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Article: Conditional Regulation of Blood Pressure in Response to Emotional Stimuli by the Central Nucleus of the Amygdala in Rats.

Yamanaka, Ko / Waki, Hidefumi

2022 Volume 13, Page(s) 820112

Abstract: Humans and animals can determine whether a situation is favorable to them and act accordingly. For this, the autonomic tuning of the cardiovascular system to supply energy to active skeletal muscles through the circulatory system is as important as motor ...

Abstract	Humans and animals can determine whether a situation is favorable to them and act accordingly. For this, the autonomic tuning of the cardiovascular system to supply energy to active skeletal muscles through the circulatory system is as important as motor control. However, how the autonomic cardiovascular responses are regulated in dynamically changing environments and the neuronal mechanisms underlying these responses remain unclear. To resolve these issues, we recorded the blood pressure and heart rate of head-restrained rats during dynamically changing appetitive and aversive classical conditioning tasks. The rats displayed various associations between conditioned stimuli and unconditioned stimuli in appetitive (sucrose water), neutral (no outcome), and aversive (air puff) blocks. The blood pressure and heart rate in the appetitive block gradually increased in response to the reward-predicting cue and the response to the actual reward vigorously increased. The reward-predictive response was significantly higher than the responses obtained in the neutral and aversive condition blocks. To investigate whether the reward-predictive pressor response was caused by orofacial movements such as anticipatory licking behavior, we separately analyzed high- and low-licking trials. The conditioned pressor response was observed even in trials with low-licking behaviors. Blood pressure and heart rate responses to the air puff-predicting cue in the aversive block were not significantly different from the responses in the neutral block. The conditioned blood pressure response rapidly changed with condition block switching. Furthermore, to examine the contribution of the amygdala as an emotion center to these conditioned responses, we bilaterally microinjected a GABA
Language	English
Publishing date	2022-06-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.820112
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Article ; Online: Functional connectivity in central nucleus of amygdala, paraventricular hypothalamus, and nucleus tractus solitarii circuits during high-intensity endurance treadmill exercise in rats

Shinichiro Ezure / Hiroyasu Ichihara / Ko Yamanaka / Hidefumi Waki

Journal of Physical Fitness and Sports Medicine, Vol 12, Iss 3, Pp 69-

2023 Volume 75

Abstract: High-intensity endurance exercise (HIE) induces negative emotions alongside fatigue, suffering, and changes in cardiovascular responses, and these regulations could be important for athletic performance. Previous studies have reported that limbic and ... ...

Abstract	High-intensity endurance exercise (HIE) induces negative emotions alongside fatigue, suffering, and changes in cardiovascular responses, and these regulations could be important for athletic performance. Previous studies have reported that limbic and brain stem regions, including the central nucleus of the amygdala (CeA), the paraventricular nucleus of the hypothalamus (PVH), and the nucleus tractus solitarii (NTS), play important roles in emotional response and autonomic cardiovascular regulation. However, how these brain regions interact during HIE remains unclear. In this study, Wistar rats were subjected to 90-min treadmill running sessions at different endurance exercise intensities (sedentary, low-intensity, and high-intensity: 0, 20, and 34 m/min, respectively; n = 9 per group). After exercise, brain tissues were extracted and examined for c-Fos immediate early gene expression in brain regions such as the CeA, PVH, and NTS at each exercise intensity. The c-Fos-positive cells were counted, and then a partial correlation analysis was performed to examine the functional connectivity during exercise. As a result, the numbers of c-Fos-positive cells in the CeA, PVH, and NTS increased in an exercise intensity-dependent manner. Furthermore, partial correlation analyses of c-Fos-positive cells between CeA and NTS (CeA-NTS), PVH and NTS (PVH-NTS), and CeA and PVH (CeA-PVH) exhibited significant correlation coefficients during HIE but not during sedentary and low-intensity endurance exercises. Thus, these results suggest that functional connectivity between CeA-PVH, PVH-NTS, and CeA-NTS may be enhanced during HIE. This enhanced functional connectivity may also be involved in emotional and cardiovascular regulation during exercise.
Keywords	high-intensity endurance exercise ; functional connectivity ; central nucleus of the amygdala ; paraventricular nucleus of the hypothalamus ; nucleus tractus solitarii ; rat ; Sports medicine ; RC1200-1245 ; Physiology ; QP1-981
Subject code	796
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Japanese Society of Physical Fitness and Sports Medicine
Document type	Article ; Online
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Article ; Online: Implication of the Central Nucleus of the Amygdala in Cardiovascular Regulation and Limiting Maximum Exercise Performance During High-intensity Exercise in Rats.

Tsukioka, Kei / Yamanaka, Ko / Waki, Hidefumi

Neuroscience

2022 Volume 496, Page(s) 52–63

Abstract: To date, the mechanism of central fatigue during high-intensity exercise has remained unclear. Here we elucidate the central mechanisms of cardiovascular regulation during high-intensity exercise with a focus on the hypothesis that amygdala activation ... ...

Abstract	To date, the mechanism of central fatigue during high-intensity exercise has remained unclear. Here we elucidate the central mechanisms of cardiovascular regulation during high-intensity exercise with a focus on the hypothesis that amygdala activation acts to limit maximum exercise performance. In the first of three experiments, we probed the involvement of the central nucleus of the amygdala (CeA) in such regulation. Wistar rats were subjected to a maximum exercise test and their total running time and cardiovascular responses were compared before and after bilateral CeA lesions. Next, probing the role of central pathways, we tested whether high-intensity exercise activated neurons in CeA and/or the hypothalamic paraventricular nucleus (PVN) that project to the nucleus tractus solitarius (NTS). Finally, to understand the potential autonomic mechanisms affecting maximum exercise performance, we measured the cardiovascular responses in anesthetized rats to electrical microstimulation of the CeA, PVN, or both. We have found that (1) CeA lesions resulted in an increase in the total exercise time and the time at which an abrupt increase in arterial pressure appeared, indicating an apparent suppression of fatigue. (2) We confirmed that high-intensity exercise activated both the PVN-NTS and CeA-NTS pathways. Moreover, we discovered that (3) while stimulation of the CeA or PVN alone both induced pressor responses, their simultaneous stimulation also increased muscle vascular resistance. These results are evidence that cardiovascular responses during high-intensity exercise are affected by CeA activation, which acts to limit maximum exercise performance, and may implicate autonomic control modulating the PVN-NTS pathway via the CeA.
MeSH term(s)	Animals ; Central Amygdaloid Nucleus ; Fatigue ; Paraventricular Hypothalamic Nucleus ; Rats ; Rats, Wistar ; Solitary Nucleus/physiology
Language	English
Publishing date	2022-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2022.06.005
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Article ; Online: Impact of exercise on brain-bone marrow interactions in chronic stress: potential mechanisms preventing stress-induced hypertension.

Nguyen, Thu Van / Yamanaka, Ko / Tomita, Keisuke / Zubcevic, Jasenka / Gouraud, Sabine S S / Waki, Hidefumi

Physiological genomics

2023 Volume 55, Issue 5, Page(s) 222–234

Abstract: We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male ... ...

Abstract	We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression.
MeSH term(s)	Rats ; Male ; Animals ; Matrix Metalloproteinase 3 ; Rats, Wistar ; Bone Marrow ; Hypertension ; Brain
Chemical Substances	Matrix Metalloproteinase 3 (EC 3.4.24.17)
Language	English
Publishing date	2023-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2038823-8
ISSN	1531-2267 ; 1094-8341
ISSN (online)	1531-2267
ISSN	1094-8341
DOI	10.1152/physiolgenomics.00168.2022
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Article ; Online: Potential Role of the Amygdala and Posterior Claustrum in Exercise Intensity-dependent Cardiovascular Regulation in Rats.

Kim, Jimmy / Yamanaka, Ko / Tsukioka, Kei / Waki, Hidefumi

Neuroscience

2020 Volume 432, Page(s) 150–159

Abstract: Tuning of the cardiovascular response is crucial to maintain performance during high-intensity exercise. It is well known that the nucleus of the solitary tract (NTS) in the brainstem medulla plays a central role in cardiovascular regulation; however, ... ...

Abstract	Tuning of the cardiovascular response is crucial to maintain performance during high-intensity exercise. It is well known that the nucleus of the solitary tract (NTS) in the brainstem medulla plays a central role in cardiovascular regulation; however, where and how upper brain regions form circuits with NTS and coordinately control cardiovascular responses during high-intensity exercise remain unclear. Here focusing on the amygdala and claustrum, we investigated part of the mechanism for regulation of the cardiovascular system during exercise. In rats, c-Fos immunostaining was used to examine whether the amygdala and claustrum were activated during treadmill exercise. Further, we examined arterial pressure responses to electrical and chemical stimulation of the claustrum region. We also confirmed the anatomical connections between the amygdala, claustrum, and NTS by retrograde tracer injections. Finally, we performed simultaneous electrical stimulation of the claustrum and amygdala to examine their functional connectivity. c-Fos expression was observed in the amygdala and the posterior part of the claustrum (pCL), but not in the anterior part, in an exercise intensity-dependent manner. pCL stimulation induced a depressor response. Using a retrograde tracer, we confirmed direct projections from the amygdala to the pCL and NTS. Simultaneous stimulation of the central nucleus of the amygdala and pCL showed a greater pressor response compared with the stimulation of the amygdala alone. These results suggest the amygdala and pCL are involved in different phases of exercise. More speculatively, these areas might coordinately tune cardiovascular responses that help maintain performance during high-intensity exercise.
MeSH term(s)	Amygdala/metabolism ; Animals ; Cardiovascular System ; Claustrum ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Solitary Nucleus/metabolism
Chemical Substances	Proto-Oncogene Proteins c-fos
Language	English
Publishing date	2020-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2020.02.024
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Article ; Online: Estradiol-dependent gene expression profile in the amygdala of young ovariectomized spontaneously hypertensive rats.

Pham, Linh T / Yamanaka, Ko / Miyamoto, Yasunori / Waki, Hidefumi / Gouraud, Sabine S S

Physiological genomics

2022 Volume 54, Issue 3, Page(s) 99–114

Abstract: Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain ... ...

Abstract	Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nuclear complex known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1 mo of estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.
MeSH term(s)	Amygdala/metabolism ; Animals ; Body Weight ; Estradiol/pharmacology ; Estrogens/metabolism ; Female ; Humans ; Ovariectomy ; Rats ; Rats, Inbred SHR ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism ; Transcriptome/genetics
Chemical Substances	Estrogens ; Receptors, Estrogen ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2022-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2038823-8
ISSN	1531-2267 ; 1094-8341
ISSN (online)	1531-2267
ISSN	1094-8341
DOI	10.1152/physiolgenomics.00082.2021
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Article ; Online: Association between flexibility activity and blood-pressure change among older adults in Japan: A 5-year longitudinal study.

Abe, Takafumi / Okuyama, Kenta / Kamada, Masamitsu / Kitayuguchi, Jun / Hamano, Tsuyoshi / Waki, Hidefumi / Nabika, Toru / Isomura, Minoru / Sundquist, Kristina

Scandinavian journal of medicine & science in sports

2023 Volume 33, Issue 8, Page(s) 1552–1559

Abstract: This longitudinal study examined the relationship between flexibility-activity and blood-pressure (BP) change among older adults in Japan. Our study included 452 older adults who took part in our survey in both 2012/2013 and 2017/2018. The seated ... ...

Abstract	This longitudinal study examined the relationship between flexibility-activity and blood-pressure (BP) change among older adults in Japan. Our study included 452 older adults who took part in our survey in both 2012/2013 and 2017/2018. The seated systolic blood pressure (SBP) and diastolic BP (DBP) were measured both at baseline and at the 5 years follow-up. The frequencies of the different physical activities at baseline were assessed using a questionnaire. A generalized linear mixed model was used to estimate the non-standardized coefficient (B) of BP change associated with flexibility activity, after adjustments for sex, age, body mass index, smoking status, alcohol consumption, antihypertensive medication use, history of heart disease, walking time, and muscle-strengthening activity as a fixed-effect, and area of residence as a random-effect. Higher flexibility-activity frequency was significantly associated with reduced SBP (B = -0.77 [95% confidence intervals = -1.36, -0.18], p for linear trend = 0.01, p for quadratic trend = 0.85) and DBP (-0.33 [-0.71, 0.05], p for linear trend = 0.09, p for quadratic trend = 0.04). Engaging in flexibility activity for 3 days per week was significantly associated with a reduction in DBP (B = -4.16, 95% CI [-7.53, -0.79], p = 0.02) compared with that in the reference group (0 days per week). Interaction tests were not significant between basic variables (sex, age, BMI, and antihypertensive medication) and flexibility. In conclusion, higher flexibility activity frequency was associated with a reduction in BP in older adults. Future longitudinal and interventional studies should examine the effects of flexibility activity on cardiovascular disease prevention.
MeSH term(s)	Humans ; Aged ; Hypertension/epidemiology ; Hypertension/drug therapy ; Longitudinal Studies ; Antihypertensive Agents/therapeutic use ; Japan ; Blood Pressure/physiology
Chemical Substances	Antihypertensive Agents
Language	English
Publishing date	2023-05-11
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	1077418-x
ISSN	1600-0838 ; 0905-7188
ISSN (online)	1600-0838
ISSN	0905-7188
DOI	10.1111/sms.14386
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Article ; Online: Central mechanisms of cardiovascular regulation during exercise

Hidefumi Waki

Journal of Physical Fitness and Sports Medicine, Vol 1, Iss 2, Pp 253-

Integrative functions of the nucleus of the solitary tract

2012 Volume 261

Abstract: Generally, a single bout of exercise induces a moderate increase in arterial pressure (AP) with marked tachycardia as a result of sympathoexcitation which induces vasoconstriction in the major organs, but not in skeletal muscles, and activates heart ... ...

Abstract	Generally, a single bout of exercise induces a moderate increase in arterial pressure (AP) with marked tachycardia as a result of sympathoexcitation which induces vasoconstriction in the major organs, but not in skeletal muscles, and activates heart function. In this review, the potential brain mechanisms underlying cardiovascular regulation during exercise are introduced, with a focus on the functions of the nucleus of the solitary tract (NTS), which is the central termination site of baroreceptor inputs. During a single bout of exercise, neuronal signals from the central command, mediated by the hypothalamus, as well as those from the muscle receptors, are directly or indirectly projected to the NTS and rostral ventrolateral medulla (RVLM). The signals to the RVLM activate sympathetic premotor neurons that, in turn, induce pressor and tachycardiac responses. However, in the absence of resetting of the baroreceptor reflex to a higher pressure range, sympathoexcitation would be dampened and parasympathetic nerves would be excited by heightened levels of baroreceptor inputs, resulting in the attenuation of continuous increases in AP and heart rate. The GABAergic inter-neurons within the NTS may be involved in baroreceptor reflex resetting by limiting the degree of excitation of barosensitive NTS neurons, and thus are capable of ‘continuous’ increases in sympathetic nerve activity. Among the central command mechanisms, the dorsomedial hypothalamus, hypothalamic paraventricular nucleus, and tuberomammillary nucleus of the posterior hypothalamus may be involved in the GABA-mediated inhibition of NTS functions. Although the recent findings of the central regulatory mechanisms are remarkable, they may provide only a partial explanation of the mechanisms. Since maintaining cardiovascular homeostasis is essential for high exercise performance, further investigations will be required to clarify all aspects of the central regulatory mechanisms underlying cardiovascular responses during exercise.
Keywords	nucleus of the solitary tract (nts) ; arterial pressure ; baroreceptor reflex ; exercise ; cardiovascular centers ; hypothalamus ; Sports medicine ; RC1200-1245 ; Physiology ; QP1-981
Subject code	796
Language	English
Publishing date	2012-09-01T00:00:00Z
Publisher	Japanese Society of Physical Fitness and Sports Medicine
Document type	Article ; Online
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Article ; Online: Effects of bilateral lesions in the central amygdala on spontaneous baroreceptor reflex in conscious rats

Kei Tsukioka / Ko Yamanaka / Hidefumi Waki

Journal of Physical Fitness and Sports Medicine, Vol 8, Iss 1, Pp 45-

2019 Volume 50

Abstract: The amygdala induces emotion and controls the cardiovascular system. We previously found that lesions in the central nucleus of amygdala (CeA), which is associated with negative emotion, chronically increase the arterial pressure (AP); however, the ... ...

Abstract	The amygdala induces emotion and controls the cardiovascular system. We previously found that lesions in the central nucleus of amygdala (CeA), which is associated with negative emotion, chronically increase the arterial pressure (AP); however, the mechanism involved in this process remains unclear. In this study we compared the heart rate (HR), high frequency (HF) component of HR variability as an index of cardiac vagal outflow, and spontaneous baroreceptor reflex gain (sBRG) before and after the occurrence of bilateral lesions in CeA for further understanding of cardiovascular regulation by CeA. The results showed that CeA lesions induced a chronic decrease in HR and increase in sBRG, suggesting that CeA regulates the autonomic nervous system. Taken together with our previous results, CeA was shown to control AP and HR as well as baroreflex gain; however, the mechanisms controlling basal AP through CeA are likely to be independent of mechanisms for baroreflex gain control. These contradictory findings may partially explain the known diverse hemodynamic patterns of the amygdala in response to a variety of stress conditions.
Keywords	amygdala ; autonomic regulatory system ; baroreflex gain ; lesion ; Sports medicine ; RC1200-1245 ; Physiology ; QP1-981
Subject code	616
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Japanese Society of Physical Fitness and Sports Medicine
Document type	Article ; Online
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Article ; Online: Clinical results of proton beam radiotherapy for inoperable stage III non-small cell lung cancer: a Japanese national registry study.

Tatebe, Hitoshi / Harada, Hideyuki / Mori, Keita / Iwata, Hiromitsu / Akimoto, Tetsuo / Murakami, Masao / Waki, Takahiro / Ogino, Takashi / Nakamura, Masatoshi / Taguchi, Hiroshi / Nakayama, Haruhiko / Satouchi, Miyako / Aoyama, Hidefumi

Journal of radiation research

2023 Volume 64, Issue Supplement_1, Page(s) i8–i15

Abstract: This study presents the first data of a Japanese nationwide multi-institutional cohort and compares them with the findings of systematic literature reviews on radiation therapies and inoperable stage III non-small cell lung cancer (NSCLC) conducted by ... ...

Abstract	This study presents the first data of a Japanese nationwide multi-institutional cohort and compares them with the findings of systematic literature reviews on radiation therapies and inoperable stage III non-small cell lung cancer (NSCLC) conducted by the Lung Cancer Working Group in the Particle Beam Therapy (PBT) Committee and Subcommittee at Japanese Society for Radiation Oncology. The Lung Cancer Working Group extracted eight reports and compared their data with those of the PBT registry from May 2016 to June 2018. All the analyzed 75 patients aged ≤80 years underwent proton therapy (PT) with concurrent chemotherapy for inoperable stage III NSCLC. The median follow-up period of the surviving patients was 39.5 (range, 1.6-55.6) months. The 2- and 3-year overall survival (OS) and progression-free survival rates were 73.6%/64.7% and 28.9%/25.1%, respectively. During the follow-up period, six patients (8.0%) had adverse events of Grade ≥ 3, excluding abnormal laboratory values. These included esophagitis in four patients, dermatitis in one and pneumonitis in one. Adverse events of Grade ≥ 4 were not observed. The results of these PBT registry data in patients with inoperable stage III NSCLC suggest that the OS rate was at least equivalent to that of radiation therapy using X-rays and that the incidence of severe radiation pneumonitis was low. PT may be an effective treatment to reduce toxicities of healthy tissues, including the lungs and heart, in patients with inoperable stage III NSCLC.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/pathology ; Protons ; East Asian People ; Lung/pathology ; Proton Therapy/adverse effects ; Neoplasm Staging
Chemical Substances	Protons
Language	English
Publishing date	2023-05-03
Publishing country	England
Document type	Journal Article
ZDB-ID	603983-2
ISSN	1349-9157 ; 0449-3060
ISSN (online)	1349-9157
ISSN	0449-3060
DOI	10.1093/jrr/rrad017
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