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We investigated cholinergic modulation effects on synchronized burst activity of neurons in rat dissociated cortical cultures on electrode arrays, using a cholinergic agonist, carbachol (CCh). Application of CCh resulted in a loss of regularity, a less precise synchronization, and a fragmentation of the burst structure. We found that temporal properties of spike trains were well-characterized by a simple Poisson cluster-process model, which provided a precise insight into the temporal structure of spike trains and allowed quantitative fitting of the spectral changes induced by CCh. These results should help to elucidate the complex actions of cholinergic modulation on cortical cells in intact neural networks.

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The basal forebrain cholinergic system strongly influences both cortical plasticity and learning. Directly relating these two roles has proven difficult. New results indicate that nucleus basalis lesions prevent motor cortex map plasticity and impair skill learning. These results strengthen the hypothesis that nucleus basalis gates neural plasticity necessary for instrumental learning.

The lateral hypothalamus (LH) is an important center for the integration of autonomic and limbic information and is implicated in the modulation of visceral motor and sensory pathways, including those underlying feeding and arousal behaviors. LH neurons in vitro release both ATP and GABA. The control of ATP and GABA co-transmission in LH may underlie the participation of LH in basic aspects of arousal and reinforcement. LH neurons receive cholinergic input from the pedunculopontine and laterodorsal tegmental nuclei as well as from cholinergic interneurons within the LH per se. This study presents evidence for nicotinic acetylcholine receptor (nAChR)-mediated enhancement of GABAergic, but not of purinergic, transmission despite the co-transmission of ATP and GABA at LH synapses in vitro. Facilitation of GABAergic transmission by nicotine is inhibited by antagonists of (αβ)*-containing nAChRs, but is unaffected by an α7-selective antagonist, consistent with a nAChR-mediated enhancement of GABA release mediated by non-α7-containing nAChRs. Activation of muscarinic ACh receptors enhances the release of ATP while concomitantly depressing GABAergic transmission. The independent modulation of ATP/GABAergic transmission may provide a new level of synaptic flexibility in which individual neurons utilize more than one neurotransmitter but retain independent control over their synaptic activity.

We read with interest the recent study by Imai et al. [7] who provide evidence that muscarinic inhibition of pre-stimulated L-type calcium current ( I CaL) may involve an increase in cGMP levels via particulate guanylyl cyclase. This mechanism is apparent when cAMP has been raised by inhibition of phosphodiesterase. The role of the cGMP pathway in the cholinergic modulation of cardiac excitability is controversial. Han et al. [3] first proposed that stimulation of muscarinic receptors in sinoatrial node cells increases nitric oxide (NO) production via endothelial NO synthase …

ior downstream from the odor source (2) but then lost the odor plume upstream in the jet field. These results suggest that successfully tracking lobsters use similar walking paths independent of signal intermittency. Counter-turning or casting behavior as described for moths (4) was rarely observed. However, tracking success dropped with increasingly intermittent signal conditions. It appears that lobsters require a minimal signal encounter rate to continue tracking the plume successfully to the source. The fact that lobsters stayed mostly within the odor plume boundaries further suggests that they use its internal fine structure for guidance. First and second authors are listed alphabetically; both authors contributed to the experiment equally and in the same manner. r downstream from the odor s urce (2) but then los the odor lume upstream in the jet field. This study was supported by NSF REU Grant (OCE-0097498) to CK and KY, and ONR Grant (N00014-981-0822) to JA.

Rationale: Nicotine is known to facilitate attentional processing, but its role in processing spatial and non-spatial cues is not well established in rodents. Objective: These experiments tested the hypothesis that nicotine facilitates the orienting of attention in space but has no effect on non-spatial cues and that the benefits are blocked by the nicotinic antagonist mecamylamine. Methods: Eight male rats were trained to insert their noses in an opening, which triggered the presentation of cue and target lights in a modified covert orienting task. Four types of trials were presented: valid cues (cue and target lights on the same side of the nose hole), invalid cues (cue and targets on opposite sides), double cues (both cue lights illuminated, target on either side), and no cue (cue lights omitted, targets on either side). The reaction time required to withdraw the nose from the fixation hole (RT) and the time for the rat to move to the feeder (MT) were measured. Results: Nicotine decreased all RTs in a dose-dependent manner but significantly lowered the invalid cue RTs and the validity effect (invalid–valid cue RT). Mecamylamine slowed RTs in a dose-dependent fashion and reduced the validity effect by significantly slowing the valid cue RTs. With mixtures of a fixed strength of nicotine and an increasing dose of mecamylamine, RTs showed nicotine-like effects at low doses and mecamylamine-like effects at high doses. Neither of these drugs had a major effect on non-orienting trials (double and no cue RTs), and the alerting effect (no cue RTs – double cue RTs). Conclusions: Taken together with recent work in humans and non-human primates, these results suggest that the nicotinic cholinergic modulation of visual covert orienting is conserved across species despite different ecological niches.

Cortical cholinergic inputs are hypothesized to mediate attentional functions. The present experiment was designed to determine the single unit activity of neurons within the medial prefrontal cortex (mPFC) of rats performing a sustained visual attention task. Demands on attentional performance were varied by the presentation of a visual distractor. The contribution of cholinergic afferents of the mPFC to performance-associated unit activity within this area was determined by recording neuronal activity before and after unilateral cholinergic deafferentation using intracortical infusion of the immunotoxin 192 IgG-saporin. Presentation of the visual distractor resulted in a decrease in the detection of brief, unpredictable visual signals. As predicted, the unilateral loss of cholinergic inputs within the recording area of the mPFC did not affect sustained attentional performance. Cholinergic deafferentation, however, resulted in a decrease in the overall firing rate of medial prefrontal neurons and a substantial reduction in the proportion of neurons whose firing patterns correlated with specific aspects of behavioral performance. Furthermore, cholinergic deafferentation attenuated the frequency and amplitude of increased mPFC neuronal firing rates that were associated with the presentation of the visual distractor. The main findings from this experiment suggest that cholinergic inputs to the mPFC strongly influence spontaneous and behaviorally correlated single unit activity and mediate increases in neuronal activity associated with enhanced demands for attentional processing, all of which may be fundamental aspects in the maintenance of attentional performance.

Kawaguchi, Yasuo. Selective cholinergic modulation of cortical GABAergic cell subtypes. J. Neurophysiol. 78: 1743–1747, 1997. Acetylcholine from the basal forebrain and γ-aminobutyric acid (GABA) from intracortical inhibitory interneurons exert strong influence on the cortical activity and may interact with each other. Cholinergic or muscarinic agonists indeed induced GABAergic postsynaptic currents in pyramidal cells by exciting inhibitory interneurons that have recently been classified into several distinct subtypes on the basis of the physiological, chemical, and morphological criteria. Cholinergic effects on GABAergic cell subtypes were investigated of rat frontal cortex by in vitro whole cell recording with intracellular staining in frontal cortex of young rats. GABAergic cell subtypes were identified physiologically by firing responses to depolarizing current pulses and immunohistochemically as containing parvalbumin, somatostatin, vasoactive intestinal polypeptide (VIP), or cholecystokinin (CCK). Carbachol (10 μM) or (+)-muscarine (3 μM) affected the activities of peptide-containing GABAergic cells with regular- or burst-spiking characteristics, but not of GABAergic cells with fast-spiking characteristics containing the calcium-binding protein parvalbumin orGABAergic cells with late-spiking characteristics. Somatostatin- or VIP-immunoreactive cells were depolarized with spike firing. CCK-immunoreactive cells were affected heterogeneously by cholinergic agonists. Larger CCK cells were hyperpolarized, followed by a slow depolarization, whereas smaller CCK cells were only depolarized. These results suggest that the excitability of cortical GABAergic cell subtypes is differentially regulated by acetylcholine. Differences in cholinergic responses suggest a distinct functional role of each GABAergic cell subtype.

1. The induction of long-term weakening of synaptic transmission in rat hippocampal slices was examined in CA1 synapses during cholinergic modulation. 2. Bath application of the cholinergic agonist carbachol (50 microM) activated an oscillation of the local field potential in the theta-frequency range (5-12 Hz), termed theta. It was previously shown that a stimulation train of 40 single shocks (at 0.1 Hz) to the Schaffer collateral-commisural afferents, each synchronized with positive peaks of theta, caused homosynaptic long-term enhancement in CA1. Furthermore, long-term depression (LTD) was sporadically observed when the stimulation train was given at negative troughs of theta. Here we have sought to determine stable conditions for LTD induction during theta. 3. Synaptic weakening was reliably obtained, by giving 40 shocks (at 0.1 Hz) at theta-troughs, only in pathways that had been previously potentiated. This decrement, termed theta-LTD, was synapse specific because it did not occur in an independent pathway not stimulated during theta. The interval between the initial potentiating tetanus and theta-LTD induction could be as long as 90 min. 4. theta-LTD could be saturated; after consecutive episodes of theta-LTD induction, no significant further depression was obtained. Moreover, theta-LTD could be reversed by tetanic stimulation. 5. theta-LTD could prevent the induction of LTD by 600-900 pulses at 1 Hz. This suggests that the two protocols may share common mechanisms at the synaptic level. 6. We conclude that single presynaptic spikes that occur at low frequency and are properly timed to the troughs of theta may be a relevant mechanism for decreasing the strength of potentiated synapses.

Cholinergic processes in anterior temporal cortex of rhesus monkeys were identified using immunocytochemical techniques for ChAT. Labeled fibers were present throughout the temporal pole and anterior aspects of the superior temporal, middle temporal, and inferior temporal gyri. ChAT-immunoreactive fibers were most dense in layer I to superficial layer III throughout anterior temporal cortex. In temporal pole, agranular and dysgranular regions had a greater density of labeled fibers in superficial layers as compared to granular regions. In addition to the superficial concentration of cholinergic fibers in lateral temporal regions, numerous labeled fibers were also present in deep cortical layers in the inferior temporal gyrus of lateral temporal cortex, with lesser concentrations of immunoreactive fibers present in these layers in superior and middle temporal gyri. These patterns of cholinergic innervation may reflect the degree of cholinergic modulation of functions in anterior temporal cortex.

Spontaneous contractions (SCs) have been shown to be increased in the overactive bladder and animal models of detrusor overactivity and may underlie the abnormal increases in intravesical pressure which lead to urgency, frequency and urge incontinence. We have previously shown increased SCs in bladder strips from a diabetic rat model. It has been suggested that SCs may be enhanced by leakage of small amounts of acetylcholine from intramural nerves (1). The aim was to study cholinergic modulation of SCs in bladder strips from streptozotocin-induced diabetic rats and the role of the mucosa.

Separate age groups of autoimmune NZB/BINJ and non-autoimmune C57BL/BNNia mice were compared for habituation of locomotor activity and its retention over four separate testing sessions spaced at 24-hr intervals. A decline in locomotion (distance in cm) or in the time spent in the center zone as a function of sessions was taken to indicate retention for habituation to stimuli within the test apparatus. The time spent in the center zone decreased as a function of sessions in young and mature C57BL/6NNia mice but failed to show reliable between-session decreases in old (24–26-months) C57BL/ 6NNia mice. When compared with the old C57BL/6NNia mice, young NZB/BINJ mice showed similar impairments. Habituation of locomotion was present in all age groups of C57BL/6NNia mice, but absent in NZB/BINJ mice regardless of age. The retention impairments of 2–4 month old NZB/BINJ mice were attenuated when i.p. injections of 0.04–0.16 mg physostigmine/kg were given just following each habituation session. The effectiveness of physostigmine was substantially reduced when injections were delayed by 20 min or longer following each habituation session. The time-dependent reversal of the aged-like retention deficits by the cholinesterase inhibitor, physostigmine, suggests that cholinergic modulation of memory storage processes may be impaired in NZB/BINJ mice.

Robert Koch (1843–1910) discovered the causal agents for tuberculosis, cholera, and anthrax. The 1905 Nobel Prize acknowledged Koch's criteria for identifying the causal agent of an infectious disease. These criteria remain useful and the data reviewed below show that the cholinergic contributions to REM sleep control are confirmed by Koch's postulates.[Hobson et al.]

The inhibition of insulin secretion in sheep exposed to cold has been reported to be mediated through adrenergic α receptors stimulated by sympathoadrenomedullary activity (Sasaki and Takahashi, 1980). Insulin secretion in Holstein non-lactating cows in response to various secretogogues was also suppressed during heat exposure (Itoh et al., unpublished data), however it is not obvious whether these responses were related to neural controls or not. However acetylcholine (parasympathetic nervous system neurotransmitter) has been shown to promote the release of glucagon and insulin (Jones et al., 1991). Therefore, the objective of this study was to examine the participation of adrenergic and cholinergic neural control on insulin secretion in thermoneutral and hot environments in non-lactating cows by administering, adrenergic and cholinergic blockers with an intravenous injection of glucose.

The present study was performed to determine the effects of the anticholinergic agent scopolamine and the cholinergic agent physostigmine on tonic immobility in rabbits. Recordings of the electroencephalographic (EEG) activity from cortex and hippocampus were also made before, during, and after each test session. Scopolamine significantly prolonged the response and produced large amplitude slow wave activity in the EEG of both cortex and hippocampus. Physostigmine significantly shortened the duration of immobility and increased rhythmic slow activity in the frequency range of 5.5-9.1 Hz in the hippocampus while producing a desynchronized cortical rhythm. It is suggested that the cortex and hippocampus play a role in modulating tonic immobility duration by inhibiting the brain-stem structures thought to control this response.

The effects of nicotine, carbachol, hexamethonium and scopolamine were investigated on distress vocalizations (DVs) of acutely isolated domestic chicks. Nicotine atenuated, while the antimuscarinic scopolamine increased the frequency of separation-induced DVs. Furthermore, the stress attenuating effects of nicotine were blocked by pretreatment with scopolamine. These results implicate muscarinic receptor participation in the control of separation-induced distress, and support the suggestion that nicotine-induced DV suppression may result from activation of behaviorally relevant muscarinic receptors via central release of acetylcholine.

Limbic evoked potentials (LEPs) were recorded from the hippocampi of three epilepsy surgery patients with unilateral medial temporal lobe seizure onset. In each patient, stable large amplitude LEPs which displayed polarity inversion across successive levels of hippocampus were present unilaterally, but were absent or rudimentary in the hippocampus corresponding to the electrographically proven seizure onset. After administration of scopolamine, LEPs in the "normal" hippocampi were markedly altered with slowing of the individual components and increased trial to trial variability. In addition, two patients developed reliable, high amplitude, polarity inverting LEPs on the side of seizure onset which had either absent or rudimentary LEPs in the baseline state. The results suggest that LEPs are under cholinergic modulation.

A paradigm for studying relations between behavioral, neurochemical, and electrophysiologic processes is presented. Scopolamine, a centrally acting anticholinergic agent, abolished the human auditory P3 event-related potential, but had no measurable effect on the pattern reversal visual evoked potential or alpha rhythm. Recent memory was significantly impaired, but assessment of digit span, reaction time, and distant memory showed no impairment. Physostigmine, an anticholinesterase, restored the P3 and reversed the recent memory impairment. These results strongly suggest a cholinergic role in generation of P3 potential and support the concept that P3 generation is related to memory processes.

1. The association of antagonism of apomorphine-induced climbing with potentiation of apomorphine-induced gnawing in mice has been suggested as a means to detect “atypical” neuroleptics. 2. Clozapine, many compounds with central anticholinergic activity and propranolol have been demonstrated to possess this profile of activities. 3. Pharmacological manipulations with cholinomimetics suggest a cholinergic modulation of the gnawing behavior induced by apomorphine. 4. The observations with propranolol cannot be explained either by a cholinergic link nor by s-adrenergic antagonism.

It is well-known that centrally-acting antagonists of acetylcholine (Ach) can reverse extrapyramidal symptoms in psychotic patients, undergoing neuroleptic drug treatment, apparently without affecting the antipsychotic efficacy of these drugs.

Central cholinergic mechanisms have been implicated in a variety of physiologic processes, including sleep and pain, as well as control of various hormones. Most of the supportive evidence for these relationships have come from laboratory studies of animals rather than man.

Central cholinergic systems have long been implicated in the modulation of learning and memory processes in animals and man. Drugs that affect the central cholinergic system have been found either to enhance or to hinder performance in tests of learning and memory. Few studies have evaluated the effects of different cholinergic drugs within a single experimental paradigm and with a relatively wide dose range. The studies reported here investigated the effects of cholinergic drugs with diverse modes of action on the retention of a passive avoidance response. Physostigmine, arecoline, oxotremorine, nicotine, and 4-aminopyridine were administered IP immediately following the acquisition of a one-trial passive avoidance task. All of the drugs were found to enhance 72-h retention of passive avoidance; however, the effective doses were different for each of the drugs studied.

Rats given d-amphetamine (1 mg/kg) engage in frequent, short-duration rearing responses, whereas rats given methylphenidate (1 mg/kg) make less frequent, long-duration responses. The effects on this behavior of mixing d-amphetamine or methylphenidate with scopolamine or physostigmine suggest that this opposed action on rearing response duration is related to cholinergic-catecholaminergic balance. The anticholinergic agent scopolamine produces changes in rearing response duration similar to those produced by d-amphetamine, while the cholinergic agent physostigmine lengthens response duration and further potentiates this effect of methylphenidate.

This study was initiated to evaluate mechanisms of release of immunoreactive substance P into the peripheral circulation and to determine whether these mechanisms are subject to cholinergic modulation. In conscious dogs, a high-protein meal significantly increased plasma concentrations of immunoreactive substance P from basal levels of 13.7 +/- 1.8 pg/ml to a peak of 20.1 +/- 2.8 pg/ml after which they returned to baseline. Prior atropinization (200 mg/kg) abolished this response and lowered the plasma levels to a nadir of 2.2 pg/ml at 20 min. Similarly, infusion of bombesin (17 ng/kg/min) increased peripheral venous substance P levels by 768 +/- 155 pg-min/ml for 120 min, whereas after prior treatment with atropine, bombesin released no significant amounts of this peptide (-10 +/- 134 pg-min/ml). The data support the concept that substance P release is under cholinergic control.

We investigated whether acetylcholine could antagonize the enhanced vulnerability to ventricular fibrillation evoked by adrenergic stimulation. Epinephrine, 5 X 10(-7)M, caused an 80% reduction in the ventricular fibrillation threshold and a 130% increase in the tissue level of cAMP. Acetylcholine 1 X 10(-7)M, 5 X 10(-7)M, and 1 X 10(-6)M, reduced the epinephrine-induced fall in the ventricular fibrillation threshold by 42%, 100%, and 94%, respectively. This antifibrillatory effect of acetylcholine could not be related to tissue levels of cGMP but rather was associated with reduced tissue levels of cAMP. These results demonstrate cholinergic modulation of the epinephrine-enhanced vulnerability to ventricular fibrillation and suggest that reduced accumulation of cAMP may underlie this effect.

The hippocampus is known to play a crucial role in the formation of long-term memory. For this, fast replays of previously experienced activities during sleep or after reward experiences are believed to be crucial. But how such replays are generated is still completely unclear. In this paper we propose a possible mechanism for this: we present a model that can store experienced trajectories on a behavioral timescale after a single run, and can subsequently bidirectionally replay such trajectories, thereby omitting any specifics of the previous behavior like speed, etc, but allowing repetitions of events, even with different subsequent events. Our solution builds on well-known concepts, one-shot learning and synfire chains, enhancing them by additional mechanisms using global inhibition and disinhibition. For replays our approach relies on dendritic spikes and cholinergic modulation, as supported by experimental data. We also hypothesize a functional role of disinhibition as a pacemaker during behavioral time.