Formosan wood mice (Apodemus semotus) exhibit more exploratory behaviors and central dopaminergic activities than C57BL/6 mice in the open field test.

Three-quarters of the lands in Taiwan are over 1000 m above sea level. Formosan wood mice (Apodemus semotus), also called Taiwanese field mice, are largely found at altitudes of 1400 ~ 3700 m and are the dominant rodents in these areas. Notably, Formosan wood mice show high levels of exploratory behaviors, not only in the wild but also in laboratory situations. Therefore, in this study, we examined the behavioral responses and central dopaminergic activities of male C57BL/6J mice and Formosan wood mice in the open field test. Dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid were used as indices of dopaminergic activities. Formosan wood mice showed higher levels of exploration and locomotor activity than C57BL/6J mice in the open field test. Higher central dopaminergic activities in the nucleus accumbens, striatum, and medial prefrontal cortex were found in Formosan wood mice than in C57BL/6J mice in the open field test. Higher levels of locomotion and central dopaminergic activities in Formosan wood mice were consistent after two exposures to the open field test; however, dramatic decreases in levels of locomotion and central dopaminergic activities in C57BL/6J mice were found after two exposures to the open field test. The present study found that Formosan wood mice exhibited higher levels of locomotor activity and exploration and central dopaminergic activities than C57BL/6J mice after one or two exposures to the open field test.

Exploratory and agile behaviors with central dopaminergic activities in open field tests in Formosan wood mice (Apodemus semotus).

Taiwan is a mountainous island, and nearly 75% of its lands are 1000 m above sea level. Formosan wood mice, Apodemus semotus, are endemic rodents and are broadly distributed at altitudes between 1400 and 3700 m in Taiwan. Interestingly, Formosan wood mice show similar locomotor activity in the laboratory as they do in the wild. Hence, we are interested in studying whether exploratory behaviors and central dopaminergic activity are changed in the open field test. We used male C57BL/6J mice as the control, comparing their behavioral responses in the open field, step-down inhibitory avoidance discrimination and novel object recognition tests with those of male Formosan wood mice. We also examined dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid in the medial prefrontal cortex, striatum and nucleus accumbens. In open field tests, Formosan wood mice revealed higher levels of locomotion and exploration than C57BL/6J mice. Learning and memory performance in the novel object recognition test was similar in both Formosan wood mice and C57BL/6J mice, but more agile responses in the inhibitory avoidance discrimination task were found in Formosan wood mice. There was no difference in behavioral responses in the open field test between new second-generation Formosan wood mice and Formosan wood mice that were inbred for more than 10 generations. After repeated exposure to the open field test, high levels of locomotion and exploration as well as central dopaminergic activities were markedly persistent in Formosan wood mice, but these activities were significantly reduced in C57BL/6J mice. Diazepam (anxiolytic) treatment reduced the higher exploratory activity and central dopaminergic activities in Formosan wood mice, but this treatment had no effect in C57BL/6J mice. This study provides comparative findings, as two phylogenetically related species showed differences in behavioral responses.

Corticosterone level and central dopaminergic activity involved in agile and exploratory behaviours in formosan wood mice (Apodemus semotus).

The native Formosan wood mouse (Apodemus semotus) is the dominant rodent in Taiwan. In their natural environment, Formosan wood mice exhibit high locomotor activity, including searching and exploratory behaviours, which is observed similarly in the laboratory environment. How the behavioural responses of Formosan wood mice exhibit in elevated plus maze and marble burying tests remains unclear. How corticosterone levels and central dopaminergic activities are related to the behaviours in these tests is also unclear. This study compared the behaviours of Formosan wood mice with that of C57BL/6J mice using the elevated plus maze and marble burying tests, and measured the corticosterone levels and central dopaminergic activities. Formosan wood mice showed greater locomotor and exploratory activity than the C57BL/6J mice. Similarly, the marble burying and rearing numbers were higher for Formosan wood mice. High locomotor and exploratory behaviours were strongly correlated with corticosterone levels after acute mild restraint stress in Formosan wood mice. The anxiolytic, diazepam, reduced the high exploratory activity, corticosterone levels and central dopaminergic activities. The high locomotor and exploratory behaviours of Formosan wood mice are related to the corticosterone levels and central dopaminergic activities. These data may explain Formosan wood mice dominance in the intermediate altitude of Taiwan.

Circadian Patterns of Rats in Their Home Cages Detected Using a Video Tracking System.

The diurnal rhythm is the common event in nature and specially shows in the behavioral patterns. Using the infrared sensor or photo beam detector to detect this 24-h rhythmicity in behaviors of mammalian, including in the rats and mice, is also the common way. The photo-sensory detecting mean is friendly and its advantage is unrestricted by light density and light-dark transition. However, this kind of equipment is cost-expensive and uneasy to fit for home cage in rodents. In this study, we tried to use the video-tracking system to detect the rhythmic activity of rats in their home cages. Adult male Sprague-Dawley rats, weighing 250-280 g, were used in this study and individual was kept in its own cage. Combined with the infrared sensitive charge-coupled device (CCD) camera and with automatically lights-off sensitive infrared illuminants as the accessory device, we found that animals exhibited the circadian locomotor activity in either light-dark cycles or constant darkness conditions. Moreover, the rhythmic patterns of locomotion in animals were affected by the one-hour exposure of white light under the constant darkness condition. The phase-advanced effects were found by the video tracking system. In summary, the video tracking system is the useful way to detect the rhythmic activity, especially in long-term circadian rhythmicity, in rats.

Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception.

BACKGROUND: Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. RESULTS: In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. CONCLUSION: Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain.

Higher exploratory and vigilant behaviors related to higher central dopaminergic activities of Formosan wood mice (Apodemus semotus) in light-dark exploration tests.

Formosan wood mice (Apodemus semotus) are endemic rodents in Taiwan. Recently Formosan wood mice exhibit similar locomotor behaviors in the laboratory environment as in the field environment has shown. Contemporaneously, Formosan wood mice have higher moving distances of and central dopaminergic (DAergic) activities than C57BL/6 mice in behavioral test. This study tried to compare the behavioral responses between male Formosan wood mice and male C57BL/6 mice in the light-dark exploration tests. We also measured the levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC), the primary metabolite of DA, to assess the dopaminergic activity of the medial prefrontal cortex, striatum, and nucleus accumbens. Our data show that Formosan wood mice revealed higher exploration and central DAergic activities than did C57BL/6 mice in the light-dark exploration tests, and diazepam (an anxiolytics) treatment reduced the exploratory activity and central dopaminergic activities in Formosan wood mice, but not in C57BL/6 mice. After repeated exposure to light-dark exploration tests, the latency to dark zone was increased, and the duration in light zone as well as the central DAergic activity were decreased in C57BL/6 mice. This study provides comparative findings; Formosan wood mice showed the higher exploratory activities than C57BL/6 mice did, and their central DAergic activities were related to the behavioral responses in these two mice. This could potentially shed light on the reasons behind the prevalence of higher exploration and central dopaminergic activities. Using Formosan wood mice as a model to study human diseases related to hyperactivity adds significant value to the potential research.

Transcranial magnetic stimulation for auditory hallucination in severe schizophrenia: partial efficacy and acute elevation of sympathetic modulation.

Repetitive transcranial magnetic stimulation (rTMS) has been reported to be an effective treatment for auditory hallucination (AH) in schizophrenia patients. The efficacy of rTMS and immediate changes in cardiac autonomic function (CAF) after rTMS in severe schizophrenia patients with AH (n = 8) were investigated. Three patients reported a >or=50% reduction of AH after rTMS. The ratio of low-frequency power to high-frequency power, an index of sympathetic modulation, increased significantly after rTMS. Further replication studies with larger sample sizes are indicated.

Heart rate variability in patients with frontal lobe epilepsy.

OBJECTIVE: To identify autonomic dysregulation in frontal lobe epilepsy (FLE). METHODS: We studied 14 male and 11 female subjects with FLE and an equal number of matched healthy control subjects. Lead I electrocardiograms were obtained for 5 min in the interictal state during daytime. Frequency-domain analysis of heart rate variability was performed and the data subsequently converted to heart rate interval and high frequency (HF; 0.15-0.45 Hz) power which representing vagal or parasympathetic regulation, as well as low frequency (LF; 0.04-0.15 Hz) power and LF/(HF+LF) expressed in normalized units (LF%) (considered to mirror sympathetic regulation). Differences in data between groups were compared using t-test. RESULTS: The epilepsy group had a lower mean heart rate interval and a lower high frequency power. CONCLUSIONS: Patients with FLE have interictally faster heart rates, attributed to lower parasympathetic drive, which may contribute to the higher incidence of sudden death that is seen in this group of patients. This suggests that the mechanism of decreased HRV in patients with FLE is probably different from that in patients with temporal lobe epilepsy.

Intermittent Hypoxia Induces Autophagy to Protect Cardiomyocytes From Endoplasmic Reticulum Stress and Apoptosis.

Intermittent hypoxia (IH), characterized as cyclic episodes of short-period hypoxia followed by normoxia, occurs in many physiological and pathophysiological conditions such as pregnancy, athlete, obstructive sleep apnea, and asthma. Hypoxia can induce autophagy, which is activated in response to protein aggregates, in the proteotoxic forms of cardiac diseases. Previous studies suggested that autophagy can protect cells by avoiding accumulation of misfolded proteins, which can be generated in response to ischemia/reperfusion (I/R) injury. The objective of the present study was to determine whether IH-induced autophagy can attenuate endoplasmic reticulum (ER) stress and cell death. In this study, H9c2 cell line, rat primary cultured cardiomyocytes, and C57BL/6 male mice underwent IH with an oscillating O2 concentration between 4 and 20% every 30 min for 1-4 days in an incubator. The levels of LC3, an autophagy indicator protein and CHOP and GRP78 (ER stress-related proteins) were measured by Western blotting analyses. Our data demonstrated that the autophagy-related proteins were upregulated in days 1-3, while the ER stress-related proteins were downregulated on the second day after IH. Treatment with H2O2 (100 µM) for 24 h caused ER stress and increased the level of ER stress-related proteins, and these effects were abolished by pre-treatment with IH condition. In response to the autophagy inhibitor, the level of ER stress-related proteins was upregulated again. Taken together, our data suggested that IH could increase myocardial autophagy as an adaptive response to prevent the ER stress and apoptosis.

Heart rate variability in children with refractory generalized epilepsy.

OBJECTIVE: Repetitive seizures can alter the regulation of cardiac activity by the autonomic nervous system (ANS), and ANS dysregulation is thought to be associated with higher morbidity and mortality in epileptic patients, especially from sudden unexpected death. Few studies of interictal dysregulation of cardiac activity in children with epilepsy have been performed. In this study we characterize heart rate variability (HRV) in children with refractory generalized epilepsy. METHODS: Fifteen male and 15 female children, average age = 10.9+/-0.6 years, all with refractory generalized epilepsy were enrolled into the study group. A control group consisted of 15 males and 15 females with average age = 10.6+/-0.6 years. A lead I ECG was recorded for 5 min in the interictal period during daylight hours from each subject while awake. Frequency-domain analysis of HRV was performed using a non-parametric method of fast Fourier transformation. Changes of HRV were categorized into high frequency power (HF; 0.15-0.45 Hz), which represented vagal regulation, and low frequency power (LF; 0.04-0.15 Hz). LF/(HF+LF) expressed in normalized units (LF%) was considered to mirror sympathetic regulation. RESULTS: There were significant reductions in RR, LF, and HF in the study group when compared to controls. There was no significant difference in LF% between the two groups. CONCLUSIONS: We postulate that the lower HRV in our patients results from parasympathetic or vagal reduction. This suggests that decreased HRV in epileptic children occurs by a different mechanism than in adults with epilepsy.

Different patterns of food consumption and locomotor activity among Taiwanese native rodents, Formosan wood mice (Apodemus semotus), and common laboratory mice, C57BL/6 (Mus musculus).

The comparisons of food consumption and locomotor activity among Taiwan native rodents, Formosan wood mice (Apodemus semotus), and laboratory mice, C57BL/6, were examined in this study. The food consumption exhibited the circadian rhythmicity, e.g. higher in the lights-off period and lower in the lights-on period, in either Formosan wood mice (WM) or C57BL/6 mice. We also found that Formosan WM ate more food than C57BL/6 mice in the lights-off period and the whole day in males, but not in females. Similarly, the male Formosan WMs had more locomotor activities than the male C57BL/6 mice in the lights-off period, but this phenomenon did not appear in female mice. These results indicated that even though the Formosan WMs have been successfully inbred in the laboratory, they still keep more native paradigm than the laboratory C57BL/6 mice do. This study is the first report to provide basic physiological comparisons on native and common laboratory mice.

Gonadal hormones-mediated effects on the stimulation of dopamine turnover in mesolimbic and nigrostriatal systems by cocaine- and amphetamine-regulated transcript (CART) peptide in male rats.

Estradiol and testosterone modulated behavioral and neurochemical activities in the mesolimbic and nigrostriatal dopaminergic systems have been reported. We examined whether estradiol and testosterone affect stimulation of cocaine- and amphetamine-regulated transcript (CART) peptide in the mesolimbic and nigrostriatal dopaminergic systems in this study. Intracerebroventricular administration of CART peptide increased dopamine turnover in the nucleus accumbens and striatum in male rats. Stimulation of dopamine turnover in nucleus accumbens and striatum by CART peptide were found in intact male rats, but not in castrated male rats. This stimulation was restored in castrated male rats by testosterone or estradiol priming, or by treatment with the water-soluble form of estradiol, but not by treatment with the membrane-impermeable form of estradiol. Estradiol and testosterone antagonists blocked testosterone's effects, but only estradiol antagonist blocked estradiol's effects. Moreover, treatment of dihydrotestosterone also restored the stimulation in castrated male rats. This dihydrotestosterone's effect was blocked by a testosterone antagonist, but not by an estradiol antagonist. All of these findings indicate that gonadal hormones play a regulatory role in stimulation of CART peptide in mesolimbic and nigrostriatal dopaminergic systems, and suggest that acts through intracellular rather than extracellular mechanisms.

Changes in Gene Expression Patterns of Circadian-Clock, Transient Receptor Potential Vanilloid-1 and Nerve Growth Factor in Inflamed Human Esophagus.

Circadian rhythm is driven by the molecular circadian-clock system and regulates many physiological functions. Diurnal rhythms in the gastrointestinal tract are known to be related to feeding pattern, but whether these rhythms are also related to the gastrointestinal damage or injuries; for example, gastroesophageal reflux disease (GERD), is unclear. This study was conducted to determine whether expression of circadian-clock genes or factors involved in vagal stimulation or sensitization were altered in the esophagus of GERD patients. Diurnal patterns of PER1, PER2, BMAL1, CRY2, TRPV1, and NGF mRNA expression were found in patient controls, and these patterns were altered and significantly correlated to the GERD severity in GERD patients. Although levels of CRY1, TIM, CB1, NHE3, GDNF, and TAC1 mRNA expression did not show diurnal patterns, they were elevated and also correlated with GERD severity in GERD patients. Finally, strong correlations among PER1, TRPV1, NGF and CRY2 mRNA expression, and among PER2, TRPV1 and CRY2 expression were found. Expression levels of CRY1 mRNA highly correlated with levels of TIM, CB1, NHE3, GDNF and TAC1. This study suggests that the circadian rhythm in the esophagus may be important for the mediation of and/or the response to erosive damage in GERD patients.

Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.

Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways.

Short-Term Sleep Disturbance-Induced Stress Does not Affect Basal Pain Perception, but Does Delay Postsurgical Pain Recovery.

UNLABELLED: Chronic sleep disturbance-induced stress is known to increase basal pain sensitivity. However, most surgical patients frequently report short-term sleep disturbance/deprivation during the pre- and postoperation periods and have normal pain perception presurgery. Whether this short-term sleep disturbance affects postsurgical pain is elusive. Here, we report that pre- or postexposure to rapid eye movement sleep disturbance (REMSD) for 6 hours daily for 3 consecutive days did not alter basal responses to mechanical, heat, and cold stimuli, but did delay recovery in incision-induced reductions in paw withdrawal threshold to mechanical stimulation and paw withdrawal latencies to heat and cold stimuli on the ipsilateral side of male or female rats. This short-term REMSD led to stress shown by an increase in swim immobility time, a decrease in sucrose consumption, and an increase in the level of corticosterone in serum. Blocking this stress via intrathecal RU38486 or bilateral adrenalectomy abolished REMSD-caused delay in recovery of incision-induced reductions in behavioral responses to mechanical, heat, and cold stimuli. Moreover, this short-term REMSD produced significant reductions in the levels of mu opioid receptor and kappa opioid receptor, but not Kv1.2, in the ipsilateral L4/5 spinal cord and dorsal root ganglia on day 9 after incision (but not after sham surgery). PERSPECTIVE: Our findings show that short-term sleep disturbance either pre- or postsurgery does not alter basal pain perception, but does exacerbate postsurgical pain hypersensitivity. The latter may be related to the reductions of mu and kappa opioid receptors in the spinal cord and dorsal root ganglia caused by REMSD plus incision. Prevention of short-term sleep disturbance may help recovery from postsurgical pain in patients.

Diurnal rhythm of agouti-related protein and its relation to corticosterone and food intake.

In the present study we examined the diurnal patterns of agouti-related protein (AGRP) and proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus and their relation to circulating glucocorticoids and food intake. Animals were killed at 4-h intervals throughout the 24-h diurnal cycle, and the expression of AGRP and POMC mRNA was evaluated by semiquantitative in situ hybridization analysis. We observed a significant diurnal rhythm in AGRP mRNA expression, with a marked peak at 2200 h (4 h after lights off) and a trough at 1000 h (4 h after lights on), consistent with the overall day-night rhythm of food intake. In contrast, POMC mRNA levels did not show a significant fluctuation across the diurnal cycle, although there was a tendency for levels to decrease after the onset of the dark cycle. Corticosterone secretion temporally coincided with the rising phase of AGRP mRNA expression. Depletion of corticosterone by adrenalectomy abolished the AGRP diurnal rhythm by suppressing the nighttime expression, but did not alter the feeding rhythm. Exposure of adrenalectomized rats to constant corticosterone replacement (10 or 50 mg continuous release corticosterone pellet) resulted in fixed AGRP mRNA expression throughout the 12-h light, 12-h dark cycle. A relatively high level of corticosterone (50 mg) significantly increased AGRP mRNA expression, with a positive correlation between these two measures. These results indicate that 1) the diurnal expression of AGRP mRNA is regulated by corticosterone independently of the light/dark cue; and 2) a normal endogenous corticosterone rhythm is required for generating the diurnal AGRP rhythm.

Effects of the cocaine- and amphetamine-regulated transcript peptide on the turnover of dopamine in tuberoinfundibular neurons and serum prolactin levels: studies using estrogen, melanin concentrating hormone, and melanocortin.

Effects of the cocaine- and amphetamine-regulated transcript (CART) peptide on tuberoinfundibular dopaminergic (TIDA) neurons were examined in female and male Sprague-Dawley rats in the morning and afternoon. We also examined the blocking effects of melanin concentrating hormone (MCH) and the antagonists of alpha-melanocyte stimulating hormone (alpha-MSH), SHU9119 and HS014, on stimulation induced by the CART peptide in TIDA systems. Intracerebroventricular administration of 1 mug CART peptide (55-102) at 45 min, either in the morning or afternoon, produced an increase in the median eminence (ME) DOPAC (3,4-dihydroxyphenylacetic acid) level and a corresponding decrease in serum prolactin (PRL) levels. This resulted from stimulation of TIDA neurons regardless of castration, and whether or not male and female rats were estrogen-primed. The stimulatory effects of the CART peptide on ME DOPAC levels were similar in the morning and afternoon in both male and female rats. Central treatment with 1 microg SHU9119, HS014, or MCH significantly decreased the ME DOPAC levels and elevated serum PRL levels in female rats. However, only MCH prevented the stimulatory effect of the CART peptide on TIDA neurons. These results indicate that stimulation by the CART peptide on TIDA neurons is gender-independent; and this stimulatory effect can be blocked by MCH, but not the antagonists of alpha-MSH.

Colocalization of estrogen beta-receptor messenger RNA with orphanin FQ, vasopressin and oxytocin in the rat hypothalamic paraventricular and supraoptic nuclei.

The functional significance of the novel estrogen receptor beta in brain areas that exclusively contain the ERbeta receptor subtype such as the paraventricular (PVN) and the supraoptic (SON) nuclei of the hypothalamus is not yet fully understood. The present study attempts to characterize the peptidergic nature of the ERbeta-containing neuronal population in the PVN and the SON using the double in situ histochemistry method in the female rat. Using this method, the ERbeta mRNA coexpressions with the novel opioid neuropeptide (orphanin FQ and its receptor ORL1) mRNA in addition to the previously reported neuropeptide (arginine vasopressin-AVP, oxytocin-OXY, corticotropin releasing hormone-CRH, enkephalin-ENK) mRNAs were assessed. In the PVN, roughly half of the ERbeta expression was colocalized with the prepro-orphanin FQ mRNA, which was comparable to the colocalization observed between the ERbeta and AVP mRNAs in the same region. In addition, there was 20% overlap between the ERbeta and ORL1 receptor mRNAs, and 10% overlap between the ERbeta and OXY mRNAs in the PVN. By contrast, the coexpression between the prepro-orphanin FQ and ERbeta mRNAs was less striking in the SON. Potential interactions between the ERbeta and the well-characterized AVP-OXY neurosecretory system as well as the novel OFQ-ORL1 opioid neuropeptide system may provide new leads for the functional significance of ERbeta, specifically in stress/autonomic responses.

Circadian-clock system in mouse liver affected by insulin resistance.

Circadian rhythms are exhibited in the physiological and behavioral processes of all mammals; they are generated by intracellular levels of circadian oscillators, which are named as a set of circadian-clock genes. These genes compose the transcriptional/translational feedback loops to regulate not only circadian rhythmicity, but also energy metabolism. Previous studies have shown that obesity and diabetes cause the dysregulation of the circadian-clock system, and vice versa. However, some diabetes subjects are lean with insulin resistance and the mechanisms of insulin resistance without obesity are much less well known. Therefore, whether insulin resistance alone is enough to influence the expression of circadian-clock genes is uncertain. This study employs a neonatal streptozotocin (STZ)-treated paradigm in mice to model the molecular and physiological progress of nonobese insulin resistance. A single injection of STZ into 2-d-old male C57BL/6 mice induces nonobese, hyperglycemic and hyperinsulinemic conditions, and the levels of gene expression in the liver by a real-time quantitative polymerase chain reaction are then measured. Although the levels of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2), and Cry1 (cryptochrome 1) mRNA expression in the liver change during the progress of insulin resistance conditions, the gene expression patterns still show circadian rhythmicity. This study suggests that changes in the hepatic circadian-clock gene expression mark an early event in the metabolic disruption associated with insulin resistance. Furthermore, 2 wks of treatment with the thiazolidinedione, pioglitazone, fully resolve the dysfunction in metabolic parameters and the changes in circadian-clock gene expression from early insulin resistance conditions. These results indicate that the circadian-clock system is sensitive to insulin resistance, and that treatment with thiazolidinediones can resolve changes in the circadian-clock system in a timely manner. Thus, strengthening the peripheral circadian-clock system may counteract the adverse physiological consequences in the metabolic syndrome.