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. 2000 Dec 1;529 Pt 2(Pt 2):413-29.
doi: 10.1111/j.1469-7793.2000.00413.x.

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

E V Golanov  1 , D A Ruggiero, D J Reis
Affiliations

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

E V Golanov et al. J Physiol. .

Abstract

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.

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Figures

Figure 1
Figure 1. Distribution at four different levels of the rat medulla (expressed as distances in mm rostral to calamus scriptorius) of sites from which electrical stimulation increased rCBF (circles)
Stimulation consisted of a 10 s train (50 Hz, 60 μA). ^, elevations of 10–20 %; 1, elevations of 21–30 %; •, elevations of > 31 %. The size of the circles is also proportional to the maximum amplitude of the increase in rCBF. Abbreviations (modified from Paxinos et al. 1997): 7, facial nucleus; 10, dorsal motor nucleus of n. vagus; 12, hypoglossal nucleus; Amb, ambiguus nucleus; CVLM, caudal ventrolateral medulla; DPGi, dorsal paragigantocellular nucleus; Ecu, external cuneate nucleus; Gi, gigantocellular reticular nucleus; GiDa, gigantocellular depressor area; IO, inferior olive; IRt, intermedial reticular nucleus; LPGi, lateral paragigantocellular nucleus; Lrt, lateral reticular nucleus; LRtPC, lateral reticular nucleus, parvicellular; MCVA, medullary cerebral vasodilator area; PCRt, parvicellular reticular nucleus; py, pyramidal tract; RM, raphe magnus nucleus; Ro, raphe obscurus nucleus; RPa, raphe pallidus nucleus; RVLM, rostral ventrolateral medulla; Sol, nucleus solitary tract; Sp5, spinal trigeminal nucleus.
Figure 2
Figure 2. Changes in rCBF, CVR, AP and EEG in response to stimulation of medullary cerebral vasodilator area (MCVA)
In this and all subsequent figures rCBF and CVR are expressed as percentage change of baseline (Δ) and AP in millimetres of mercury. Except when otherwise noted studies were performed in anaesthetized ventilated rats. A, left panel, changes in rCBF, CVR and AP averaged from 6 rats. In each animal the MCVA was stimulated 3–4 times with a 10 s train (50 Hz, 60 μA). Upper trace, ΔrCBF; middle trace, ΔCVR; lower trace, AP. See text for details. Right panel, effects on rCBF, CVR and AP in 3 spinalized rats of co-administration of a V1 vasopressin and nicotinic cholinergic antagonist on responses to stimulation of MCVA. [deamino-Pen1,Val4,D-Arg8]-vasopressin (10 mg kg−1) and hexamethonium (10 mg kg−1) were administered together to 3 rats 2 min before electrical stimulation of MCVA. Averaged responses (n = 9, 3 trials in each animals before and after) to electrical stimulation of MCVA before (continuous line) and after (dotted line) simultaneous administration of drugs. Vertical bar designates duration of stimulation. Note that treatment abolishes the early hypotension and delayed hypertension without significantly altering rCBF and CVR (P > 0.05). B, typical stimulated site in MCVA (shaded area), from which electrical stimulation increased rCBF, decreased CVR and synchronized the EEG in animals depicted in this figure. Abbreviations as in Fig. 1. C, effects on EEG. Upper trace, EEG recorded monopolarly over parietal cortex in a representative animal before MCVA stimulation. Lower panel, EEG immediately after electrical stimulation of MCVA. Note synchronization. D, fast Fourier transformation analysis (FFT) of EEG recorded before (•) and immediately after (▴) MCVA stimulation in 6 rats. The values are recorded over a 10 s trial averaged with each point representing the mean ±s.e.m. Note MCVA stimulation significantly (*P < 0.05, Student's paired t test) increases power of 5–7 Hz and reduces the power of the 3 Hz epochs.
Figure 3
Figure 3. Changes in rCBF, CVR and AP elicited by microinjection of L-glutamate (5 nmol, 20 nl) into MCVA (n = 3) in anaesthetized spinalized rats
Vertical bar designates period of injection. Note comparability on rCBF and CVR between l-Glu and electrical (Fig. 2) stimulation. Upper trace, ΔrCBF; middle trace, ΔCVR; lower trace, AP.
Figure 4
Figure 4. Changes in rCBF, CVR, AP, and EEG in response to stimulation of rostral ventrolateral medulla (RVLM) in anaesthetized spinalized rats
A, a typical averaged response (16 trials averaged from 5 rats) to electrical stimulation of RVLM. Upper trace, rCBF expressed as a percentage of baseline (Δ); middle trace, CVR expressed as a percentage of baseline (Δ); lower trace, arterial pressure (AP) in millimetres of mercury. Vertical bar designates period of stimulation. Note potent elevation of rCBF with reciprocal fall of CVR. B, typical site of stimulation of RVLM (shaded area) (2.5 mm rostral to calamus scriptorius), from which 10 s of electrical stimulation increased rCBF, decreased CVR and synchronized the EEG in the same rats. Abbreviations as in Fig. 1. C and D depicted as in Fig. 2. C, typical changes of EEG in response to electrical stimulation of RVLM. D, fast Fourier transformation (FFT) analysis of EEG recorded before (•) and immediately after (▴) MCVA stimulation. *P < 0.05, Student's paired t test.
Figure 5
Figure 5. Changes in rCBF, CVR, AP and EEG in response to stimulation of MCVA (A), RVLM (B) and caudal ventrolateral medulla (CVLM) (C) in anaesthetized spinal cord-intact rats (5 in each group)
The area of stimulation (shaded area) for each group is depicted in line drawing above each trace. Upper trace, rCBF expressed as a percentage of baseline (Δ); middle trace, CVR expressed as a percentage of baseline (Δ); lower trace, arterial pressure (AP) in mmHg. Traces represent averaged responses observed in 5 rats for each different location. Vertical bar designates period of stimulation. Note that stimulation of MCVA and RVLM elicit stimulus locked elevations of AP and rCBF with post-stimulation elevations of rCBF. In contrast stimulation of CVLM elicits a fall.
Figure 6
Figure 6. Distribution of sites at two different levels of the ventral medulla of anaesthetized spinalized rats from which microinjection of nicotine (1.2 nmol in 40 nl) or NaCN (300 pmol in 20 nl) elevated rCBF and synchronized the EEG
The cross-section at 2.5 mm rostral to calamus scriptorius corresponds to RVLM, while the cross-section 1.1 mm rostral to calamus scriptorius corresponds to MCVA. Effects of NaCN injections are depicted on the right and effects of nicotine injections on the left side of diagram. The injection sites are also reflected onto the ventral medullary surface. ^, sites from which no or less than 5 % responses were elicited; ^, elevations of 5–10 %; •, elevations of >10 %. The diameter of circles is proportional to the elevation in rCBF. Note that NaCN elicits responses only from RVLM, while nicotine is only effective in MCVA. Abbreviations as in Fig. 1.
Figure 7
Figure 7. Effects of NaCN (300 pmol) microinjected into RVLM in anaesthetized rats on rCBF, CVR, AP and EEG
A, averaged responses (n = 5) of rCBF (upper trace), CVR (middle trace) and AP (lower trace) to microinjection of 300 pmol of NaCN (indicated by vertical bars) into RVLM in spinal cord-intact (left panel) (n = 5) or spinalized (right panel) rats (n = 5). Note that NaCN elevates rCBF from RVLM in intact and spinalized rats with minimal acute and also delayed elevations of AP. In spinalized rat it increases rCBF and reduces CVR. B, EEG before (upper trace) and after (lower trace) microinjection of NaCN into RVLM in spinalized rat. C, changes in power of different frequency components of cortical EEG (FFT) evoked by administration of NaCN into RVLM. ▾, before NaCN; •, after microinjection. n = 5; *P < 0.05, Student's paired t test. Note: NaCN synchronizes EEG by increasing 6 Hz component.
Figure 8
Figure 8. Effects of nicotine (1.2 nmol) microinjected into MCVA in anaesthetized rats on rCBF, CVR, AP and EEG
A, averaged responses (n = 5) to injection of 1.2 nmol nicotine (indicated by vertical bars) in spinal cord-intact rat (n = 5) (left panel) and in spinalized rat (n = 5) (right panel). Note that nicotine lowers AP in intact rat, an effect abolished by spinalization and that after spinalization rCBF is still elevated. B, EEG recordings before (upper trace) and after (lower trace) microinjection of nicotine into MCVA in spinalized rats. C, changes in power of different frequency components of cortical EEG (FFT transform) evoked by administration of nicotine into MCVA. ▾, before nicotine; •, after nicotine. n = 5, *P < 0.05, Student's paired t test. Note nicotine synchronizes EEG. See text for details.
Figure 9
Figure 9. Effects of bilateral acute electrolytic lesion of RVLM on the changes in rCBF and EEG evoked by electrical stimulation of MCVA
A, averaged (n = 15, 3 trials in each of 5 rats) changes in rCBF, CVR and AP in response to stimulation of MCVA before (continuous line) and after (dotted line, n = 15) acute lesions of RVLM. B, changes in power of different frequency components of cortical EEG (FFT transform) evoked by stimulation of MCVA before stimulation (•), after stimulation (no lesion, ▴) and after lesions (▪). Note that lesions do not affect the synchronization of the EEG elicited from MCVA. *P < 0.05, Student's paired t test compared to baseline. C, contours of individual lesions in 5 animals projected onto a representative cross-section of medulla. The shaded area represents the area common to all lesions and corresponds to RVLM. Abbreviations as in Fig. 1.
Figure 10
Figure 10. Effects of electrolytic lesion of MCVA on responses to stimulating RVLM
A, average (n = 15, 3 trials in each of 5 rats) changes in rCBF, CVR, AP and EEG evoked by electrical stimulation of the RVLM. Note that the elevation of rCBF is reduced by ≈50 % after lesion of MCVA. B, changes in power of different frequency components of cortical EEG (FFT transform) in non-stimulated rat (•), in response to electrical stimulation of RVLM before (▴), and after lesion (▪). *P < 0.05, Student's paired t test. Note lesions blocked the increase in 6 Hz component of EEG. C, localization of electrolytic lesions represented as in Fig. 9. Abbreviations as in Fig. 1.
Figure 11
Figure 11. Anterogradely labelled projections form RVLM to MCVA
Photomicrograph (A) and camera lucida drawing (C) demonstrating the dense central core of a representative injection deposit of biotinylated dextranamine (BDA) in the sympathoexcitatory region of the rostral ventrolateral medulla (RVLM). Photomicrograph (B) and camera lucida drawing (D) demonstrating anterogradely labelled terminals in the paraambigual region of intermediate and parvicellular reticular zones coinciding with medullary cerebrovasodilator area (MCVA). The cerebrovasodilator region contains fibres en passant admixed with clusters of punctate processes with morphological characteristics of terminal boutons. Scale bar, 105 μm. Abbreviations as in Fig. 1.
Figure 12
Figure 12. Anterogradely labelled projections from MCVA to RVLM
A, camera lucida drawings illustrating a representative injection site in the medullary cerebrovasodilator area (MCVA) corresponding to the paraambigual region of ventral tegmentum (compare to Fig. 11D). B and C, camera lucida drawing and photomicrograph demonstrating the terminal field in the sympathetic premotor region in rostral ventrolateral medulla (RVLM). Scale bar, 105 μm. Abbreviations as in Fig. 1.
Figure 13
Figure 13. Diagrammatic representation of distribution of MCVA, in relationship to other cardiovascular areas of ventral medulla including RVLM, CVL and GiDA
Abbreviations as in Fig. 1. See text for details.
See this image and copyright information in PMC

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