Abstract
Background and objectives
Dexmedetomidine (DEX) is widely used in clinical sedation which has little effect on cardiopulmonary inhibition, however the mechanism remains to be elucidated. The basal forebrain (BF) is a key nucleus that controls sleep-wake cycle. The horizontal limbs of diagonal bundle (HDB) is one subregions of the BF. The purpose of this study was to examine whether the possible mechanism of DEX is through the α2 adrenergic receptor of BF (HDB).
Methods
In this study, we investigated the effects of DEX on the BF (HDB) by using whole cell patch clamp recordings. The threshold stimulus intensity, the inter-spike-intervals (ISIs) and the frequency of action potential firing in the BF (HDB) neurons were recorded by application of DEX (2 µM) and co-application of a α2 adrenergic receptor antagonist phentolamine (PHEN) (10 µM).
Results
DEX (2 µM) increased the threshold stimulus intensity, inhibited the frequency of action potential firing and enlarged the inter-spike-interval (ISI) in the BF (HDB) neurons. These effects were reversed by co-application of PHEN (10 µM).
Conclusion
Taken together, our findings revealed DEX decreased the discharge activity of BF (HDB) neuron via α2 adrenergic receptors.
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Introduction
General anesthetic dexmedetomidine (DEX) is one of the most widely used for sedation and analgesia in intensive care because of its good tolerance and few adverse reactions [1, 2]. Since it produces similar natural sleep effects, most researchers have speculated that it may work through sleep-wake nuclei or related projections [3, 4]. Studies confirmed that it produces sedative or hypnotic effects mainly through the locus coeruleus (LC) which mediates arousal [5, 6]. Because of the electroencephalogram (EEG) produced by DEX similarity to the non-rapid eye movement (NREM) sleep, the idea that an endogenous NREM sleep-promoting system to exert its sedative effects has been proposed [3]. Bilateral ventrolateral preoptic (VLPO) lesions, one of the nuclei regulating NREM sleep, can attenuate the sedative effect of DEX via gamma-aminobutyric (GABA) acid receptor and a α2 adrenergic receptor in rats [7]. However, the role of DEX in regulating other nuclei of NREM sleep remains to be elucidated.
The involvement of hypothalamic sleep pathway plays an important role in general anesthesia [8, 9]. The basal forebrain (BF) is a key nucleus that regulates NREM sleep in hypothalamus [10, 11]. There are four main types of neurons in BF, including cholinergic neuron, glutamatergic neuron, parvalbumin positive GABAergic (GABAPV+) neuron and somatostatin positive GABAergic (GABASOM+) neuron [12,13,14]. Among the four types of neurons in the BF nucleus, only GABASOM+ neuron has the effect of promoting NREM sleep [15, 16]. There are some co-expressed receptors in BF, such as adenosine receptor related to homeostasis and 5-hydroxytryptamine (5-HT) receptor related to sleep-wake [17, 18].
DEX, a selective α2 adrenergic receptor agonist, whose sedative effects may occur through interactions with sleep-related neurons in the hypothalamus [19]. GABAergic neurons of BF innervate neocortex inhibitory interneurons in sleep-wake regulation [20]. GABAergic neurons co-expressed α2 adrenergic receptor in BF express c-Fos during sleep [21]. Immunohistochemical evidence suggests that cholinergic and GABAergic neuron distributed in the horizontal limbs of diagonal bundle (HDB) subarea of BF, which associated with sleep-wake regulation [22, 23]. These evidences suggest that DEX may have an effect on neuronal activity of HDB nuclei, but direct evidence is still lacking. Therefore, in this study, we hypothesize that DEX may have an effect on the neuronal activity of the BF (HDB) nucleus, and through α2 adrenergic receptors.
Materials and methods
Drugs were diluted with extracellular bathing solution to a final concentration of DEX (2 µM, Orion Pharma and Abott, USA) and α2 adrenergic receptor antagonist phentolamine (PHEN) (10 µM, Wedily, Hubei) immediately before the experiments [24]. All other drugs (Sigma-Aldrich, St. Louis, USA) and all solutions (Sigma-Aldrich, St. Louis, USA) were applied using a perfusion pump system (Longerpump, Baoding, China).
Animals
Electrophysiological experiments on brain slices and immunofluorescent staining experiments were performed in male C57BL/6 mice (4 weeks old). Animals were housed under 22–24℃, 40 − 60% humidity with a 12 h:12 h light/dark cycle (lights on at 8:00 am, lights off at 20:00 pm). Food and water were available ad libitum. All experiments were approved by the Experimental Animal Ethics Committee of Anhui Medical University, and adhered to the guidelines of the Institutional Animal Care Unit Committee of Anhui Medical University. All methods were carried out in accordance with relevant guidelines and regulations.
Brain slices preparation
Mice were anesthetized with isoflurane and their brains were quickly decapitated. The slices (300 μm) were cut using a vibratome (Leica Biosystems Inc. Buffalo Grove, United States) which using the prepared continuous in oxygenated (95% O2/5% CO2) artificial cerebrospinal fluid (ACSF) containing (mM) 60 NaCl, 1.25 KCl, 25 NaHCO3, 1.25 NaH2PO4, 25 D-Glucose, 120 Sucrose, 0.1 CaCl2, 3 MgCl2, 5 sodium pyruvate, 2.5 ascorbic acid, pH (7.4 ± 0.5), at 4 °C. Then, the slices were removed and placed into oxygenated ACSF containing (mM) 125 NaCl, 1.25 KCl, 1.25 NaH2PO4, 25 NaHCO3, 25 D-Gluose, 5 sodium pyruvate, 2.5 ascorbic acid, pH (7.4 ± 0.5), at 25 °C for 1 h. The slices were transferred to a submersion chamber perfused with the oxygenated ACSF (30 °C) with a constant perfusion rate at 3ml/min for whole-cell patch clamp recordings.
Whole-cell patch clamp recordings
The neurons were recorded using a MultiClamp-700B amplifier (Molecular Device, San Jose, CA, USA) in current-clamp mode. Electrical signals were recorded using the pClamp-10 software (Axon Instrument Inc., San Jose, CA, USA) for data acquisition and analysis. The pipette solution for recording the spikes contained (in mM) 135 K-gluconate, 10 KCl, 10 HEPES, 0.1 EGTA, 5 Mg-ATP, 0.5 Na-GTP, pH (7.4 ± 0.1). The pipette solutions were freshly made and filtered (0.22 μm) before use. The osmolarity was 305–310 mOsmol, and the pipette resistance was 4–6 MΩ.
BF (HDB) neuron excitability activity was assessed by the threshold stimulus intensity, the inter-spike intervals (ISIs) and the firing frequency of action potentials (APs). The threshold stimulus intensity and ISIs were induced by injecting depolarization pulses under the current mode. The neural-intrinsic properties of the threshold stimulus intensity were used to evaluate the neuronal excitability, which were obtained by injecting a current of threshold stimulus pulses that just enough generated the APs. The ISIs, which represented the time interval between two neighboring spikes under the same stimulus intensity and duration was evaluated the ability to convert excitatory inputs into digital spikes. The firing frequency of spontaneous APs recorded in gap-free mode represents the state of neurons under normal physiological conditions without giving any stimulation. We recorded threshold stimulus intensity, ISIs and frequency before the drug application (approximately 10 min). The three indexes were recorded again during and after the drug application.
Histology and immunohistochemistry
Mice were deeply anesthetized by isoflurane and transcardially perfused with saline (0.9%) followed by 4% paraformaldehyde in PBS. After removal, brains stayed in 4% paraformaldehyde overnight. For cryoprotection, brains were stored in sequence in 20% and 30% sucrose (w/v) in PBS solution at least 1 night. Brains were sliced in 40 μm sections using a frozen slicing machine (CM3050S, Leica). For immunohistochemistry, membrane permeability were increased by using triton-100 (0.03%) and binding sites were blocked by incubating the brain sections in 5% bovine serum albumin (BSA). Brain sections were incubated with the rabbit polyclonal antibody anti-ADRA2 (BIOSS, 1:200, 1062R) diluted in blocking solution overnight. A species-specific secondary antibody anti-Rabbit IgG (H + L) 488 (Thermo A-21,206, 1:800) was diluted in PBS and applied for 2 h at room temperature. Fluorescence images were taken using a confocal microscope (LSM 880 + airyscan, Zeiss).
Statistical analyses
The data from the electrophysiological recordings are presented as the mean ± standard error of the mean (SEM). Statistical analysis was performed using Prism 7.0 (GraphPad Software). The software that analyzes is Clamfit 11. Repeated-measures one-way ANOVA with post hoc comparisons was used in the statistical comparisons of the experimental data before, during and after drug administration in the threshold stimulus intensity, ISIs and firing frequency.
Results
DEX decreased the activity of BF (HDB) nucleus neurons
The specific patterns generated by injection current can characterize the intrinsic characteristics of neurons. We recorded the threshold stimulus intensity and ISIs to detect the excitability of neurons in BF (HDB). The intensity of the injected depolarization pulse that just induced an APs was called the threshold stimulus intensity. Results showed that the threshold stimulus intensity was increased significantly after administration DEX (Fig. 1A-C, P < 0.05, one-way ANOVA followed by Tukey’s test, Baseline vs. DEX, n = 4 neurons from 4 mice). After perfusing the ASCF, the threshold stimulus intensity recovered to the baseline level (Fig. 1C, P < 0.05, one-way ANOVA followed by Tukey’s test, DEX vs. Wash, n = 4 neurons from 4 mice). Then, the ISIs, which represented the time interval between two neighboring spikes under the same stimulus intensity and duration, were also measured (Fig. 2A). DEX significantly enlarged ISIs (Fig. 2B-D, P < 0.05, one-way ANOVA followed by Tukey’s test, Baseline vs. DEX, n = 8 neurons from 8 mice). At the end of the experiments, ISIs recovered to the baseline level (Fig. 2B-D, P < 0.05, one-way ANOVA followed by Tukey’s test, DEX vs. Wash, n = 8 neurons from 8 mice).
Similarly, spontaneous firing frequency of APs were recorded in current gap-free mode. Spontaneous discharge traces before, during after DEX were recorded (Fig. 3A-D). DEX significantly decreased the firing frequency (Fig. 3E, P < 0.05, one-way ANOVA followed by Tukey’s test, Baseline vs. DEX, n = 8 neurons from 8 mice). At the end of the experiments, the firing frequency recovered to the baseline level (Fig. 3E, P < 0.05, one-way ANOVA followed by Tukey’s test, DEX vs. Wash, n = 8 neurons from 8 mice).
Dex modulates neuronal activity of BF (HDB) via α2 adrenergic receptor
In order to understand the mechanism of the effect of DEX on BF (HDB), we first conducted immunofluorescence staining experiment. Given that DEX is a α2 adrenergic receptor agonist, we observe the distribution of α2 adrenergic receptors in the BF (HDB) first. The results showed that there were a large number of α2 adrenergic receptors in BF (HDB) (Fig. 4A). Therefore, we detected whether could reverse this inhibitory effect by administration a α2 adrenergic receptors antagonists PHEN. We found the effects of threshold stimulus intensity (Fig. 4B, P < 0.05, one-way ANOVA followed by Tukey’s test, Baseline vs. DEX, DEX vs. DEX + PHEN, n = 5 neurons from 5 mice), ISI (Fig. 4C-E, P < 0.05, one-way ANOVA followed by Tukey’s test, Baseline vs. DEX, DEX vs. DEX + PHEN, n = 8 neurons from 8 mice) and firing frequency (Fig. 5A-E, P < 0.05, one-way ANOVA followed by Tukey’s test, Baseline vs. DEX, DEX vs. DEX + PHEN, n = 8 neurons from 8 mice) of APs above by administration DEX were reversed after perfusing DEX + PHEN.
Discussion
In this study, we confirmed that in the presence of DEX, the threshold stimulation intensity of the evoked APs in BF (HDB) neurons increased, ISIs of the evoked APs enlarged and the frequency of spontaneous APs decreased. Furthermore, we found that α2 adrenergic receptor antagonists PHEN could reverse the effects of DEX on neurons in the BF (HDB). This founding may add a certain theoretical basis for the use of anesthetics in clinic.
DEX decreased the activity of BF (HDB) nucleus neurons
It was suggested that DEX can reduce neuronal activity of BF (HDB) by comparing the threshold stimulation intensity, ISIs of the evoked APs, and the firing frequency of spontaneous APs (Figs. 1, 2 and 3). This is consistent with previous studies showing that other anesthetics have an inhibitory effect on neurons of the sleep-wake nucleus in the brain. For example, propofol can reduce the intrinsic excitability of cholinergic neurons in substantia innominata (SI) subregion of BF nucleus [25]. There is also evidence that propofol significantly decreased c-Fos expression in wake-related systems [26]. Arousal-related nuclei tuberomammillary nucleus (TMN) histaminergic neurons might be a potential mediator of general anesthetic actions [27]. Activation of serotonergic neurons in the dorsal raphe nucleus (DRN) could facilitate emergence from general anesthesia [28]. Isoflurane and halothane have effect on sleep-active neurons in VLPO [29]. Sleep-promoting preoptic area (POA) neurons are activated by various anesthetics [30]. Zhang et al. found neurons in the mouse lateral preoptic hypothalamic area were sufficient for DEX-induced sedation, as these neurons became active during dex-induced sedation and reactivating them using c-fos activity tagging produced NREM-like sedation [31]. Furthermore, within the lateral preoptic area, genetically lesioning galanin neurons reduced DEX’s ability to induce sedation [32]. Due to the limitation of technology, the research of anesthetics on the central brain is usually limited to a few brain areas or a specific neural circuit. However, whether the inhibitory effect of anesthetics on neurons in the brain is limited or widespread remains unclear. In the future, this is still a problem worth paying attention to.
Dex modulates neuronal activity of BF (HDB) via α2 adrenergic receptor
After administration of antagonist PHEN, the effect of DXE on neuronal activity of BF (HDB) was eliminated (Figs. 4 and 5). The results of immunofluorescence showed that there were a large number of α2 adrenergic receptors in the BF (HDB) (Fig. 4), this is consistent with the above results. However, the types of neurons affected in our study remain unclear. Previous studies focused more on cholinergic neurons in BF (HDB), which are normally arousal-active neurons [33, 34]. Previous studies demostrated alterations of cholinergic neurons in BF (HDB) may give rise to cognitive alterations in neuropsychiatric disorders, Parkinson’s disease and Alzheimer’s disease [35,36,37]. As we all know, The α2 adrenergic receptors is both excitatory and inhibitory. It can be excitatory and couple via Gs [38]. For example, in the dorsal bed nucleus of the stria terminalis, alpha2 agonists can direct cause excitation of target neurons [39]. In our study, Dex activated α2 adrenergic receptor of BF (HDB) neurons has an inhibitory effect, suggests that the neurons affected here may be on inhibitory GABAergic neurons. The action potential firing pattern we recorded was consistent with the fast-firing neuron which is GABAergic of BF (HDB) in previous studies [40, 41]. Studies shown that HDB contain distinct populations of GABAergic neuron, meanwhile it can interact with cholinergic neurons [42,43,44]. There are two main types of GABAergic neurons in the BF (HDB), GABAPV+ and GABASOM+. PV-labelled neurons was be predominately located in vertical limb of the diagonal band (VDB), and much lower in BF (HDB) [45]. We speculate that the neurons recorded in our experiment may be GABASOM+ neurons, but this needs to be further verified in the future.
Conclusion
In the present study, Dex modulates neuronal activity of BF (HDB) via α2 adrenergic Receptor in mice were demonstrated. The key findings of this study are: (1) DEX have an inhibitory effect on the neuronal activity of the BF (HDB) nucleus. (2) Dex modulates neuronal activity of BF (HDB) partly via α2 adrenergic receptor.
Availability of data and material
All materials used for the preparation of this manuscript are publicly available.
The datasets generated available from the corresponding author upon reasonable request.
Abbreviations
- DEX:
-
dexmedetomidine
- LC:
-
locus coeruleus
- EEG:
-
electroencephalogram
- NREM:
-
non-rapid eye movement
- VLPO:
-
ventrolateral preoptic
- GABA:
-
gamma-aminobutyric
- α2A:
-
α2 adrenergic
- BF:
-
basal forebrain
- GABAPV+ :
-
parvalbumin positive GABAergic
- GABASOM+ :
-
somatostatin positive GABAergic
- 5-HT:
-
5-hydroxytryptamine
- HDB:
-
horizontal limbs of diagonal band
- PHEN:
-
phentolamine
- ACSF:
-
artifificial cerebrospinal fluid
- ISIs:
-
inter-spike intervals
- APs:
-
action potentials
- BSA:
-
bovine serum albumin
- SEM:
-
standard error of the mean
- SI:
-
substantia innominata
- TMN:
-
tuberomammillary nucleus
- DRN:
-
dorsal raphe nucleus
- POA:
-
preoptic area
- VDB:
-
vertical limb of the diagonal band
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Acknowledgements
We are grateful to all the participants in this study. Thanks to Qiao-ling Jin and Su-mei Fan for helping me in the experiment.
Funding
This work was supported by National Natural Science Foundation of China (81971236 & 81571293 to Liecheng Wang), the Natural Science Foundation of Anhui Province (2108085QH332 to Lei Chen), the Clinical Trial Fundation of the First Affiliated Hospital of Anhui University of Chinese Medicine (2020yfyzc50 to Lei Chen).
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X.W.Z: conceptualization, methodology, software, analysis. L.C:methodology, software, writing-original draft, writing-review and editing. C.F.C: reanalysis, writing-review. J.C: methodology. P.P.Z: analysis. L.C.W: resources, supervision, writing-original draft, and writing-review & editing. All the authors reviewed the manuscript.
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All experiments were approved by the Experimental Animal Ethics Committee of Anhui Medical University, and adhered to the guidelines of the Institutional Animal Care Unit Committee of Anhui Medical University, with project number LLSC20190763. All methods were carried out in accordance with ARRIVE guidelines for the reporting of animal experiments.
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Zhang, Xw., Chen, L., Chen, Cf. et al. Dexmedetomidine modulates neuronal activity of horizontal limbs of diagonal band via α2 adrenergic receptor in mice. BMC Anesthesiol 23, 327 (2023). https://doi.org/10.1186/s12871-023-02278-8
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DOI: https://doi.org/10.1186/s12871-023-02278-8