Inhibition of the dorsomedial hypothalamus substantially decreases brown adipose tissue sympathetic discharge induced by activation of the lateral habenula.

Abstract

The lateral habenula (LHb) is an evolutionarily ancient nucleus that plays an important role in the detection of salient/adverse environmental events. We have previously shown that the LHb is involved in brown adipose tissue (BAT) thermogenesis elicited by stressful situations, and that the medullary raphé, a key lower brainstem sympathetic control centre, mediates BAT thermogenesis elicited by stimulating the LHb. Since there are no direct projections from the LHb to the medullary raphé, it is plausible that the dorsomedial hypothalamus (DMH), a brain region known to be important for thermoregulatory responses to stress, is involved in this thermogenic pathway. In this study we aimed to test this possibility. In anaesthetized Sprague-Dawley rats, we recorded electrical discharges directly from sympathetic fibres that innervate BAT, as well as BAT temperature. Injections of bicuculline (1nmol in 100nl), a neuronal activator by disinhibition, into the LHb increased BAT sympathetic nerve discharge by 4.9±1.4dBμV (n=7, P<0.05) and BAT temperature by 1.0±0.1°C (n=7, P<0.01). Subsequent injections of muscimol (0.25nmol in 100nl), a neuronal inhibitor, into the DMH promptly reduced BAT sympathetic nerve discharge by 4.7±1.3 dBμV (n=7, P<0.05) and BAT temperature by 0.3±0.1°C (n=7, P<0.05). Injections of a mixture of the ionotropic glutamate receptor antagonists, DL-2-Amino-5-phosphonopentanoic acid (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dioneis (CNQX) into the DMH, after activation of the LHb, also significantly decreased BAT sympathetic nerve discharge and BAT temperature. These results suggest that, for sympathetically-mediated BAT thermogenesis, the DMH is part of the neural circuitry linking the LHb with the medullary raphé.