Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation.

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

Corticosterone-activated mineralocorticoid receptor contributes to salt-induced sympathoexcitation in pressure overload mice.

Abstract We previously reported that pressure overload (PO) activates the hypothalamic mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT1R). Moreover, salt intake further activates the hypothalamic MR and AT1R, resulting in salt-induced sympathoexcitation. However, the mechanism underlying this pathway activation in response to a high salt intake remains unknown. Although the role of aldosterone is extensively examined as a ligand for MR, corticosterone is able to bind to MR. Therefore, we hypothesized that corticosterone contributes to salt-induced sympathoexcitation in PO-mice. Four weeks after aortic banding to produce PO-mice, or a sham operation for controls, the mice were fed a high-salt diet for an additional 4 weeks. Compared to Sham-mice, the expression levels of hypothalamic MR, serum glucocorticoid-induced kinase 1 (a marker of MR activity) and AT1R increased in PO-mice. Salt intake further increased the expression levels of these proteins only in PO-mice with the increases in sympathetic activity evaluated on the basis of the excretion of 24-h urinary norepinephrine excretion. Bilateral adrenalectomy or the intraperitoneal infusion of metyrapone, a corticosterone synthase inhibitor, attenuated salt-induced sympathoexcitation via inhibition of the hypothalamic MR and AT1R activity. These adrenalectomy-induced alterations disappeared after corticosterone replacement therapy. We also found decreased expression levels of 11ß-hydroxysteroid dehydrogenase type 2, suggesting that corticosterone is apt to bind to MR. These results indicate that salt intake in PO-mice causes sympathoexcitation via, at least in part, corticosterone-induced MR and AT1R activation in the hypothalamus.

Brain sigma-1 receptor stimulation improves mental disorder and cardiac function in mice with myocardial infarction.

Mental disorder after myocardial infarction (MI) is reported by many epidemiological studies and is associated with a poor prognosis. The reduction of brain sigma-1 receptor (S1R) plays an important role in the pathogenesis of mental disorder, and we recently demonstrated that the reduction of brain S1R causes sympathoexcitation. However, the role of brain S1R in the association between MI and mental disorder, such as depression or cognitive impairment, remains unclear. To investigate this, we performed left coronary artery ligation on mice to produce an MI model (MI-mice). Compared with sham-operated controls (Sham-mice), MI-mice showed augmented sympathetic activity, decreased cardiac function, and lower S1R expression in both the hypothalamus and hippocampus. Furthermore, MI-mice displayed decreased Y-maze spontaneous alternation (a maker of spatial working memory), decreased circadian variation in locomotor activity, and increased immobility time in the tail suspension test (markers of depression-like behavior). Intracerebroventricular infusion of the S1R agonist PRE084 in MI-mice improved both mental disorder and cardiac function with lowered sympathetic activity and the recovery of the S1R expression in both the hypothalamus and hippocampus. These results indicate that brain S1R is decreased in MI-mice and that this plays an important role in the coexistence of increased heart failure via sympathoexcitation and mental disorders, such as depression or cognitive impairment.

Role of hypothalamic angiotensin type 1 receptors in pressure overload-induced mineralocorticoid receptor activation and salt-induced sympathoexcitation.

Pressure overload enhances salt-induced sympathoexcitation through hypothalamic mineralocorticoid receptor (MR)-epithelial Na channel activation. Pressure overload also increases hypothalamic angiotensin type 1 receptors (AT1R). However, the role of AT1R in pressure overload-induced MR activation and salt-induced sympathoexcitation remains unknown. Therefore, the aim of the present study was to address this question. We performed aortic banding (AB) on mice from the Institute of Cancer Research. The expression of hypothalamic MR, serum/glucocorticoid-induced protein kinase-1 (SGK-1) and AT1R increased independently of plasma renin activity at 2 or 4 weeks after AB. Next, we performed AB in AT1aR-knockout (KO) mice and c57BL6/J wild-type (WT) mice. Sham-operated (Sham) mice were used as a control. Four weeks after AB (AB-KO or AB-WT), the expression of hypothalamic MR and SGK-1 increased in both AB-WT and AB-KO compared with Sham-WT and Sham-KO, respectively. The expression of AT1R was also greater in AB-WT than in Sham-WT. In addition, mice were fed a high-salt (8%) diet for an additional 4 weeks (ABH-KO and ABH-WT). High salt loading increased the urinary excretion of norepinephrine, a marker of sympathetic activity in ABH-WT, concomitant with hypothalamic MR activation, but not in ABH-KO. These results indicate that pressure overload activated hypothalamic MR independently of AT1R. After salt intake, however, AT1R was necessary to maintain hypothalamic MR activation and salt-induced sympathoexcitation.

Event related desynchronization-modulated functional electrical stimulation system for stroke rehabilitation: a feasibility study.

BACKGROUND: We developed an electroencephalogram-based brain computer interface system to modulate functional electrical stimulation (FES) to the affected tibialis anterior muscle in a stroke patient. The intensity of FES current increased in a stepwise manner when the event-related desynchronization (ERD) reflecting motor intent was continuously detected from the primary cortical motor area. METHODS: We tested the feasibility of the ERD-modulated FES system in comparison with FES without ERD modulation. The stroke patient who presented with severe hemiparesis attempted to perform dorsiflexion of the paralyzed ankle during which FES was applied either with or without ERD modulation. RESULTS: After 20 minutes of training, the range of movement at the ankle joint and the electromyography amplitude of the affected tibialis anterior muscle were significantly increased following the ERD-modulated FES compared with the FES alone. CONCLUSIONS: The proposed rehabilitation technique using ERD-modulated FES for stroke patients was feasible. The system holds potentials to improve the limb function and to benefit stroke patients.

Motor imagery facilitates force field learning.

Humans have the ability to produce an internal reproduction of a specific motor action without any overt motor output. Recent findings show that the processes underlying motor imagery are similar to those active during motor execution and both share common neural substrates. This suggests that the imagery of motor movements might play an important role in acquiring new motor skills. In this study we used haptic robot in conjunction with motor imagery technique to improve learning in a robot-based adaptation task. Two groups of subjects performed reaching movements with or without motor imagery in a velocity-dependent and position-dependent mixed force field. The groups performed movements with motor imagery produced higher after effects and decreased muscle co-contraction with respect to no-motor imagery group. These results showed a positive influence of motor imagery on acquiring new motor skill and suggest that motor learning can be facilitated by mental practice and could be used to increase the rate of adaptation.

Influence of motor imagery on learning under complex external dynamics.

Humans are remarkable in their ability to adapt to changes in the dynamics of a movement. The mechanisms by which the brain controls body movements are important in the fields of robotics and neurosciences. Robots are largely used to study the adaptive properties of human motor system. If rehabilitation robots are used in conjunction with techniques for functional brain imaging, in principle the motor learning can be facilitated for rehabilitation purposes. In this study, we use motor imagery technique to improve the learning rate in a robot-based adaptation task. We tried to determine whether humans can learn an internal model of a complex mixed force field (V+P) that was the sum of a velocity-dependent force field (V) and a position-dependent force field (P). The results suggest that the motor learning can be influenced by mental practice and could be used to increase the rate of adaptation.