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R Metherate

Publications and source records attributed to R Metherate.

At least 19 recordsLinked to original sources
PubMed1998

Nicotine selectively enhances NMDA receptor-mediated synaptic transmission during postnatal development in sensory neocortex.

The neurotransmitters acetylcholine (ACh) and glutamate have been separately implicated in synaptic plasticity during development of sensory neocortex. Here we show that these neurotransmitters can, in fact, act synergistically via their actions at nicotinic ACh receptors (nAChRs) and NMDA receptors, respectively. To determine how activation of nAChRs modifies glutamatergic EPSPs, we made whole-cell recordings from visualized pyramidal neurons in slices of rat auditory cortex. Pulsed (pressure) ejection of nicotine onto apical dendrites selectively enhanced EPSPs mediated by NMDA receptors without affecting AMPA/kainate (AMPA/KA) receptor-mediated EPSPs. The enhancement occurred during a transient, postnatal period of heightened cholinergic function [neurons tested on postnatal day 8-16 (P8-16)], and not in the mature cortex (>P19). Three related findings indicated the mechanism of action: (1) The specific alpha7 nAChR antagonist methyllycaconitine citrate (MLA) blocked the effect of nicotine; (2) pulsed nicotine did not enhance postsynaptic depolarizations induced by iontophoretically applied NMDA; and (3) bath exposure to nicotine for several minutes produced apparent nAChR desensitization and precluded enhancement of EPSPs by pulsed nicotine. Together, the data suggest that nicotine acts at rapidly desensitizing, presynaptic alpha7 nAChRs to increase glutamate release onto postsynaptic NMDA receptors. The synergistic actions mediated by alpha7 nAChRs and NMDA receptors may contribute to experience-dependent synaptic plasticity in sensory neocortex during early postnatal life.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1998

Synaptic mechanisms in auditory cortex function.

Neurons in the auditory cortex (AC) respond to acoustic stimuli in diverse ways. Short latency responses code for the physical properties of stimuli, i.e., their frequency and intensity, whereas longer latency potentials may code for behavioral significance or other features. Despite a huge number of studies that, over the years, have reported on acoustic-evoked short and long-latency potentials, remarkably little is understood regarding the cellular mechanisms underlying these responses. Such information is critical to a full understanding of auditory information processing. This review summarizes the available data on synaptic and cellular mechanisms in AC neurons that have been obtained using electrophysiological methods with in vivo and in vitro preparations. It is apparent that the fundamental mechanisms identified in recent studies can be used in the near future to develop an integrated understanding of the cellular bases of information processing in auditory cortex.

Animals↗
PubMed1995

GABAergic suppression prevents the appearance and subsequent fatigue of an NMDA receptor-mediated potential in neocortex.

We have investigated the regulation of an N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potential by gamma-aminobutyric acid (GABA)-mediated inhibition using extracellular and whole-cell voltage clamp recordings in rat auditory cortex in vitro. Single afferent stimulus pulses at low intensity elicited a slow extracellular negativity (Component C) that was mediated by NMDA receptors. At higher intensities, Component C was suppressed by recruitment of GABAergic inhibition. To understand the actions of GABAergic inhibition on Component C, we determined the effects of: (i) paired-pulse stimulation, which depresses GABAergic inhibition; (ii) pharmacological antagonism of GABA receptors; and (iii) afferent stimulation in slices from neonatal rats prior to the development of cortical inhibition. The results indicate that GABAergic inhibition prevents Component C from occurring, thereby preventing its reduction upon repeated stimulation. Whole-cell voltage clamp recordings were used to test the hypothesis that GABAergic suppression occurred by way of membrane hyperpolarization. At hyperpolarized holding potentials no NMDA receptor-mediated synaptic current was elicited, even with paired-pulse stimulation. At depolarized holding potentials a significant NMDA synaptic current was elicited despite the presence of GABAergic synaptic currents. We conclude that membrane hyperpolarization by GABAergic inhibition prevents the appearance and subsequent fatigue of an NMDA receptor-mediated synaptic potential. Reduction of inhibition can act as a 'switch' to fully release the NMDA potential as frequently as once every 10-20 s.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Synaptic interactions involving acetylcholine, glutamate, and GABA in rat auditory cortex.

Using electrophysiological techniques in the in vitro rat auditory cortex, we have examined how spontaneous acetylcholine (ACh) release modifies synaptic potentials mediated by glutamate and gamma-aminobutyric acid (GABA). Single stimulus pulses to lower layer VI elicited in layer III a four-component (A-D) extracellular field response involving synaptic potentials mediated by glutamate and GABA. The cholinesterases inhibitor eserine (10-20 microM) or the cholinergic agonist carbachol (25-50 microM) depressed by 10-50% the glutamatergic components A and C, and the GABAergic components B and D. Atropine reversed the depressive effects of eserine and carbachol. A novel finding was that the degree of depression of component A varied inversely with stimulus intensity. However, during partial pharmacological antagonism of GABAA receptors, depression of A varied directly, not inversely, with stimulus intensity. Normally, then, depression of A is offset by reduced GABAergic inhibition of A. We also tested for differential depression of responses mediated by N-methyl-D-aspartate (NMDA) versus non-NMDA glutamate receptors. Following physiological and pharmacological isolation of the responses, eserine depressed the non-NMDA, but not the NMDA, receptor-mediated potential. Since the isolated NMDA potential still could be depressed by carbachol, the data suggested that activation of NMDA receptors may reduce spontaneous ACh release. In support of this, preincubation of slices in NMDA (10-20 microM) largely prevented eserine's, but not carbachol's, depression of components A and B. These results permit three conclusions of relevance to cortical information processing: (1) spontaneous ACh release tonically depresses synaptic potentials mediated by glutamate and GABA; (2) ACh depresses responses to weak inputs to a greater degree than responses to strong inputs: (3) activation of NMDA receptors may "feedback" to reduce ACh release, a mechanism that could place regulation of local ACh release under glutamatergic afferent control.

Acetylcholine↗
PubMed1994

Facilitation of an NMDA receptor-mediated EPSP by paired-pulse stimulation in rat neocortex via depression of GABAergic IPSPs.

1. Tight seal, whole-cell recordings from auditory cortex in vivo and in vitro were obtained to investigate modification of N-methyl-D-aspartate (NMDA) receptor-mediated synaptic activity by paired-pulse afferent stimulation. 2. In recordings from urethane-anaesthetized rats (at 37 degrees C), or from cortical slices maintained in vitro (32 degrees C), afferent stimulation elicited a monosynaptic early EPSP and polysynaptic early and late IPSPs. In addition, a late EPSP could be elicited when the stimulus was preceded by an identical priming stimulus (interval approximately 200 ms). The late EPSP was attenuated by the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (APV, 50 microM). 3. Bath application of the gamma-aminobutyric acid-B (GABAB) receptor antagonist 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid (2-OH-saclofen; 50 microM) attenuated the late IPSP and clearly revealed a late EPSP. However, 2-OH-saclofen had lesser effects on the second late EPSP elicited during paired-pulse stimulation. Membrane depolarization in 2-OH-saclofen increased the magnitude of the early IPSP, which suppressed the late EPSP once again. Since pharmacological blockade of EPSPs revealed paired-pulse depression of monosynaptically elicited early and late IPSPs, these data indicate that (1) both early and late IPSPs were capable of suppressing the late EPSP, and (2) these effects were reduced during paired-pulse stimulation. 4. Pharmacological isolation of the late EPSP allowed testing of the direct effect of paired-pulse stimulation. Application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20 microM), picrotoxin (10 microM) and 2-OH-saclofen (50 microM) isolated the late EPSP (onset, 3 ms; peak latency, 28 ms; peak amplitude, 7 mV; duration, 240 ms), which grew in magnitude with membrane depolarization and was largely (> 90%) blocked by APV. Paired-pulse stimulation depressed the isolated late EPSP by 30%. 5. Thus, apparent paired-pulse facilitation of the late EPSP is attributable to release from GABAergic inhibition, and not to direct facilitation. Facilitation of the late EPSP is a functional consequence of IPSP depression. The results indicate the importance of inhibition in regulating synaptic activity mediated by NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1994

Modulation of cellular excitability in neocortex: muscarinic receptor and second messenger-mediated actions of acetylcholine.

Muscarinic-type acetylcholine (ACh) receptor are involved in a variety of cortical functions. ACh "activates" neocortex; simultaneously modifying spontaneous subthreshold activity, intrinsic neuronal oscillations and spike discharge modes, and responsiveness to fast (putative glutamatergic) synaptic inputs. However, beyond the general involvement of muscarinic receptors, a mechanistic understanding of integrated cholinergic actions, and interactions with non-cholinergic transmission, is lacking. We have addressed this problem using intracellular recordings from the in vitro auditory neocortex. First, we investigated cholinergic modification of responses to the excitatory amino acid glutamate. ACh, or the muscarinic agonist methacholine, produced a lasting enhancement of glutamate-mediated membrane depolarizations. Muscarinic receptors of the M1 and/or M3 subtype, rather than M2 or nicotinic receptors, mediated this enhancement. Subsequently, we investigated whether second messenger systems contribute to observed muscarinic actions. Activation of protein kinase C with phorbol 12,13-dibutyrate (4 beta-PDBu), enhanced neuronal responses to glutamate. The effect of 4 beta-PDBu was attenuated by the kinase antagonist H7. Finally, we attempted to identify postsynaptic actions of endogenous ACh. Tetanic stimulation of cholinergic afferents elicited voltage-dependent effects, including reduced spike frequency adaptation and reduced slow afterhyperpolarization (sAHP) elicited by transmembrane depolarizing stimuli. These effects were mimicked by methacholine, enhanced by eserine, and antagonized by muscarinic receptor antagonists. These data suggest that cholinergic modulation in neocortex likely involves the integrated actions of diverse mechanisms, primarily gated by muscarinic receptors, and at least partly involving second messenger systems.

Acetylcholine↗
PubMed1993

Nucleus basalis stimulation facilitates thalamocortical synaptic transmission in the rat auditory cortex.

Nucleus basalis (NB) neurons are a primary source of neocortical acetylcholine (ACh) and likely contribute to mechanisms of neocortical activation. However, the functions of neocortical activation and its cholinergic component remain unclear. To identify functional consequences of NB activity, we have studied the effects of NB stimulation on thalamocortical transmission. Here we report that tetanic NB stimulation facilitated field potentials, single neuron discharges, and monosynaptic excitatory postsynaptic potentials (EPSPs) elicited in middle to deep cortical layers of the rat auditory cortex following stimulation of the auditory thalamus (medial geniculate, MG). NB stimulation produced a twofold increase in the slope and amplitude of the evoked short-latency (onset 3.0 +/- 0.13 ms, peak 6.3 +/- 0.21 ms), negative-polarity cortical field potential and increased the probability and synchrony of MG-evoked unit discharge, without altering the preceding fiber volley. Intracortical application of atropine blocked the NB-mediated facilitation of field potentials, indicating action of ACh at cortical muscarinic receptors. Intracellular recordings revealed that the short-latency cortical field potential coincided with a short-latency EPSP (onset 3.3 +/- 0.20 ms, peak 5.6 +/- 0.47 ms). NB stimulation decreased the onset and peak latencies of the EPSP by about 20% and increased its amplitude by 26%. NB stimulation also produced slow membrane depolarization and sometimes reduced a long-lasting IPSP that followed the EPSP. The combined effects of NB stimulation served to increase cortical excitability and facilitate the ability of the EPSP to elicit action potentials. Taken together, these data indicate that NB cholinergic neurons can modify neocortical functions by facilitating thalamocortical synaptic transmission.

Animals↗
PubMed1993

Ionic flux contributions to neocortical slow waves and nucleus basalis-mediated activation: whole-cell recordings in vivo.

Slow, rhythmic membrane potential (Vm) fluctuations occur spontaneously in cortical neurons of urethane-anesthetized rats, and likely underlie EEG activity in the same low-frequency (1-4 Hz or delta) range. Nucleus basalis (NB) stimulation elicits neocortical activation, simultaneously modifying Vm and EEG fluctuations, by way of cortical muscarinic ACh receptors (Metherate et al., 1992). To investigate the nature of spontaneous fluctuations and their modification by NB stimulation, we have obtained intracellular recordings from auditory cortex using the whole-cell recording technique in vivo. Spontaneous Vm fluctuations appeared to contain three components whose polarity and time course resembled the EPSP, putative Cl(-)-mediated IPSP, and putative K(+)-mediated, long-lasting IPSP elicited by thalamic stimulation. The spontaneous, long-lasting hyperpolarization, whose rhythmic occurrence appeared to set the slow-wave rhythm, was associated with an increased conductance that could shunt the thalamocortical EPSP. We hypothesized that spontaneous Vm fluctuations arise from intermixed rapid depolarizations, rapid Cl(-)-mediated hyperpolarizations, and long-lasting, K(+)-mediated hyperpolarizations. NB-mediated cortical activation might then result from muscarinic suppression of K+ permeability, allowing the rapid depolarizations and Cl- fluxes to continue uninterrupted. Tests of this hypothesis showed that (1) intracellular blockade of K+ channels by rapid diffusion of Cs+ from the recording pipette resulted in suppression of spontaneous, long-lasting hyperpolarizations, mimicking the effect of NB stimulation, and reducing shunting of the thalamocortical EPSP; (2) effects of Cs+ and NB stimulation suggested overlapping, or converging, mechanisms of action; however, there were important differential effects on the spontaneous, long-lasting hyperpolarizations and the K(+)-mediated IPSP; and (3) modifying Cl- fluxes with intracellular picrotoxin or high intracellular Cl- concentrations resulted in spontaneous and NB-elicited large-amplitude depolarizations. We conclude that spontaneous, long-lasting hyperpolarizations are K+ fluxes, but are not "spontaneous" K(+)-mediated IPSPs. Since NB-mediated reduction of spontaneous hyperpolarizations implies muscarinic suppression of a K+ conductance, the spontaneous hyperpolarizations more likely result from the calcium-activated K+ current, IK(Ca). Finally, Cl- fluxes form an important component of activated Vm fluctuations that acts to restrain excessive depolarization.

Action Potentials↗
PubMed1992

Synaptic potentials and effects of amino acid antagonists in the auditory cortex.

Neurons of in vitro guinea pig and rat auditory cortex receive a complex synaptic pattern of afferent information. As many as four synaptic responses to a single-stimulus pulse to the gray or white matter can occur; an early-EPSP followed, sequentially, by an early-IPSP, late-EPSP, and late-IPSP. Paired pulse stimulation and pharmacological studies show that the early-IPSP can modify information transmission that occurs by way of the early-EPSP. Each of these four synaptic responses differed in estimated reversal potential, and each was differentially sensitive to antagonism by pharmacological agents. DNQX (6,7-dinitroquinoxaline-2,3-dione), a quisqualate/kainate receptor antagonist, blocked the early-EPSP, and the late-EPSP was blocked by the NMDA receptor antagonist APV (D-2-amino-5-phosphonovalerate). The early-IPSP was blocked by the GABA-a receptor antagonist bicuculline, and the late-IPSP by the GABA-b receptor antagonists 2-OH saclofen or phaclofen. Presentation of stimulus trains, even at relatively low intensities, could produce a long-lasting APV-sensitive membrane depolarization. Also discussed is the possible role of these synaptic potentials in auditory cortical function and plasticity.

Amino Acids↗
PubMed1992

Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine.

In the mammalian neocortex, the EEG reflects the state of behavioral arousal. The EEG undergoes a transformation, known as activation, during the transition from sleep to waking. Abundant evidence indicates the involvement of the neurotransmitter acetylcholine (ACh) in EEG activation; however, the cellular basis of this involvement remains unclear. We have used electrophysiological techniques with in vivo and in vitro preparations to demonstrate actions of endogenous ACh on neurons in auditory neocortex. In vivo stimulation of the nucleus basalis (NB), a primary source of neocortical ACh, (1) elicited EEG activation via cortical muscarinic receptors, (2) depolarized cortical neurons, and (3) produced a change in subthreshold membrane potential fluctuations from large-amplitude, slow (1-5 Hz) oscillations to low-amplitude, fast (20-40 Hz) oscillations. The NB-mediated change in pattern of membrane potential fluctuations resulted in a shift of spike discharge pattern from phasic to tonic. Stimulation of afferents in the in vitro neocortex elicited cholinergic actions on putative layer 5 pyramidal neurons. Acting via muscarinic receptors, endogenous ACh (1) reduced slow, rhythmic burst discharge and facilitated higher-frequency, single-spike discharge in burst-generating neurons, and (2) facilitated the appearance and magnitude of intrinsic membrane potential oscillations. These in vivo and in vitro observations suggest that neocortical activation results from muscarinic modulation of intrinsic neural oscillations and firing modes. Rhythmic-bursting pyramidal neurons in layer 5 may act as cortical pacemakers; if so, then modifying their discharge characteristics could alter local cortical networks. Larger, intercortical networks could also be modified, due to the widespread projections of NB neurons. Thus, NB cholinergic neurons may play a critical role in producing different states of neocortical function.

Acetylcholine↗
PubMed1991

Basal forebrain stimulation modifies auditory cortex responsiveness by an action at muscarinic receptors.

We have hypothesized that auditory cortex plasticity involves modification of thalamocortical transmission by basal forebrain (BF) cholinergic neurons, and that this action may involve muscarinic receptors. In a first test of this hypothesis, we report that BF stimulation can suppress or facilitate, depending on the intensity of stimulation, auditory cortical responses elicited by thalamic stimulation. BF-mediated facilitation is antagonized by atropine, implicating muscarinic receptors. These data suggest that BF cholinergic neurons functionally modify auditory cortex by regulating thalamocortical transmission.

Animals↗
PubMed1991

Amino acids as transmitters of synaptic excitation in neocortical sensory processes.

Few synaptic transmitters are known to exist that are not represented in some region or another, or at some layer or other, in the cerebral cortex of mammalian brain. The more difficult job than mere identification of which substances are present, is that of the assignment of particular functional role(s) of such substances, and as well, of determining upon exactly which element(s) of the known synaptic circuitry of neocortex, such transmitters operate. Current wisdom subscribes to the view that the excitatory amino acids, most likely L-glutamate, and L-aspartate but perhaps also L-cysteate, L-homocysteate, L-cysteine sulfinate or even (although much less likely) the endogenous dipeptide substance, N-acetyl-L-aspartyl-L-glutamate, are the major excitatory synaptic transmitters of intracortical (associational) fibres, of corticofugal projections, and, as this article will attest, of thalamocortical inputs, as well. What particular limits, or restrictions, are imposed upon these generalizations, such as whether the data pertain only to primary sensory areas or follow some other yet to be determined rule, remains to be discovered in future experiments. This paper first presents an overview of the advances in understanding that have come about during the past few decades concerning the synaptic roles of amino acid transmitters. Next, an experimental section presents new evidence based on release studies and the microiontophoretic approach, which supports the view that the amino acids, glutamate and aspartate, interact with specific, pharmacologically identified subtypes of receptors in neocortex as transmitters of synaptic excitation released from thalamic afferent terminals.

2-Amino-5-phosphonovalerate↗
PubMed1990

Cholinergic modulation of responses to single tones produces tone-specific receptive field alterations in cat auditory cortex.

Acetylcholine (ACh), acting via muscarinic receptors, is known to modulate neuronal responsiveness in primary sensory neocortex. The administration of ACh to cortical neurons facilitates or suppresses responses to sensory stimuli, and these effects can endure well beyond the period of ACh application. In the present study, we sought to determine whether ACh produces a general change in sensory information processing, or whether it can specifically alter the processing of sensory stimuli with which it was "paired". To answer this question, we restricted acoustic stimulation in the presence of ACh to a single frequency, and determined single neuron frequency receptive fields in primary auditory cortex before and after this pairing. During its administration, ACh produced mostly facilitatory effects on spontaneous activity and on responses to the single frequency tone. Examination of frequency receptive fields after ACh administration revealed receptive field modifications in 56% of the cells. In half of these cases, the receptive field alterations were highly specific to the frequency of the tone previously paired with ACh. Thus ACh can produce stimulus-specific modulation of auditory information processing. An additional and unexpected finding was that the type of modulation during ACh administration did not predict the type of receptive field modulation observed after ACh administration; this may be related to the physiological "context" of the same stimulus in two different conditions. The implications of these findings for learning-induced plasticity in the auditory cortex is discussed.

Acetylcholine↗
PubMed1990

Acetylcholine modifies neuronal acoustic rate-level functions in guinea pig auditory cortex by an action at muscarinic receptors.

Cholinergic modification of neuronal responsiveness in auditory cortex includes alteration of spontaneous and tone-evoked neuronal discharge. Previously it was suggested that the effects of acetylcholine (ACh) and muscarinic agonists on neuronal discharge resembled those due to increases in the intensity of acoustic stimuli (Ashe et al. 1989). To determine the relationship between neuronal modifications due to ACh acting at muscarinic receptors and those due to changes in stimulus intensity, we determined acoustic rate-level functions for neurons in the auditory cortex of barbiturate-anesthetized guinea pigs before, during and after administration of ACh. ACh facilitated acoustic rate-level functions in 82% of the cells tested. In addition, during ACh administration 66% of neurons responded to stimuli that were previously subthreshold, that is, ACh decreased the response threshold. Cholinergic facilitation of rate-level functions was attenuated by the general muscarinic antagonist atropine. The nature of the muscarinic receptors involved in the actions of ACh was further examined by presenting single tones before, during, and after administration of ACh and specific muscarinic receptor subtype antagonists, either pirenzepine (M1) or gallamine (M2). ACh-induced facilitation of spontaneous and tone evoked neuronal discharge was antagonized by pirenzepine, but not by gallamine, suggesting the involvement of the M1 muscarinic receptor subtype. These data indicate that ACh can facilitate stimulus-evoked responses and decrease response thresholds for neurons in auditory cortex, possibly via activation of M1 muscarinic receptors. Such effects of ACh acting at muscarinic receptors could underly cholinergic regulation of information processing in the auditory cortex.

Acetylcholine↗
PubMed1989

Acetylcholine produces stimulus-specific receptive field alterations in cat auditory cortex.

Frequency receptive fields (RFs) were determined before and after pairing iontophoretic administration of acetylcholine (ACh) with a repeated single-frequency stimulus in the auditory cortex of barbiturate-anesthetized cats. In 58% of the cells, the paired ACh + tone treatment produced subsequent alterations of frequency RFs. In half of these cases, the RF modifications were highly specific to the frequency that had been paired with ACh. Atropine antagonized the frequency-specific effects of ACh, suggesting that they were mediated via muscarinic cholinergic receptors.

Acetylcholine↗
PubMed1988

The effects of acetylcholine on response properties of cat somatosensory cortical neurons.

1. Two-hundred thirty-three single neurons were isolated and studied in somatosensory cortex of cats anesthetized with pentobarbital sodium or urethane. Two-hundred and three were studied during iontophoretic administration of acetylcholine (ACh), 173 during administration of glutamate, and 24 during administration of atropine. 2. Fifty-six percent of the 218 neurons tested responded to somatic stimuli. Another 21% did so during glutamate administration. In 11 cases ACh iontophoresis uncovered a receptive field in a previously unresponsive cell. 3. Forty-six percent of the 160 cells tested responded to thalamic stimulation. Another 17% did so in the presence of glutamate, but 19 cells responded to neither cutaneous nor thalamic stimuli. 4. Sixteen percent of the 203 cells tested were overtly excited by ACh and the responses to somatic stimulation of 29% were modulated by administration of ACh. Cells displaying overt excitation and/or modulation of responses were said to be cholinoceptive and made up 39% of the sample. These cells were located in all cortical layers. 5. Cholinoceptive neurons were more likely than noncholinoceptive cells to be driven by thalamic stimulation. 6. The changes observed during ACh administration tended to be facilitatory: an enhanced responsiveness to somatic stimuli, an increased firing rate, or an increased receptive-field size. However, in 10 of the 203 cases tested one or more of these variables decreased. 7. The enhanced responsiveness during ACh administration was a robust phenomenon; responses were often increased by as much as 200% and the discharge pattern was altered so that bursts of impulses following stimulation were more common. 8. ACh tended to enhance one attribute of a cell selectively rather than to act as a general excitant. 9. ACh is a powerful neuromodulatory agent in somatosensory cortex that, when released in specific behavioral states, should enhance the responsiveness of cortical neurons.

Acetylcholine↗