Social isolation is a direct determinant of decreased home-cage activity in mice: A within-subjects study using a body-implantable actimeter.

NEW FINDINGS: What is the central question of this study? It is generally recognized that social isolation is associated with physical inactivity, but is social isolation a direct determinant of decreased physical activity? What is the main finding and its importance? We conducted a within-subjects experiment with the aid of a body-implantable actimeter. Our results clearly demonstrated that social isolation decreased home-cage activity in mice. This might have resulted from increased immobility and decreased vigorous activity, suggesting that avoidance of social isolation is important to prevention of physical inactivity. ABSTRACT: An inactive lifestyle can have a negative impact on physiological and mental health. Social isolation is associated with physical inactivity; however, it remains uncertain whether social isolation is a direct determinant of decreased physical activity. Hence, we assessed whether social isolation decreases home-cage activity using a within-subjects design and examined the effects of social isolation on hippocampal neurogenesis in mice. This study used a body-implantable actimeter called nanotag, which enabled us to measure home-cage activity despite housing the mice in groups. Initially, we examined the influence of the intraperitoneal implantation of nanotag on home-cage activity. Although nanotag implantation decreased home-cage activity temporarily, at 7 days postimplantation the activity recovered to the same level as that of control (non-implanted) mice, suggesting that implantation of nanotag does not have a negative influence on home-cage activity if mice undergo a 1 week recovery period after implantation. In the main experiment, after the 1 week baseline measurement performed with mice in group housing, the mice were placed in a group or in isolation. Home-cage activity was measured for an additional 4 weeks. Home-cage activity in isolated mice during the dark period decreased by 26% from pre-intervention to the last week of intervention. Furthermore, the reduction in the number of 5 min epochs during which the activity count exceeded 301 (an index of vigorous activity) was significantly larger for isolated mice. Contrary to expectations, social isolation did not impair hippocampal neurogenesis. Our results demonstrate that social isolation is a direct determinant of decreased physical activity, possibly because of reduced vigorous physical activity.

Stress drives deliberative tendencies by influencing vicarious trial and error in decision making.

Previous studies have reported the effects of stress on decision making. However, the wide range of findings make it difficult to identify the fundamental effects of stress on decision making and, therefore, how stress affects decision making remains unknown. To investigate the influence of stress on decision making, we employed "vicarious trial and error" (VTE), which refers to a rat's behavior of orienting the head toward options at a decision point. VTE is thought to reflect mental simulation for possible options preceding a decision. We examined effects of acute restraint stress on VTE in a T-maze choice task. VTE depended on learning and past reward outcomes. Acute restraint stress before rats ran the T-maze choice task induced VTE, especially in trials with low demand of VTE, and increased the number of head orientations and time spent during each VTE. On the other hand, stress did not affect task performance (probability of advantageous choice) and patterns of behavioral choice (win-stay lose-shift, exploration-exploitation). In addition, stress activated serotonergic and noradrenergic neurons in the dorsal raphe nucleus and locus coeruleus, which are modulators of impulsivity and attentional control in decision making. These results suggest that stress in decision making drives the VTE process, which may lead to deep consideration, over-thinking, and indecisiveness.

Negative rebound in hippocampal neurogenesis following exercise cessation.

Physical exercise can improve brain function, but the effects of exercise cessation are largely unknown. This study examined the time-course profile of hippocampal neurogenesis following exercise cessation. Male C57BL/6 mice were randomly assigned to either a control (Con) or an exercise cessation (ExC) group. Mice in the ExC group were reared in a cage with a running wheel for 8 wk and subsequently placed in a standard cage to cease the exercise. Exercise resulted in a significant increase in the density of doublecortin (DCX)-positive immature neurons in the dentate gyrus (at week 0). Following exercise cessation, the density of DCX-positive neurons gradually decreased and was significantly lower than that in the Con group at 5 and 8 wk after cessation, indicating that exercise cessation leads to a negative rebound in hippocampal neurogenesis. Immunohistochemistry analysis suggests that the negative rebound in neurogenesis is caused by diminished cell survival, not by suppression of cell proliferation and neural maturation. Neither elevated expression of ΔFosB, a transcription factor involved in neurogenesis regulation, nor increased plasma corticosterone, were involved in the negative neurogenesis rebound. Importantly, exercise cessation suppressed ambulatory activity, and a significant correlation between change in activity and DCX-positive neuron density suggested that the decrease in activity is involved in neurogenesis impairment. Forced treadmill running following exercise cessation failed to prevent the negative neurogenesis rebound. This study indicates that cessation of exercise or a decrease in physical activity is associated with an increased risk for impaired hippocampal function, which might increase vulnerability to stress-induced mood disorders.

[A case of recurrent sigmoid colon cancer with multiple peritoneal and liver metastases controlled effectively by resection].

A 71 year -old man underwent sigmoid colectomy for sigmoid colon cancer. A solitary liver metastasis found on examination 8 months after the initial surgery was resected. One year after the second surgery, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and computed tomography (CT) revealed multiple peritoneal and liver metastases, and laparotomy was performed. All metastatic lesions were resectable or controllable. Eight peritoneal and 3 hepatic lesions were removed surgically and 1 hepatic lesion was treated with radiofrequency ablation. Eight months after the third surgery FDGPET and CT examination again revealed recurrence of liver and peritoneal metastases. Chemotherapy was ineffective and metastases progressed and resulted in death 26 months after the third surgery (39 months after the initial recurrence). We suggest that aggressive resection for multiple peritoneal and liver metastases can be an effective therapy for selected patients with recurrent colon cancer.

Effects of substituting sedentary time with physical activity on body mass index in Japanese adults with Down syndrome: A cross-sectional study.

Objective: and Rationale: Obesity is a health challenge for adults with Down syndrome. Therefore, a physical activity promotion program is required to prevent or reduce obesity in adults with this condition. However, there is a lack of evidence of useful risk reduction initiatives. The objective of this study was to suggest a rationale for behaviors that should replace time of inactivity to reduce obesity in Japanese adults with Down syndrome. Methods: The participants were adults with Down syndrome, aged 18-48 years, living in Japan. The snowball sampling method was used. To detect an effect size of 0.20 for body mass index using an F-test, 80 participants were required, generating a statistical power of 0.8 and a risk level of 0.05. Survey items included sex, age, height, weight, body mass index, and physical activity (min/d). Physical activity was categorized by intensity and further divided into ambulatory and non-ambulatory activities. The body mass index categories were compared using analysis of covariance. An isotemporal substitution model was used to confirm the interdependence of behaviors. Results: Half of the participants were obese, with a body mass index of 25 kg/m2 or higher. The obese group had significantly fewer light physical activity, moderate-to-vigorous physical activity, and ambulatory moderate-to-vigorous physical activity times than the non-obese group. Replacing 10 min of sedentary behavior with ambulatory moderate-to-vigorous physical activity was significantly associated with a lower body mass index. Conclusions: This study suggests a rationale for behaviors that should replace time of inactivity to reduce obesity in adults with Down syndrome. Specifically, replacing 10 min of sedentary behavior with ambulatory moderate-to-vigorous physical activity time may contribute to obesity reduction.

[A case of recurrent duodenal carcinoma successfully controlled with FOLFOX treatment].

A 60-year-old woman was diagnosed as having duodenal cancer by upper gastrointestinal endoscopy and biopsy. Pylorus-preserving pancreatoduodenectomy was performed. Pathological findings suggested T4(CBD)N1M0 primary duodenal carcinoma. Adjuvant chemotherapy with S-1(80 mg/m² of S-1 administered for 2 weeks followed by a 1-week drug-free period)was administered after surgery. One year after the surgery, computed tomography(CT)scans showed swelling of the paraaortic lymph nodes. Recurrence of the duodenal carcinoma was diagnosed, and gemcitabine chemotherapy was initiated. Eight months later, CT scans revealed lung metastasis. The patient was then treated with oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin(FOLFOX regimen). After completing 6 courses of the chemotherapy regimen, CT scans showed a partial response(PR). Currently, at 1 year, PR has been maintained. Therefore, we suggest that the FOLFOX regimen can be highly effective for the treatment of patients with duodenal carcinoma.

[A case in which chemotherapy-resistant sigmoid colon cancer was controlled effectively by radiotherapy and resection].

A 53-year-old woman underwent sigmoid colectomy for sigmoid colon cancer with peritoneal metastasis. Liver and intrapelvic metastases were found upon examination 6 months after surgery during adjuvant chemotherapy with XELOX plus bevacizumab. After hepatic subsegmentectomy, the patient received S-1 treatment in combination with radiotherapy for the intrapelvic metastasis. One year after the second surgery, abdominoperineal rectal resection was performed as the intrapelvic tumor had increased in size. At 16 months after the third surgery, computed tomography( CT) revealed a small lung nodule that gradually increased in size. The patient underwent partial lung resection. The nodule was a recurrence of the sigmoid colon cancer. During this period, the patient was treated again with S-1 combined with radiotherapy because 2 intrapelvic metastases had been identified. At present, these metastases have been well controlled for 3 years after the initial recurrence. Thus, it is suggested that aggressive radiotherapy and resection are effective therapies for recurrence of chemotherapy-resistant colon cancer.

[A case of advanced gastric cancer responding to combined systemic and intraperitoneal chemotherapy with docetaxel, cisplatin, and S-1].

The patient was a 50-year-old man diagnosed as having a large type 3 advanced gastric cancer with para-aortic lymph node metastasis and with positive peritoneal cytology. We administered a combined systemic and intraperitoneal chemotherapy involving docetaxel, cisplatin, and S-1 (DCS). After 2 courses of treatment, the primary tumor and lymph nodes were significantly reduced in size, suggesting that this therapy induced a partial response (PR). No cancer cells were observed in the peritoneal cytology, and therefore, we performed curative total gastrectomy with para-aortic lymph node dissection. Histological findings revealed that there were no cancer cells in either the primary tumor or the lymph nodes, and pathological grading indicated that the resected lesions were grade 3. Adjuvant chemotherapy with S-1 was administered after surgery. At 18 months after surgery, the patient is still alive and free of disease.

Neural pathways from the central nucleus of the amygdala to the paraventricular nucleus of the hypothalamus are involved in induction of yawning behavior due to emotional stress in rats.

As yawning is often observed in stressful or emotional situations such as tension and anxiety, this suggests that yawning can be considered to be an emotional behavior. However, the neural mechanisms underlying emotion-induced yawning remain unclear. It is well known that the hypothalamic paraventricular nucleus (PVN) is the most important brain structure for induction of yawning behavior. We previously showed that induction of yawning involves the central nucleus of the amygdala (CeA), as well as the PVN. Therefore, emotion-induced yawning could potentially be induced through activation of the direct/indirect neural pathways from the CeA to the PVN. Our present study used a combination of retrograde tracing (injection of Fluoro-Gold (FG) into the PVN) and c-Fos immunohistochemistry to examine the neural pathways that evoke emotion-induced yawning. We additionally performed lesion experiments on the CeA using ibotenic acid, a neurotoxin, to determine whether the CeA is involved in the induction of emotion-induced yawning. Emotional stress by fear conditioning induced yawning behavior, and induced expression of double-labeled cells for c-Fos and FG in the bed nucleus of the stria terminalis (BNST), but not in the CeA. Furthermore, the CeA lesions caused by ibotenic acid abolished the induction of emotion-induced yawning. These results suggest that a neural pathway from the CeA to the PVN via the BNST may be primarily involved in the induction of emotion-induced yawning behavior.

Enlarged housing space and increased spatial complexity enhance hippocampal neurogenesis but do not increase physical activity in mice.

Introduction: Environmental enrichment (EE) improves various health outcomes, such as hippocampal neurogenesis, in rodents, which is thought to be caused, in part, by increased physical activity. However, the specific effect of each enrichment component, such as enlarged housing spaces and increased spatial complexity with a variety of objects, on physical activity remains unclear because of methodological limitations in measuring physical activity. We aimed to examine whether enlarged housing spaces and increased spatial complexity increase physical activity in mice using a body-implantable actimeter. Methods: Adult male C57BL/6J mice were assigned to either standard housing or EE groups. The housing environment in the EE mice was gradually enriched by enlarging the housing space and the placement of a variety of objects. Physical activity was measured using a body-implanted actimeter. Hippocampal neurogenesis was immunohistochemically examined. Results: Enlarged housing spaces and the placement of a variety of objects did not increase physical activity in mice. In contrast, hippocampal neurogenesis was enhanced in the EE mice, suggesting that environmental interventions successfully provided enriched housing conditions for these mice. Conclusions: These results indicate that enlarged housing spaces and increased spatial complexity do not increase physical activity in mice. Furthermore, we found that EE enhanced hippocampal neurogenesis without increasing activity volume. Besides the current understanding that increasing the amount of physical activity is key to improving hippocampal function, our result suggests that the environment in which physical activity takes place is also a crucial contextual factor in determining the impact of physical activity on hippocampal function.

The Amount of Light to Vigorous Physical Activity (Met's-Hours/Day) in Children with and without Down Syndrome Attending Elementary School in Japan.

Children with Down syndrome (DS) have physical characteristics such as hypotonus of the musculature. Therefore, their attainment rate of physical activity guidelines is low, and guidelines alone may not be sufficient in assessing the amount of physical activity in children with DS. Compared with normal children (NC) of the same grade, light physical activity (LPA) must be considered while assessing physical activity of children with DS, owing to muscle hypotonia. This study included 69 children with DS and 68 NC in grades 4−6 attending elementary school in Japan. The measurements for physical characteristics included age, height, weight, and body mass index. Physical activity was measured using a triaxial accelerometer, which indicated physical activity volume. Children with DS had less moderate-to-vigorous physical activity duration (DS: 53.1 min/day, NC: 65.0 min/day; p < 0.001) but significantly longer LPA duration (DS: 376.4 min/day, NC: 287.7 min/day; p < 0.001) than NC. Conversely, the amount of light to vigorous physical activity (Met's-hours/day) was greater in children with DS (DS: 16.0 Met's-hours/day, NC: 14.4 Met's-hours/day; p = 0.037). In children with DS with muscular hypotonia, vigorous physical activity is challenging, but LPA is feasible. Developing and validating educational programs that promote physical activity with intensity level depending on individual's physical characteristic are warranted.

Internalization and Decrease of Duodenal DMT1 Involved in Transient Suppression of Iron Uptake in Short-Acting Mucosal Block.

Mucosal block (MB) is induced by the oral administration of excess iron (10 mg) and suppresses intestinal iron absorption for 3-72 h. The inhibition of iron absorption is accompanied by the downregulation of molecules associated with intestinal iron absorption. Recently, we found that a smaller amount of iron (1 mg) also induced a transient suppression of iron uptake without affecting gene expression levels (short-acting mucosal block, SAMB), which is specific to iron-deficient rats. In this study, we investigated how the nonheme iron transporters divalent metal transporter 1 (DMT1) and ferroportin (FPN) are involved in the transient suppression of iron uptake in SAMB. To induce SAMB, a test solution containing 1 mg iron was infused into the duodenum loop in iron-sufficient and iron-deficient rats. Total duodenal DMT1 and DMT1-IRE expression were increased during iron deficiency. After 15 min of 1 mg iron loading, the fluorescence intensity of duodenal DMT1 in iron-deficient rats was decreased and was comparable to that in iron-sufficient rats. Internalized DMT1-IRE as puncta was observed at 15 and 60 min after 1 mg iron loading, and the number of punctas was significantly increased after 60 min compared with control. There was no effect of 1 mg iron loading on the intracellular distribution of duodenal FPN. Our results suggest that the decrease and internalization of DMT1-IRE protein may be related, at least in part, to iron uptake suppression in SAMB.

Effects of Warm-up Focused on the Mind-Body on Choral Performance.

OBJECTIVE: In choral performance, a wide variety of musical expression is required to deliver the worldview of the work to the audience. Singers need to regulate their mind-body to be in the optimal state, which includes relaxed concentration and flexible kinesthetic controllability in sensation, expression, and vocalization, for the chorus. Therefore, a choral warm-up focused on the mind-body could be crucial for various musical expressions. However, what kind of warm-up helps the singer achieve the optimal condition for the chorus remains unclear. Here, we investigated the effects of a warm-up method focusing on breathing, physical movement, imagery, and the combination of those factors on singing performance. METHOD: Twenty-five choral singers were randomly assigned to five groups, and then singers for each group online conducted one of five warm-up conditions (breathing / stretching / imagery work / all works / control) and performed singing tasks to evaluate singing performance, including sensation, expression, and vocalization, both subjectively and objectively. Changes in mood were also measured using the second edition of the Profile of Mood States. RESULTS: The results showed that the warm-up with imagery work or all works could objectively and subjectively enhance singing performance. By contrast, the warm-up with breathing or stretching did not significantly improve performance, but did enhance subjective evaluations in general. In addition, no significant correlations were found between the objective performance evaluations and changes in individual mood. CONCLUSIONS: These results suggest that a warm-up focusing on mind-body interventions, especially imagery work, may enhance choral performance, thereby providing new insight for the establishment of more effective choral warm-up methods.

Exercise type influences the effect of an acute bout of exercise on hippocampal neuronal activation in mice.

The effects of exercise on the hippocampus depend on exercise conditions. Exercise intensity is thought to be a dominant factor that influences the effects of exercise on the hippocampus; however, it is uncertain whether the type of exercise influences its effectiveness. This study investigated whether the effect of an acute bout of exercise on hippocampal neuronal activation differs between two different types of exercise: treadmill and rotarod exercise. The intensities of both exercises were matched at just below the lactate threshold (LT), based on blood lactate concentration. Immunohistochemical examination of c-Fos, a marker of neuronal activation, revealed that treadmill exercise at 15 m/min (T15) significantly increased c-Fos expression in all subfields of the hippocampus (dentate gyrus DG, CA1, CA3), but rotarod exercise at 30 rpm (R30) did not, as compared with the respective control groups. These results demonstrate that moderate treadmill exercise more efficiently evokes hippocampal neuronal activation than does intensity-matched rotarod exercise. This suggests that exercise type is another important factor affecting the effects of exercise on the hippocampus.

Interaction between intensity and duration of acute exercise on neuronal activity associated with depression-related behavior in rats.

We examined the activities of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) and corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) during acute treadmill running at different speeds (control, low, high) and durations (15, 30, 60 min) in male Wistar rats using c-Fos/5-HT or CRF immunohistochemistry. We also performed elevated plus maze test (EPM) and forced swim test (FST) after acute treadmill running in rats. Acute treadmill running at low speed, regardless of exercise duration, significantly increased c-Fos expression in 5-HT neurons in the DRN compared with controls, whereas high-speed running significantly activated 5-HT neurons only at 60-min duration. In contrast, c-Fos expression in CRF neurons in the PVN was enhanced in an intensity-dependent manner, regardless of exercise duration. c-Fos expression in 5-HT neurons in the DRN induced by the acute treadmill running for 30 or 60 min, but not 15 min, was positively correlated with the time spent on the open arms in the EPM and was negatively correlated with the immobility time in the FST. These results suggest an interaction between exercise intensity and duration on the antidepressant effects of acute physical exercise.

The association between obesity and sedentary behavior or daily physical activity among children with Down's syndrome aged 7-12 years in Japan: A cross-sectional study.

BACKGROUND: An assessment of the adverse health effects of obesity in children with Down's syndrome (DS) is required to develop programs that facilitate the acquisition of healthy behaviors. Individuals with DS are often obese. These individuals must develop health related behaviors in childhood. For this reason, it is necessary to clarify the factors associated with obesity in children with DS. AIMS: This study had two purposes. The first was to assess the obesity and to evaluate the sedentary behavior (SB) and physical activity of Japanese elementary school children with Down's syndrome. The second was to investigate the association between obesity and SB or moderate to vigorous physical activity (MVPA). METHODS AND PROCEDURES: Ninety-three children (male/female: 51/42) with DS in elementary school grades 1 to 6 (aged 7-12 years) participated in this study in Japan. Physical characteristics were obtained from the questionnaire completed by their parents. The questionnaire provided information on regular school checkups. SB and MVPA were evaluated using a triaxial accelerometer. RESULTS: Approximately 20% of the children with DS were obese. Nearly half of the children with DS achieved 60 min of MVPA. SB time was significantly longer in the upper grades (aged 11-12 years) than in the lower grades (aged 7-8 years). Comparing weekdays and weekend days, the middle (aged 9-10 years) and upper grades had significantly shorter MVPA times on weekend days. The frequency of obesity was significantly associated with shorter MVPA times in the lower grades and longer SB time in the middle grades. CONCLUSIONS AND IMPLICATIONS: Children with DS may increase their SB time as their age group (grade category) increases. Increasing opportunities for MVPA during weekends may increase physical activity. The observed relationship between obesity and SB time or MVPA time may apply only to younger and middle grade children with DS. Further investigation is necessary to confirm these relationships.

Hyperactive and impulsive behaviors of LMTK1 knockout mice.

Lemur tail kinase 1 (LMTK1), previously called Apoptosis-Associated Tyrosine Kinase (AATYK), remains an uncharacterized Ser/Thr protein kinase that is predominantly expressed in the brain. It is recently reported that LMTK1A, an isoform of LMTK1, binds to recycling endosomes through its palmitoylation and regulates endosomal trafficking by suppressing the activity of Rab11 small GTPase. In neurons, knockdown or knockout of LMTK1 results in longer axons, greater branching of dendrites and increased number of spines, suggesting that LMTK1 plays a role in neuronal circuit formation. However, its in vivo function remained to be investigated. Here, we examined the brain structures and behaviors of LMTK1 knockout (KO) mice. LMTK1 was expressed in most neurons throughout the brain. The overall brain structure appeared to be normal in LMTK1 KO mice, but the numbers of synapses were increased. LMTK1 KO mice had a slight impairment in memory formation and exhibited distinct psychiatric behaviors such as hyperactivity, impulsiveness and high motor coordination without social interaction deficits. Some of these abnormal behaviors represent core features of attention deficit hyperactive disorder (ADHD), suggesting the possible involvement of LMTK1 in the pathogenesis of ADHD.

Central nucleus of the amygdala is involved in induction of yawning response in rats.

Yawning behavior is characterized by mouth opening accompanied by deep inspiration, as well as arousal response, and is often observed not only in states of boredom or drowsiness, but also in stressful emotional situations in humans and animals. These phenomena suggest that yawning response may be an emotional behavior, possibly through activation of the central nucleus of amygdala (CeA), which is a critical region for emotional responses. However, the involvement of the CeA in triggering yawning remains unknown. Here, we investigated whether neuronal activation of the CeA by microinjection of L-glutamate into the CeA is able to induce stereotyped yawning responses in anesthetized, spontaneously breathing rats. In addition, we assessed the effects of the CeA stimulation on the activation of oxytocin (OT) and CRF (corticotropin-releasing factor) neurons in the paraventricular nucleus of the hypothalamus (PVN), which is responsible for induction of yawning, using c-Fos immunohistochemistry. Microinjection of L-glutamate into the CeA causes an initial depressor response in the blood pressure and an arousal shift on the electrocorticogram followed by a single inspiration, which is the same as the typical pattern of the stereotyped yawning response induced by the PVN stimulation. In addition, the CeA stimulation activated the neuronal activities of both OT and CRF neurons in the PVN, as well as yawning responses. These results indicate that activation of the CeA is involved in the induction of yawning response, suggesting that yawning is an emotional behavior.

Intracerebroventricular administration of corticotropin-releasing factor antagonist attenuates arousal response accompanied by yawning behavior in rats.

We have reported that an arousal response accompanied by yawning behavior can be evoked by electrical and chemical stimulation of the hypothalamic paraventricular nucleus (PVN) in rats, although the mechanism responsible for the arousal response accompanied by yawning evoked by PVN stimulation is still unknown. In the present study, we examined the involvement of corticotropin-releasing factor (CRF) in the arousal response during yawning induced by electrical stimulation of the PVN in anesthetized, spontaneous breathing rats using intracerebroventricular (icv) injection of alpha-helical CRF, a CRF antagonist (4.2 microg, lateral ventricle). The electrocorticogram (ECoG) was recorded to evaluate arousal responses during yawning. Fast Fourier transform was used to obtain the power spectrum in delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-20 Hz) bands. We also recorded the intercostal electromyogram as an index of inspiratory activity and blood pressure (BP) as an index of autonomic function to evaluate yawning response. PVN stimulation induced significant increases in relative powers of theta, alpha, and beta bands, but not delta band, concurrent with yawning events regardless of icv injection, though the relative powers after icv injection of alpha-helical CRF were significantly lower than those after saline injection. These findings suggest that CRF neurons in the PVN are primarily responsible for the arousal response accompanied by yawning behavior.

Effects of spontaneous and forced running on activation of hypothalamic corticotropin-releasing hormone neurons in rats.

Corticotropin-releasing hormone (CRH)-containing neurons in the hypothalamic paraventricular nucleus (PVN) are known to be activated during physical or psychological stress, and play an important role as one of the central activators of integrated stress response. Physical exercise has also been suggested as one of the stressors activating CRH neurons in the PVN. Spontaneous wheel running (SWR) has recently been reported to result in improved mental health or mood, unlike treadmill running that commonly forces the animal to run. Thus, forced running may strongly induce an activation of CRH neurons compared with spontaneous running, and spontaneous running may not represent a strong stressor. However, whether the effects of spontaneous running on activation of CRH neurons in the PVN differ from those of forced running is unknown. The present study examined the activity of CRH neurons in 1-h forced wheel running (FWR) and SWR using c-Fos/CRH immunohistochemistry in male Wistar rats. No significant differences in 1-h running distance were observed between FWR and SWR, indicating that amount of work was almost equal between exercises. Number of double-labeled neurons for c-Fos and CRH in the PVN was markedly higher in FWR than in SWR. In addition, no significant differences in Fos expression in the LC, which is related to various stress responses, were found between FWR and SWR. These results indicate that FWR strongly activates CRH neurons in the PVN compared with SWR, suggesting that spontaneous running is not an intense stressor even though running distance does not differ significantly from forced running.