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

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 (1 nmol in 100 nl), 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 (0.25 nmol in 100 nl), 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.

Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons.

Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24-26°C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is "spontaneous" and when the interaction is provoked by threatening or salient environmental events.