Basal forebrain acetylcholine release during REM sleep is significantly greater than during waking

Cholinergic neurons of the basal forebrain supply the neocortex with ACh and play a major role in regulating behavioral arousal and cortical electroencephalographic activation. Cortical ACh release is greatest during waking and rapid eye movement (REM) sleep and reduced during non-REM (NREM) sleep. Loss of basal forebrain cholinergic neurons contributes to sleep disruption and to the cognitive deficits of many neurological disorders. ACh release within the basal forebrain previously has not been quantified during sleep. This study used in vivo microdialysis to test the hypothesis that basal forebrain ACh release varies as a function of sleep and waking. Cats were trained to sleep in a head-stable position, and dialysis samples were collected during polygraphically defined states of waking, NREM sleep, and REM sleep. Results from 22 experiments in four animals demonstrated that means +/- SE ACh release (pmol/10 min) was greatest during REM sleep (0.77 +/- 0.07), intermediate during waking (0.58 +/- 0.03), and lowest during NREM sleep (0.34 +/- 0.01). The finding that, during REM sleep, basal forebrain ACh release is significantly elevated over waking levels suggests a differential role for basal forebrain ACh during REM sleep and waking.     

Role of the melanin-concentrating hormone neuropeptide in sleep regulation

Melanin-concentrating hormone (MCH), a neuropeptide secreted by a limited number of neurons within the tuberal hypothalamus, has been drawn in the field of sleep only fairly recently in 2003. Since then, growing experimental evidence indicates that MCH may play a crucial role in the homeostatic regulation of paradoxical sleep (PS). MCH-expressing neurons fire specifically during PS. When injected icv MCH induces a 200% increase in PS quantities in rats and the lack of MCH induces a decrease in sleep quantities in transgenic mice. Here, we review recent studies suggesting a role for MCH in the regulation of the sleep–wake cycle, in particular PS, including insights on (1) the specific activity of MCH neurons during PS; (2) how they might be controlled across the sleep–wake cycle; (3) how they might modulate PS; (4) and finally whether MCH might take part in the expression of some symptoms observed in primary sleep disorders.     

Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep

In vivo microdialysis in C57BL/6J (B6) mouse was used to test the hypothesis that activating adenosine A(2A) receptors in the pontine reticular formation (PRF) increases acetylcholine (ACh) release and rapid eye movement (REM) sleep. Eight concentrations of the adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; CGS) were delivered to the PRF and ACh in the PRF was quantified. ACh release was significantly increased by dialysis with 3 mum CGS and significantly decreased by dialysis with 10 and 100 microm CGS. Co-administration of the adenosine A(2A) receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 30 nM) blocked the CGS-induced increase in ACh release. In a second series of experiments, CGS (3 microm) was delivered by dialysis to the PRF for 2 h while recording sleep and wakefulness. CGS significantly decreased time in wakefulness (-51% in h 1; -54% in h 2), increased time in non-rapid eye movement (NREM) sleep (90% in h 1; 151% in h 2), and increased both time in REM sleep (331% in h 2) and the number of REM sleep episodes (488% in h 2). The enhancement of REM sleep is consistent with the interpretation that adenosine A(2A) receptors in the PRF of the B6 mouse contribute to REM sleep regulation, in part, by increasing ACh release in the PRF. A(2A) receptor activation may promote NREM sleep via GABAergic inhibition of arousal promoting neurons in the PRF.     

Muscle tone regulation during REM sleep: neural circuitry and clinical significance

Rapid eye movement (REM) sleep is a distinct behavioral state characterized by an activated cortical and hippocampal electroencephalogram (EEG) and concurrent muscle atonia. Research conducted over the past 50 years has revealed the neuronal circuits responsible for the generation and maintenance of REM sleep, as well as the pathways involved in generating the cardinal signs of REM sleep such as cortical activation and muscle atonia. The generation and maintenance of REM sleep appear to involve a widespread network in the pons and medulla. The caudal laterodorsal tegmental nucleus (cLDT) and sublaterodorsal nucleus (SLD) within the dorsolateral pons contain REM-on neurons, and the ventrolateral periaqueductal grey (vlPAG) contains REM-off neurons. The interaction between these structures is proposed to regulate REM sleep amounts. The cLDT-SLD neurons project to the basal forebrain via the parabrachial-precoeruleus (PB-PC) complex, and this pathway may be critical for the EEG activation seen during REM sleep. Descending SLD glutamatergic projections activate the ventromedial medulla, and spinal cord interneurons mediate muscle atonia and suppress phasic muscle twitches in spinal musculature. In contrast, phasic muscle twitches in the masseter muscles may be driven by glutamatergic neurons in the rostral parvicellular reticular nucleus (PCRt); however, the brain region responsible for generating phasic twitches in the other cranial muscles including facial muscles and tongue are not clear.     

Transcranial electrical currents to probe EEG brain rhythms and memory consolidation during sleep in humans

Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (～0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8-12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25-45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies.     

Neuronal models for sleep-wake regulation and synaptic reorganization in the sleeping hippocampus

In this article, we discuss mathematical models that address the control of sleep-wake behavior in the infant and adult rodent and a model that addresses changes in single-cell firing patterns in the hippocampus across wake and rapid eye movement (REM) sleep states. Each of the models describes the dynamics of experimentally identified neuronal components--either the firing activity of wake-and sleep-promoting neuronal populations or the spiking activity of hippocampal pyramidal neurons. Our discussion of each model illustrates how a mathematical model that describes the temporal dynamics of the modeled neuronal components can reveal specifics about proposed neuronal mechanisms that underlie sleep-wake regulation or sleep-specific firing patterns. For example, the dynamics of the models developed for sleep-wake regulation in the infant rodent lend insight into the involved brain-stem neuronal populations and the evolution of the network during maturation. The results of the model for sleep-wake regulation in the adult rodent suggest distinct properties of the involved neuronal populations and their interactions that account for long-lasting and brief waking bouts. The dynamics of the model for sleep-specific hippocampal neural activity proposes neural mechanisms to account for observed activity changes that can invoke synaptic reorganization associated with learning and memory consolidation.     

Effects of an alkaloid-rich extract from Mitragyna speciosa leaves and fluoxetine on sleep profiles,EEG spectral frequency and ethanol withdrawal symptoms in rats

BackgroundMany antidepressants are effective in alleviating ethanol withdrawal symptoms. However, most of them suppress rapid eye movement (REM) sleep. Thus, development of antidepressants without undesirable side effects would be preferable. Previously, crude alkaloid extract from Mitragyna speciosa (MS) Korth was found to produce antidepressant activities. It was hypothesized that the alkaloid extract from MS may attenuate ethanol withdrawal without REM sleep disturbance.MethodsAdult male Wistar rats implanted with electrodes over the frontal and parietal cortices were used for two separated studies. For an acute study, 10 mg/kg fluoxetine or 60 mg/kg alkaloid extract from MS were administered intragastrically. Electroencephalographic (EEG) signals were recorded for 3 h to examine sleep profiles and EEG fingerprints. Another set of animal was used for an ethanol withdrawal study. They were rendered dependent on ethanol via a modified liquid diet (MLD) containing ethanol ad libitum for 28 days. On day 29, fluoxetine (10 mg/kg) or alkaloid extract from MS (60 mg/kg) were administered 15 min before the ethanol-containing MLD was replaced with an isocaloric ethanol-free MLD to induced ethanol withdrawal symptoms.ResultsThe sleep analysis revealed that alkaloid extract from MS did not change any REM parameters which included average duration of each REM episode, total REM time, number of REM episode and REM latency whereas fluoxetine significantly suppressed all REM parameters and delayed REM latency. However, power spectral analysis revealed similar fingerprints for fluoxetine and alkaloid extract from MS characterized by decreasing powers in the slow frequency range in frontal and parietal cortical EEG. Neither treatment affected spontaneous motor activity. Finally, both alkaloid extract from MS and fluoxetine were found to significantly attenuate ethanol withdrawal-induced hyperexcitability (increases gamma activity) in both cortices and to reduce locomotor activity.ConclusionThe present study demonstrated that the alkaloid extract from MS alleviates ethanol withdrawal severity with no side effect on REM sleep. In addition, these data suggest that suppressive effects on slow frequency powers but not REM sleep may be hallmarks of effective antidepressants for ethanol withdrawal treatment.     

Formation and Dynamics of Waves in a Cortical Model of Cholinergic Modulation

Acetylcholine (ACh) is a regulator of neural excitability and one of the neurochemical substrates of sleep. Amongst the cellular effects induced by cholinergic modulation are a reduction in spike-frequency adaptation (SFA) and a shift in the phase response curve (PRC). We demonstrate in a biophysical model how changes in neural excitability and network structure interact to create three distinct functional regimes: localized asynchronous, traveling asynchronous, and traveling synchronous. Our results qualitatively match those observed experimentally. Cortical activity during slow wave sleep (SWS) differs from that during REM sleep or waking states. During SWS there are traveling patterns of activity in the cortex; in other states stationary patterns occur. Our model is a network composed of Hodgkin-Huxley type neurons with a M-current regulated by ACh. Regulation of ACh level can account for dynamical changes between functional regimes. Reduction of the magnitude of this current recreates the reduction in SFA the shift from a type 2 to a type 1 PRC observed in the presence of ACh. When SFA is minimal (in waking or REM sleep state, high ACh) patterns of activity are localized and easily pinned by network inhomogeneities. When SFA is present (decreasing ACh), traveling waves of activity naturally arise. A further decrease in ACh leads to a high degree of synchrony within traveling waves. We also show that the level of ACh determines how sensitive network activity is to synaptic heterogeneity. These regimes may have a profound functional significance as stationary patterns may play a role in the proper encoding of external input as memory and traveling waves could lead to synaptic regularization, giving unique insights into the role and significance of ACh in determining patterns of cortical activity and functional differences arising from the patterns.     

Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle

Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca²⁺/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.     

Nitrergic Modulation of Hippocampal Acetylcholine Release Is Independent of Endothelial NO Synthase Activity

Nitric oxide (NO) is involved in hippocampal phenomena of synaptic plasticity. The present microdialysis study investigated a possible role of NO and of endothelial NO synthase (eNOS) activity in the control of hippocampal acetylcholine (ACh) release. 3-Morpholinosydnonimine (SIN-1), an NO donor, stimulated ACh release by 50%–70% when infused into the hippocampus of wild type C57B16 mice. Infusion of l-nitroarginine (L-NA), a broad-spectrum inhibitor of NO synthases, decreased hippocampal ACh efflux by approximately 50%. Mice lacking eNOS (eNOS knockouts) had identical basal effluxes of hippocampal ACh as wild type mice, and the responses to SIN-1 and L-NA were unchanged in the absence of eNOS activity. We conclude that nitric oxide (NO) stimulates hippocampal ACh release in a tonic fashion, but independently of eNOS activity.     

Characteristics of rapid eye movement sleep behavior disorder in narcolepsy

The basal forebrain (BF) plays an important role in regulating cortical activity and sleep/wake states. Both cholinergic and non-cholinergic neurons of the BF project to the cerebral cortex and hippocampus, whereas the hypothalamus and brainstem nuclei are mostly innervated by non-cholinergic BF neurons. Neurons in the BF show various discharge profiles in relation to cortical activity and behavioral states and are differentially modulated by neurotransmitters of other sleep/wake regulatory neurons. Recent technical advances have made it possible to correlate discharge profiles of single BF neurons during sleep/wake states with their neurochemical phenotypes, and to make selective lesions of certain cell types. The goal of this review is to summarize the current knowledge of the anatomy and sleep/wake regulatory functions of cholinergic and non-cholinergic BF neurons. We will first review the anatomical heterogeneity of BF neurons, and then discuss recent evidence for the firing patterns of BF cholinergic and non-cholinergic neurons during natural sleep–wake patterns, and finally, discuss their roles in sleep homeostasis. It is proposed that through different neurotransmitters, projections, and state-regulated activity, the cholinergic and non-cholinergic BF neurons collectively and differently regulate cortical activity and sleep-wake states.

     

Odor fear conditioning modifies piriform cortex local field potentials both during conditioning and during post-conditioning sleep

Background

Sleep plays an active role in memory consolidation. Sleep structure (REM/Slow wave activity [SWS]) can be modified after learning, and in some cortical circuits, sleep is associated with replay of the learned experience. While the majority of this work has focused on neocortical and hippocampal circuits, the olfactory system may offer unique advantages as a model system for exploring sleep and memory, given the short, non-thalamic pathway from nose to primary olfactory (piriform cortex), and rapid cortex-dependent odor learning.

Methodology/Principal Findings

We examined piriform cortical odor responses using local field potentials (LFPs) from freely behaving Long-Evans hooded rats over the sleep-wake cycle, and the neuronal modifications that occurred within the piriform cortex both during and after odor-fear conditioning. We also recorded LFPs from naïve animals to characterize sleep activity in the piriform cortex and to analyze transient odor-evoked cortical responses during different sleep stages. Naïve rats in their home cages spent 40% of their time in SWS, during which the piriform cortex was significantly hypo-responsive to odor stimulation compared to awake and REM sleep states. Rats trained in the paired odor-shock conditioning paradigm developed enhanced conditioned odor evoked gamma frequency activity in the piriform cortex over the course of training compared to pseudo-conditioned rats. Furthermore, conditioned rats spent significantly more time in SWS immediately post-training both compared to pre-training days and compared to pseudo-conditioned rats. The increase in SWS immediately after training significantly correlated with the duration of odor-evoked freezing the following day.

Conclusions/Significance

The rat piriform cortex is hypo-responsive to odors during SWS which accounts for nearly 40% of each 24 hour period. The duration of slow-wave activity in the piriform cortex is enhanced immediately post-conditioning, and this increase is significantly correlated with subsequent memory performance. Together, these results suggest the piriform cortex may go offline during SWS to facilitate consolidation of learned odors with reduced external interference.     

Dynamics of spontaneous activity in random networks with multiple neuron subtypes and synaptic noise

During slow-wave sleep, brain electrical activity is dominated by the slow (< 1 Hz) electroencephalogram (EEG) oscillations characterized by the periodic transitions between active (or Up) and silent (or Down) states in the membrane voltage of the cortical and thalamic neurons. Sleep slow oscillation is believed to play critical role in consolidation of recent memories. Past computational studies, based on the Hodgkin-Huxley type neuronal models, revealed possible intracellular and network mechanisms of the neuronal activity during sleep, however, they failed to explore the large-scale cortical network dynamics depending on collective behavior in the large populations of neurons. In this new study, we developed a novel class of reduced discrete time spiking neuron models for large-scale network simulations of wake and sleep dynamics. In addition to the spiking mechanism, the new model implemented nonlinearities capturing effects of the leak current, the Ca²⁺ dependent K⁺ current and the persistent Na⁺ current that were found to be critical for transitions between Up and Down states of the slow oscillation. We applied the new model to study large-scale two-dimensional cortical network activity during slow-wave sleep. Our study explained traveling wave dynamics and characteristic synchronization properties of transitions between Up and Down states of the slow oscillation as observed in vivo in recordings from cats. We further predict a critical role of synaptic noise and slow adaptive currents for spike sequence replay as found during sleep related memory consolidation.     

Alterations in acetylcholine release in the rat hippocampus during sleep-wakefulness detected by intracerebral dialysis

Acetylcholine (ACh) release from the dorsal hippocampus was continuously monitored in freely moving rats during a light period using an intracerebral dialysis technique. A dialysate was collected every 6 min and polygraph recordings including cortical and hippocampal electroencephalograms, electromyogram, and electrooculogram were simultaneously made to determine the stage of sleep-wakefulness. The content of ACh was measured by high-performance liquid chromatography with electrochemical detection. ACh output showed profound and state-dependent fluctuations. ACh levels during waking increased approximately 300% compared to slow wave sleep. In contrast, the rate of ACh release during paradoxical sleep was as high as during waking and appeared to be even higher. These results revealed that the intracerebral dialysis technique provides a useful method to monitor changes in spontaneous neurotransmitter release during the sleep-waking cycle.     

Acetylcholine-gated current translates wake neuronal firing rate information into a spike timing-based code in Non-REM sleep,stabilizing neural network dynamics during memory consolidation

Sleep is critical for memory consolidation, although the exact mechanisms mediating this process are unknown. Combining reduced network models and analysis of in vivo recordings, we tested the hypothesis that neuromodulatory changes in acetylcholine (ACh) levels during non-rapid eye movement (NREM) sleep mediate stabilization of network-wide firing patterns, with temporal order of neurons’ firing dependent on their mean firing rate during wake. In both reduced models and in vivo recordings from mouse hippocampus, we find that the relative order of firing among neurons during NREM sleep reflects their relative firing rates during prior wake. Our modeling results show that this remapping of wake-associated, firing frequency-based representations is based on NREM-associated changes in neuronal excitability mediated by ACh-gated potassium current. We also show that learning-dependent reordering of sequential firing during NREM sleep, together with spike timing-dependent plasticity (STDP), reconfigures neuronal firing rates across the network. This rescaling of firing rates has been reported in multiple brain circuits across periods of sleep. Our model and experimental data both suggest that this effect is amplified in neural circuits following learning. Together our data suggest that sleep may bias neural networks from firing rate-based towards phase-based information encoding to consolidate memories.     

Sleep Supports Memory of Odors in Adults but Not in Children

Sleep supports the consolidation of declarative memory in children and adults. However, it is unclear whether sleep improves odor memory in children as well as adults. Thirty healthy children (mean age of 10.6, ranging from 8–12 yrs.) and 30 healthy adults (mean age of 25.4, ranging from 20–30 yrs.) participated in an incidental odor recognition paradigm. While learning of 10 target odorants took place in the evening and retrieval (10 target and 10 distractor odorants) the next morning in the sleep groups (adults: n = 15, children: n = 15), the time schedule was vice versa in the wake groups (n = 15 each). During encoding, adults rated odors as being more familiar. After the retention interval, adult participants of the sleep group recognized odors better than adults in the wake group. While children in the wake group showed memory performance comparable to the adult wake group, the children sleep group performed worse than adult and children wake groups. Correlations between memory performance and familiarity ratings during encoding indicate that pre-experiences might be critical in determining whether sleep improves or worsens memory consolidation.     

Dopaminergic Regulation of Septohippocampal Cholinergic Neurons

Abstract: The extent to which acetylcholine (ACh) release in the hippocampus is regulated by dopaminergic mechanisms was assessed using in vivo microdialysis in freely moving rats. Systemic administration of the dopamine (DA) receptor agonist apomorphine (1.0 mg/kg) or the specific D₁ agonist CY 208–243 (1.0 mg/kg) increased microdialysate concentrations of ACh in the hippocampus. The D₂ receptor agonist quinpirole (0.5 mg/kg) produced a small but statistically significant decrease in hippocampal ACh release. d -Amphetamine (2.0 mg/kg) increased ACh release, an effect that was blocked by the D₁ receptor antagonist SCH 23390 (0.3 mg/kg) but not by the D₂ antagonist raclopride (1.0 mg/kg). These findings suggest that endogenous DA stimulates septo-hippocampal cholinergic neurons primarily via actions at D₁ receptors. In addition, these results are similar to previous findings regarding the dopaminergic regulation of cortical ACh release, and suggest that the anatomical continuum formed by basal forebrain cholinergic neurons that project to the cortex and hippocampus acts as a functional unit, at least with respect to its regulation by DA.     

Hippocampal ripples and memory consolidation

During slow wave sleep and quiet wakefulness, the hippocampus generates high frequency field oscillations (ripples) during which pyramidal neurons replay previous waking activity in a temporally compressed manner. As a result, reactivated firing patterns occur within shorter time windows propitious for synaptic plasticity within the hippocampal network and in downstream neocortical structures. This is consistent with the long-held view that ripples participate in strengthening and reorganizing memory traces, possibly by mediating information transfer to neocortical areas. Recent studies have confirmed that ripples and associated neuronal reactivations play a causal role in memory consolidation during sleep and rest. However, further research will be necessary to better understand the neurophysiological mechanisms of memory consolidation, in particular the selection of reactivated assemblies, and the functional specificity of awake ripples.