Senescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated.

Rhinitis and rhinosinusitis are olfactory disorders caused by inflammation of the nasal passage and paranasal sinuses. Although patients with chronic rhinosinusitis have smaller olfactory bulbs (OBs), there is limited knowledge regarding the influence of chronic nasal inflammation on OB neurons.

Senescence-accelerated mouse prone 10 (SAMP10) exhibits cerebral atrophy and depression-like behavior. A line of SAMP10 with spontaneous mutation in the Slc5a2 gene encoding the sodium-glucose cotransporter (SGLT) 2 was named SAMP10/TaSlc-Slc5a2slc (SAMP10-ΔSglt2) and was identified as a renal diabetes model. In contrast, a line of SAMP10 with no mutation in SGLT2 (SAMP10/TaIdrSlc, SAMP10(+)) was recently established under a specific pathogen-free condition. Here, we examined the mutation effect in SGLT2 on brain function and longevity. No differences were found in the survival curve, depression-like behavior, and age-related brain atrophy between SAMP10-ΔSglt2 and SAMP10(+). However, memory retention was lower in SAMP10-ΔSglt2 mice than SAMP10(+). Amyloid beta (A4) precursor-like protein 1 (Aplp1) expression was significantly lower in the hippocampus of SAMP10-ΔSGLT2 than in SAMP10(+) at 2 months of age, but was similar at 12 months of age. CaM kinase-like vesicle association (Camkv) expression was remarkably lower in SAMP10(+). These genes have been reported to be involved in dendrite function. Amyloid precursor proteins have been reported to involve in maintaining homeostasis of glucose and insulin. These results suggest that mutation in SGLT2 results in down-regulation of Aplp1 in young age, which can lead to poor memory retention in old age.

Systemic inflammation affects brain functions. In our previous study in which lipopolysaccharide (LPS) was injected intraperitoneally into mice at sublethal doses, choroid plexus macrophages produced interleukin-1β and stimulated neighboring stromal cells. Activated stromal cells stimulate choroid plexus epithelial cells, and then choroid plexus epithelium-derived cytokines enter the brain parenchyma and stimulate astrocytes. Stimulated astrocytes then produce cytokines such as CCL11, CXCL10 and G-CSF and change the brain parenchymal microenvironment. However, the effects of an altered brain microenvironment on other brain cells remain to be determined. In the present study, we hypothesized that microglia are activated in response to astrocyte-induced changes in the brain microenvironment. Using the brains of mice treated with intraperitoneal LPS injection, Luminex multiplex cytokine immunoassays revealed increased hippocampal concentrations of CCL11, CXCL10 and G-CSF at 48 h after systemic LPS challenge. The concentrations of all cytokines examined returned to control levels at 72 h after LPS injection, which indicated a resolution of the neuroinflammation. Immunohistochemistry revealed that microglia were hypertrophied in mice at 48 h after systemic LPS challenge. Following isolation of microglial cells from the brain using magnetic-activated cell sorting, gene expression assays were performed with real-time reverse transcriptase-polymerase chain reaction. Isolated microglial cells exhibited much higher gene expression of the receptors for CCL11, CXCL10 and G-CSF than other brain cells. Microglial cells isolated from the brains of mice at 48 h after systemic LPS challenge exhibited the M2-like phenotype. In conclusion, microglial hypertrophy occurs following astrocytic reactions in a mouse model of sublethal endotoxemia-induced systemic inflammation, and hypertrophic microglia are polarized toward the M2-like phenotype and involved in the resolution of neuroinflammation.

Sepsis-associated encephalopathy (SAE) is characterized as diffuse brain dysfunction in patients with excessive systemic inflammatory reaction to an infection. In our previous studies using a mouse model of SAE with intraperitoneal injection of lipopolysaccharide (LPS), tissue concentrations of various cytokines were elevated in the entire brain parenchyma 4 and 24 h following LPS administration. Cytokines elevated at 4 h were produced by the choroid plexus, leptomeninges and vascular endothelium, while those at 24 h were produced by astrocytes. Interleukin (IL)-1β did not increase in the concentration in the brain parenchyma during the period from 1 to 24 h following LPS. In the present study, we hypothesized that the intracranial cells that initially respond to systemic inflammation are situated in the choroid plexus and produce IL-1β to initiate cytokine-mediated reactions. We quantified the transcript levels of related cytokines within the choroid plexus and specified the choroid plexus cells that are involved in the immediate cytokine-mediated responses. Mice received LPS or saline by intraperitoneal injection. Four hours after treatments, the choroid plexuses were isolated and subjected to cytokine gene expression analyses using real-time reverse transcription-polymerase chain reaction. Another group of mice was fixed at 1, 4 and 24 h after treatments and the expression of cytokines and receptors was studied with double immunohistofluorescence staining. The transcript levels of IL-1β, CC-motif ligand (CCL)2, CXC-motif ligand (CXCL)1, CXCL2 and IL-6 in the choroid plexus were significantly increased in mice treated with LPS compared to saline control. The IL-1β expression was remarkable in choroid plexus macrophages at 1 and 4 h but not in the brain parenchyma. Choroid plexus stromal cells expressed IL-1 receptor type 1 (IL-1R1). The IL-1R1-bearing stromal cells produced CCL2, CXCL1, CXCL2 and IL-6 at 4 h. Choroid plexus epithelial cells expressed CXCR2, a common receptor for CXCL1 and CXCL2. Choroid plexus epithelial cells also expressed CCL2, CXCL1 and CXCL2 at 4 h, and IL-1R1-bearing stromal cells expressed CXCR2. Therefore, in response to systemic LPS injection, one of the intracranial reactions was initiated within the choroid plexus using IL-1β derived from macrophages. The choroid plexus stromal cells subsequently had elevated expression of CCL2, CXCL1, CXCL2 and IL-6. The choroid plexus epithelial cells also had elevated expression of CCL2, CXCL1 and CXCL2. The presence of receptors for these cytokines on both epithelial and stromal cells raised the possibility of reciprocal interactions between these cells. The results suggested that the immediate early responses exerted by the choroid plexus are relevant to understanding how SAE is initiated in clinical settings.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction induced by the systemic response to infection in septic patients. In the present study, we modeled SAE by administering lipopolysaccharide (LPS) intraperitoneally to mice at a concentration of 3.0 mg/kg. We investigated regional preferences for cytokine-mediated brain reactions to endotoxemia and at what time point brain inflammation begins, as well as what cytokines are involved in acute brain reactions. Brains were divided into seven parts: cortex (CTX), olfactory system (Olf), hippocampus (Hip), striatum (Str), diencephalon (Die), brain stem (BS), and cerebellum (CBL). In each brain region, we determined the tissue concentrations of 11 cytokines: CCL2, CCL3, CCL11, CXCL1, CXCL2, CXCL9, CXCL10, G-CSF, IL-1β, IL-6, and TNF-α, in mice injected with LPS or saline, at 1, 4, and 24 h after injection using multiplex cytokine assays. Every brain region responded with the production of multiple cytokines to LPS-induced systemic inflammation during the acute phase (4-24 h) after LPS injection. IL-6, CCL2, CCL3, CXCL1, CXCL2, CXCL9, and TNF-α were "early cytokines" that increased only at 4 h but not at 24 h after LPS injection in most brain regions. CCL11, CXCL10, and G-CSF were "late cytokines" that were elevated up to 24 h after LPS injection in selected brain regions. The regions Olf, Hip, and Die were the most responsive to endotoxemia; these regions produced ten cytokines and continued to produce three "late cytokines" up to 24 h after LPS injection. Str was the least responsive to endotoxemia. The widespread nature of brain cytokine production explains the characteristics of SAE. Further studies on the roles of CCL11, CXCL10, and G-CSF may be especially important in terms of potential prevention of SAE between 4 and 24 h after the onset of sepsis.

Harmful environmental agents cause nasal inflammation, and chronic nasal inflammation induces a loss of olfactory sensory neurons (OSNs) and reversible atrophy of the olfactory bulb (OB). Here, we investigated the mechanisms underlying this inflammation-induced OB atrophy by histologically and biochemically comparing the OB changes in mouse models of nasal inflammation and odor deprivation. In addition, we examined whether odor stimulation is necessary for OB recovery from atrophy. One group of adult male C57BL/6 mice was administered lipopolysaccharide (LPS) unilaterally for 10 weeks to induce nasal inflammation (control animals received saline), and a second group received unilateral naris closures (NCs) for 10 weeks of odor deprivation. The OBs atrophied in both models, but odor deprivation shrank the glomerular, external plexiform, mitral, and granule cell layers (GCLs), whereas the olfactory nerve, glomerular, and external plexiform layers (EPLs) atrophied as a result of nasal inflammation. Additionally, nasal inflammation, but not odor deprivation, caused neuroinflammation in the OB, inducing glial activation and elevated expression of interleukin-1β (IL-1β) and TNFα. After 10 weeks of nasal inflammation, mice were housed for another 10 weeks with no additional treatment or with unilateral NC. Nasal inflammation and glial activation subsided in both groups, but glomerular and EPLs recovered only in those with no additional treatment. Our findings demonstrate that nasal inflammation and odor deprivation differentially induce layer-specific degeneration in the OB, that loss of OSN activity rather than neuroinflammation is a major cause of inflammation-induced OB atrophy, and that odor stimulation is required for OB recovery from atrophy.

Chronic nasal inflammation induces robust olfactory bulb (OB) atrophy in mice. Here we examined initial events that occur in the OB after bilateral intranasal administration of lipopolysaccharide, focusing on the olfactory nerve fibers and meninges. We analyzed the time course of OB and meninges inflammation using histological and biochemical approaches. Within 12 h, we observed increased chemokine expression and transient infiltration of peripheral immune cells into the OB, resulting in the development of pro-inflammatory status in the OB. Meningeal immunity was activated. Resident microglia produced anti-inflammatory cytokines within 24 h. These could be the initial events that lead to OB atrophy.

A growing body of evidence suggests a relationship between olfactory dysfunction and the pathogenesis of mental disorders. Our previous studies indicated that chronic nasal inflammation caused loss of olfactory sensory neurons and gross atrophy of the olfactory bulb, which may lead to olfactory dysfunction. Simultaneously, increasing numbers of reports have elucidated the importance of gut microbiota to maintain brain function and that dysbiosis may be associated with neuropsychiatric disorders. Here we examined whether chronic nasal inflammation perturbed gut microbiota and whether there were sex differences in this pattern. Eight-week-old C57BL/6 mice repeatedly received bilateral nasal administration of lipopolysaccharide (LPS) 3 times/week to cause chronic nasal inflammation or saline as a control. At 9 weeks, cecal feces were used for 16S metagenomic analysis and whole blood and fresh tissue of spleen were used for ELISA analyses. Microbiome analysis demonstrated a remarkable change of the gut microbiota in male mice with chronic nasal inflammation which was different from that in female mice. In both mice, systemic inflammation did not occur. This has shown for the first time that chronic nasal inflammation correlates with sex-dependent changes in the gut microbiota. The detailed mechanism and potential alteration to brain functions await further studies.

The senescence-accelerated mouse prone10 (SAMP10) strain, a model of aging, exhibits cognitive impairments and cerebral atrophy. We noticed that SAMP10/TaSlc mice, a SAMP10 substrain, have developed persistent glucosuria over the past few years. In the present study, we characterized SAMP10/TaSlc mice and further identified a spontaneous mutation in the Slc5a2 gene encoding sodium-glucose co-transporter (SGLT) 2. The mean concentration of urine glucose was high in SAMP10/TaSlc mice and increased further with advancing age, whereas other strains of senescence-accelerated mice, including SAMP1/SkuSlc, SAMP6/TaSlc and SAMP8/TaSlc or normal aging control SAMR1/TaSlc mice, exhibited no detectable glucose in urine. SAMP10/TaSlc mice consumed increasing amounts of food and water compared to SAMR1/TaSlc mice, suggesting the compensation of polyuria and the loss of glucose. Oral glucose tolerance tests showed decreased glucose reabsorption in the kidney of SAMP10/TaSlc mice. In addition, blood glucose levels decreased in an age-dependent fashion. The kidney was innately larger than that of control mice with no histological alterations. We examined the expression levels of glucose transporters in the kidney. Among SGLT1, SGLT2, glucose transporter (GLUT) 1 and GLUT2, we found a significant decrease only in the level of SGLT2. DNA sequencing of SGLT2 in SAMP10/TaSlc mice revealed a single nucleotide deletion of guanine at 1236, which resulted in a frameshift mutation that produced a truncated protein. We designate this strain as SAMP10/TaSlc-Slc5a2(slc) (SAMP10-ΔSglt2). Recently, SGLT2 inhibitors have been demonstrated to be effective for the treatment of patients with type 2 diabetes (T2D). SAMP10-ΔSglt2 mice may serve as a unique preclinical model to study the link between aging-related neurodegenerative disorders and T2D.

Systemic inflammation shifts the brain microenvironment towards a proinflammatory state. However, how peripheral inflammation mediates changes in the brain remains to be clarified. We aimed to identify hippocampal cells and cytokines that respond to endotoxemia. Mice were intraperitoneally injected with lipopolysaccharide (LPS) or saline, and examined 1, 4, and 24 h after injection. Tissue cytokine concentrations in the spleens and hippocampi were determined by multiplex assays. Another group of mice were studied immunohistologically. Fourteen cytokines showed an increased concentration in the spleen, and 10 showed an increase in the hippocampus after LPS injection. Cytokines increased at 4 h (CCL2, CXCL1, CXCL2, and interleukin-6) were expressed by leptomeningeal stromal cells, choroid plexus stromal cells, choroid plexus epithelial cells, and hippocampal vascular endothelial cells, all of which were located at the brain-immune interface. Receptors for these cytokines were expressed by astrocytic endfeet. Cytokines increased at 24 h (CCL11, CXCL10, and granulocyte-colony stimulating factor) were expressed by astrocytes. Cells of the brain-immune interface therefore respond to endotoxemia with cytokine signals earlier than hippocampal parenchymal cells. In the parenchyma, astrocytes play a key role in responding to signals by using endfeet located in close apposition to the interface cells via cytokine receptors.

Aging is a result of damage accumulation, and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) has been established as an inbred strain exhibiting accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescence-resistant control (SAMR1) strain. We hypothesized that tissue-protective responses of glial cells are impaired in SAMP10 mice. We injected kainic acid (KA) to induce hippocampal injury and studied how cytokines were upregulated on Day 3 using 3-month-old SAMP10 and SAMR1 mice. Following microarray-based screening for upregulated genes, we performed real-time RT-PCR and immunohistochemistry. Results indicated well-orchestrated cytokine-mediated glial interactions in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon (IFN)-γ stimulated astrocytes via IFN-γ receptor and thereby induced expression of CXCL10 and macrophage inflammatory protein (MIP)-1α, and activated microglia produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and osteopontin (OPN). OPN was the most strongly upregulated cytokine. CD44, an OPN receptor, was also strongly upregulated in the neuropil, especially on neurons and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice compared to SAMR1 mice. On Day 30 after KA injection, SAMP10 but not SAMR1 mice exhibited hippocampal layer atrophy. Since the OPN-CD44 system is essential for neuroprotection and remodeling, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration.

Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered to be a CD4+ Th1 cell-mediated autoimmune disease. To investigate the role of platelet-activating factor (PAF) in this disease, PAF receptor (PAFR) KO (PAFR-KO) and wild-type (WT) mice, on a C57BL/6 genetic background, were immunized with myelin oligodendrocyte glycoprotein 35-55. The levels of PAF production and PAFR mRNA expression in the spinal cord (SC) correlated with the EAE symptoms. PAFR-KO mice showed lower incidence and less severe symptoms in the chronic phase of EAE than WT mice. However, no difference was observed in T cell proliferation, Th1-cytokine production, or titer of IgG2a between both genotypes. Before onset, as revealed by microarray analysis, mRNAs of inflammatory mediators and their receptors-including IL-6 and CC chemokine receptor 2-were down-regulated in the SC of PAFR-KO mice compared with WT mice. Moreover, in the chronic phase, the severity of inflammation and demyelination in the SC was substantially reduced in PAFR-KO mice. PAFR-KO macrophages reduced phagocytic activity and subsequent production of TNF-alpha. These results suggest that PAF plays a dual role in EAE pathology in the induction and chronic phases through the T cell-independent pathways.

Glycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been reported to exert certain physiological role in vitro, whereas its impact on glucose metabolism in vivo remains unclear. Here, we report the characterization of Pgam1 knockout mice. We observed that homozygous knockout mice of Pgam1 were embryonic lethal. Although we previously reported that both PGAM-1 and -2 affect global glycolytic profile of cancers in vitro, in vivo glucose parameters were less affected both in the heterozygous knockout of Pgam1 and in Pgam2 transgenic mice. Thus, the impact of PGAM on in vivo glucose metabolism is rather complex than expected before.

Chronic stress can impair the health of human brains. An important strategy that may prevent the accumulation of stress may be the consumption of functional foods. When senescence-accelerated mice prone 10 (SAMP10), a stress-sensitive strain, were loaded with stress using imposed male mouse territoriality, brain volume decreased. However, in mice that ingested theanine (6 mg/kg), the main amino acid in tea leaves, brain atrophy was suppressed, even under stress. On the other hand, brain atrophy was not clearly observed in a mouse strain that aged normally (Slc:ddY). The expression level of the transcription factor Npas4 (neuronal PAS domain protein 4), which regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity, decreased in the hippocampus and prefrontal cortex of stressed SAMP10 mice, but increased in mice that ingested theanine. Lipocalin 2 (Lcn2), the expression of which increased in response to stress, was significantly high in the hippocampus and prefrontal cortex of stressed SAMP10 mice, but not in mice that ingested theanine. These data suggest that Npas4 and Lcn2 are involved in the brain atrophy and stress vulnerability of SAMP10 mice, which are prevented by the consumption of theanine, causing changes in the expression of these genes.

The c-RET proto-oncogene encodes a receptor-tyrosine kinase. Loss-of-function mutations of RET have been shown to be associated with Hirschsprung disease and Down's syndrome (HSCR-DS) in humans. DS is known to involve cerebellar hypoplasia, which is characterized by reduced cerebellar size. Despite the fact that c-Ret has been shown to be associated with HSCR-DS in humans and to be expressed in Purkinje cells (PCs) in experimental animals, there is limited information about the role of activity of c-Ret/c-RET kinase in cerebellar hypoplasia. We found that a loss-of-function mutation of c-Ret Y1062 in PCs causes cerebellar hypoplasia in c-Ret mutant mice. Wild-type mice had increased phosphorylation of c-Ret in PCs during postnatal development, while c-Ret mutant mice had postnatal hypoplasia of the cerebellum with immature neurite outgrowth in PCs and granule cells (GCs). c-Ret mutant mice also showed decreased numbers of glial fibers and mitogenic sonic hedgehog (Shh)-positive vesicles in the external germinal layer of PCs. c-Ret-mediated cerebellar hypoplasia was rescued by subcutaneous injection of a smoothened agonist (SAG) as well as by reduced expression of Patched1, a negative regulator for Shh. Our results suggest that the loss-of-function mutation of c-Ret Y1062 results in the development of cerebellar hypoplasia via impairment of the Shh-mediated development of GCs and glial fibers in mice with HSCR-DS.

The olfactory mucosa (OM) is exposed to environmental agents and therefore vulnerable to inflammation. To examine the effects of environmental toxin-initiated OM inflammation on the olfactory bulb (OB), we induced persistent rhinitis in mice and analyzed the spatial and temporal patterns of histopathological changes in the OM and OB. Mice received unilateral intranasal administration of lipopolysaccharide (LPS) or saline three times per week, and were immunohistologically analyzed at 1, 3, 7, 14 and 21 days after the first administration. LPS administration induced an inflammatory response in the OM, including the infiltration of Ly-6G-, CD11b-, Iba-1- and CD3-positive cells, the production of interleukin-1β by CD11b- and Iba-1-positive cells, and loss of olfactory sensory neurons (OSNs). In the OB, we observed activation of microglia and astrocytes and decreased expression of tyrosine hydroxylase in periglomerular cells, vesicular glutamate transporter 1, a presynaptic protein, in mitral and tufted projection neurons, and 5T4 in granule cells. Thus, the OM inflammation exerted a detrimental effect, not only on OSNs, but also on OB neurons, which might lead to neurodegeneration.

Hippocampal sclerosis (HS) is the most common neuropathological condition in adults with drug-resistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy (MTLE) syndrome. Although epileptogenic brain tissue is associated with glutamate excitotoxicity leading to oxidative stress, the proteins that are targets of oxidative damage remain to be determined. In the present study we designed comprehensive analyses of changes in protein expression level and protein oxidation status in the hippocampus or neocortex to highlight proteins associated with excitotoxicity by comparing MTLE patients with relatively mild excitotoxicity (MTLE patients without HS, MTLE-non-HS) and those with severe excitotoxicity (MTLE patients with HS, MTLE-HS). We performed 2-dimensional fluorescence difference gel electrophoresis, 2D-oxyblot analysis, and mass spectrometric amino acid sequencing. We identified 16 proteins at 18 spots in which the protein expression levels differed between sclerotic and non-sclerotic hippocampi. In the sclerotic hippocampus, the expression levels of several synaptic proteins were decreased, and those of some glia-associated proteins increased. We confirmed histologically that all MTLE-HS cases examined exhibited severe neuronal cell loss and remarkable astrocytic gliosis in the hippocampi. In all MTLE-non-HS cases examined, neurons were spared and gliosis was unremarkable. Therefore, we consider that decreased synaptic proteins are a manifestation of loss of neuronal cell bodies and dendrites, whereas increased glia-associated proteins are a manifestation of proliferation and hypertrophy of astrocytes. These are considered to be the result of hippocampal sclerosis. In contrast, the expression level of d-3-phosphoglycerate dehydrogenase (PHGDH), an l-serine synthetic enzyme expressed exclusively by astrocytes, was decreased, and that of stathmin 1, a neurite extension-related protein expressed by neurons, was increased in the sclerotic hippocampus. These findings cannot be explained solely as the result of hippocampal sclerosis. Rather, these changes can be involved in the continuation of seizure disorders in MTLE-HS. In addition, the protein carbonylation detection, an indicator of protein oxidation caused by excitotoxicity of multiple seizures and/or status epilepticus, revealed that the carbonyl level of collapsin response mediator protein 2 (CRMP2) increased significantly in the sclerotic hippocampus. In conclusion, protein identification following profiling of protein expression levels and detection of oxidative proteins indicated potential pathognomonic protein changes. The decreased expression of PHGDH, increased expression of stathmin 1, and carbonylation of CRMP2 differentiate between MTLE with and without HS. Therefore, further investigations of PHGDH, stathmin 1 and CRMP2 are promising to study more detailed effects of excitotoxicity on epileptogenic hippocampal tissue.

By comprehensively measuring changes in metabolites in the hippocampus of stress-loaded mice, we investigated the reasons for stress vulnerability and the effect of theanine, i.e., an abundant amino acid in tea leaves, on the metabolism. Stress sensitivity was higher in senescence-accelerated mouse prone 10 (SAMP10) mice than in normal ddY mice when these mice were loaded with stress on the basis of territorial consciousness in males. Group housing was used as the low-stress condition reference. Among the statistically altered metabolites, depression-related kynurenine and excitability-related histamine were significantly higher in SAMP10 mice than in ddY mice. In contrast, carnosine, which has antidepressant-like activity, and ornithine, which has antistress effects, were significantly lower in SAMP10 mice than in ddY mice. The ingestion of theanine, an excellent antistress amino acid, modulated the levels of kynurenine, histamine, and carnosine only in the stress-loaded SAMP10 mice and not in the group-housing mice. Depression-like behavior was suppressed in mice that had ingested theanine only under stress loading. Taken together, changes in these metabolites, such as kynurenine, histamine, carnosine, and ornithine, were suggested to be associated with the stress vulnerability and depression-like behavior of stressed SAMP10 mice. It was also shown that theanine action appears in the metabolism of mice only under stress loading.