It is well known that immunological functions are influenced by stressors. Psychological stressors influence also usual behaviors such as eating, sleep and exercise. In this paper, we report effects of emotional behavior, restriction, sleep deprivation or nutrition on immunological functions using animal model.
Using mature cats which were implanted electrode in hypothalamus, emotional behaviors such as attack and retreat were elicited by stimulation of the hypothalamus. T cell mitogen responses were significantly increased with attack, but decreased with retreat.
Chemotactic activity of macrophages and number of peripheral white blood cells were almost 50% decreased by 24 hr restriction. Chemotactic activity of macrophages was suppressed by injection of ACTH at dose dependent manner in mice.
Sleep deprivation for 3 days suppressed several immune functions in rats.
(NZB × NZW) Fl autoimmune-prone mice which were used for animal models of systemic lupus erythematosus were compared under the influence of different calorie intakes and different calorie sources. When the energy intake was reduced to 60 % of the intake of high calorie groups, survival was doubled in fat diet group and tripled in carbohydrate diet group compared to that of high calorie groups. Immunological functions were well maintained in low calorie groups.
These results indicate that immunological functions are influenced by various stressors. It depends on the period, degree and method of stressors.

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We investigated whether pretreatment with an interleukin-1 receptor antagonist (IL-1RA) is capable of inhibiting immobilization stress (IS) -induced elevations of hypothalamic norepinephrine (NE) and the levels of their metabolites as well as the plasma adrenocorticotropic hormone (ACTH) . IL-1 RA was administered directly into the anterior hypothalamus, and monoamines were determined using a microdialysis technique and an HPLC system. IL-1 RA (2μg) significantly inhibited IS-induced increases in hypothalamic NE level. In addition, IL-1RA (2μg) also inhibited the IS-induced elevation of plasma ACTH levels. In summary, these results suggest that hypothalamic interleukin-1 (IL-1) plays a role in the regulation of IS-induced responses including elevated monoamine release in the hypothalamus and activation of the hypothalamo-pituitary-adrenal axis.

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Recently several psychiatric disorders, such as seasonal affective disorders, sleep-wake rhythm disorders and nocturnal behavioral disorders in demented patients have been paid attention, because those disorders are considered to have some causal relation with biological rhythm. Patients with these disorders show some disorders of circadian rhythms and are well treated with bright light, which is able to shift the phase of the circadian rhythm. In an attempt to develop an animal model for such rhythm disorders, we investigated the effect of various stresses on the biological rhythm in rats.
When blinded rats were given acute or chronic stresses, such as cold-restrain stress or foot-shock stress, the period of the free-running rhythm of the animal was elongated. The repeated stress given at the same time in a day for more than one week failed to entrain the free-running rhythm in adult rats.
On the other hand, forced exercise in the running wheel resulted in shortening of the free-running period. The motor activity determined by the number of the wheel revolution was found to be negatively correlated with the period of free-running rhythm.
We determined the content of serotonin in the suprschiasmatic nucleus (SCN), the center of the biological clock, in all animals subjected to stress experiments. Both cold-restrain stress and foot-shock stress caused a marked increase in serotonin content in the SCN. Furthermore, exercise also caused an increase of serotonin content. These results suggested that serotonin content itself has no causal relation with change of free-running period caused by stresses, because change of free-running period was different in spite of the similar change of serotonin content in the SCN.
Repeated mother deprivation for more than 10 days from blinded pups only during light period under 12: 12 light dark cycle caused a reversal of the phase of the N-acetyltransferase activity (NAT) in the pineal gland. In this experiment, warming pups by a heat plate during mother deprivation prevented the NAT rhythm to reverse caused by mother deprivation. Thus, low temperature stress seemed to play an important role in reversal of the NAT rhythm caused by mother deprivation in blinded pups. Since a thermo-regulating mechanism is still immature in pups, cold stress presumably exerts a significant effect. This may explain the difference in mode of entrainement of the rhythm by repeated stress between adult and infant rats.
In the former group repeated cold-restrain stress did not cause an entrainment of the circadian rhythms.
Further study will be necessary to clarify a mechanism involved in the change of the period of free-running rhythm caused by various stresses.

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To more precisely understand the predisposition factors for depressive illness and post-traumatic stress disorder, it is necessary to make an animal model revealing the dysregulation of Hypothalamo-Pituitary-Adrenal (HPA) axis, which is frequently seen in depressive illness and stress-related disorder. In the present study, we have investigated the effects of prenatal stress on the adrenocortical response and behavioral alterations to stressful stimuli in adult offspring, since the decreased or the enhanced suppression of HPA response are frequently observed in depressive illness and post-traumatic stress disorder, respectively. Our results are summarized as follows :
1. Prenatal saline injection stress produced the disinhibition of HPA response to conditioned fear stress in adult male offspring. In addition, the prolonged immobility duration in the forced swimming stress was observed in the prenatally stressed groups compared with controls. Taken together, the prenatal saline injection stress model may have a face validity as an animal model of depression.
2. In contrast, prenatal saline injection stress produced the enhanced suppression of HPA response to conditioned fear stress in adult female offspring, suggesting that the prenatal saline injection stress model modified by some sex steroids may provide a good tool to investigate the pathophysiology of post-traumatic stress disorder.

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Stress is a daily occurrence, and the ability to adapt to or cope with stressors is a fundamental necessity of human life. Stressors activate neural and hormonal mechanisms, which interact with each other to produce the behavioral responses to stress, as well as the adaptation and sometimes the maladaption, to the stressful situation. Histological studies in the animal models have demonstrated that stressors induce multiple changes in the nervous system including alterations in the neural structure as well as neuronal loss under certain circumstances. Most of researchers have been believed that stress-induced neuronal damage is caused by neurotoxicity of cortico-sterone, released from the adrenal glands abundantly during stress, associating glucocorticoid receptors (GR) and/or glutamate input. However, our results described here required to propose another hypothesis for this phenomenon.
We have recently found that vulnerability to repeated stress of the hippocampal neurons in the CA3 and CA4 subfield is enhanced in the orchidectomized (ORX) rats. In the behavioral learning test using Morris water maze, carried out to investigate the cognition of the stressed an-imals, impairement of spatial memory resulted from repeated stress was augmented by ORX, and was not improve by adrenalectomy (ADX) against our expectation based on the traditional hypotheses. On the contrary, we obtained the result by the morphological study that ADX causes the increase in vulnerability to the stress of the hippocampal neurons. In the further experiments, we clarified that pituitary-adrenal function is accelerated, and down-regulation of GR in the hippocampus after repeated stress is enhanced in the ORX rats compared with sham-operated rats.
These results indicate the possibility that stress-induced neuronal damage in the hippocampus is caused by the decrease in response to corticosterone of neurons and/or glia mediating receptor down-regulation.

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Gene targeting technology (homologous recombination between specific chromosomal DNA sequences and exogenously introduced DNA sequences) has been improved and applied to pluripotent, mouse embryonic stem (ES) cells, providing the means to create mice of specifically altered genotype.
In this review, some of the background and recent advances of gene targeting in mouse ES cells are described.

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Part of the behavior in mammalian species is genetically programmed, and gene targeting technology using embryonic stem cells provides a powerful tool for the molecular analysis of genes involved in such behavior. Here we present how behavioral alterations were produced by disruption of an endogenous Fyn tyrosine kinase. These results may indicate that mutant mice produced by the gene targeting are useful for molecular analyses in mammalian behaviors and supply of animal models for human diseases.

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Considerable evidence supports the hypothesis that tau, one of the major neuronal microtubule-associated proteins (MAPs), is essential for neuronal cell morphogenesis and axonal maintenance. To examine this hypothesis in detail, we have produced mice lacking tau. Surprisingly, tau-deficient mice were viable and fertile. Histological and immunocytochemical examination of the nervous system in general revealed no abnormalities throughout development. Furthermore, selective axonal elongation was not affected in cultured neurons. We observed increase in another MAP which may partially compensate for the loss of tau. However, in some small caliber axons, decrease in microtubule (MT) stability was observed and MP organization was significantly changed. Our results argue against the hypothesized role of tau in neuronal cell morphogenesis but support its crucial role in the stabilization and organization of axonal MTs in a certain type of axons.

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The endothelin-1 (ET-1) gene was disrupted in mouse embryonic stem cells by homologous recombination to generate mice deficient for ET-1. ET-1-/- homozygous mice die of respiratory failure at birth and have morphological abnormality of the pharyngeal arch-derived craniofacial tissues and organs. ET-1 +/- heterozygous mice, which produce lower levels of ET-1 than wild-type mice, develop elevated blood pressure. These results suggest that ET-1 is essential for normal mouse development and may also play a physiological role in cardiovascular homeostasis.

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NF-IL6 is a basic-leucine zipper transcriptional factor and belongs to the CJEBP family. To investigate the role of NF-IL6 in vivo, we have generated NF-IL6 deficient mice by gene targeting. NF-IL6 deficient mice were highly susceptible to infection with Listeria monocytogenes, and all died within 5 days after intraperitoneal injection of only 500 cfu of Listeria monocytogenes. Intracellular listeria killing by macrophages from NF-IL6 deficient mice were severely impaired. However, nitric oxide (NO) was produced similar extent between wild-type and NF-IL6 deficient mice. These data demonstrated that NF-IL6 is essential for macrophage bactericidal activity and there exists NO-independent mechanism of that activity.

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T cells transduce antigen-recognition signals by T cell receptor (TCR) through the associated CD3 chains. The CD3 complex was composed of two signaling modules : CD3γ δ ε and ζ dimer. We have generated CD3ζ -deficient mice which showed reduced expression of the surface TCR complex and developmental block of T cells. To dissect the function of ζ chain on TCR expression and signaling, ζ -deficient mice were reconstituted by a mutant ζ lacking the cytoplasmic domain. The reconstituted mice expressing the mutant ζ revealed that signals through ζ are important for development of immature thymocytes whereas signals through other CD3 chains are enough to develop mature T cells. The ζ -knockout mice showed a new subset of T cells expressing the FcRy chain instead of ζ . We found that T cells in epithelia such as small intestine, skin, vagina and uterus utilize FcRγ in the TCR complex. To analyze the function of FcRγ, we produced FcRydeficient mice. These mice confirmed the importance of FcRγ for TCR expression and development in T cells present in epithelia. The proportion between ζ and FcRγ determined developmental block of T cells in ζ -or FcRγ -deficient mice.

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