Neurons of a limited subthalamic area mediate elevations in cortical cerebral blood flow evoked by hypoxia and excitation of neurons of the rostral ventrolateral medulla

Abstract

Sympathoexcitatory reticulospinal neurons of the rostral ventrolateral medulla (RVLM) are oxygen detectors excited by hypoxia to globally elevate regional cerebral blood flow (rCBF). The projection, which accounts for >50% of hypoxic cerebral vasodilation, relays through the medullary vasodilator area (MCVA). However, there are no direct cortical projections from the RVLM/MCVA, suggesting a relay that diffusely innervates cortex and possibly originates in thalamic nuclei. Systematic mapping by electrical microstimulation of the thalamus and subthalamus revealed that elevations in rCBF were elicited only from a limited area, which encompassed medial pole of zona incerta, Forel's field, and prerubral zone. Stimulation (10 sec train) at an active site increased rCBF by 25 +/- 6%. Excitation of local neurons with kainic acid mimicked effects of electrical stimulation by increasing rCBF. Stimulation of the subthalamic cerebrovasodilator area (SVA) with single pulses (0.5 msec; 80 microA) triggered cortical EEG burst-CBF wave complexes with latency 24 +/- 5 msec, which were similar in shape to complexes evoked from the MCVA. Selective bilateral lesioning of the SVA neurons (ibotenic acid, 2 microg, 200 nl) blocked the vasodilation elicited from the MCVA and attenuated hypoxic cerebrovasodilation by 52 +/- 12% (p < 0.05), whereas hypercarbic vasodilation remained preserved. Lesioning of the vasodilator site in the basal forebrain failed to modify SVA-evoked rCBF increase. We conclude that (1) excitation of intrinsic neurons of functionally restricted region of subthalamus elevates rCBF, (2) these neurons relay signals from the MCVA, which elevate rCBF in response to hypoxia, and (3) the SVA is a functionally important site conveying vasodilator signal from the medulla to the telencephalon.

Fig. 1.

Cerebrovasodilator area (circled in bold) (A) and distribution at three different levels of the rat brain (B) (expressed as distances in millimeters caudal from bregma) of sites from which electrical stimulation increased cerebral blood flow (closed circles). Stimulation consisted of a 10 sec train (50 Hz at 50 μA). BF, Basal forebrain;BST, bed nucleus of stria terminalis; CM, centrum medianum; Cpu, caudate putamen;DLG, dorsal lateral geniculate nucleus;DMH, dorsomedial hypothalamic nucleus;GP, globus pallidus; LP, lateral posterior nucleus; LH, lateral hypothalamus;M, medial vestibular nucleus; MCVA, medullary cerebrovasodilator area; MD, mediodorsal nucleus, MG, medial geniculate nucleus;MM, medial mammillary nucleus; ML, lateral mammillary nucleus; MP, medial preoptic nucleus;NTS, nucleus tractus solitarius; PAG, pariaqueductal gray; PH, posterior hypothalamic area;PF, parafascicular nucleus; Po, posterior nucleus; PR, prerubral nucleus; PT, paratenial nucleus; PVP, paraventricular nucleus;RI, rostral interstitial nucleus; RN, red nucleus; RO, nucleus raphe obscurus; SG, superior colliculus; SNR, substantia nigra;VLG, ventrolateral geniculate nucleus;VMH, ventromedial hypothalamic nucleus;VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus; ZID, dorsal zona incerta;ZIV, ventral zona incerta.

Fig. 2.

Averaged responses in cortical rCBF (top trace), CVR (middle trace), and AP (bottom trace) in response to electrical stimulation (Stim; 10 sec train, 50 Hz, 5× threshold current) of the SVA in spinal-intact rats (A) and rats with transected spinal cord (B) and dependency of the SVA-evoked rCBF responses on the frequency (C) and intensity (D) of stimulation.

Fig. 3.

Sample of EEG response (A) and changes in power of components of cortical EEG (B) evoked by electrical stimulation of the SVA.

Fig. 4.

Averaged responses (three animals) of rCBF (top trace), CVR (middle trace), and AP (bottom trace) to microinjection of kainate (300 pmol, 20 nl) in the SVA.

Fig. 5.

Cortical EEG burst–cerebrovascular wave complexes evoked by single pulse stimulation of the SVA (A) and MCVA (B). Single electrical pulses delivered to the SVA or MCVA triggered a burst of EEG activity (second trace) followed by an increase in rCBF (top trace). Averaging of burst–wave complexes (bottom traces) demonstrated a stable initial potential of EEG followed by highly reproducible cerebrovasodilation.

Fig. 6.

Effect of electrolytic lesion of the SVA on the increase in rCBF (C), evoked by electrical stimulation of the MCVA in spinalized rats. Contours of lesions in different animals (A) are superimposed, and the area common for all lesions is blackened. The site of the MCVA stimulation in B is circled and filled with gray. C, Changes in rCBF [top trace and middle trace indicate changes in CVR; bottom trace indicates AP before (solid line) and after (dotted line) the lesion]. Abbreviations are as in Figure 1.

Fig. 7.

Effect of excitotoxic lesion of the SVA on the increase in rCBF, evoked by hypoxia, hypercarbia, and electrical stimulation of the MCVA. Representative area with gliosis iscircled on the photo of brain slice.

Fig. 8.

Localization of the lesion sites in the BF (A) and effect of stimulation of these sites (B) before the lesions on rCBF (top trace), CVR (middle trace), and AP (bottom trace). Contours of all lesions are superimposed, and the area common for all lesions isblackened. Abbreviations are as in Figure 1.