A brainstem area mediating cerebrovascular and EEG responses to hypoxic excitation of rostral ventrolateral medulla in rat

We sought to identify the medullary relay area mediating the elevations of regional cerebral blood flow (rCBF) and synchronization of the electroencephalogram (EEG) in the rat cerebral cortex elicited by hypoxic excitation of reticulospinal sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM). In anaesthetized spinalized rats electrical stimulation of RVLM elevated rCBF (laser-Doppler flowmetry) by 31 ± 6 %, reduced cerebrovascular resistance (CVR) by 26 ± 8 %, and synchronized the EEG, increasing the power of the 5–6 Hz band by 98 ± 25 %. Stimulation of a contiguous caudal region, the medullary cerebral vasodilator area (MCVA), had comparable effects which, like responses of RVLM, were replicated by microinjection of L-glutamate (5 nmol, 20 nl). Microinjection of NaCN (300 pmol in 20 nl) elevated rCBF (17 ± 5 %) and synchronized the EEG from RVLM, but not MCVA, while nicotine (1.2 nmol in 40 nl) increased rCBF by 13 ± 5 % and synchronized the EEG from MCVA. In intact rats nicotine lowered arterial pressure only from MCVA (101 ± 3 to 52 ± 9 mmHg). Bilateral electrolytic lesions of MCVA significantly reduced, by over 59 %, elevations in rCBF and, by 78 %, changes in EEG evoked from RVLM. Bilateral electrolytic lesions of RVLM did not affect responses from MCVA. Anterograde tracing with BDA demonstrated that RVLM and MCVA are interconnected. The MCVA is a nicotine-sensitive region of the medulla that relays signals elicited by excitation of oxygen-sensitive reticulospinal neurons in RVLM to reflexively elevate rCBF and slow the EEG as part of the oxygen-conserving (diving) reflex initiated in these neurons by hypoxia or ischaemia. Hypoxia or ischaemia of the medulla oblongata increases sympathetic nerve activity, elevates arterial pressure (AP), and induces expiratory apnoea and bradycardia (Dampney et al. 1979; Sun et al. 1992; Reis et al. 1994; Golanov & Reis, 1996a) in rat. It also increases regional cerebral blood flow (rCBF), but not regional cerebral glucose utilization (rCGU), and synchronizes the EEG (Golanov & Reis, 1994, 1996a). This integrated response simulates, in most respects, the diving reflex (Blix & Folkow, 1983), the prototypical oxygen-conserving reflex of mammals. The autonomic responses have been attributed to direct hypoxic excitation of tonically active sympathoexcitatory reticulospinal vasomotor neurons of the rostral ventrolateral reticular nucleus of the medulla (RVLM) (Sun & Reis, 1994a). In vivo these neurons are selectively, rapidly and reversibly excited by blockade of the respiratory chain by microinjection or microiontophoresis of NaCN (histotoxic hypoxia) (Sun & Reis, 1993). Moreover, restricted lesions of RVLM block the systemic and cerebrovascular responses to ischaemia and/or hypoxaemia (Dampney & Moon, 1980; Underwood et al. 1994; Golanov & Reis, 1996a). Indeed, to protect the brain from lack of oxygen may be an important function of the RVLM (Reis et al. 1994). Reticulospinal neurons of the RVLM function as premotor neurons, acting to initiate the integrated responses to hypoxia by activation of effector (motor) neurons distributed elsewhere in the CNS. Thus, the sympathetic responses can be attributed to activation of the RVL-spinal sympathoexcitatory pathway (Sun & Reis, 1996a), apnoea from activation through short intramedullary projections of the adjacent ventral respiratory cell group (Kita et al. 1994; Sun & Reis, 1996b), and bradycardia – from excitation of medullary cardiovagal neurons (Ross et al. 1984; Benarroch et al. 1986). However, the pathway(s) through which rCBF and the EEG are modified is unknown. Since the RVLM does not innervate the cerebral cortex (Ruggiero et al. 1989), the projection must be indirect. In this study we investigate whether a small area of the ventrolateral medulla serves to relay the signals generated by hypoxic excitation of the RVLM to elevate rCBF and synchronize the EEG in the cerebral cortex of rats. We report that an heretofore unrecognized paraambigual region of the bulbar reticular formation, which we term the medullary cerebral vasodilator area (MCVA), subserves this role.