Brainstem Cholinergic System Research Articles

The hyperexcitability of laterodorsal tegmentum cholinergic neurons accompanies adverse behavioral and cognitive outcomes of prenatal stress

Exposure to prenatal stress (PS) leads to the offspring's vulnerability towards the development of cognitive and behavioral disorders. Laterodorsal tegmentum (LDT) is a part of the brainstem cholinergic system that is believed to play a pivotal role in the stress-associated progression of anxiety, memory impairment, and addictive behaviors. In this study, we aimed to investigate the electrophysiological alterations of LDT cholinergic neurons and its accompanied behavioral and cognitive outcomes in the offspring of mice exposed to physical or psychological PS. Swiss Webster mice were exposed to physical or psychological stress on the tenth day of gestation. Ex vivo investigations in LDT brain slices of adolescent male offspring were performed to evaluate the effects of two stressor types on the activity of cholinergic neurons. Open field test, elevated plus maze, passive avoidance test, and conditioned place preference were conducted to assess behavioral and cognitive alterations in the offspring. The offspring of both physical and psychological PS-exposed mice exhibited increased locomotor activity, anxiety-like behavior, memory impairment, and preference to morphine. In both early- and late-firing cholinergic neurons of the LDT, stressed groups demonstrated higher firing frequency, lower adaptation ratio, decreased action potential threshold, and therefore increased excitability compared to the control group. The findings of the present study suggest that the hyperexcitability of the cholinergic neurons of LDT might be involved in the development of PS-associated anxiety-like behaviors, drug seeking, and memory impairment.

Immunohistochemical study of the brainstem cholinergic system in the alpaca (Lama pacos) and colocalization with CGRP.

Several cholinergic regions have been detected in the brainstem of mammals. In general, these regions are constant among different species, and the nuclear complement is maintained in animals belonging to the same order. The cholinergic system of the brainstem has been partially described in Cetartiodactyla, except for the medulla oblongata. In this work carried out in the alpaca, the description of the cholinergic regions in this order is completed by the immunohistochemical detection of the enzyme choline acetyltransferase (ChAT). In addition, using double immunostaining techniques, the relationship between the cholinergic system and the distribution of calcitonin gene-related peptide (CGRP) previously described is analysed. Although these two substances are found in several brainstem regions, the coexistence in the same cell bodies was observed only in the laterodorsal tegmental nucleus, the nucleus ambiguus and the reticular formation. These results suggest that the interaction between ChAT and CGRP may be important in the regulation of voluntary movements, the control of rapid eye movement sleep and states of wakefulness as well as in reward mechanisms. Comparing the present results with others previously obtained by our group regarding the catecholaminergic system in the alpaca brainstem, it seems that CGRP may be more functionally related to the latter system than to the cholinergic system.

Carbachol and Nicotine in Prefrontal Cortex Have Differential Effects on Sleep-Wake States.

The role of the brainstem cholinergic system in the regulation of sleep-wake states has been studied extensively but relatively little is known about the role of cholinergic mechanisms in prefrontal cortex in the regulation of sleep-wake states. In a recent study, we showed that prefrontal cholinergic stimulation in anesthetized rat can reverse the traits associated with anesthesia and restore a wake-like state, thereby providing evidence for a causal role for prefrontal cholinergic mechanisms in modulating level of arousal. However, the effect of increase in prefrontal cholinergic tone on spontaneous sleep-wake states has yet to be demonstrated. Therefore, in this study, we tested the hypothesis that delivery of cholinergic agonists – carbachol or nicotine – into prefrontal cortex of rat during slow wave sleep (SWS) would produce behavioral arousal and increase the time spent in wake state. We show that unilateral microinjection (200 nL) of carbachol (1 mM) or nicotine (100 mM) into prefrontal cortex during SWS decreased the latency to the onset of wake state (p = 0.03 for carbachol, p = 0.03 for nicotine) and increased the latency to the onset of rapid eye movement sleep (p = 0.008 for carbachol, p = 0.006 for nicotine). Although the infusion of 1 mM carbachol increased the time spent in wake state (p = 0.01) and decreased the time spent in SWS (p = 0.01), infusion of 10 or 100 mM nicotine did not produce any statistically significant change in sleep-wake architecture. These data demonstrate a differential role of prefrontal cholinergic receptors in modulating spontaneous sleep-wake states.

Effects of chronic alcohol consumption and withdrawal on the cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei of the rat: An unbiased stereological study

The brain cholinergic system comprises two main recognized subdivisions, the basal forebrain and the brainstem cholinergic systems. The effects of chronic alcohol consumption on the basal forebrain cholinergic nuclei have been investigated extensively, but there is only one study that has examined those effects on the brainstem cholinergic nuclei. The last one comprises the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei, which are known to give origin to the main cholinergic projection to the ventral tegmental area, a key brain region of the neural circuit, the mesocorticolimbic system, that mediates several behavioral and physiological processes, including reward. In the present study, we have examined, using stereological methods, the effects of chronic alcohol consumption (6 months) and subsequent withdrawal (2 months) on the total number and size of PPT and LDT choline acetyltransferase (ChAT)-immunoreactive neurons. The total number of PPT and LDT ChAT-immunoreactive neurons was unchanged in ethanol-treated and withdrawn rats. However, ChAT-immunoreactive neurons were significantly hypertrophied in ethanol-treated rats, an alteration that did not revert 2 months after ethanol withdrawal. These results show that prolonged exposure to ethanol leads to long-lasting, and potentially irreversible, cytoarchitectonic and neurochemical alterations in the brainstem cholinergic nuclei. These alterations suggest that the alcohol-induced changes in the brainstem cholinergic nuclei might play a role in the mechanisms underlying the development of addictive behavior to alcohol.

A spatial covariance 123I-5IA-85380 SPECT study of α4β2 nicotinic receptors in Alzheimer's disease

Alzheimer's disease (AD) is characterized by widespread degeneration of cholinergic neurons, particularly in the basal forebrain. However, the pattern of these deficits and relationship with known brain networks is unknown. In this study, we sought to clarify this and used 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (1235IA-85380) single photon emission computed tomography to investigate spatial covariance of α4β2 nicotinic acetylcholine receptors in AD and healthy controls. Thirteen AD and 16 controls underwent 1235IA-85380 and regional cerebral blood flow (99mTc-exametazime) single photon emission computed tomography scanning. We applied voxel principal component (PC) analysis, generating series of principal component images representing common intercorrelated voxels across subjects. Linear regression generated specific α4β2 and regional cerebral blood flow covariance patterns that differentiated AD from controls. The α4β2 pattern showed relative decreased uptake in numerous brain regions implicating several networks including default mode, salience, and Papez hubs. Thus, as well as basal forebrain and brainstem cholinergic system dysfunction, cholinergic deficits mediated through nicotinic acetylcholine receptors could be evident within key networks in AD. These findings may be important for the pathophysiology of AD and its associated cognitive and behavioral phenotypes.

Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline.

In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions.

Study on effect and mechanism of cinnabaris and realgar in promoting awake of endotoxin-induced brain injury rat applied with Angong Niuhuang Wan

To explore the effect and mechanism of cinnabaris and realgar in promoting awake effect of endotoxin- induced brain injury rat applied with Angong Niuhuang Wan. Normal rats implanted cortical electrode in advance were divided into 6 groups: control, model, the Angong Niuhuang Wan (AGNH, 0.4, 0.2 g · kg(-1)), the Angong Niuhuang Wan without cinnabaris and realgar (QZX-AGNH, 0.32, 0.16 g · kg(-1)). Rats in the control and model groups were given distilled water. After three days of intragastric administration, the brain injury model was injected with endotoxin through tail vein. Then trace electro-corticogram (EcoG) 1-6 h after LPS injection, and compare the power and relative power of beta (β) and delta-waves (δ) at 6 h of these groups. The content of acetylcholine (Ach) and the affinity of M-receptor (M-R) in cortex and brainstem were detected by alkaline hydroxylamine colorimetric method and radioactive ligand binding assay, respectively. AGNH (0.4, 0.2 g · kg(-1)) could increase the power and relative power of β and AGNH (0.4 g · kg(-1)) showed better action on brain electrical activation. QZX-AGNH showed weak effect on it. AGNH (0.4 g · kg(-1)) could increase the affinity of M-R in cortex and the content of Ach in brainstem. The action of QZX-AGNH was not obvious. In endotoxin-induced brain injury rats, AGNH can raise the cholinergic system function of cortex, and strengthen the uplink of cortex activation of brainstem cholinergic system, improve the level of cortical activity and enhance the activation of EcoG to promote the body's awakening. QZX-AGNH show weak effect. Cinnabaris and realgar play an important role in promoting awake effect in endotoxin-induced brain injury applied with Angong Niuhuang Wan. The mechanism may be related to cortical and brainstem cholinergic system function.

Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits

Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity.

Muscarinic Receptor Occupancy and Cognitive Impairment: A PET Study with [11C](+)3-MPB and Scopolamine in Conscious Monkeys

The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with the mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre-, 2, 6, 24, and 48 h post-intramuscular administration of scopolamine in doses of 0.01 and 0.03 mg/kg. Occupancy levels of mAChR were maximal 2 h post-scopolamine in cortical regions innervated primarily by the basal forebrain, thalamus, and brainstem, showing that mAChR occupancy levels were 43-59 and 65-89% in doses of 0.01 and 0.03 mg/kg, respectively. In addition, dose-dependent impairment of working memory performance was measured 2 h after scopolamine. A positive correlation between the mAChR occupancy and cognitive impairment 2 and 6 h post-scopolamine was the greatest in the brainstem (P<0.00001). Although cognitive impairment was not observed 24 h post-scopolamine, sustained mAChR occupancy (11-24%) was found with both doses in the basal forebrain and thalamus, but not in the brainstem. These results indicate that a significant degree of mAChRs occupancy is needed to produce cognitive impairment by scopolamine. Furthermore, the importance of the brainstem cholinergic system in working memory in monkey is described.

Cholinergic Responses in Crossed Tecto-Reticular Neurons of Rat Superior Colliculus

Neurons in the intermediate gray layer (SGI) of mammalian superior colliculus (SC) receive cholinergic innervation from the brain stem parabrachial region, which seems to modulate the signal processing in the SC. To clarify its role particularly in orienting behaviors, we studied cholinergic effects on the major output neuron group of the SGI, crossed tecto-reticular neurons (cTRNs), identified by retrograde labeling from the contralateral brain stem gaze center in SC slices obtained from rats (PND 17-22) by whole cell patch-clamp techniques. Bath application of carbachol induced either 1) nicotinic inward (nIN) + muscarinic inward (mIN) (11/24) or 2) nIN + mIN + muscarinic outward (mOUT) (13/24) current responses. Transient pressure application of 1 mM acetylcholine elicited nIN in all neurons tested (n = 58). In a majority of these neurons (52/58), the nIN was completely suppressed by dihydro-beta-erythroidine, a specific antagonist for alpha4beta2 nicotinic receptor subtype. The remaining 6/58 neurons exhibited not only the slower alpha4beta2 receptor-mediated component but also a faster component that was inhibited by a specific antagonist for alpha7 nicotinic receptor, alpha-bungarotoxin. cTRNs expressing alpha7 nicotinic receptors tended to be smaller in size than those lacking alpha7 receptors. Bath application of muscarine induced two response patterns: mIN only (17/38) and mIN+ mOUT (21/38). The mIN and mOUT were mediated by M3 (plus M1) and M2 muscarinic receptors, respectively. These results suggest that a major response to cholinergic inputs to cTRNs is excitatory. This would indicate the facilitatory role of the brain stem cholinergic system in the execution of orienting behaviors including saccadic eye movements.

Do multiple cortical–subcortical interactions support different aspects of consciousness?

Merker's core idea, that the experience of being conscious reflects the interactions of actions, targets, and motivations in the upper brainstem, with cortex providing the content of the conscious experience, merits serious consideration. However, we have two areas of concern: first, that his definition of consciousness is so broad that it is difficult to find any organisms with a brain that could be non-conscious; second, that the focus on one cortical–subcortical system neglects other systems (e.g., basal forebrain and brainstem cholinergic systems and their cortical and thalamic target areas) which may be of at least equal significance.

Cholinergic Regulation of the Posterior Medial Thalamic Nucleus

We previously showed that the GABAergic nucleus zona incerta (ZI) suppresses vibrissae-evoked responses in the posterior medial (POm) thalamus of the rodent somatosensory system. We proposed that this inhibitory incertothalamic pathway regulates POm responses during different behavioral states. Here we tested the hypothesis that this pathway is modulated by the ascending brain stem cholinergic system, which regulates sleep-wake cycles and states of vigilance. We demonstrate that cholinergic inputs facilitate POm responses to vibrissae stimulation. Activation of the cholinergic system by stimulation of brain stem cholinergic nuclei (laterodorsal tegmental and the pedunculopontine tegmental) or by tail pinch significantly increased the magnitude of POm responses to vibrissae stimulation. Microiontophoresis of the muscarinic receptor agonist carbachol enhanced POm responses to vibrissae stimulation. Application of carbachol to an in vitro slice preparation reduced the frequency but not the amplitude of miniature inhibitory postsynaptic currents, indicating a presynaptic site of action for carbachol. We conclude that the cholinergic system facilitates POm responses by suppressing GABAergic inputs from ZI. We propose the state-dependent gating hypothesis, which asserts that differing behavioral states, regulated by the brain stem cholinergic system, modulate the flow of information through POm.

State-Dependent Gating of Sensory Inputs by Zona Incerta

We have previously shown that the GABAergic nucleus zona incerta (ZI) suppresses vibrissae-evoked responses in the posterior medial (POm) thalamus of the rodent somatosensory system. We proposed that this inhibitory incerto-thalamic pathway regulates POm responses during different behavioral states. Here we tested the hypothesis that the cholinergic reticular activating system, implicated in regulating states of arousal, modulates ZI activity. We show that stimulation of brain stem cholinergic nuclei (laterodorsal tegmental and pedunculopontine tegmental) results in suppression of spontaneous firing of ZI neurons. Iontophoretic application of the cholinergic agonist carbachol to ZI neurons suppresses both their spontaneous firing and their vibrissae-evoked responses. We also found that carbachol application to an in vitro slice preparation suppresses spontaneous firing of neurons in the ventral sector of ZI (ZIv). Finally, we demonstrate that the majority of ZIv neurons contain parvalbumin and project to POm. Based on these results, we present the state-dependent gating hypothesis, which states that differing behavioral states-regulated by the brain stem cholinergic system-modulate ZI activity, thereby regulating the response properties of higher-order nuclei such as POm.

Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes

The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3alpha,5alpha THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory. To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems. We carried out keyword searches in "Medline" to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents. Peripheral and central administrations of PREGS, DHEAS, and 3alpha,5alpha THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneurons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting reports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions. The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.

Cognitive function of the brainstem cholinergic system

A major population of cholinergic projection neurons is located in the pedunculopontine and laterodorsal tegmental nuclei in the midbrain. Although much work has been performed on their role in the regulation of sleep and wakefulness, their function in the awake state is not well understood. We made single unit recordings in the pedunculopontine tegmental nucleus (PPTN) of macaque monkeys during visually guided saccade tasks. Three major types of neuron activities were observed. The first was tonic or phasic increase in activity around the time of fixation point onset and closely correlated with the performance of the monkey in the coming saccade task. The second was the activity related to preparation and execution of saccades. The third was the activity related to reward delivery. A subpopulation of PPTN neurons exhibited more than two types of activities. We conclude from these findings that the PPTN may serve as an integrative interface between various signals required for performance of purposive behaviors.

Sensory-motor gating and cognitive control by the brainstem cholinergic system

As an essential component of ascending activating systems, cholinergic neurons with diffuse projections are supposed to be involved in the regulation of cognitive processes such as attention, consciousness, learning, and memory. As for the role of cholinergic projections from the basal forebrain nuclei to cerebral cortical regions including hippocampus, a couple of models have been proposed that acetylcholine facilitates extrinsic inputs to the cortex and inhibits intracortical processing. In this review, to explore the possibility that there exists a generalized principle on the role of cholinergic systems in the brain, we summarized the knowledge so far obtained on the action of a brainstem cholinergic nucleus, the pedunculopontine tegmental nucleus (PPTN) at their target regions. By in vitro experiments we clarified that cholinergic inputs to the intermediate layer of the superior colliculus, presumably originating from the PPTN, facilitate generation of its motor outputs for the initiation of saccades. Furthermore, cholinergic inputs may enhance excitatory responses of mesopontine dopaminergic cells, for instance to reward-related signals. In addition, we observed that PPTN neurons showed multi-modal activities in behaving monkeys; their activities were related to execution and preparation of saccades, the level of task performance, and reward. The multi-modal activities encoded in the PPTN may suggest that PPTN associates movement-related activities with those related to task performance and reward. Together with the already reported facilitatory action on the sensory processing at the visual thalamus, these observations suggest that the brainstem cholinergic system facilitates the central processes for motor command generation and extrinsic sensory processing. For our final goal of exploring the general working principle of the cholinergic systems, further studies are needed to clarify the effects of the brainstem cholinergic system on the intrinsic processing in the brain.

Evaluation of Muscarinic M2 Receptor Sites in Basal Forebrain and Brainstem Cholinergic Systems of Behaviorally Characterized Young and Aged Long-Evans Rats

Aged (23–25-month-old) male Long-Evans rats were assessed for deficits in spatial cognition relative to young (4–6-month-old) rats. An in vitro autoradiography study was then conducted for muscarinic M2 sites using [ 3H]AF-DX 384 to assess binding in basal forebrain and brainstem areas where cholinergic neurons are localized. The analysis of basal forebrain included the medial septal/diagonal band region that provides cholinergic innervation of the hippocampus; the laterodorsal tegmental nucleus and pedunculopontine tegmental nucleus were analyzed in the brainstem. A significant age-related reduction in M2 binding was found in both the basal forebrain and brainstem. Only the reduction in the basal forebrain, however, was correlated with spatial learning impairment. Although the basal forebrain and brainstem cholinergic systems are each vulnerable in normal aging, contributions to the behavioral effects of aging may be distinctive for the two systems.

Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep-related symptoms, such as cataplexy. The exact pathophysiology underlying the disease is unknown but may involve central cholinergic systems. It is known that the brainstem cholinergic system is activated during REM sleep. Furthermore, REM sleep and REM sleep atonia similar to cataplexy can be triggered in normal and narcoleptic dogs by stimulating cholinergic receptors within the pontine brainstem. The pontine cholinergic system is, therefore, likely to play a role in triggering cataplexy and other REM-related abnormalities seen in narcolepsy. The other cholinergic system that could be involved in the pathophysiology of narcolepsy is located in the basal forebrain (BF). This system sends projections to the entire cerebral cortex. Since acetylcholine release in the cortex is increased both during REM and wake, the basocortical cholinergic system is believed to be involved in cortical desynchrony. In the current study, we analyzed the effect of cholinergic compounds injected into the forebrain structures of narcoleptic and control dogs. We found that carbachol (a cholinergic agonist) injected into the BF triggers cataplexy in narcoleptic dogs while it increases wakefulness in control dogs. Much higher doses of carbachol bilaterally injected in the BF were, however, shown to trigger muscle atonia even in control dogs. These results suggest that a cholinoceptive site in the BF is critically implicated in triggering muscle atonia and cataplexy. Together with similar results previously obtained in the pontine brainstem, it appears that a widespread hypersensitivity to cholinergic stimulation may be central to the pathophysiology of canine narcolepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal activity in the peribrachial area: Relationship to behavioral state control

Extensive studies have ascribed a role to the brainstem cholinergic system in the generation of rapid eye movement (REM) sleep and ponto-geniculo-occipital (PGO) waves. Much of this work stems from systemic and central cholinergic drug administration studies. The brainstem cholinergic system is also implicated in cortical activation via basal forebrain, thalamic, and hypothalamic relay neurons. This cholinergic ascending reticular activating hypothesis has also been suggested by in vivo experiments under anesthetics and by in vitro studies using cholinergic agonists in thalamic and hypothalamic slices. During the last ten years, brainstem cholinergic neurons have been discovered to be in the peribrachial area (PBL). With the discovery of PBL cholinergic neurons, many studies were devoted to the examination of PBL neuronal activity and their connectivity. This article reviews PBL neuronal activity in behaving animals and the anatomical features of these neurons in relation to behavioral state control. The role of the PBL in the generation of REM sleep, PGO waves, and the ascending reticular activating system (ARAS) has been evaluated at the cellular and neurochemical level. Based on recent literature, tentative mechanisms of REM sleep generation, PGO waves generation, and the cortical activation process are also outlined.

Extracellular characteristics of putative cholinergic neurons in the rat laterodorsal tegmental nucleus

The extracellular electrophysiological properties of neurons in the laterodorsal tegmental nucleus (LDT), a major source of cholinergic afferents to the thalamus, were studied in chloral hydrate-anesthetized rats. A combination of antidromic activation from the thalamus and histological verification of recording sites was used to correlate the identity of extracellular recordings in the rat LDT with cholinergic neurons in that region. All neurons antidromically activated by stimulation of the anteroventral thalamus were histologically verified to be within clusters of cholinergic (NADPH-d-positive) cells in the LDT or in the adjacent nucleus locus coeruleus (LC). The thalamically projecting LDT neurons had a homogeneous neurophysiological profile consisting of long duration action potentials (mean= 2.5 ms), slow conduction velocities (mean= 0.78 m/s), and lengthy chronaxie values (mean= 0.725 ms). The appearance and axonal characteristics of these neurons resembled those of noradrenergic LC neurons, but the two populations exhibited substantially different spontaneous activity patterns and sensory responsiveness. These characteristics may be useful in the preliminary identification of putative cholinergic neurons in vivo, and thereby provide a foundation for exploring the neuropharmacology, afferent modulation, sensory responsiveness and behavioral correlates of the brainstem cholinergic system.