Behavior of mice with robertsonian translocations of chromosomes

The behaviour of mice with normal karyotype and those with robertsonian translocations was studied. The ability of the animals to solve an extrapolatory task was analysed. The experimental procedure was initiated with presentation of a food bait which the animal could reach only through a small opening in a screen. As the mouse started drinking, the food cup was moved leftward or rightward disappearing from the animal's view. The problem was to move in the direction of food, in which case the mouse could find it behind one of two feeding holes, to the right or to the left of the starting point. Laboratory mice were not able to solve this problem, whereas mice containing Rb(8, 17)1 IEM in karyotype demonstrated the extrapolatory ability - they solve the task correctly in a significant majority of cases. By means of a series of backcrosses of Rb(8, 17)1 IEM carriers on CBA strain (these mice have no extrapolatory ability) and subsequent inbreeding, a novel inbred strain was obtained, coisogenic to CBA and possessing the robertsonian translocation Rb(8, 17)1 IEM. These mice with the CBA genetic background solve the extrapolatory problem successfully, the level of correct choices being significantly above the 50% chance level. At the same time, their performance was lower than that of outbred mice with Rb(8, 17)1 IEM, the phenomenon possibly being the result of the influence of CBA genetic background. Mice with Rb(8, 17)6 Sic were also shown to possess the extrapolatory ability.(ABSTRACT TRUNCATED AT 250 WORDS)     

The level of noradrenaline and serotonin in mice differing in behavior

Laboratory mice possessing Robertsonian translocation Rb (8, 17) 1IEM in their karyotype, reveal statistically significant ability for extrapolation of the direction of stimulus movement which disappears from animal's view. Inbred CBA mice with the same translocation are less capable, and CBA mice with normal karyotype are totally incapable of solving this task. Cortical noradrenaline levels in mice with Rb (8, 17) 1IEM were the lowest and brain stem levels the highest among the three groups investigated. Serotonin levels reveal no changes among these groups.     

Genotype-dependent mice behavior in cognitive tasks. Effect of noopept

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.     

Are learning and attention related to the sequence of amino acids in ACTH/MSH peptides?

Learning and attention were examined in rats after injections of one of several molecules related to adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH). The initial phase of the learning process was linearly related to the length of the peptide with the smallest fragment (MSH/ACTH 4–10) improving learning the most and the largest molecule (ACTH 1–24) exerting no effect. Later stages of the learning problem, which were sensitive to the attentional state of the organism, resulted in U-shaped relations with the length of the same peptides. Enhancement of attention was significant only for the MSH compounds. These data indicate that some behaviors may be influenced as a function of the redundant information contained in the molecule while other behaviors may be discretely related to the specific conformation of the molecule.     

Neonatal Semax and saline injections induce open-field behavior changes in mice of different genotypes

DBA/2, CBA mice, and their F1 hybrids (first series) and 101/HY and C3H mice (second series) were injected as neonates (2-7 days of life) with Semax (sc., 7 microg per animal). Semax is a peptide analogue of ACHT4-10 fragment which is resistant to degradation. The common feature of remote effects of both Semax and saline injections was the set of changes in the open-field behavior in adult (2.5- to 3-month-old) animals as compared to intact mice. Unexpectedly, the neonatal saline injections induced many changes in adult behavior, part of these effects being genotype-dependent. The most conspicuous shifts (genotype-dependent increase or decline) in freezing, grooming and rearing scores were displayed by DBA/2 and C3H mice, whereas the hole-poke frequencies were significantly changed in CBA and C3H mice. Squares crossed in the center of arena and rearing number were significantly increased in saline group of DBA/2 mice, whereas in Semax-injected DBA/2 group they were approximately equal to the level of intact mice. This means that the remote effects of noxious stimulation (injections of saline) were in some ways "compensated" as the result of concomitant peptide effect. At the same time, the numbers of freezing and grooming episodes were also increased in these groups. Because exploratory behavior and manifestations of anxiety increased or decreased simultaneously, it proves to be difficult to ascribe these changes to behavioral modulation along the "novelty seeking--anxiety" axis. In mice of other genotypes, changes in the same indices of the open-field behavior were revealed, but these changes were different in their direction. It was suggested that the complex patterns of postnatal behavior was the result of neonatal injections modulating subsequent brain development.     

Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests

One of the characteristic manifestations of several neurodegenerative diseases is the progressive decline in cognitive ability. In order to determine the suitability of six mouse strains (129S2/Sv, BALB/c, C3H/He, C57BL/6j, CBA/Ca and DBA/2) as transgenic background strains, we investigated the performance on a variety of tasks designed to identify subtle changes in cognition. In addition, a test of exploratory behaviour was used to probe the level of underlying anxiety in these mouse strains, as anxiety can be a confounding factor on behavioural performance generally. The C3H/He mice exhibited the least anxiogenic behavioural profile spending most time on the open arms of the maze, in contrast to the 129S2/Sv mice which spent the least amount of time in this location and were the quickest to move into a closed arm. The C3H/He mouse strain failed to acquire a visual discrimination task and failed to demonstrate learning on a water maze spatial learning task, in contrast to the CBA/Ca, DBA/2 and C57BL/6j strains which demonstrated a degree of learning in both tasks. No significant strain differences were identified on the object recognition task. These data, taken together, suggest that care must be taken when choosing cognitive tasks to be used with particular mouse strains and that task sensitivity must be considered as a critical element to research protocols with regard to these mouse strains.     

Low-stress Route Learning Using the Lashley III Maze in Mice

Many behavior tests designed to assess learning and memory in rodents, particularly mice, rely on visual cues, food and/or water deprivation, or other aversive stimuli to motivate task acquisition. As animals age, sensory modalities deteriorate. For example, many strains of mice develop hearing deficits or cataracts. Changes in the sensory systems required to guide mice during task acquisition present potential confounds in interpreting learning changes in aging animals. Moreover, the use of aversive stimuli to motivate animals to learn tasks is potentially confounding when comparing mice with differential sensitivities to stress. To minimize these types of confounding effects, we have implemented a modified version of the Lashley III maze. This maze relies on route learning, whereby mice learn to navigate a maze via repeated exposure under low stress conditions, e.g. dark phase, no food/water deprivation, until they navigate a path from the start location to a pseudo-home cage with 0 or 1 error(s) on two consecutive trials. We classify this as a low-stress behavior test because it does not rely on aversive stimuli to encourage exploration of the maze and learning of the task. The apparatus consists of a modular start box, a 4-arm maze body, and a goal box. At the end of the goal box is a pseudo-home cage that contains bedding similar to that found in the animal’s home cage and is specific to each animal for the duration of maze testing. It has been demonstrated previously that this pseudo-home cage provides sufficient reward to motivate mice to learn to navigate the maze¹. Here, we present the visualization of the Lashley III maze procedure in the context of evaluating age-related differences in learning and memory in mice along with a comparison of learning behavior in two different background strains of mice. We hope that other investigators interested in evaluating the effects of aging or stress vulnerability in mice will consider this maze an attractive alternative to behavioral tests that involve more stressful learning tasks and/or visual cues.Download video file.^{(94M, mp4)}     

Effects of testosterone on spatial learning and memory in adult male rats

A male advantage over females for spatial tasks has been well documented in both humans and rodents, but it remains unclear how the activational effects of testosterone influence spatial ability in males. In a series of experiments, we tested how injections of testosterone influenced the spatial working and reference memory of castrated male rats. In the eight-arm radial maze, testosterone injections (0.500 mg/rat) reduced the number of working memory errors during the early blocks of testing but had no effect on the number of reference memory errors relative to the castrated control group. In a reference memory version of the Morris water maze, injections of a wide range of testosterone doses (0.0625-1.000 mg/rat) reduced path lengths to the hidden platform, indicative of improved spatial learning. This improved learning was independent of testosterone dose, with all treatment groups showing better performance than the castrated control males. Furthermore, this effect was only observed when rats were given testosterone injections starting 7 days prior to water maze testing and not when injections were given only on the testing days. We also observed that certain doses of testosterone (0.250 and 1.000 mg/rat) increased perseverative behavior in a reversal-learning task. Finally, testosterone did not have a clear effect on spatial working memory in the Morris water maze, although intermediate doses seemed to optimize performance. Overall, the results indicate that testosterone can have positive activational effects on spatial learning and memory, but the duration of testosterone replacement and the nature of the spatial task modify these effects.     

A dietary supplement abolishes age-related cognitive decline in transgenic mice expressing elevated free radical processes

We previously found that transgenic mice overexpressing growth hormone (TGM) have elevated and progressively increasing free radical processes in brain that strongly correlates with reduced survivorship. Young mature TGM, however, displayed vastly enhanced learning of an eight-choice cued maze and qualitatively different learning curves than normal controls. Here we document the age-related patterns in learning ability of TGM and normal mice. Learning appeared inferior in both genotypes of very young mice but TGM were confirmed to be superior to normal mice upon maturity. Older TGM, however, showed rapid age-related loss of their exceptional learning, whereas normal mice at 1 year of age showed little change. The cognitive decline of TGM was abolished by a complex "anti-aging" dietary supplement formulated to promote membrane and mitochondrial integrity, increase insulin sensitivity, reduce reactive oxygen and nitrogen species, and ameliorate inflammation. Results are discussed in the context of reactive oxygen and nitrogen species, long-term potentiation, learning, aging and neuropathology, based on known impacts of the growth hormone axis on the brain, and characteristics of TGM.     

T cell regulation of polyclonal B cell responsiveness. II. Evidence for a deficit in T cell function in mice with an X-linked B lymphocyte defect.

In addition to the x-linked B cell maturation deficit previously reported in CBA/N mice, a functional T cell defect has now been observed. T lymphocyte regulation of the polyclonal PFC response was studied within the context of this x-linked immunodeficiency model. The ability of 1) B cells from (CBA X CBA/CaJ)F1, male mice to respond to nonspecific T cell helper signals and 2) T cells from NCF1 male mice to provide such signals was investigated under in vitro conditions by using bacterial lipopolysaccharide (LPS) as the polyclonal activator. B lymphocytes from both male and female NCF1 mice were receptive to T cell help rendered by NCF1 female T cells. Male T cells. however, were unable to augment polyclonal B cell responses of either NCF1 male or female B cells to LPS. Treatment with ATS + C reduced the polyclonal response of female but not male spleen cells to LPS. This deficit could not be overcome by the use of greater numbers of NCF1 male T cells. The observation that this deficiency in T cell regulation is not due to active suppression suggests that the results may be attributable to an intrinsic T cell defect.     

Splenic and inguinal lymph node T cells of aged mice respond differently to polyclonal and antigen-specific stimuli.

Numerous changes have been reported to occur in T cell responsiveness of mice with increasing age. However, most of these studies have examined polyclonal stimulation of spleen cells from a limited number of mouse strains. This study investigated the influence of genetic background, source of lymphocytes, and type of stimulus on age-associated changes in T cells response. Con A-induced proliferation and IL-2 and IFN-gamma production by splenic lymphocytes (SL) was significantly greater in CBA/Ca mice compared to C57BL/6 mice, regardless of age. SL of both strains exhibited the predicted age-dependent decline in proliferative response and an increase in IFN-gamma production in response to Con A. In contrast, however, only SL from C57BL/6 mice demonstrated the predicted age-dependent decline in Con A-induced IL-2 production; Con A-induced SL of young and aged CBA/Ca mice produced comparable amounts of IL-2. Differences in age-associated responses to Con A were also observed between SL and inguinal lymph node (ILN) cells of CBA/Ca mice. In contrast to SL, ILN cells demonstrated an increased proliferative response to Con A. However, lymphokine production by Con A-stimulated ILN cells from aged CBA/Ca mice was similar to that of Con A-stimulated SL from aged CBA/Ca mice. To determine if aged ILN T cells respond similarly to polyclonal and antigen-specific stimuli, keyhole limpet hemocyanin (KLH) responses of T cells isolated from ILN of aged and young CBA/Ca mice were examined. KLH-specific T cells from aged mice cultured with KLH-pulsed macrophages (M phi) from aged mice were significantly reduced in their ability to proliferate compared to KLH-specific T cells of young mice cultured with young KLH-pulsed M phi. In contrast to the expected results, the defect was not at the level of the T cells; proliferation of young T cells cultured with aged KLH-pulsed M phi was equivalent to the proliferation of aged T cells cultured with aged M phi. These results suggest that aging has differential effects on polyclonal and antigen-specific T cell proliferation and on polyclonal stimulation of T cells isolated from different lymphoid organs and from different strains of mice.     

Induction of T15-specific suppressor T cells in mice with the CBA/N defect by neonatal injection with anti-T15 idiotype antibody

Mice with the CBA/N defect (xid) are unresponsive to phosphorylcholine (PC), To determine whether idiotype-specific suppressor T cells can also be generated in these defective mice, defective (CBA/N X BALB/c)F1 male and nondefective (CBA/N X BALB/c)F1 female or (BALB/c X CBA/N)F1 male mice were neonatally injected with antibodies specific for the major idiotype of anti-PC antibody, i.e., anti-TEPC-15 idiotype (T15id) antibody. Suppressor cell activity was examined by co-culturing spleen cells from neonatally treated F1 mice with spleen cells of normal nondefective F1 mice in the presence of antigen. Spleen cells from defective (CBA/NM X BALB/c)F1 mice treated with anti-T15id antibody demonstrated a level of suppressor activity (greater than 83% suppression) comparable to that of similarly treated nondefective F1 mice. This suppression was specific for the T15id of anti-PC response, and a Lyt-1-2+-bearing T cell population appeared to be responsible for the active suppression. These suppressor T cells recognized T15 but not PC, based on a functional absorption test. These results indicate that the CBA/N defects, including the deficiency in the anti-PC response by B lymphocytes and a possible T cell defect, do not influence the generation of T15id-specific suppressor T cells by neonatal injection with anti-T15id antibody.     

The course of experimental staphylococcal sepsis in opposite mouse strains and first-generation hybrids]

The survival time and histological lesions of the kidneys, liver, heart, and lungs were studied in CBA/Sto, C3HA/Mv and F1 (C3HA/Mv x CBA/Sto) mice for 15 days after i.v. injections with S. aureus pathogenic strains CFU B-243 in doses of 10(9), 10(8) and 2.5 x 10(8) microbial cells. CBA/Sto mice were found relatively resistant and C3HA/Mv mice, susceptible to infection caused by different doses of S. aureus, this being associated with different morphological picture in the viscera. F1 hybrids were at least as susceptible to the infections as any of the parent strains, suggesting recessive inheritance of resistance to staphylococcal infection.     

CD4+ T cells from lupus-prone mice avoid antigen-specific tolerance induction in vivo

Activated T cells in spontaneous lupus presumably bypass normal tolerance mechanisms in the periphery, since thymic tolerance appears intact. To determine whether such T cells indeed avoid in vivo peripheral tolerance mechanisms, we assessed their activation and recall responses after in vivo Ag stimulation in the absence of exogenously supplied costimulatory signals. Naive CD4(+) AND (transgenic mice bearing rearranged TCR specific for pigeon cytochrome c, peptides 88-104) TCR-transgenic T cells, specific for pigeon cytochrome c, from lupus-prone Fas-intact MRL/Mp+(Fas-lpr) and from H-2(k)-matched control CBA/CaJ and B10.BR mice (MRL.AND, CBA.AND, and B10.AND, respectively) were adoptively transferred into (MRL x CBA)F(1) or (MRL x B10)F(1) recipients transgenically expressing membrane-bound pigeon cytochrome c as a self-Ag. MRL.AND and control CBA.AND and B10.AND-transgenic T cells were activated and divided after transfer, indicating encounter with their cognate Ag; however, T cells from CBA.AND and B10.AND mice were impaired in their ability to proliferate and produce IL-2 after challenge with pigeon cytochrome c in ex vivo recall assays, a typical phenotype of anergized cells. By contrast, MRL.AND T cells proliferated more, and a significantly higher percentage of such cells produced IL-2, compared with control T cells. This observation that MRL T cells avoided anergy induction in vivo was confirmed in an in vitro system where the cells were stimulated with an anti-CD3 in the absence of a costimulatory signal. These experiments provide direct evidence that CD4(+) T cells from Fas-intact lupus-prone MRL mice are more resistant than nonautoimmune control cells to anergy induction. Anergy avoidance in the periphery might contribute to the characteristic finding in lupus of inappropriate T cell activation in response to ubiquitous self-Ags.     

Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice

Protein tyrosine phosphatase delta (PTPdelta) is a receptor-type PTP expressed in the specialized regions of the brain including the hippocampal CA2 and CA3, B lymphocytes and thymic medulla. To elucidate the physiological roles of PTPdelta, PTPdelta-deficient mice were produced by gene targeting. It was found that PTPdelta-deficient mice were semi-lethal due to insufficient food intake. They also exhibited learning impairment in the Morris water maze, reinforced T-maze and radial arm maze tasks. Interestingly, although the histology of the hippocampus appeared normal, the magnitudes of long-term potentiation (LTP) induced at hippocampal CA1 and CA3 synapses were significantly enhanced in PTPdelta-deficient mice, with augmented paired-pulse facilitation in the CA1 region. Thus, it was shown that PTPdelta plays important roles in regulating hippocampal LTP and learning processes, and that hippocampal LTP does not necessarily positively correlate with spatial learning ability. To our knowledge, this is the first report of a specific PTP involved in the regulation of synaptic plasticity or in the processes regulating learning and memory.     

初步探讨鸟嘌呤核苷、姜黄素对AD双转基因小鼠学习记忆的影响

目的通过Morris水迷宫检测学习记忆和记忆保持能力,判断鸟嘌呤核苷、姜黄素对4月龄APPswe/PS1dE9双转基因小鼠认知功能的影响。方法将3月龄APPswe/PS1dE9双转基因小鼠随机分为模型组、盐酸多奈哌齐组0.92 mg/(kg·d)、鸟嘌呤核苷组20 mg/(kg·d)、姜黄素组200 mg/(kg·d)、姜黄素200 mg/(kg·d)和鸟嘌呤核苷组20 mg/(kg·d),每组12只;并以同月龄野生型C57/BL6J小鼠作对照。每天给药1次,连续给药1个月。应用Morris水迷宫进行行为学检测。结果鸟嘌呤核苷、姜黄素对空间探索、定位航行障碍有改善作用,尤其以姜黄素组明显。结论鸟嘌呤核苷、姜黄素能改善APPswe/PS1dE9双转基因小鼠的早期出现的认知障碍。     

Mouse Leydig Cells with Different Androgen Production Potential Are Resistant to Estrogenic Stimuli but Responsive to Bisphenol A Which Attenuates Testosterone Metabolism

It is well known that estrogens and estrogen-like endocrine disruptors can suppress steroidogenic gene expression, attenuate androgen production and decrease differentiation of adult Leydig cell lineage. However, there is no information about the possible link between the potency of Leydig cells to produce androgens and their sensitivity to estrogenic stimuli. Thus, the present study explored the relationship between androgen production potential of Leydig cells and their responsiveness to estrogenic compounds. To investigate this relationship we selected mouse genotypes contrasting in sex hormone levels and differing in testosterone/estradiol (T/E₂) ratio. We found that two mouse genotypes, CBA/Lac and C57BL/6j have the highest and the lowest serum T/E₂ ratio associated with increased serum LH level in C57BL/6j compared to CBA/Lac. Analysis of steroidogenic gene expression demonstrated significant upregulation of Cyp19 gene expression but coordinated suppression of LHR, StAR, 3βHSDI and Cyp17a1 in Leydig cells from C57BL/6j that was associated with attenuated androgen production in basal and hCG-stimulated conditions compared to CBA/Lac mice. These genotype-dependent differences in steroidogenesis were not linked to changes in the expression of estrogen receptors ERα and Gpr30, while ERβ expression was attenuated in Leydig cells from C57BL/6j compared to CBA/Lac. No effects of estrogenic agonists on steroidogenesis in Leydig cells from both genotypes were found. In contrast, xenoestrogen bisphenol A significantly potentiated hCG-activated androgen production by Leydig cells from C57BL/6j and CBA/Lac mice by suppressing conversion of testosterone into corresponding metabolite 5α-androstane-3α,17β-diol. All together our data indicate that developing mouse Leydig cells with different androgen production potential are resistant to estrogenic stimuli, while xenoestrogen BPA facilitates hCG-induced steroidogenesis in mouse Leydig cells via attenuation of testosterone metabolism. This cellular event can cause premature maturation of Leydig cells that may create abnormal intratesticular paracrine milieu and disturb proper development of germ cells.     

Effect of diiodobenzotefa on the functionally different subpopulations of T-lymphocytes]

Diiodobenzo-tepa (DIB) was given orally to CBA mice in a dose of 25 mg/kg for 3 successive days. The number of nucleus-containing cells decreased 3.9 fold in the thymus and 1.4 fold in the bone marrow. In experiments on transplantation of lymphoid cells to intact or lethally irradiated (CBA X C57BL/6J)F1 mice treated with DIB this substance did not influence the helper activity of T lymphocytes but inhibited the activity or B and T lymphocytes, inducing "graft-versus-host" and T cell-suppressor functions.     

Inhibition of macrophage-induced antigen-specific T lymphocyte proliferation by poly I:C: strain and antigen independence

We have previously demonstrated that IFN-alpha/beta, poly I:C (an inducer of IFN-alpha/beta), and IFN-gamma can inhibit the ability of KLH-pulsed peritoneal macrophages to induce proliferation of syngeneic, KLH immune T lymphocytes in CBA/J mice. In this study, we show that this IFN-induced immunosuppression is not restricted to CBA/J (H-2k) mice but is also seen in BALB/cJ (H-2d) mice. A similar inhibition of proliferation is observed with the KLH-specific T cell hybridoma BDK, 100, which requires KLH-pulsed macrophages for optimum proliferation and IL-2 production. The immunosuppression produced by IFN was also independent of the antigen employed. Inhibition of T lymphocyte proliferation was observed when casein, instead of KLH, was used to immunize T cells and to pulse peritoneal macrophages in vivo. Utilizing KLH and casein, the antigen specificity of the inhibition was demonstrated. Therefore, the inhibition by the IFN-inducer poly I:C of macrophage-induced, antigen-specific T cell proliferation is not limited by H-2 type of the mice or to one antigen.     

Strain-specific response in mice to the neonatal administration of ACTH(4-10) fragment: behavior, neurochemistry, and brain morphology

Neonatal injection of the ACTH4-10 fragment (5 micrograms daily for five days) caused genotype-dependent changes in concentrations of some monoaminergic neuromediators and their metabolites in hippocampus and brain stem of adult CBA and 101/HY mice. The catecholaminergic neurons increased in number in hypothalamic zona incerta of adult 101/HY mice. Neonatal injection of the peptide caused also genotype-dependent changes in the exploratory behavior of adult animals. Sound sensitivity was reduced in the 101/HY mice, whereas no sensitivity was revealed in both control and experimental groups of the CBA mice. The effects discovered were suggested to be caused by changes in neuronal differentiation.