Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) rats: performance in an operant conflict paradigm.

The present studies were designed to characterize the behavior of Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) rats in a modification of the Geller-Seifter operant conflict paradigm. Food-restricted (85% of free-feeding weights) female MR/Har and MNRA/Har rats were trained to lever press for food reinforcement in a multiple-schedule operant conflict paradigm. In the absence of a tone, a fixed ratio-30 (FR-30) schedule for reinforcement only was in effect (i.e., every 30th lever press resulted in the delivery of a 45-mg food pellet). During the presence of a tone, a fixed ratio-1 (FR-1) schedule of both reinforcement (food) and punishment (0.20 mA footshock applied for 500 ms) was in effect (i.e., each lever press resulted in both food and shock delivery). The tone periods were 27 s in duration and were presented on a variable interval (VI)-120-s schedule (approximately 20 tones/40-min session). Behavioral testing was conducted 5 days/week for 35 weeks. Initially, punished responding between the MR/Har and MNRA/Har rat strains did not differ dramatically. However, over the course of many weeks of conflict testing, rats of the MNRA/Har strain came to accept significantly more shocks than did subjects of the MR/Har strain. A direct examination of footshock sensitivity in these rats revealed that this difference in conflict behavior over time was not due to strain differences in shock sensitivity. The mechanism for this time-dependent difference in conflict behavior between the MR/Har and MNRA/Har rats remains undetermined.     

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.     

MR/Har and MNRA/Har Maudsley rat strains: Differences in acoustic startle habituation

Female Maudsley Reactive (MR/Har) and Nonreactive (MNRA/Har) rats were tested for initial acoustic startle reactivity and within-session startle habituation. Subjects were exposed in each of five weekly sessions to 12 acoustic startle noise bursts at a 20-s interstimulus interval, a procedure in which genetically heterogeneous Sprague Dawley rats have been shown to exhibit robust within-session habituation. Although initial startle reactivity was comparable in the two strains, significant differences in withinssession habituation were observed. Specifically, MR/Har rats were observed to exhibit substantial within-session habituation to these acoustic stimuli, while rats of the MNRA/Har strain exhibited little, if any, habituation to these repeated acoustic stimuli. The basis for this dramatic difference in within-session startle habituation in these Maudsley rats is at present unexplained and under investigation.This work was supported in part by the WSU Biomedical Research Award Program, the American Heart Association of Michigan Grant-in-Aid Program, the Pharmaceutical Manufacturers Association Research Starter Grant and MH 42501-01 to R.L.C., and the National Science Foundation to G.M.H.     

Maudsley reactive and nonreactive rats in the forced swim test: comparison in fresh water and soiled water.

Maudsley reactive (MR) and nonreactive (MNRA) and Sprague-Dawley (SD) male rats were tested for their immobility response in the forced swim test when the water was fresh or soiled by a rat of the same or other strain. For all strains, rats tested in soiled water were less immobile than rats in fresh water. The three strains did not differ as producers of soiling substance, but did differ in their response to it. The MR strain was least responsive, whereas the MNRA and SD did not differ from one another. These results support a previous study suggesting that MR rats are more immobile than MNRA rats in the forced swim test. The interpretation of these findings regarding the use of the Maudsley rat strains as an animal model for studying anxiety and/or depression is discussed.     

The Maudsley Reactive and Nonreactive strains: a new perspective

Research on the Maudsley Reactive and Maudsley Nonreactive strains conducted primarily between 1980 and 2001 is reviewed. One line of research, which has found consistent differences between the Harrington derivation of the Maudsley Reactive (MR/Har) and Maudsley Nonreactive (MNRA/Har) strains in conflict situations, appears to support the traditional view of the two strains as representing models of global differences in emotionality. In contrast, comparisons of the two strains in two commonly used tests that involve a component of fear either do not reveal differences between the strains (escape-avoidance conditioning) or are inconsistent in expression (elevated plus maze). Emphasis is placed on the importance of recognizing that most of the phenotypic differences discovered among selected inbred strains, including the Maudsleys, will inevitably be unrelated to the original selection criterion, but that many of these phenotypic differences will have their own intrinsic interest. For example, the fact that, relative to MNRA/Har, two bottle ethanol preference is greater in MR/Har rats and that MR/Har rats exhibit greater exploration of novel stimuli when these are presented in a familiar environment may have little to do with the hypothesized differences in emotionality among the strains. It is suggested the MR/Har drinking pattern in alcohol preference tests, which is characterized by considerable variability, may complement other models of alcoholism, especially in the investigation of environmental influences which contribute to the variability. In the case of strain differences in response to novelty, this may help explain some of the inconsistencies in findings in the elevated plus maze, which, aside from provoking fear, also contains an important element of novelty. Finally, it has been found that alterations in the peripheral sympathetic nervous system (PSNS) are correlated with strain differences in open-field defecation (OFD) in the Maudsley model, and it has been proposed that the lower OFD of MNRA/Har rats is a direct result of sympathetic inhibition of colonic motility. These strain differences in the PSNS are furthermore associated with important alterations in the response of the central noradrenergic system to acute and chronic stress. It is hypothesized that genes may have influenced PSNS tone by altering CNS structures with descending projections. If the link between low levels of OFD and higher peripheral sympathetic tone is supported by additional experiments, this will force reconsideration of OFD as an index of emotionality.     

Genetic variation, chronic stress, and the central and peripheral noradrenergic systems

Male rats from two inbred strains genetically selected for variation in response to stress were exposed for 9 consecutive days to 50 min of intermittent foot shock and killed 24 h after the last stress session. Maudsley Nonreactive (MNRA/Har) rats, genetically selected for decreased reactivity to stress, exhibited a significantly greater elevation (114% above control levels) in tyrosine hydroxylase activity in the locus ceruleus after chronic stress than Maudsley Reactive (MR/Har) animals (63% above control levels), genetically selected for heightened reactivity to stress. In the peripheral noradrenergic system, chronic stress produced an increase in norepinephrine (NE) content of small intestine and submaxillary gland of MNRA/Har rats, whereas chronic stress had no effect on NE content of these same tissues in MR/Har animals. These results are consistent with the proposition that genetic selection for variation in susceptibility to stress has altered the capacity of the central and peripheral noradrenergic system to adapt to chronic stress.     

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.Supported by Grant GM 28874 from the National Institute of General Medical Sciences.     

Environmental influences on the failure to drink in inbred rats with an ethanol preference

To investigate the environmental influences on the initiation of voluntary consumption of 10% ethanol (EtOH) in rats with differing genetic susceptibility to excessive EtOH consumption, Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) inbred rats were observed in different types of caging environments. Singly housed male and female rats of both strains living in Observational (O) cages drank markedly less EtOH during 3 weeks of two-bottle choice than did rats living in standard-control (C) individual cages. When male rats had a preexisting moderate or heavy pattern of EtOH intake (manipulated through prior EtOH experience), moving to the O cage did not reduce EtOH intake. To investigate the nature of the above cage effect (the reduced initiation of EtOH consumption), we compared the manner in which food had been distributed (traditional food hopper in C cages versus loose distribution in O cages) independently of cage type. The results showed that MR/Har male rats that obtained food through a hopper in both O or C cages drank significantly more EtOH than rats that had food loosely distributed in the O or C cages. The results suggest that differences in the mode of food procurement and caging can play a large role in whether the phenotype for excessive EtOH intake is expressed in the acquisition of an EtOH preference in genetically vulnerable rats.     

Behavior and corticosteroid response of Maudsley reactive and nonreactive rats in the open field and forced swimming test

Maudsley reactive (MR) and nonreactive (MNRA) male rats were tested in the open field and in the forced swimming test. MR rats defecated more and were less active than MNRA rats in the open field. MR rats also defecated more, but were more immobile in the forced swim test. The two strains did not differ significantly in basal corticosteroid levels or corticosteroid levels in response to either test. These results suggest that the increased defecation rates exhibited by MR rats in various tests are not indicative of a general increase in "emotionality" or stress level.     

Effect of septal lesions on conditioned defensive burying

Every control rat shocked by a wire-wrapped prod mounted on the wall of a test chamber buried the prod with bedding material from the floor of the chamber. Although this conditioned defensive burying was also observed in every rat with a lesion of the anterior septum (Experiment 2), no rat with a lesion of the entire septum (Experiment 1) or a lesion limited to the posterior septum (Experiment 2) was observed to engage in this behavior. These results confirm previous reports of the involvement of the septal area in defensive behavior and provide the first demonstration of the utility of the conditioned defensive burying paradigm in assessing the behavioral effects of limbic lesions.     

Emotionality and the temporospatial organization of instantaneous EEG potentials

The characteristics of the temporospatial organization of cerebral cortical potentials at different levels of genetically determined emotionality were analyzed by constructing topograms of instantaneous EEG levels in the inbred rat strains MR and MNRA. Two parameters were calculated for each topogram: the total level and the similarity coefficient. Power spectra were calculated for the values and these were found to change in an oscillatory manner. Interstrain differences were found in the correlated changes in total levels and similarity coefficients, in the durations of changes in the total level, which were more marked than those of similarity coefficients, and the nature of interhemisphere asymmetry. In MR rats, the power spectra of both measures showed significant peaks with modes at 2.0, 6.5, and 9.0 Hz. In MNRA rats, peaks in the spectra of these measures both coincided (2.0 Hz) and differed (7.0 Hz in the spectrum of the total level and 3.0, 4.5, and 6.0 Hz in the spectrum of the similarity coefficient). These data suggest different types of functioning of the reticulothalamocortical and hippocampocortical systems in rats of these strains. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, vol. 55, No. 4, pp. 518–526, July–August, 2005.     

Housing influences exploration and social interaction of control and DSP-4-treated rats.

Exploratory behavior and social interaction were investigated in rats that were reared in different social environments following neonatal injection with either water vehicle or the norepinephrine neurotoxin, DSP-4. At weaning, they were placed in a familiar or novel bedding type and were housed in either vehicle control-only, DSP-4-only, or mixed vehicle control and DSP-4 groups for 10 days. They were then observed in three different situations: the home cage, the cage of an unfamiliar rat, and an open field. Compared to rats housed in vehicle control-only or DSP-4-only groups, rats housed in mixed DSP-4 and vehicle control groups showed elevated exploration behavior in the home cage. Also, rats housed in mixed groups in the familiar bedding, but not the novel one, showed abnormally low levels of rearing in an open field test and reduced social interaction with unfamiliar rats. The implications of these results for a new animal model of anxiety are discussed.     

Plasma catecholamine and corticosterone levels during active and passive shock-prod avoidance behavior in rats: effects of chlordiazepoxide

Plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) concentrations were determined in rats before, during and after 15-min exposure to a constantly electrified (2 mA) or nonelectrified prod which was mounted on the wall of the home cage either with or without bedding material on the floor. Concomitantly, exploration of the prod, freezing and prod-burying behavior were recorded. Both in the presence and absence of bedding material, rats explored the nonelectrified prod and showed a small increase in plasma NA and CS contents. Exploration of the prod was strongly reduced when the prod was electrified. In the presence of bedding material, shocked rats typically displayed burying behavior (active avoidance), whereas in the absence of bedding (i.e., burying option eliminated) shocked rats engaged in freezing behavior (passive avoidance). The passive avoidance situation was accompanied by larger A and CS increases but a lower NA rise as compared to the hormonal responses associated with the active avoidance situation. Administration of the anxiolytic chlordiazepoxide (CDP; 9 mg/kg intragastrically) attenuated the shock-induced suppression of prod exploration, decreased prod-burying behavior but, paradoxically, increased freezing behavior. Irrespective of bedding condition, the prod shock-induced elevations in plasma CS and A contents were completely abolished in CDP-treated rats. The rise in plasma NA was attenuated only in CDP-treated rats tested on a bedding-floor. The results indicate that passive (e.g., freezing) and active (e.g., burying) behavioral coping are each accompanied by specific and dissociated patterns of neurosympathetic, adrenomedullary and adrenocortical outflow. CDP-treatment shifts an animal's behavioral coping style from an active to a passive form of avoidance responding, but abolishes the accompanying adrenocortical and adrenomedullary activation.     

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.This work was supported by NIH Grants HD 08187, 9MMH 26962, and NYC HRC Grant U-2355 to D.A.B.     

Sex and strain differences in the developmental activity profile of the rat tested over clean vs home cage bedding

In the first of two experiments, CD rat litters were used to characterize activity patterns obtained in a size-adjustable, single photodetector chamber. Beginning on postnatal Day 10 or 12, pups were tested repeatedly over clean bedding (C) or over bedding removed from each pup's home cage (HC). In C rats of both sexes and in HC females, short-term activity levels peaked on Day 16. However, HC males displayed an earlier and even greater elevation in activity from Day 12 to 16. This overall pattern was found in rats tested either every second or fourth day. In the second experiment, Long-Evans pups were assigned to each testing condition (C vs HC) and activity measured beginning on Day 12. Peak levels were seen in all Long-Evans rats on Day 16 and only females showed significant alterations as a function of bedding condition. When overall activity levels of the two strains were compared, significant differences were found on Days 12, 24, 30, and 120 in males, and 12, 24, and 30 in females. Significant differences between strains in activity as a function of bedding condition were found in males on Days 12, 20, 24, and 120 and in females on Days 12, 30, and 60. These data confirm the generality of a developmental hyperactivity phase in isolated juvenile rats. However, different patterns of hyperactivity were found in male vs female rats across strains. CD males were more active in the presence of HC olfactory cues, while in Long-Evans rats, female activity was affected more by bedding condition.     

Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: models for depression and anxiety?

Impaired corticosteroid receptor signaling is a key mechanism in the pathogenesis of stress-related psychiatric disorders such as depression and anxiety. Since in vivo expression and functional studies of corticosteroid receptors are not feasible in the human central nervous system, such analyses have to be done in animal models. Transgenic mice with mutations of corticosteroid receptors are promising tools, which allow us to investigate the role of these proteins in the pathogenesis of symptoms characteristic for depression and anxiety. This review summarizes the neuroendocrinological and behavioral findings that have been obtained in six different mouse strains with specific mutations that influence the expression or the function of the glucocorticoid or the mineralocorticoid receptor (MR). The analyses of these mice helped to define molecular concepts of how corticosteroid receptors regulate the activity of the hypothalamic-pituitary-adrenal (HPA) system. Furthermore, some of these mutant mice exhibited characteristic alterations in behavioral tests for anxiety and despair. However, so far, none of the mouse strains described here can be viewed as an animal model of a specific psychiatric disease defined by common diagnostic criteria. Using high throughput technologies for the identification of genes regulated by glucocorticoid receptor (GR) and MR in brain areas responsible for specific symptoms of stress-related disorders will yield potential new drug targets for the treatment of depression and anxiety.     

Olfactory, thermal, and tactual influences on infantile ultrasonic vocalization in rats.

The amount of time infant rats 3-13 days old spent emitting ultrasounds was greater when pups were placed in an empty dish than when placed in a dish containing clean bedding or soiled bedding from the nest. Pups from 5-13 days of age vocalized more when on the clean bedding than when on the soiled bedding. When placed on cloth covered dishes, pups vocalized most to the empty dish and least to the dish containing soiled bedding. The odor of clean bedding elicited less ultrasonic vocalization than the odor of the empty dish only when less than 7 days old. Pups vocalized more to room temperature than to heated conditions. The results indicate that olfactory, tactual, and thermal nest cues influence infantile ultrasonic vocalization in the rat.     

Construction of an MR/P fimbrial mutant of Proteus mirabilis: role in virulence in a mouse model of ascending urinary tract infection.

Proteus mirabilis, a cause of acute pyelonephritis, produces at least four types of fimbriae, including MR/P (mannose-resistant/Proteus-like) fimbriae. To investigate the contribution of MR/P fimbriae to colonization of the urinary tract, we constructed an MR/P fimbrial mutant by allelic exchange. A 4.2-kb BamHI fragment carrying the mrpA gene was subcloned into a mobilizable plasmid, pSUP202. A 1.3-kb Kanr cassette was inserted into the mrpA open reading frame, and the construct was transferred to the parent P. mirabilis strain by conjugation. Following passage on nonselective medium, 1 of 500 transconjugants screened was found to have undergone allelic exchange as demonstrated by Southern blot. Colony immunoblot, Western immunoblot, and immunogold labeling with a monoclonal antibody to MR/P fimbriae revealed that MrpA was not expressed. Complementation with cloned mrpA restored MR/P expression as shown by hemagglutination, Western blot, and immunogold electron microscopy. To assess virulence, we challenged 40 CBA mice transurethrally with 10(7) CFU of wild-type or mutant strains. After 1 week, geometric means of log10 CFU per milliliter of urine or per gram of bladder or kidney for the wild-type and mutant strains were as follows: urine, 7.79 (wild type) versus 7.02 (mutant) (P = 0.035); bladder, 6.22 versus 4.78 (P = 0.019); left kidney, 5.02 versus 3.31 (P = 0.009); and right kidney, 5.28 versus 4.46 (P = 0.039). Mice challenged with the wild-type strain showed significantly more severe renal damage than did mice challenged with the MR/P-negative mutant (P = 0.007). We conclude that MR/P fimbriae contribute significantly to colonization of the urinary tract and increase the risk of development of acute pyelonephritis.     

An empirical study of the structure of the patrol/marking motivational system in the rat

The existence and structure of an hypothesized motivational system of patrol/marking was supported and elucidated by a behavioral study on untrained highly inbred laboratory rats. One rat (the "runner") was placed into a test chamber containing a wire-mesh running wheel flanked by two chambers, one of which contained another rat (the "target"). Four conditions of runners (socially-isolated males, socially-housed males, non-estrous females, and estrous females) were exposed to four types of targets (socially-housed males, non-estrous females, estrous females, and blank targets consisting of any empty target chamber). Also placed in the chamber was a Petri dish containing scent-markings of the target rat. The experiment was designed in a counterbalanced way with 10 replications and repeated two times in two separate years. As predicted from the hypothesis, scent-marking, sniffing the dish, locomotion (number of wheel revolutions), and approach (differential running towards the target) were all correlated with each other and varied in the same way as a function of the hormonal and experiential condition of the runner and the type of target. They were interpreted to reflect motor patterns of a single unitary patrol/marking motivational system. Grooming, on the other hand, did not correlate with the other behaviors and facial gland secretion was, therefore, rejected as a motor pattern of patrol/marking.     

Behavioral selection of odor cues by young female mice affects age of puberty.

Female house mice were reared from weaning at 21 days of age until first vaginal estrus in 40 1 aquaria in which they were given a choice of exposing themselves to bedding placed on opposite halves of the aquarium floor and sprayed with water or urine containing puberty-influencing chemosignals. In Experimental 1, mice housed with only male urine cues sprayed on the bedding matured significantly earlier and mice housed with only grouped female urine sprayed on the bedding matured significantly later than control mice where water was sprayed on the bedding for both halves of the aquarium. In Experiment 2, there were no significant differences in mean ages at vaginal introitus or first estrus for females reared with choices between (a) bedding sprayed with male urine versus bedding sprayed with water, (b) bedding sprayed with urine from grouped females versus bedding sprayed with water, (c) bedding sprayed with male urine versus bedding sprayed with urine from grouped females, or (d) the control condition where both sides of the aquarium contained bedding sprayed with water. Analysis of continuous video tapes of the locations of the females for Experiment 2 revealed that females chose initially to spend more time on the half of the floor with bedding that delayed puberty relative to the other side, but shifted their preference toward a more puberty-enhancing signal at about the time of first estrus. Female house mice appear to be able to exert some behavioral control over their own sexual maturation.