Investigation into the Mechanism to Regulate Autonomic Cardiovascular System by the Lateral Habenula

概要

目 的：
(Purpose)
The lateral habenula (LHb) is a highly conserved structure across species. It acts as a hub to connect the limbic system at the forebrain to the monoaminergic systems at the midbrain. This makes the LHb a candidate to process unpredicted psychological stress. The behavioral function of the LHb which relates to emotion and motivation has been well studied. However, the autonomic responses, especially cardiovascular responses, that have been found to bond with those behaviors are still poorly understood. Therefore, the study of this study was to answer the question of whether and how the LHb regulates the cardiovascular system to stressful events.

対象と方法：
(Material and method)
Male urethane-anesthetized Wistar rats were used to probe the cardiovascular function of the LHb. The LHb was electrically stimulated and cardiovascular parameters were recorded, including the heart rate (HR) and mean arterial pressure (MAP). The autonomic mechanism of the response was investigated using either pharmacologic blockade of the cardiac sympathetic effect with propranolol, incision of cardiovascular parasympathetic vagus nerves, or blockade of muscarinic receptors. After examining the autonomic mechanism, impact of the serotonergic system on these responses was tested. Serotonergic antagonists were systemically administrated via the femoral vein. To test the hypothesis that the dorsal raphé nucleus (DRN) might be required to modulate the LHb-induced cardiovascular responses, the DRN neurons were inhibited by microinjection of muscimol and the effect on the LHb-induced cardiovascular response was examined.

結 果：
(Result)
In this study, electrical stimulation of the LHb evoked bradycardia and a pressor response in urethane- anesthetized rats. The LHb-induced HR change was completely attenuated by incision of bilateral vagus nerves or systemic administration of a muscarinic receptor antagonist but these treatments did not affect the blood pressure response. On the other hand, propranolol, a β-adrenergic receptor antagonist, partly suppressed the LHb-induced MAP change but did not influence the HR response.
Results of interventions to the serotonergic system showed that administration of methysergide, a nonselective serotonergic receptor antagonist, and mianserin, a 5-HT2 receptor antagonist, attenuated both the LHb-induced bradycardia and pressor response. Meanwhile, administration of NAD-299, a 5- HT1A receptor antagonist, revealed dose-dependent effects with enhanced responses at a low dose but attenuated responsed at a high dose. On the other hand, GR-127935, a 5-HT1B/1D antagonist, and SB- 269970, a 5-HT7 antagonist, did not affect these responses. Moreover, inhibiting the DRN neurons suppressed the LHb-induced pressor response but did not change the LHb-induced bradycardia.

考 察：
(Discussion)
Stimulation of the LHb induced bradycardia and a pressor response similar to those observed in the fear-evoked freezing responses of animals. This was confirmed by the activation of both the sympathetic and parasympathetic nervous systems that has been reported in passive coping animal studies. Therefore, the activation of the LHb neurons may mimic the brain state of freezing behavior. Furthermore, this study investigated the modulation of the serotonergic system to the LHb-induced cardiovascular responses. The serotonergic system participates in many psychological conditions, including emotional behaviors. The cooperation between the LHb and the serotonergic system may expand the mechanism of cardiovascular responses when animals or humans encounter aversive stimuli.

結 論：
(Conclusion)
The findings of this study establish a cardiovascular function and its mechanism of the LHb, a structure that is positioned to connect the forebrain and midbrain and processes aversive stimuli. Electrical stimulation of the LHb activates both the sympathetic and parasympathetic nervous system. Excitation of the sympathetic nervous system results in an increase in blood pressure and activation of the parasympathetic nervous system causes a decrease in heart rate. The LHb-induced cardiovascular responses are modulated by the serotonergic system via the 5-HT1A receptors and 5-HT2 receptors.
The DRN is a central serotonergic structure that might mediate the LHb-induced activation of the sympathetic nervous system.