Douglas D. Rasmusson

The role of acetylcholine in cortical synaptic plasticity.

This review examines the role of acetylcholine in synaptic plasticity in archi-, paleo- and neocortex. Studies using microiontophoretic application of acetylcholine in vivo and in vitro and electrical stimulation of the basal forebrain have demonstrated that ACh can produce long-lasting increases in neural responsiveness. This evidence comes mainly from models of heterosynaptic facilitation in which acetylcholine produces a strengthening of a second, noncholinergic synaptic input onto the same neuron. The argument that the basal forebrain cholinergic system is essential in some models of plasticity is supported by studies that have selectively lesioned the cholinergic basal forebrain. This review will examine the mechanisms whereby acetylcholine might induce synaptic plasticity. It will also consider the neural circuitry implicated in these studies, namely the pathways that are susceptible to cholinergic plasticity and the neural regulation of the cholinergic system.

Long-term enhancement of evoked potentials in cat somatosensory cortex produced by co-activation of the basal forebrain and cutaneous receptors

SummaryAveraged evoked potentials from primary somatosensory cortex (SEPs) were recorded before and after pairing the peripheral stimuli with electrical activation of the basal forebrain (BF) in anesthetized cats. Four pulses at 400 Hz were delivered to the BF 120 ms before each cutaneous stimulus and 10 to 660 such pairings were found to produce an enlargement of the SEP in 10 of 11 animals. The average increase in amplitude of the initial peak of the SEP was 69%. The SEP remained enhanced in five of six animals that were tested an hour or more after the pairing, and in one case the SEP was tested 4.5 h after pairing without diminution. The effective BF sites were located in the substantia innominata and at the rostral pole of the globus pallidus, regions known to contain many cholinergic cell bodies. Enhancement occurred consistently only if stimulation of the BF site elicited a positive wave in the cortex at a latency of 11 to 18 ms. Repeated BF stimulation without cutaneous input did not produce a change in subsequent SEPs. The long-term changes described here may be involved in experimentally- and naturally-induced cortical reorganization.

The role of basal forebrain neurons in tonic and phasic activation of the cerebral cortex

The basal forebrain and in particular its cholinergic projections to the cerebral cortex have long been implicated in the maintenance of cortical activation. This review summarizes evidence supporting a close link between basal forebrain neuronal activity and the cortical electroencephalogram (EEG). The anatomy of basal forebrain projections and effects of acetylcholine on cortical and thalamic neurons are discussed along with the modulatory inputs to basal forebrain neurons. As both cholinergic and GABAergic basal forebrain neurons project to the cortex, identification of the transmitter specificity of basal forebrain neurons is critical for correlating their activity with the activity of cortical neurons and the EEG. Characteristics of the different basal forebrain neurons from in vitro and in vivo studies are summarized which might make it possible to identify different neuronal types. Recent evidence suggests that basal forebrain neurons activate the cortex not only tonically, as previously shown, but also phasically. Data on basal forebrain neuronal activity are presented, clearly showing that there are strong tonic and phasic correlations between the firing of individual basal forebrain cells and the cortical activity. Close analysis of temporal correlation indicates that changes in basal forebrain neuronal activity precede those in the cortex. While correlational, these data, together with the anatomical and pharmacological findings, suggest that the basal forebrain has an important role in regulating both the tonic and the phasic functioning of the cortex.

Modification of neocortical acetylcholine release and electroencephalogram desynchronization due to brainstem stimulation by drugs applied to the basal forebrain.

Acetylcholine released from the cerebral cortex was collected using microdialysis while stimulating the region of the pedunculopontine tegmentum in urethane-anesthetized rats. Electrical stimulation in the form of short trains of pulses delivered once per minute produced a 350% increase in acetylcholine release and a desynchronization of the electroencephalogram, as measured by relative power in the 20-45 Hz range (low-voltage fast activity). Perfusion of the region of cholinergic neurons believed to be responsible for the cortical release of acetylcholine, the nucleus basalis magnocellularis, was carried out using a second microdialysis probe. Exposure of the nucleus basalis magnocellularis to blockers of neural activity (tetrodotoxin or procaine) or to blockers of synaptic transmission (calcium-free solution plus magnesium or cobalt) produced a substantial decrease in the release of acetylcholine and desynchronization evoked by brainstem stimulation. Exposure of the nucleus basalis magnocellularis to the glutamate antagonist, kynurenate, resulted in a decrease in evoked acetylcholine release and electroencephalogram desynchronization similar in magnitude to that produced by nonspecific blockers, whereas application of muscarinic or nicotinic cholinergic blockers to the nucleus basalis magnocellularis did not reduce acetylcholine release or electroencephalogram desynchronization. Application of tetrodotoxin to the collection site in the cortex abolished the stimulation-evoked acetylcholine release, but not the low baseline release indicating that cholinergic nucleus basalis magnocellularis neurons have a low spontaneous firing rate in urethane-anesthetized animals. The results of this study suggest that the major excitatory input to the cholinergic neurons of the nucleus basalis magnocellularis from the pedunculopontine tegmentum is via glutamatergic and not cholinergic synapses.

Frequency-dependent increase in cortical acetylcholine release evoked by stimulation of the nucleus basalis magnocellularis in the rat ☆

Acetylcholine was collected from the somatosensory cortex of anesthetized rats, using the microdialysis technique. Electrical stimulation of the nucleus basalis magnocellularis (NBM) with trains of 10 pulses at 100 Hz delivered every second produced a 3-4-fold increase in acetylcholine release. Stimulation with an intratrain frequency of 10, 50, 100 or 200 Hz demonstrated that 100 Hz trains produced the greatest increase, while the other frequencies were about half as effective. The cortical release of acetylcholine in this paradigm supports the hypothesis that the previously demonstrated enhancement by NBM stimulation of cortical sensory inputs is due to cholinergic activation.

Time course and effective spread of lidocaine and tetrodotoxin delivered via microdialysis: an electrophysiological study in cerebral cortex

Microdialysis is a useful tool for administering drugs into localized regions of brain tissue, but the diffusion of drugs from the probe has not been systematically examined. Lidocaine (10%) and tetrodotoxin (TTX, 10 microM), drugs typically used in neural inactivation studies, were infused through a microdialysis probe into raccoon somatosensory cortex while evoked responses were recorded at four electrodes equally spaced 0.5--2.0 mm from the probe. The decreases in evoked response amplitude as a function of time and distance from the probe were used as functional measures to describe the time course and spread of the drugs. TTX inactivated distant sites more quickly and to a greater extent than lidocaine. Responses recovered within approximately 40 min after termination of lidocaine, but did not recover for at least 2 h after TTX. Based on these measurements, we estimated that, at the concentrations used, lidocaine has a maximal spread of 2.1 mm, while TTX could spread as far as 4.8 mm from the microdialysis probe. However, in terms of significant inactivation of neuronal activity, lidocaine and TTX have an effective spread of 1 and 2 mm, respectively.

Modality- and region-specific acetylcholine release in the rat neocortex

The basal forebrain is the major source of acetylcholine in the neocortex, and this projection has been variously described as either diffuse or highly specific. We used in vivo microdialysis to examine this discrepancy by collecting acetylcholine release simultaneously from visual, somatosensory and prefrontal cortical areas. Urethane-anesthetized rats were presented with visual and somatosensory stimulation in counter-balanced order and acetylcholine was measured using HPLC. Evoked acetylcholine release was modality-specific, i.e. visual stimulation evoked a large (75%) increase from visual cortex and little (24%) change from the somatosensory area whereas skin stimulation had the opposite effect. No increase was apparent in prefrontal cortex with either stimulation protocol. This experiment extends early studies using cortical cups to collect acetylcholine, and is consistent with the concept of functional specificity within the cholinergic basal forebrain with respect to both its sensory inputs and projections to the neocortex. This functional specificity within the cholinergic basal forebrain might be utilized in the modulation of different cortical regions during selective attention and plasticity.

Long-term enhancement of evoked potentials in raccoon somatosensory cortex following co-activation of the nucleus basalis of Meynert complex and cutaneous receptors

Long-term enhancement of the evoked potential was induced in the primary somatosensory cortex of anaesthetized raccoons after mechanical stimulation of the skin was paired with electrical stimulation of the nucleus basalis of Meynert (NBM). Sets of 4 pulses, 0.5 ms duration at 300 Hz were delivered at 2-s intervals to the basal forebrain 80 ms before the glabrous skin on the 4th digit of the contralateral forepaw was stimulated mechanically. The average waveform of 30 evoked potentials was separated into an initial positive, a negative and a second positive component. During pairing of the skin and NBM stimuli, the area under the initial positive component was smaller than before or after pairing. The negative and second positive waves were unchanged. One minute after pairing, the initial positive wave returned to control values and continued to increase until the end of the experiment 50 min later, at which time it was 300% above control. The negative and second positive waves increased after the pairing to between 130 and 200% and remained at that level for the duration of the experiment. The effective NBM site for stimulation was the area rich in cholinergic neurons corresponding to the NBM. In control animals, repeated stimulation of the skin or NBM alone, or their random, unpaired stimulation together, did not enhance the somatosensory evoked potential. The results suggest that the NBM input enhances the efficacy of cortical responses to cutaneous input and thus may play a role in cortical neuronal plasticity.

Acute Effects of Total or Partial Digit Denervation on Raccoon Somatosensory Cortex

The immediate effects of total or partial denervation of single digits (0-16 hr after nerve transection) on primary somatosensory cortex were studied electrophysiologically. Comparisons of response properties and cortical somatotopy were made between intact raccoons and four groups of raccoons with transection of some or all of the nerves innervating the fourth or fifth digit. Animals with all four digital nerves cut (amputation of the digit) were most different from normal. Approximately half of the penetrations in the affected cortical region showed inhibitory responses to stimulation of adjacent skin regions. These consisted of a strong response to stimulus offset and/or a suppression of spontaneous activity during indentation. Since these responses were substantially different from those recorded several months after digit amputation, additional changes in connectivity and synaptic strength must occur with chronic denervation. These inhibitory responses were not seen in animals with one, two, or three nerves cut per digit. In the animals with partial denervation of a digit, the greatest disruption occurred when both ventral nerves to the glabrous skin were transected. This yielded cell clusters with abnormally large receptive fields, disruptions in somatotopic organization, and a decreased occurrence of low-threshold responses. If only one nerve to glabrous skin was transected, there was less change, even if it was combined with transection of both nerves to hairy skin. These results suggest that the release of inhibitory responses in a cortical digital region by amputation is prevented by the retention of even one ventral nerve. None of the denervation conditions produced large nonresponsive areas of cortex, which would have indicated a loss of all inputs.

Phasic relationship between the activity of basal forebrain neurons and cortical EEG in urethane-anesthetized rat

Previous studies have shown that a large number of neurons in the basal forebrain have higher firing rates when the cortical electroencephalogram (EEG) is characterized by low-voltage fast activity compared to states characterized by slow waves. A smaller number of cells with increased discharge rates during slow waves have also been observed. This putative ascending effect is thought to be tonic, but no attempt has been made to analyze a closer temporal correlation between the activity of basal forebrain neurons and the cortical EEG. Recordings were made from single units in the basal forebrain concurrently with the cortical EEG in urethane-anesthetized rats. A total of 52 neurons consistently showed higher firing during low-voltage fast activity (F-cells), whereas 14 neurons were consistently more active during cortical slow waves (S-cells). In most of the F- (90%) and S-cells (86%) the change in firing rate occurred prior to the change in the EEG. The average delay was 300-400 ms. At a deep level of anesthesia, the EEG was characterized by an alternation of flat periods and large waves. Most F-cells became active near the start of the first large wave, which is known to correspond to the onset of depolarization of cortical pyramidal neurons. In contrast, most S-cells were less active during the large waves. These data show that the activity of basal forebrain neurons is phasically correlated with the EEG in addition to the tonic correlation that has been demonstrated previously. Both types of basal forebrain neurons change their firing rate prior to the change in cortical EEG, suggesting that the basal forebrain neurons may have a regulatory influence on the EEG.