The lateral habenula regulates stress-related respiratory responses via the monoaminergic system

Psychologic stress induces behavioral and autonomic responses such as acceleration of respiration. The lateral habenula (LHb) is noted to be involved in stress-induced behavioral responses. However, its involvement in stress-induced respiratory responses is unknown. In this study, we aimed to analyze whether and how the LHb regulates respiration. Electrical stimulation of the LHb of anesthetized Wistar male rats increased respiratory frequency and minute ventilation, calculated by respiratory frequency × thoracic movement amplitude. Systemic administration of a dopaminergic receptor antagonist, clozapine, suppressed the LHb-induced respiratory responses. On the other hand, administration of a serotonergic receptor antagonist, methysergide, significantly accelerated the LHb-induced increase in respiratory frequency, together with suppressing the thoracic movement amplitude. To clarify the source of dopaminergic modulation, we inhibited the ventral tegmental area (VTA), which contains dopaminergic neurons and receives inputs from the LHb, by administering microinjections of a GABA_A agonist, muscimol. The bilateral inhibition of the VTA almost abolished the LHb-induced respiratory responses. These results suggest that LHb activation causes respiration acceleration, mainly mediated by dopaminergic neurons in the VTA and suppressively modulated by the serotonergic system. Neural circuits originating in the LHb may be a key modulator for respiration during psychological stress.