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

Abstract

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23 μg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3 h with 0.3 mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24 h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate.

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

“…The basal forebrain, a region wherein KYNA was both elevated with kynurenine challenge and reduced with PF-04859989 pre-treatment, is richly implicated in modulation of sleep and arousal behavior. 50–52 A large amount of acetylcholine is released from the basal forebrain during REM sleep, 53–55 and we postulate that KYNA-mediated modulation of cholinergic neurotransmission may impede these dynamics. 56 Within the extracellular milieu, KYNA is present within low micromolar concentrations and optimally positioned to inhibit receptor targets including α7nACh receptors and NMDA receptors.…”

Microdialysis and microperfusion electrodes in neurologic disease monitoring

“…Incorporating multiple probes, especially commercially purchased probes, can expedite experimental progress at the expense of collecting data that overlooks localized neurochemical fluctuations. Most of these published experiments have been conducted in rodents while utilizing commercially-available microdialysis probes in separate locations from the brain-penetrating electrodes [96,102,104,[106][107][108][109][110][111][112][113][114] despite evidence that extracellular biomarker diffusion is severely limited by tissue resistance [51,110]. Therefore, it is crucial that the neurochemical sampling probe is spatially coincident with the target neurons to properly correlate fluctuations in analytes with electrophysiology data.…”

“…Several microdialysis and microperfusion electrodes have been designed and tested to tackle the in vivo sensing challenge of simultaneously measuring changes in biomarkers during passive electrophysiological recording or active electrical stimulation of brain tissue [16,[95][96][97][98][99][100][101][102][103][104][105]. Some of the more elementary designs involve two separate probes for neurochemical sampling and EEG recording [95,96,102,104,[106][107][108][109][110][111][112][113][114]. Other designs successfully incorporate both technologies into a single probe [98][99][100][101]103] or even fix separate probes together through various means [115][116][117][118][119][120][121].…”

“…The default setup for concurrently measuring neurochemicals along with EEG is commercially purchased microdialysis probes located separately from implanted stimulating/recording electrodes [96,102,104,[106][107][108][109][110][111][112][113][114]. Separate microdialysis and electrochemistry probes have been deliberately placed in rat striatal locations at least 2 mm apart to determine local gradients of dopamine and dopamine metabolites following amphetamine administration [102].…”

Neural Substrates for the Regulation of Sleep and General Anesthesia

“…Electrophysiological studies have suggested that BF glutamatergic neurons excite local cholinergic and PV-expressing GABAergic neurons and that cholinergic neurons also excite nearby PV-expressing GABAergic neurons, thus forming a hierarchical excitatory microcircuit; this may partially mediate the strong wake-promoting effect of glutamatergic neurons [ 21 ]. Lesions within local BF cholinergic neurons barely impede glutamatergic neurons from robustly promoting wakefulness, indicating the involvement of long-range projections [ 31 ]. In addition, an opto-dialysis study showed that infusion of cholinergic antagonists within the BF could prevent the wake-promoting effect of activation of BF cholinergic neurons [ 32 ], indicating the involvement of local non-cholinergic neurons in the cholinergic regulation of sleep and wakefulness.…”