Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline

Abstract

SUMMARYCholinergic basal forebrain structures are implicated in cortical arousal and regulation of the sleep-wake cycle. Cholinergic neurones are innervated by noradrenergic terminals, noradrenaline excites them via alpha-1 receptors and microinjection of noradrenaline into the basal forebrain enhances wakefulness. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing effects of noradrenaline. To elucidate the roles of cholinergic basal forebrain structures we administered methoxamine, an alpha-1-adrenergic agonist into the basal forebrain, in intact animals and again after selective destruction of the basal forebrain cholinergic cells by 192 IgG-saporin. In eight male Han-Wistar rats implanted with electroencephalogram/electromyogram electrodes, a microdialysis probe targeted into the basal forebrain was perfused with artificial cerebrospinal fluid for 6 h on a baseline day, and with cerebrospinal fluid in the first and with methoxamine in the second 3-h period of the subsequent day. The sleep-wake activity was recorded for 24 h on both days. Saporin was then injected into the basal forebrain and 2 weeks later the same experimental schedule (with cerebrospinal fluid and methoxamine) was repeated. In the intact animals, methoxamine exhibited a robust arousing effect and nonrapid eye movement (NREM) and REM sleep was suppressed. Lesioning of the basal forebrain cholinergic neurones abolished almost completely the NREM sleep-suppressing effect of methoxamine, whereas the REM sleep-suppressing effect remained intact. Thus, the basal forebrain cholinergic neurones mediate, at least in part, cortical arousal and non-REM sleep-suppression, but they are not involved in the REM sleep-suppressing effects of noradrenaline.

Using MEG to Understand the Progression of Light Sleep and the Emergence and Functional Roles of Spindles and K-Complexes

“…Sleep onset and sleep stage evolution has been associated to ascending influence by specific modulatory systems with both aminergic and cholinergic systems being deactivated in NREM (see (Lelkes et al, 2013) and references therein). Our results show decreases in relatively high frequencies in brainstem and increases in slow wave activity in frontal cortical areas (first row of Figures 4, 5A), consistent with established view of sleep onset resulting from inactivation of brainstem reticular activating system (Brown et al, 2012; Saper and Sehgal, 2013).…”

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

“…The largest population of relaxin-3 expressing neurons is located within the tegmental area known as the nucleus incertus (NI), and these neurons project broadly throughout the brain [15][16][17][18][19]. The neuroanatomy of the relaxin-3/RXFP3 system suggests a broad role as an ascending neuromodulatory network [20,21], akin to the monoamine systems including serotonin, and noradrenaline [22][23][24][25]. Anatomical and functional data [15][16][17][18] suggest that relaxin-3/RXFP3 systems may interact directly with monoamine [19,26] and other peptide systems [27][28][29], and/or act at shared downstream limbic and hypothalamic target areas to modulate 'anxiety' and other stress-related responses [30][31][32][33][34].…”

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate

“…Ink was injected through a modified microdialysis probe inserted into the guide cannula. To verify only the probe location, the brain was removed, stored at −80, cut, stained with Toluidine blue and inspected visually, as described previously (Lelkes et al ., ; Fig. ).…”

“…The EEG and EMG signals were amplified, filtered (high‐pass: 0.3 and 10 Hz for the EEG and EMG, respectively; low‐pass: 100 Hz) and sampled at 278 and 139 Hz for the EEG and EMG, respectively. Vigilance states [W, non‐REM (NREM) and REM sleep] were scored manually in 4‐s epochs according to standard criteria, as described previously (Lelkes et al ., ); in addition, power spectra values were calculated by fast‐Fourier transformation for consecutive 4‐s epochs with the aid of the Spike2 program version 6 (Cambridge Electronic Devices, Cambridge, UK) using the script Sleepscore version 1.01. Vigilance‐state‐specific EEG delta (1–4 Hz), low theta (4–6 Hz), high theta (6–9 Hz), alpha (9–13 Hz) and beta (13–30 Hz) powers were calculated.…”

“…However, the function of the cholinergic neurones has been addressed by using the immunotoxin 192 immunoglobulin (Ig)G‐saporin (SAP) to destroy the cholinergic cells specifically (Pizzo et al ., ). It has been found that the cortical activation by both histamine and noradrenaline is mediated via the BF cholinergic cells (Lelkes et al ., ; Zant et al ., ), whereas these neurones do not seem to be important for the arousing action of hypocretin (Blanco‐Centurion et al ., ).…”