship between ethanol preference and ethanol-induced motor stimulation and suggest that hyperactivity may be an expression of the positive reinforcing effect of ethanol for alcohol-preferring rats.

Maudsley reactive and non-reactive rat strains: Differential performance in a conflict task

Based on open field defecation rates, distinct strains of Maudsley rats have been identified. The Maudsley Reactive strains exhibit high levels of open field defecation, while the Maudsley Non-Reactive strains exhibit low levels of open field defecation. This difference in open field behavior has been interpreted as an indicator of “emotionality.” The present studies were designed to compare the performance of two Maudsley strains, MR/Har and MNRA/Har, in the conditioned suppression of drinking (CSD) paradigm, another “model” behavior for the study of emotionality and/or anxiety in animals. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.5 mA), electrification being signalled by a tone. In this procedure, MNRA/Har rats accepted significantly more shocks than did MR/Har rats. This difference between MR/Har and MNRA/Har strains, initially somewhat slight, became quite impressive over weeks of repeated testing. Although present in both male and female subjects, this strain difference was more prominent in the males. Thus, the MR/Har and MNRA/Har rat strains, bred originally for their differences in open field behavior, also differ markedly in their performance in the CSD paradigm. These findings suggest that the Maudsley rat strains may represent a useful genetically-based “animal model” for the study of emotionality and/or anxiety.

Interstrain comparison of avoidance behavior and neurochemical parameters of brain cholinergic function

Five rat strains (Long-Evans Hooded, Zivic Miller, Lewis, Buffalo and Fischer-344) were tested in a shuttlebox conditioned avoidance task and the differences in the performance levels among the strains were noted. In parallel experiments using naive rats, the acetylcholine concentrations in eight brain regions and the acetylcholine turnover rate in five brain regions were determined for these strains. Interstrain differences in these parameters were found but no correlation between avoidance performance and either of these measures was apparent in any brain region studied. In separate experiments, no differences were found in the hippocampal acetylcholine concentration or the turnover rate among good performing Hooded, poor performing Hooded or untested Hooded rats. Similarly, no differences in regional acetylcholine turnover rates were found between naive rats of the Iowa Reactive and Nonreactive strains. [ 3H]-QNB (quinuclidinyl benzilate) binding was studied in three brain regions in the five strains, but no large interstrain differences in binding characteristics were found. In contrast to interpretations of other workers based on less direct assay methods involving fewer strains, we conclude that no strong correlation exists between avoidance performance ability and basal levels of brain cholinergic activity.

Open-field behavior in the Maudsley reactive and nonreactive strains: procedural variations.

Procedural differences were examined to account for interlaboratory discrepancies in open-field defecation (OFD) scores of the Maudsley reactive and Maudsley nonreactive strains. It was found that the use of a continuous 24-h light diurnal cycle was associated with increased OFD in Maudsley reactive and nonreactive rats. If a 15-h light/9-h dark diurnal cycle was used, OFD scores typical of the progenitors of the Maudsley strains were obtained.

Cardiac β-receptor variation in rat strains selectively bred for differences in susceptibility to stress

The radioligand 3H-DHA was used to estimate the density and affinity of cardiac β-receptors in rat strains selectively bred for differences in response to stress. Maudsley Reactive rats selected for heightened reactivity to stress had a greater density of β-adrenergic binding in cardiac membranes than rats of two genetically distinct Maudsley Non-Reactive strains selected for decreased reactivity to stress, and compared with one of these Non-Reactive strains the MNR/Har, increased affinity for 3H-DHA. Together with previous findings the present results demonstrate a negative correlation between estimates of basal sympathetic activity on the one hand, and post-synaptic β-receptors in heart on the other, that are consistent with the notion that these receptor alterations have occurred as a result of long-term differences in pre-synaptic release of transmitter. The Maudsley strains may, therefore, provide a useful model for the study of β-adrenergic receptors as a physiological locus for regulation of end-target responsiveness to sympathetic stimulation.

Open-field behavior and the peripheral sympathetic nervous system in the MR/N and MNR/N rat strains.

The Maudsley Reactive (MR) and Maudsley Non-Reactive (MNR) strains of rats, respectively selected by P. L. Broadhurst for high and low open-field defecation (OFD), were acquired by the National Institutes of Health in 1963 at the 21st generation of inbreeding and have been inbred as the MR/N and MNR/N strains at that location for more than 40 generations. The present experiment shows that, despite the lack of deliberate selection for more than 40 generations, the strains still differ predictably in OFD. Strain differences in open-field activity, originally found to be inversely associated with those in OFD, have also been preserved. The existence of an association between the peripheral sympathetic system and OFD originally established in the Har derivation of the Maudsley strains was also confirmed in the MR/N and MNR/N strains: MR/N male rats, with the relatively higher levels of OFD, exhibited lower concentrations of norepinephrine (NE) in spleen and descending colon than MNR/N rats. The pattern of biochemical and morphological findings obtained in this study and previous data indicate that the MNR/N and the MNR/Har strains are both derived from the British stocks of this strain carrying the agouti allele (AA). A distinction should be made between these strains and the MNRA/Har strain, which carries the nonagouti allele (aa) and which has been genetically isolated from the Nonreactive strains bearing the agouti allele since early in the selection experiment.

Emotional correlates of selection for avoidance learning in rats

The Roman high-avoidance (RHA) and low-avoidance (RLA) strains of rats were tested and compared with Maudsley reactive (MR) and non-reactive (MNR) strains to assess the relative contributions of emotionality and conditionability to differences between the two Roman strains. The RHA learned significantly faster in active avoidance, but slightly slower in passive avoidance, significantly faster in acquisition of an active approach task, but slightly slower in extinction of active approach tasks despite extensive adaptation and gentling. The RHA showed more ‘rearing’, more activity in the open field and more variety-seeking. Crossing with MNR showed the RHA less reactive in the open field. Results show RLA equivocal in conditionability, more emotional, and perhaps less active.

Central serotonergic function and behavior in the Maudsley reactive and nonreactive strains: a reevaluation.

Confirming earlier research, Maudsley Reactive (MR) male rats had higher concentrations of serotonin (5-hydroxytryptamine) in brain stem than did Maudsley Nonreactive (MNR) rats. Comparisons of MR with a second MNR substrain (MNRA) revealed no strain differences in brain stem serotonin. The two MNR substrains exhibit similar levels of open-field defecation, and both differ substantially from MR animals. The present results suggest that, contrary to previous claims, brain stem serotonin is not consistently related to open-field defecation in the Maudsley strains.

Emotionality in selectively bred strains of rats mediates prior shock effects on escape-avoidance conditioning

Rats of the Maudsley Reactive and Maudsley Non-reactive strains were given 25 trials of escape-avoidance conditioning after exposure to inescapable shock. Prior shock exposure (PSE) did not affect avoidance or escape latencies, but decreased the number of avoidances made by the Maudsley non-reactive animals and increased the number of their failures to escape. The results are interpreted as demonstrating an interference with the classical conditioning of a conditioned emotional response, through a reduction in the information content of the CS following PSE. The strain differences are interpreted as due to the non-reactive animals being especially sensitive to PSE.