Effects of repeated aggressive encounters on approach to a female and plasma testosterone in male mice

Effects of repeated experience of aggression accompanied by social victories or social defeat in 10 daily agonistic confrontations on testosterone levels in and the behavioral response of CBA/Lac male mice exposed to a receptive female from behind a perforated transparent partition have been examined. Testosterone levels were not changed significantly in the mice that had consistently been victorious over 10 days (winners) or in the mice that had consistently been defeated over 10 days (losers). Losers and controls (mice that had been caged individually for 5 days) responded with increased levels of behavioral activity near the partition and elevated testosterone. Winners showed a significantly poorer behavioral and hormonal response. It is concluded that the repeated display of aggression by male mice led to a reduction in both their behavioral and neuroendocrine responses to an estrous female.     

Does my mouse have Alzheimer's disease?

Small animal models that manifest many of the characteristic neuropathological and behavioral features of Alzheimer's disease (AD) have been developed and have proven of great value for studying the pathogenesis of this disorder at the molecular, cellular and behavioral levels. The great progress made in our understanding of the genetic factors that either cause or contribute to the risk of developing AD has prompted many laboratories to create transgenic (tg) mice that overexpress specific genes which cause familial forms of the disease. Several of these tg mice display neuropathological and behavioral features of AD including amyloid β-peptide (Aβ) and amyloid deposits, neuritic plaques, gliosis, synaptic alterations and signs of neurodegeneration as well as memory impairment. Despite these similarities, important differences in neuropathology and behavior between these tg mouse models and AD have also been observed, and to date no perfect animal model has emerged. Moreover, ascertaining which elements of the neuropathological and behavioral phenotype of these various strains of tg mice are relevant to that observed in AD continues to be a challenge. Here we provide a critical review of the AD-like neuropathology and behavioral phenotypes of several well-known and utilized tg mice that express human APP transgenes.     

Multi-phenotype behavioral characterization of inbred strains derived from wild stocks of Mus musculus

Many aspects of mouse behavior have been studied by using only a relatively small sample of available laboratory strains. These laboratory mice were derived from the so-called ``fancy mouse' and in most cases underwent extensive domestication before inbreeding. Thus, the behavioral repertoire of the laboratory mouse may be very different from that exhibited by stocks that have not been deliberately domesticated. Another inherent problem in analyzing mouse behavior is that genetic diversity is limited among currently available strains. In this respect, the use of strains that are derived from a variety of wild mice should provide a means to identifying novel behavioral phenotypes. We have investigated several behavioral phenotypes, using females of a number of mouse strains derived from wild mice of different subspecies, BFM/2, NJL, BLG2, HMI, CAST/Ei, KJR, SWN and MSM; a strain derived from fancy mice, JF1; and two laboratory strains, C57BL/6 and DBA/1. In this report, tests for locomotor activity, light-dark transitions, passive and active avoidance, and nociception were conducted. The results show great diversity of behavioral patterns between strains in contrast to less within-strain variability. We also found that two strains, KJR and SWN, both have good learning ability, whereas BLG2 mice exhibit impairment in both passive and active avoidance learning. Received: 11 January 2000 / Accepted: 27 March 2000     

Effect of Ninjin-yoei-to (Rensheng-Yangrong-Tang) on olfactory behavior after olfactory nerve transection

Ninjin-yoei-to (NYT), a Japanese traditional medicine, is used to treat athrepsia due to surgery, anorexia, cold constitution, and anemia. There are reports of the effects of NYT on the nervous system; however, there have been no behavioral studies of the effect of NYT on olfactory function. The olfactory system undergoes continuous replacement of sensory neurons. Morphologic and behavioral studies have shown that the olfactory system recovers after bilateral olfactory nerve transection (BNX). However, in the humans, olfactory function does not always recover. In this study, we examined the effect of oral NYT on behavioral recovery after BNX. Fourteen mice were subjected to BNX. The regular diet was mixed with 2% NYT (NYT diet). Mice were separated into two groups; seven mice were fed the regular diet (control group), and seven mice were fed the NYT diet (NYT group). NYT was administered beginning 7 days prior to BNX and continuing for 35 days after BNX. Mice in both groups had free access to food and water. Olfactory function was evaluated by testing each mouse's ability to avoid cotton balls treated with acetic acid. After BNX, mice lost their ability to avoid cotton balls treated with acetic acid. In the control group, the time for behavioral recovery after BNX was 28 days. In the NYT group, the time for behavioral recovery after BNX was 21 days. NYT hastened behavioral recovery after BNX. NYT may have therapeutic benefits for patients with olfactory disorders.     

Paternal experience and stress responses in California mice (Peromyscus californicus)

Paternal behavior greatly affects the survival, social development, and cognitive development of infants. Nevertheless, little research has been done to assess how paternal experience modifies the behavioral characteristics of fathers, including fear and stress responses to a novel environment. We investigated long-term behavioral and physiologic effects of parental experience in mice (Peromyscus californicus) and how this response activates the hypothalamic-pituitary-adrenal axis (as measured by corticosterone and dehydroepiandrosterone [DHEA] levels) and interacts with anxiety-related behaviors. Three groups of adult males were tested--fathers exposed to pups, virgins exposed to pups, and virgins never exposed to pups--in 2 environments designed to elicit anxiety response: an open field with a novel object placed in the center and a closed cage containing a sample of a component of fox feces. Behavioral responses were measured by using traditional methods (duration and frequency) and behavioral-chain sequences. Results indicated that paternal experience significantly modifies a male mouse's behavioral and physiologic responses to stress-provoking stimuli. Compared with inexperienced male mice, experienced male mice had a significant decrease in the occurrence of incomplete behavioral chains during the exposure to the novel object, an index of reduced stress. Further, even moderate pup exposure induced behavioral modifications in virgin male mice. These behavioral responses were correlated with changes in corticosterone and DHEA levels. Together, these data provide evidence that interactions between male mice and offspring may have mutually beneficial long-term behavioral and physiologic effects.     

Daily rhythmic behaviors and thermoregulatory patterns are disrupted in adult female MeCP2-deficient mice

Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2) have been associated with neurodevelopmental and neuropsychiatric disorders including Rett Syndrome, X-linked mental retardation syndrome, severe neonatal encephalopathy, and Angelman syndrome. Although alterations in the performance of MeCP2-deficient mice in specific behavioral tasks have been documented, it remains unclear whether or not MeCP2 dysfunction affects patterns of periodic behavioral and electroencephalographic (EEG) activity. The aim of the current study was therefore to determine whether a deficiency in MeCP2 is sufficient to alter the normal daily rhythmic patterns of core body temperature, gross motor activity and cortical delta power. To address this, we monitored individual wild-type and MeCP2-deficient mice in their home cage environment via telemetric recording over 24 hour cycles. Our results show that the normal daily rhythmic behavioral patterning of cortical delta wave activity, core body temperature and mobility are disrupted in one-year old female MeCP2-deficient mice. Moreover, female MeCP2-deficient mice display diminished overall motor activity, lower average core body temperature, and significantly greater body temperature fluctuation than wild-type mice in their home-cage environment. Finally, we show that the epileptiform discharge activity in female MeCP2-deficient mice is more predominant during times of behavioral activity compared to inactivity. Collectively, these results indicate that MeCP2 deficiency is sufficient to disrupt the normal patterning of daily biological rhythmic activities.     

Interval timing in genetically modified mice: a simple paradigm

We describe a behavioral screen for the quantitative study of interval timing and interval memory in mice. Mice learn to switch from a short-latency feeding station to a long-latency station when the short latency has passed without a feeding. The psychometric function is the cumulative distribution of switch latencies. Its median measures timing accuracy and its interquartile interval measures timing precision. Next, using this behavioral paradigm, we have examined mice with a gene knockout of the receptor for gastrin-releasing peptide that show enhanced (i.e. prolonged) freezing in fear conditioning. We have tested the hypothesis that the mutants freeze longer because they are more uncertain than wild types about when to expect the electric shock. The knockouts however show normal accuracy and precision in timing, so we have rejected this alternative hypothesis. Last, we conduct the pharmacological validation of our behavioral screen using d -amphetamine and methamphetamine. We suggest including the analysis of interval timing and temporal memory in tests of genetically modified mice for learning and memory and argue that our paradigm allows this to be done simply and efficiently.     

Transgenic mice expressing a human mutant beta1 thyroid receptor are hyperactive, impulsive, and inattentive

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed childhood psychiatric disorder. We have found that a transgenic mouse bearing a human mutant thyroid receptor (TRbeta1) expresses all of the defining symptoms of ADHD--inattention, hyperactivity, and impulsivity--as well as a 'paradoxical' response to methylphenidate (MPH). As with ADHD, the behavioral phenotypes expressed by the TRbeta transgenic mice are dynamic and sensitive to changes in environmental conditions, stress, and reinforcement. TRbeta transgenic mice are euthyroid except for a brief period during postnatal development, but the behavioral phenotypes, elevated dopamine turnover, and paradoxical response to MPH persist into adulthood. Thus, like the vast majority of children with ADHD, the TRbeta transgenic mice exhibit the symptoms of ADHD in the complete absence of thyroid abnormalities. This suggests that even transient perturbations in developmental thyroid homeostasis can have long-lasting behavioral and cognitive consequences, including producing the full spectrum of symptoms of ADHD.     

Variations in the behaviors to novel objects among five inbred strains of mice

Novelty stimuli cause various behavioral responses, such as exploration and avoidance, and contextual variables may contribute to the behavioral outputs. Here, we tried to compare the behavioral responses to novel objects of five inbred strains of mice (C57BL/6J, 129/svJae, C3H/HeJ, BALB/cJ and DBA/2J) by using a modified novel object test where a small light-weight cube wrapped with paper was presented to mice in a home cage without beddings. In response to these objects, the C57BL/6J, 129/svJae and C3H/HeJ mice showed mild exploratory behaviors, such as approaching, sniffing or brief contact. In striking contrast, the BALB/cJ and DBA/2J mice, which have been known to show high avoidance/low exploration in other behavioral paradigms, exhibited play-like secondary reactions toward the objects after initial primary exploratory behaviors. Specifically, DBA/2J mice would move the object around in the cage, holding it with their mouths, and BALB/cJ mice would gnaw the object, eventually stripping off the wrapping paper. Such behaviors decreased when similar objects were presented repeatedly. The present results suggest that active manipulations of novel objects may be a relevant parameter for measuring novelty-induced behaviors in mice and appear to be strongly influenced by genetic factors.     

Substrain specific behavioral responses in male C57BL/6N and C57BL/6J mice to a shortened 21-hour day and high-fat diet

ABSTRACT

Altered circadian rhythms have negative consequences on health and behavior. Emerging evidence suggests genetics influences the physiological and behavioral responses to circadian disruption. We investigated the effects of a 21 h day (T = 21 cycle), with high-fat diet consumption, on locomotor activity, explorative behaviors, and health in male C57BL/6J and C57BL/6N mice. Mice were exposed to either a T = 24 or T = 21 cycle and given standard rodent chow (RC) or a 60% high-fat diet (HFD) followed by behavioral assays and physiological measures. We uncovered numerous strain differences within the behavioral and physiological assays, mainly that C57BL/6J mice exhibit reduced susceptibility to the obesogenic effects of (HFD) and anxiety-like behavior as well as increased circadian and novelty-induced locomotor activity compared to C57BL/6N mice. There were also substrain-specific differences in behavioral responses to the T = 21 cycle, including exploratory behaviors and circadian locomotor activity. Under the 21-h day, mice consuming RC displayed entrainment, while mice exposed to HFD exhibited a lengthening of activity rhythms. In the open-field and light-dark box, mice exposed to the T = 21 cycle had increased novelty-induced locomotor activity with no further effects of diet, suggesting daylength may affect mood-related behaviors. These results indicate that different circadian cycles impact metabolic and behavioral responses depending on genetic background, and despite circadian entrainment.     

A parametric analysis of factors affecting acquisition and extinction of contextual fear in C57BL/6 and DBA/2 mice

Behavioral analyses of genetically modified and inbred strains of mice have revealed neural systems and molecules that are involved in memory formation. Many of these studies have examined memories that form in contextual fear conditioning, in which an organism learns that a particular context signals the occurrence of a footshock. During fear extinction, nonreinforced exposure to the context results in the loss of the conditioned fear response. The study of extinction has been instrumental for behavioral and molecular theories of memory. However, many of the transgenic, knockout, and inbred strains of mice that have been widely studied in memory have behavioral deficits in contextual fear conditioning, which makes the study of extinction in these mice particularly challenging. Here we explore several strategies for studying extinction in C57BL/6 and DBA/2 mice, two strains known to differ in contextual fear conditioning. First, we attempt to equate performance prior to extinction through several extensive conditioning protocols. Second, we examine extinction in subsets of mice matched for initial levels of context conditioning. Third, we examine within-strain effects of variables known to affect extinction. Differences between the strains persisted across extensive conditioning and extinction protocols, but both strains were sensitive to session duration and context manipulations during extinction. We describe the implications of our results for behavioral and neurobiological approaches to extinction, and we examine the general challenges in studying extinction in subjects that differ in learning or performance prior to extinction.     

Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice

Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.     

5-羟色胺转运体敲除小鼠的分子和细胞改变

5-羟色胺转运体(5-HTT)在神经精神心理正常功能的维持及疾病的发生和发展中起重要作用。5-HTT的表达能力减低或消失的小鼠(称为:5-HTT敲除小鼠)表现出许多行为的改变,例如:焦虑类似行为增多、对应激更加敏感和攻击性行为减少。这些行为的改变有的与携带5-HTTLPR短等位基因的人很相似。因此5-HTT敲除小鼠被作为研究5-HTTLPR多态性导致情感性精神障碍发病机制的动物模型。本文主要就5-HTT敲除小鼠的5-HT浓度和代谢、下丘脑-垂体-肾上腺皮质轴以及对其他神经递质转运体影响的分子和细胞改变进行综述。     

Behavioral characterization of mice lacking the neurite outgrowth inhibitor Nogo-A

The membrane protein Nogo-A inhibits neurite outgrowth and regeneration in the injured central nervous system, primarily because of its expression in oligodendrocytes. Hence, deletion of Nogo-A enhances regeneration following spinal cord injury. Yet, the effects of Nogo-A deletion on general behavior and cognition have not been explored. The possibility of potential novel functions of Nogo-A beyond growth inhibition is strongly suggested by the presence of subpopulations of neurons also expressing Nogo-A – not only during development but also in adulthood. We evaluated here Nogo-A ^−/− mice in a series of general basic behavioral assays as well as functional analyses related to brain regions with notable expression levels of Nogo-A. The SHIRPA protocol did not show any major basic behavioral changes in Nogo-A ^−/− mice. Anxiety-related behavior, pain sensitivity, startle reactivity, spatial learning, and associative learning also appeared indistinguishable between Nogo-A ^−/− and control Nogo-A^+/+ mice. However, motor co-ordination and balance were enhanced in Nogo-A ^−/− mice. Spontaneous locomotor activity was also elevated in Nogo-A ^−/− mice, but this was specifically observed in the dark (active) phase of the circadian cycle. Enhanced locomotor reaction to systemic amphetamine in Nogo-A ^−/− mice further pointed to an altered dopaminergic tone in these mice. The present study is the first behavioral characterization of mice lacking Nogo-A and provides significant insights into the potential behavioral relevance of Nogo-A in the modulation of dopaminergic and motor functions.     

Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice

We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild-type mice. Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O-phosphoserine were decreased in the midbrain of the saline-treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild-type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.     

Enriched early experiences of mice underexpressing the beta-amyloid precursor protein restore spatial learning capabilities but not normal openfield behavior of adult animals

We have previously reported severely impaired spatial learning in mutant mice underexpressing a shortened variant of the beta-amyloid precursor protein (beta-APPtheta/theta). This targeted mutation is functionally equivalent to a null mutation. It also disturbs behavioral and neurological maturation with deficits emerging mainly between postnatal day (pd) 11 and 19. Such early tested mice exhibited almost no genotype-related difference in Morris water maze learning, raising the possibility that early handling might have compensated for genetic deficits. To verify this effect, we compared watermaze learning and open field behavior of 66 adult mutant and wildtype mice having been handled during pd 3-27 with that of 70 non-handled mutant and wildtype mice. Neurological testing during pd 3-27 markedly reduced time near wall and improved spatial retention of adult mutants, restoring their learning capabilities to wildtype levels. Early handling did not cure the mutation associated activity deficit in the open field, but mainly increased center field exploration in both mutants and wildtypes. In a follow-up experiment we analyzed whether an early (pd 3-10, n = 22) or middle (pd 11-19, n = 24) period of handling in form of neurological testing had differential effects on adult behavior. Mice handled during pd 11-19 had slightly shorter escape times than mice handled during pd 3-10 but were not significantly different in other behavioral measures. There were no sex related differences. Correlational and factor analysis showed that both the mutation and early handling had pleiotropic behavioral effects, resulting in differentially impaired mutants depending on the test situation. Likewise, early handling affected not only thigmotactic tendencies but also, more subtly, other behavioral components underlying water maze learning. We conclude that early postnatal stimulation can prevent mutation induced learning deficits in adult mice, but probably through other developmental mechanisms than those affected by the mutation. This implies that some behavioral impairments related to beta-APP malfunction may be corrected through simple treatments.     

Enhanced BDNF Signaling is Associated with an Antidepressant-like Behavioral Response and Changes in Brain Monoamines

1. Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments. 2. Brain-derived neurotrophic factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor. 3. Transgenic mice overexpressing the full-length trkB receptor (TrkB.TK+) and showing increased trkB activity in brain, and their wild type (WT) littermates, were injected with the antidepressant fluoxetine or saline, and analyzed behaviorally in the forced swimming test paradigm and biochemically for the concentrations of brain monoamines and their metabolites. 4. The TrkB.TK+ mice displayed increased latency to immobility in the forced swim test, suggesting resistance to behavioral despair. 5. Fluoxetine increased the latency to immobility in wild-type mice to a similar level as seen in the trkB.TK+ mice after saline treatment, but had no further behavioral effect in the swimming behavior of the trkB.TK+ mice. 6. Only minor differences in the levels of brain monoamines and their metabolites were observed between the transgenic and wild-type mice. 7. These data, together with other recent observations, suggest that trkB activation may play a critical role in the behavioral responses to antidepressant drugs in mice.     

Light/dark transition test for mice

Although all of the mouse genome sequences have been determined, we do not yet know the functions of most of these genes. Gene-targeting techniques, however, can be used to delete or manipulate a specific gene in mice. The influence of a given gene on a specific behavior can then be determined by conducting behavioral analyses of the mutant mice. As a test for behavioral phenotyping of mutant mice, the light/dark transition test is one of the most widely used tests to measure anxiety-like behavior in mice. The test is based on the natural aversion of mice to brightly illuminated areas and on their spontaneous exploratory behavior in novel environments. The test is sensitive to anxiolytic drug treatment. The apparatus consists of a dark chamber and a brightly illuminated chamber. Mice are allowed to move freely between the two chambers. The number of entries into the bright chamber and the duration of time spent there are indices of bright-space anxiety in mice. To obtain phenotyping results of a strain of mutant mice that can be readily reproduced and compared with those of other mutants, the behavioral test methods should be as identical as possible between laboratories. The procedural differences that exist between laboratories, however, make it difficult to replicate or compare the results among laboratories. Here, we present our protocol for the light/dark transition test as a movie so that the details of the protocol can be demonstrated. In our laboratory, we have assessed more than 60 strains of mutant mice using the protocol shown in the movie. Those data will be disclosed as a part of a public database that we are now constructing. Visualization of the protocol will facilitate understanding of the details of the entire experimental procedure, allowing for standardization of the protocols used across laboratories and comparisons of the behavioral phenotypes of various strains of mutant mice assessed using this test.