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

Frequency receptive fields (RFs) were determined before and after pairing iontophorectic administration of acetylcholine (ACh) with a repeated single-frequency stimulus in the auditory cortex of barbiturate-anesthesized 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 antagoized the frequency-effects of ACh, suggesting that they were mediated via muscarinic cholinergic receptors.     

Cholinergic modulation of frequency receptive fields in auditory cortex: II. Frequency-specific effects of anticholinesterases provide evidence for a modulatory action of endogenous ACh

Exogenously applied muscarinic agonists--for example, acetylcholine (ACh) and acetyl-beta-methacholine (MCh)--modify frequency receptive fields in auditory cortex of unanesthetized animals in a frequency-specific rather than global manner. The present study sought to relate these findings to endogenous actions of ACh by using the anticholinesterase agents eserine sulphate and soman (0-1,2,2-trimethylpropylmethylphosphonofluoridate) to facilitate the effects of endogenous ACh. Frequency receptive fields (FRF) were determined by presenting sequences of different isointensity tones before, during, and after application of ACh, MCh, eserine, or soman; also the cholinesterase blockers were applied between applications of ACh or MCh. The major effects produced by the inhibitors were similar to those of the agonists. Predominant effects were frequency-specific changes in FRF. Further, eserine and soman, similar to ACh and MCh, produced shifts in the best frequency (BF) of FRF due mainly to coordinated depression of responses to the BF and increased responses to adjacent, non-BF. The results indicate that exogenous and endogenous ACh, acting via muscarinic receptors, can significantly influence the physiological functioning of cortical neurons and consequently their processing of sensory information.     

Cholinergic modulation of frequency receptive fields in auditory cortex: I. Frequency-specific effects of muscarinic agonists

Previously we reported that acetylcholine (ACh) and acetyl-beta-methacholine (MCh) modify responses of neurons in auditory cortex to individual frequencies. The purpose of this study was to determine whether muscarinic agonists produce frequency-specific alterations or general changes in cellular responses. Frequency-specific modifications would be evident in alterations of frequency receptive fields (FRF) that differed across frequencies while general effects would be seen as changes that were more or less the same over frequencies. Responses of single neurons to designated sets of tones were recorded in the auditory cortex of chronically prepared awake cats before, during, and following ejection of ACh or MCh by iontophoresis or micropressure using multibarrel micropipettes. Frequency receptive fields were determined by presenting isointensity tones across a range of frequencies including the cell's best frequency (BF) to tone onset. FRF for "off" and "sustained (through)" responses were also determined quantitatively. The effects of ACh and MCh were predominantly frequency-specific (77%, 39/51 cells); general changes (19%, 10/51) and no effects (4%, 2/51) were less likely. Frequency-specific effects involved both facilitation and reduction of the same response component to different frequencies within the same neuron. For responses to tone onset (but not "through" and "off" responses), agonists were more likely to produce a decrease at the BF while simultaneously increasing responses to other frequencies. Agonists could increase or decrease frequency selectivity. Effects of agonists could be blocked by atropine, suggesting involvement of muscarinic receptors.     

Functional connectivity and cholinergic modulation in auditory cortex

Although it is known that primary auditory cortex (A1) contributes to the processing and perception of sound, its precise functions and the underlying mechanisms are not well understood. Recent studies point to a remarkably broad spectral range of largely subthreshold inputs to individual neurons in A1 - seemingly encompassing, in some cases, the entire audible spectrum - as evidence for potential, and potentially unique, cortical functions. We have proposed a general mechanism for spectral integration by which information converges on neurons in A1 via a combination of thalamocortical pathways and intracortical long-distance, “horizontal”, pathways. Here, this proposal is briefly reviewed and updated with results from multiple laboratories. Since spectral integration in A1 is dynamically regulated, we also show how one regulatory mechanism - modulation by the neurotransmitter acetylcholine (ACh) - could act within the hypothesized framework to alter integration in single neurons. The results of these studies promote a cellular understanding of information processing in A1.     

Sensitization induced receptive field plasticity in the auditory cortex is independent of CS-modality

Sensitization training with an auditory stimulus produces a general increase in response magnitude across the entire receptive field (RF) of neurons in the primary auditory cortex of the guinea pig (Bakin, J.S. and Weinberger, N.M., Brain Res., 536 (1990) 271-286). To determine if this effect reflects an auditory system-specific process or is caused by a process independent of the training stimulus modality, RFs in primary auditory cortex were characterized before and immediately after adult guinea pigs were given sensitization training with either an auditory or a visual training stimulus. General increases in auditory response magnitude across the RF were observed in 7 out of 7 auditory sensitization cases and 4 out of 5 visual sensitization cases. There were no statistical differences between the effects of auditory and visual sensitization training. These findings indicate that the general increases observed following sensitization training are the result of processes independent of CS modality, in contrast to the highly specific RF modifications that are caused by classical conditioning. The findings suggest that the 2 forms of RF plasticity, CS-specific re-tuning due to associative conditioning and polymodal general increases in gain due to non-associative sensitization, may reflect neural mechanisms involved in selective attention and vigilance, respectively.     

Classical conditioning induces CS-specific receptive field plasticity in the auditory cortex of the guinea pig

To determine if classical conditioning produces general or specific modification of responses to acoustic conditioned stimuli (CS), frequency receptive fields (RF) of neurons in guinea pig auditory cortex were determined before and up to 24 h after fear conditioning. Highly specific RF plasticity characterized by maximal increased responses to the CS frequency and decreased responses to the pretraining best frequency (BF) and other frequencies was observed in 70% of conditioning cases. These opposing changes were often sufficient to produce a shift in tuning such that the frequency of the CS became the new BF. CS frequency specific plasticity was maintained as long as 24 h. Sensitization training produced general increased responses across the RF without CS specificity. The findings indicate that associative processes produce systematic modification of the auditory system's processing of frequency information and exemplify the advantages of combining receptive field analysis with behavioral training in the study of the neural bases of learning and memory.     

Correlations between neural discharges are related to receptive field properties in cat primary auditory cortex

The functional role of correlated neural activity in auditory cortex for the processing of sounds was explored by investigating whether and how cross-correlation parameters are related to receptive field similarities of neurons. Multi-unit activity was recorded simultaneously from several sites of isofrequency domains in primary auditory cortex. At each site various receptive field properties were determined. From the discharges of pairs of clusters, normalized cross-correlation histograms (CCH) were calculated for extended periods of spontaneous activity and for periods with noise-burst stimulation. In both conditions, most CCHs exhibited a symmetrical positivity near the origin of the CCH, a few to several tens of milliseconds wide. Cross-correlation histograms were characterized with two parameters: the correlation strength, which was estimated from the peak correlation, and the correlation width, i.e. the time period of correlated firing, which was measured as the width of the positivity at half height. It was found that correlation strength increased and correlation width narrowed with increasing similarity of the receptive fields of two clusters. These relationships were observed both in the acoustically-driven and spontaneous conditions. Specifically, correlation strength was most strongly associated with similarity in binaural interaction and in temporal response properties such as response onset, response offset and the temporal pattern of the response. Correlation width was predominantly associated with similarity in characteristic frequency, bandwidth and intensity threshold. Results suggest that correlated activity, reflecting potential mechanisms involved in the neural computation in auditory cortex, provides a means to evaluate the properties of the functional organization of auditory cortex. Systematic relationships were found between correlation properties and the receptive field-based organization of cortical processing, suggesting that similar general mechanisms are utilized in many parts of the sensory cortex. In particular, the magnitude and/or the time period of synchronized firing of neurons is increased if the receptive field properties of the involved neurons are similar.     

Cholinergic modulation of status epilepticus in the rat barrel field region of primary somatosensory cortex

Status epilepticus (SE) represents a serious medical emergency that can produce long-lasting brain damage as well as cognitive and memory deficits. However, the mechanisms that determine the emergence of SE from a single seizure and the prolonged duration of SE are unknown. Therefore, we used pharmacological tools to investigate the cellular mechanisms that underlie this prolonged epileptic activity in the rat barrel field region of somatosensory cortex (S1BF). Electrocortical and unitary extracellular field recording in the rat S1BF region was used to assess abnormal epileptiform activity induced by intracerebral application of 4-aminopyridine (4-AP). Simultaneously, electromyographic (EMG) activity was recorded from mystacial pad musculature. Intracerebral injection of 4-AP induced an SE that was paralleled by an increase of whisker activity that was not synchronized with the electrocortical recording. The seizures were originated ipsilaterally in the cortex of the injected hemisphere and propagated to the contralateral cortex with lower amplitude. The application of the glutamatergic NMDA receptor antagonist D (-)-2-amino-5-phosphonopentanoic acid (AP5) strongly increased the seizure-onset latency. The muscarinic receptor antagonist atropine changed the continuous rapid spiking pattern of SE to periodic discharges, while glutamatergic or GABAergic antagonist did not modify the electrographic features of SE. Our data suggest that the muscarinic cholinergic system plays an important role in the seizure modulation during SE in the somatosensory cortex, while their emergence is controlled, in part, by glutamatergic NMDA receptors.     

Phase-locked responses to pure tones in guinea pig auditory cortex

Phase-locked responses to pure tones are a characteristic of most auditory cells at the level of the brain stem and allow sophisticated analyses based on coincidence detection. Phase-locking to tones has not previously been shown at the level of the auditory cortex in single unit studies. We have now identified phase-locked responses in 10% of low-frequency (< 1 kHz) units in the ventrorostral belt, a strip of cortex immediately ventral to the primary auditory area. All of these units showed phase-locking in their response to binaural tone pips of 60-200 Hz and showed narrow band pass characteristics within this range.     

Cholinergic modulation of neuronal responses to cholecystokinin in anesthetized rats

The aim of this study was to investigate whether the effects of the neuropeptide cholecystokinin on neuronal firing can be changed by acetylcholine in various structures of the brain. Single unit activity was extracellularly recorded in rats anesthetized with urethane. The neurons were located in several nuclei of the thalamus, the basal ganglia and the cerebral cortex. Neurons responding to the sulfated octapeptide of cholecystokinin (CCK-8S) were mainly activated by the drug [Wilcoxon test (Wt) p < 0.0001, n = 113]. Thalamic neurons could also increase the number of burst discharges (Wt p < 0.005, n = 39). Iontophoretically administered acetylcholine could reduce the activating effects of CCK-8S on firing and burst discharges. In its presence, even inhibitory effects of CCK-8S predominated (Wt p < 0.0001, n = 113). The suppressive action seemed not to depend on the direction of the effect of acetylcholine itself and concerned neurons of all locations studied. Atropine could diminish or block the suppressive action of acetylcholine. In the presence of both drugs, CCK-8S mainly activated the neurons (Wt p < 0.005, n = 43). Atropine itself did not significantly change the responses to CCK-8S (Wt p > 0.05). It can be concluded that cholecystokinin may reduce neuronal firing instead of increasing it during activation of the cholinergic system.     

Cholinergic modulation of basal and amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

Behavioral evidence suggests that muscarinic/cholinergic inhibition of brain dopaminergic activity may be a useful principle for developing novel antipsychotic drugs (APDs). Thus, oxotremorine, a muscarinic agonist, attenuates amphetamine-induced locomotor activity in rodents, an effect also produced by a wide variety of proven APDs, whereas scopolamine, a muscarinic antagonist, has the opposite effect. Since atypical APDs such as clozapine, olanzapine, risperidone, ziprasidone and quetiapine, increase brain acetylcholine as well as dopamine (DA) release in a region-specific manner, their effects on cholinergic and dopaminergic neurotransmission may also contribute to various actions of these drugs. Oxotremorine (0.5-1.5 mg/kg) dose-dependently and preferentially increased DA release in rat medial prefrontal cortex (mPFC), compared to the nucleus accumbens (NAC). However, S-(-)-scopolamine (0.5-1.5 mg/kg) produced similar increases in DA release in the mPFC, but the effect was much less than that of oxotremorine. Whereas a dose of S-(-)-scopolamine of 0.5 mg/kg comparably increased DA release in the mPFC and NAC, 1.5 mg/kg had no effect on DA release in the NAC. Oxotremorine-M (0.5 mg/kg), a M(1/4)-preferring agonist, also increased DA release in the mPFC, but not the NAC, an effect completely abolished by telenzepine (3 mg/kg), a M(1/4)-preferring antagonist, which by itself had no effect on DA release in either region. Oxotremorine (0.5, but not 1.5, mg/kg) attenuated amphetamine (1 mg/kg)-induced DA release in the NAC, whereas S-(-)-scopolamine did not. Oxotremorine (1.5 mg/kg) and S-(-)-scopolamine (0.5 mg/kg) modestly but significantly potentiated amphetamine (1 mg/kg)-induced DA release in the mPFC. These results suggest that stimulation of muscarinic receptors, in particular M(1/4), as indicated by the effect of oxotremorine-M and telenzepine, may preferentially increase cortical DA release and inhibit amphetamine-induced DA release in the NAC.     

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 discharges, 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. © 1993 Wiley-Liss, Inc.     

Muscarinic agonists modulate spontaneous and evoked unit discharge in auditory cortex of cat

The present experiments studied the effects of cholinergic agonists and antagonists on the spontaneous and acoustic-evoked discharge of auditory cortical neurons and examined whether these effects were mediated by muscarinic cholinergic receptors. A primary focus of this report is the analysis of specific effects of these agents on the spontaneous and tone-evoked discharge and on different temporal components of the evoked discharge. Single neurons were recorded in the auditory cortex of chronically prepared, awake cats with multibarrel micropipette electrodes. The responses to acoustic stimuli were obtained before, during, and following continuous ejection of cholinergic agonist or antagonists by micropressure. The mean rate of discharge of the neurons was analyzed quantitatively for spontaneous discharge and for different peaks of the tone-evoked PSTH corresponding to tone "on," "through," and "off" responses. Acetylcholine (ACh) and acetyl-beta-methacholine (MCh) produced significant effects on spontaneous activity in 72% and 68% of neurons tested, respectively. Tone-evoked responses were effected in 92% and 82% of cells tested, respectively. The ability of these agonists to modify spontaneous or evoked activity was dose-dependent. Agonist effects on spontaneous and evoked activity were often different in the same cell; however, effects on spontaneous activity did predict effects on "through" responses. The most common effect of ACh or MCh on evoked activity was facilitation of the tone "on" response. For neurons with multicomponent discharge patterns in response to tones, the agonists had nonuniform effects on different response components. However, the effects of ACh on the "on" and "off" responses covaried. Hence cholinergic agonists produce heterogeneous, selective effects on different components of the responses of auditory cortical neurons rather than simple increases or decreases in discharge level. The effects of cholinergic agonists were modified in the presence of atropine. The effects of MCh were blocked by atropine in a higher proportion of cases than those of ACh.     

Diversity of receptive field changes in auditory cortex during natural sleep

Twenty years ago, the study by Livingstone and Hubel [(1981) Nature, 291, 554] was viewed as a first step toward understanding how changes in state of vigilance affect sensory processing. Since then, however, very few attempts have been made to progress in this direction. In the present study, 56 cells were recorded in the auditory cortex of adult, undrugged guinea pigs, and the frequency tuning curves were tested during continuous and stable periods of wakefulness and of slow‐wave sleep (SWS). Twelve cells were also tested during paradoxical sleep. Over the whole cell population, the reponse latency, the frequency selectivity and the size of the suprathreshold receptive field were not significantly modified during SWS compared with waking. However, this lack of global effects resulted from the heterogeneity of response changes displayed by cortical cells. During SWS, the receptive field size varied as a function of the changes in evoked responses: it was unchanged for the cells whose evoked responses were not modified (38% of the cells), reduced for the cells whose responses were decreased (48%) and enlarged for the cells whose responses were increased (14%). This profile of changes differs from the prevalent receptive field shrinkage that was observed in the auditory thalamus during SWS [Edeline et al. (2000), J. Neurophysiol., 84, 934]. It also contrasts with the receptive field enlargement that was described under anaesthesia when the EEG spontaneously shifted from a desynchronized to a synchronized pattern [Wörgötter et al. (1998), Nature, 396, 165]. Reasons for these differences are discussed.     

Reactions of tonic-type neurons in the cat auditory cortex to tones of various frequency and intensity

Extra- and intracellularly recorded responses of the acoustic cortex neurons to sound tones of different frequency and intensity and peculiarities of the organization of receptive fields of these units were studied in immobilized cats. Special attention was paid to neurons with tonic spike responses to these stimuli. Such tonic-type neurons were met in different cortical layers but most of them (93%) were localized at depth of 1.0-2.2 mm. Mean response threshold of these cells was lower by 7.7 dB than that of phasic-type neurons. Tonic-type units were characterized by lower frequency-discriminative ability in comparison with phasic ones: mean values of Q10 were 4.1 +/- 0.4 and 9.1 +/- 0.7, respectively. Dimensions of receptive fields of tonic-type units were 3.5 times as large as those of phasic ones. Most of tonic-type neurons (80%) differed from phasic ones in 1.5-2.0 time shorter action potentials. Tonic neurons demonstrated high sensitivity to variations of duration and intensity of the acoustic stimulation.     

Cholinergic modulation of sensory responses in rat primary somatic sensory cortex

Responses evoked in single neurons of the primary somatic sensory cortex following tactile stimulation were examined before, during and after local iontophoretic application of acetylcholine (ACh) in urethane-anesthetized rats. The most common effect of ACh was an enhancement of the discharge evoked by sensory stimuli. Some cells responded to sensory input only in the presence of ACh. Response enhancement was observed in both supra- and infragranular layers, whereas response suppression was the most common effect in layer IV. These studies suggest that cholinergic systems modify sensory processing in cerebral neocortex by modulating the effectiveness of afferent inputs to cortical neurons in all layers.     

Cholinergic modulation of the sleep state-dependent P13 midlatency auditory evoked potential in the rat

Injections into the pedunculopontine nucleus (PPN) of the cholinergic receptor agonist, carbachol (CAR), were found to reduce the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential in a dose- and time-dependent manner. This effect was blocked or reduced by pretreatment with the muscarinic receptor antagonist, scopolamine, injected into the PPN.     

Properties of single neurons in the anterior auditory field (AAF) of cat cerebral cortex

In the cortex of 6 anesthetized cats, the anterior auditory field (AAF) was defined by microelectrode maps of its frequency organization, and the responses to monaural and binaural tonal stimuli of single neurons in that field were examined qunatitatively. AAF neurons were sharply tuned to tonal frequency, had intensity dynamic ranges of less than 30–40 dB at best frequency, and had minimum response latencies generally in the order of 10–15 ms. The binaural interactions of AAF neurons were qualitatively similar to those of AI cells, with the possible exception of a relatively greater proportion of AAF neurons receiving stronger excitatory input from the ipsilateral ear. On the basis of these data and recent anatomical evidence, the proposal that AAF and AI function as parallel processors of ascending acoustic information is discussed.     

Activity-dependent receptive field changes in the surround of adult cat visual cortex lesions

Extracellular single cell spike activity was recorded in the visual cortex of anaesthetized adult cats at identical sites before and 2 days after focal excitotoxic lesions induced by injections of ibotenic acid. In the surround of the lesions (up to 5 mm from the border of the lesion), the average postlesion receptive field (RF) sizes were not different from the prelesion RFs. However, RFs of neurons with increased postlesion excitability were slightly enlarged; such neurons were mainly found close to the anterior border of the lesion (< or = 1 mm). After applying a visual training procedure for 1 h to the postlesion RFs (repetitive, synchronous stimulation of a part of the RF and the neighbouring unresponsive part of the visual field), there was a small (0.4-0.8 degrees ) but significant and specific increase of RF size in about half of the tested neurons. This RF enlargement was similar to that observed with the same training procedure in the visual cortex of normal cats. Thus, small RF changes can be induced by visual stimulation within one hour in normal cells as well as in cells at the border of cortical lesions. Any differences between normal and lesioned animals appear to be related to lesion-induced changes of excitability.