Search PubMed⌕ Search

Biomedical subjects

D A McCormick

Publications and source records attributed to D A McCormick.

At least 91 records · Page 5Linked to original sources
PubMed1987

Actions of acetylcholine in the guinea-pig and cat medial and lateral geniculate nuclei, in vitro.

1. The mechanisms of action of acetylcholine (ACh) in the medial (m.g.n.) and dorsal lateral geniculate (l.g.n.d.) nuclei were investigated using intracellular recordings techniques in guinea-pig and cat in vitro thalamic slices. 2. Application of ACh to neurones in guinea-pig geniculate nuclei resulted in a hyperpolarization in all neurones followed by a slow depolarization in 52% of l.g.n.d. and 46% of m.g.n. neurones. Neither the hyperpolarization nor the slow depolarization were eliminated by blockade of synaptic transmission and both were activated by acetyl-beta-methylcholine and DL-muscarine and blocked by scopolamine, indicating that these responses are mediated by direct activation of muscarinic receptors on the cells studied. 3. The ACh-induced hyperpolarization was associated with an increase in apparent input conductance (Gi) of 4-13 nS. The reversal potential of the ACh-induced hyperpolarization varied in a Nernstian manner with changes in extracellular [K+] and was greatly reduced by bath application of the K+ antagonist Ba2+ or intracellular injection of Cs+. These findings show that the muscarinic hyperpolarization is mediated by an increase in K+ conductance. 4. The ACh-induced slow depolarization was associated with a decrease in Gi of 2-15 nS, had an extrapolated reversal potential near EK, and was sensitive to [K+]o, indicating that this response is due to a decrease in K+ conductance. 5. In contrast to effects on guinea-pig geniculate neurones, applications of ACh to cat l.g.n.d. and m.g.n. cells resulted in a rapid depolarization in nearly all cells, followed in some neurones by a hyperpolarization and/or a slow depolarization. The rapid excitatory response was associated with an increase in membrane conductance, had an estimated reversal potential of -49 to -4 mV and may be mediated by nicotinic receptors. The hyperpolarization and slow depolarization were similar to those of the guinea-pig in that they were associated with an increase and decrease, respectively, of Gi, and were mediated by muscarinic receptors. 6. The muscarinic hyperpolarization interacted with the intrinsic properties of the thalamic neurones to inhibit single-spike activity while promoting the occurrence of burst discharges. The muscarinic slow depolarization had the opposite effect; it brought the membrane potential into the range where burst firing was blocked and single-spike firing predominated. Depending upon the membrane potential, the rapid excitatory response of cat geniculate neurones could activate either a burst or a train of action potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1987

Post-natal development of electrophysiological properties of rat cerebral cortical pyramidal neurones.

1. The post-natal development of the electrophysiological properties of cortical layer V pyramidal neurons was investigated with intracellular recordings from rat sensorimotor cortical slices, in vitro. 2. At all ages post-natally (post-natal day 1 to day 36; P1-P36) neurons were capable of generating a train of Na+-dependent action potentials in response to intracellular injection of sufficient depolarizing current. During the second and third week post-natally, these action potentials changed substantially, becoming faster in both their rising and falling phases, shorter in duration, and larger in amplitude. 3. Both mature (greater than P21) and immature (P2-P4) cortical neurones could generate Ca2+-dependent action potentials only if a substantial portion of K+ conductances were blocked. The maximum rate of rise of Ca2+ spikes also increased with age. 4. The apparent input resistance, specific membrane resistance, and membrane time constant all decreased with age from P1 to P30. Immature neurones had I-V relationships that were substantially more linear than those of adult cells, although rectification was often present in both the hyperpolarizing and depolarizing range. Inward rectification in the depolarizing range was Na+ dependent and was substantially larger in mature versus immature neurones. 5. Single, or trains of, action potentials in immature neurones were followed by short duration (10-50 ms) and long duration (1-5 s) after-hyperpolarizations (a.h.p.s) respectively. The duration of the latter appeared to decrease with age. The presence of large a.h.p.s indicates that Ca2+ entry occurs during the action potential of immature, as well as mature, neurones. 6. Responses to intracellular injection of depolarizing current pulses indicated that immature neurones have frequency versus injected current (f-I) relationships which are in general less steep than those for adult neurones and more limited in terms of the range of firing frequencies. 7. Our results are consistent with the hypothesis that there is a considerable increase in the density of voltage-dependent ionic channels underlying the electro-responsiveness of cortical pyramidal neurones during post-natal development.

Action Potentials↗
PubMed1987

Acetylcholine causes rapid nicotinic excitation in the medial habenular nucleus of guinea pig, in vitro.

The actions of ACh in the medial habenular nucleus (MHb) were investigated using extra- and intracellular recording techniques in guinea pig thalamic slice maintained in vitro. Applications of ACh to MHb neurons resulted in rapid excitation followed by inhibition. Neither of these responses was abolished by blockade of synaptic transmission, indicating that they are consequences of ACh action directly on MHb cells. Local applications of the nicotinic agonists nicotine and cytisine caused long-lasting excitation, while applications of another nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium caused both the excitatory and inhibitory responses. Applications of the muscarinic agonists DL-muscarine and acetyl-beta-methylcholine did not consistently cause either the excitatory or inhibitory response. Adding the nicotinic antagonist hexamethonium to the bathing medium blocked both the excitatory and inhibitory ACh responses, while addition of the muscarinic antagonists atropine or scopolamine had no effect. These results indicate that the effects of ACh on MHb neurons are mediated by nicotinic receptors. Intracellular recordings revealed that ACh or nicotine cause an increase in membrane conductance associated with depolarizations that had an average reversal potential of -16 to -11 mV. These results indicate that the ACh-induced excitation is due to an increase in membrane cation conductance. The inhibitory response that follows ACh-induced depolarization and repetitive firing was associated with a hyperpolarization and an increase in membrane conductance. Similar postexcitatory inhibition could also be elicited by direct depolarization or by applications of glutamate, indicating that the hyperpolarizing response to ACh may be an endogenous postexcitatory potential that is not directly coupled to activation of nicotinic receptors. These results suggest that cholinergic transmission in the MHb may be largely of the nicotinic type. This nucleus may be of one of the major regions of the nervous system through which nicotine mediates its central effects.

Acetylcholine↗
PubMed1986

Mechanisms of action of acetylcholine in the guinea-pig cerebral cortex in vitro.

The mechanisms of action of acetylcholine (ACh) in the guinea-pig neocortex were investigated using intracellular recordings from layer V pyramidal cells of the anterior cingulate cortical slice. At resting membrane potential (Vm = -80 to -70 mV), ACh application resulted in a barrage of excitatory and inhibitory post-synaptic potentials (p.s.p.s) associated with a decrease in apparent input resistance (Ri). ACh, applied to pyramidal neurones depolarized to just below firing threshold (Vm = -65 to -55 mV), produced a short-latency hyperpolarization concomitant with p.s.p.s and a decrease in Ri, followed by a long-lasting (10 to greater than 60 s) depolarization and action potential generation. Both of these responses were also found in presumed pyramidal neurones of other cortical regions (sensorimotor and visual) and were blocked by muscarinic, but not nicotinic, antagonists. The ACh-induced hyperpolarization possessed an average reversal potential of -75.8 mV, similar to that for the hyperpolarizing response to gamma-aminobutyric acid (GABA; -72.4 mV) and for the i.p.s.p. generated by orthodromic stimulation (-69.6 mV). This cholinergic inhibitory response could be elicited by ACh applications at significantly greater distance from the cell than the slow depolarizing response. Blockade of GABAergic synaptic transmission with solution containing Mn2+ and low Ca2+, or by local application of tetrodotoxin (TTX), bicuculline or picrotoxin, abolished the ACh-induced inhibitory response but not the slow excitatory response. In TTX (or Mn2+, low Ca2+) the slow excitatory response possessed a minimum onset latency of 250 ms and was associated with a voltage-dependent increase in Ri. Application of ACh caused short-latency excitation associated with a decrease in Ri in eight neurones. The time course of this excitation was similar to that of the inhibition seen in pyramidal neurones. Seven of these neurones had action potentials with unusually brief durations, indicating that they were probably non-pyramidal cells. ACh blocked the slow after-hyperpolarization (a.h.p.) following a train of action potentials, occasionally reduced orthodromically evoked p.s.p.s, and had no effect on the width or maximum rate of rise or fall of the action potential. It is concluded that cholinergic inhibition of pyramidal neurones is mediated through a rapid muscarinic excitation of non-pyramidal cells, resulting in the release of GABA. In pyramidal cells ACh causes a relatively slow blockade of both a voltage-dependent hyperpolarizing conductance (M-current) which is most active at depolarized membrane potentials, and the Ca2+-activated K+ conductance underlying the a.h.p.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1985

Lesions of the inferior olivary complex cause extinction of the classically conditioned eyeblink response.

The dentate-interpositus nuclei of the cerebellum are known to be critically involved in the production of the classically conditioned eyeblink response in the rabbit. The rostro-medial portions of the inferior olivary complex (rmIO) project to these nuclei as well as receive projections from the fifth sensory nuclei. Lesions of the rmIO caused a previously classically conditioned eyeblink response to slowly decrease in amplitude and frequency with continued paired conditioned stimulus-unconditioned stimulus (CS-UCS) training in a manner which was identical to extinction of the learned response in control animals. The lesion had no effect on the performance of the unconditioned response. Lesions of the rmIO before training prevented learning from occurring. Lesions of other portions of the IO or of the reticular formation did not specifically affect the learned response. We conclude that the rmIO is critically involved in the learning and maintenance of the classically conditioned eyeblink response. We propose that the rmIO may serve as a pathway for information from the unconditioned stimulus to reach the cerebellum, and as such may in fact be the essential reinforcing or teaching input for the learning of classically conditioned responses. These results support the hypothesis that the cerebellum contains neuronal changes which are a critical portion of the memory trace for the conditioned response.

Animals↗
PubMed1985

Two types of muscarinic response to acetylcholine in mammalian cortical neurons.

Applications of acetylcholine (AcCho) to pyramidal cells of guinea pig cingulate cortical slices maintained in vitro result in a short latency inhibition, followed by a prolonged increase in excitability. Cholinergic inhibition is mediated through the rapid excitation of interneurons that utilize the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This rapid excitation of interneurons is associated with a membrane depolarization and a decrease in neuronal input resistance. In contrast, AcCho-induced excitation of pyramidal cells is due to a direct action that produces a voltage-dependent increase in input resistance. In the experiments reported here, we investigated the possibility that these two responses are mediated by different subclasses of cholinergic receptors. The inhibitory and slow excitatory responses of pyramidal neurons were blocked by muscarinic but not by nicotinic antagonists. Pirenzepine was more effective in blocking the AcCho-induced slow depolarization than in blocking the hyperpolarization of pyramidal neurons. The two responses also varied in their sensitivity to various cholinergic agonists, making it possible to selectively activate either. These data suggest that AcCho may produce two physiologically and pharmacologically distinct muscarinic responses on neocortical neurons: slowly developing voltage-dependent depolarizations associated with an increase in input resistance in pyramidal cells and short-latency depolarizations associated with a decrease in input resistance in presumed GABAergic interneurons.

Acetylcholine↗
PubMed1985

Comparative electrophysiology of pyramidal and sparsely spiny stellate neurons of the neocortex.

Slices of sensorimotor and anterior cingulate cortex from guinea pigs were maintained in vitro and bathed in a normal physiological medium. Electrophysiological properties of neurons were assessed with intracellular recording techniques. Some neurons were identified morphologically by intracellular injection of the fluorescent dye Lucifer yellow CH. Three distinct neuronal classes of electrophysiological behavior were observed; these were termed regular spiking, bursting, and fast spiking. The physiological properties of neurons from sensorimotor and anterior cingulate areas did not differ significantly. Regular-spiking cells were characterized by action potentials with a mean duration of 0.80 ms at one-half amplitude, a ratio of maximum rate of spike rise to maximum rate of fall of 4.12, and a prominent afterhyperpolarization following a train of spikes. The primary slope of initial spike frequency versus injected current intensity was 241 Hz/nA. During prolonged suprathreshold current pulses the frequency of firing adapted strongly. When local synaptic pathways were activated, all cells were transiently excited and then strongly inhibited. Bursting cells were distinguished by their ability to generate endogenous, all-or-none bursts of three to five action potentials. Their properties were otherwise very similar to regular-spiking cells. The ability to generate a burst was eliminated when the membrane was depolarized to near the firing threshold with tonic current. By contrast, hyperpolarization of regular-spiking (i.e., nonbursting) cells did not uncover latent bursting tendencies. The action potentials of fast-spiking cells were much briefer (mean of 0.32 ms) than those of the other cell types.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1984

Effect of bilateral lesions of the dentate and interpositus cerebellar nuclei on conditioning of heart-rate and nictitating membrane/eyelid responses in the rabbit.

It has been shown that unilateral lesions of the medial dentate/lateral interpositus nuclear region of the cerebellum abolish the learned nictitating membrane (NM)/eyelid response of the eye ipsilateral to the lesion. The present study examined the effects of bilateral cerebellar lesions on acquisition of heart-rate conditioning (often viewed as a measure of 'conditioned fear') and both its short-and long-term effects on NM/eyelid learning and relearning. The results demonstrate that cerebellar lesions that completely and permanently abolish acquisition or retention of the somatic response (NM/eyelid) bilaterally have no effect on heart-rate conditioning. The neuronal circuits necessary for learning of the heart-rate response and for learning of the adaptive somatic response are thus in significant part different. Results are tentatively interpreted within the context of a two-process theory of aversive learning: an initial phase indexed by conditioned autonomic and 'non-specific' responses such as heart-rate and a subsequent phase of learning the specific adaptive responses.

Animals↗
PubMed1984

Cerebellum: essential involvement in the classically conditioned eyelid response.

Classical conditioning of the eyelid response in the rabbit was used to investigate the neuronal structures mediating basic associative learning of discrete, adaptive responses. Lesions of the ipsilateral dentate-interpositus nuclei, but not of the cerebellar cortex, abolished the learned eyeblink response. Recordings from these nuclei have revealed neuronal responses related to the learning of the response. Stimulating these recording sites produced the eyelid response. The dentate-interpositus nuclei were concluded to be critically involved in the learning and production of classically conditioned responses.

Acoustic Stimulation↗
PubMed1984

Effects of lesions of cerebellar nuclei on conditioned behavioral and hippocampal neuronal responses.

Rabbits were overtrained using classical conditioning of the rabbit nictitating membrane (NM)/eyelid response. Unilateral electrolytic lesions were then made through electrodes previously implanted in dentate and interpositus cerebellar nuclei ipsilateral to the trained (left) eye. Lesions caused a complete or near-complete abolition of conditioned behavioral responses on the ipsilateral side, but had no effect on unconditioned responses to corneal airpuff. When training was switched to the contralateral (right) side, animals learned within the first few trials, but did not relearn when training was returned to the left (lesioned) side. Control animals in which lesions spared the deep nuclei showed no such learning deficits. Lesions of cerebellar nuclei also abolished conditioned increases in hippocampal CAl neural activity evoked by the tone conditioned stimulus in this paradigm. As with the behavior, training on the right (non-lesioned) side reinstated the conditioned neuronal response within the first few trials of training, even though behavioral responding on lesioned side showed little or no improvement. These results indicate that the cerebellum is an essential structure for the behavioral expression of learning, and plays an important role in the generation of conditioned hippocampal responses observed in this paradigm.

Animals↗
PubMed1984

Neuronal responses of the rabbit cerebellum during acquisition and performance of a classically conditioned nictitating membrane-eyelid response.

Neuronal activity was recorded from regions of the cerebellar cortex and dentate-interpositus nuclei during learning and/or performance of a classically conditioned nictitating membrane (NM-a third eyelid)/eyeblink response in the rabbit. It was found that neurons located within restricted portions of the ansiform lobule and anterior lobe cortical regions and of the dentate-interpositus nuclei respond in relation to the performance of the learned eyeblink response. Furthermore, chronic recordings from the dentate-interpositus nuclei revealed that these responses develop in close relation to the learning of the conditioned eyeblink response. Stimulation of the dentate-interpositus nuclei through the recording electrodes in some cases yielded eyelid closure and NM extension in both trained and untrained animals. Lesion of the axons of the dentate-interpositus nuclei (superior cerebellar peduncle), a manipulation which is known to abolish the learned eyeblink response, abolished the stimulation effect. We have previously reported that lesions of the dentate-interpositus nuclei cause abolition of the learned eyeblink response. In the present study, we report that lesions of the regions of cerebellar cortex projecting to the dentate-interpositus nuclei do not permanently abolish the conditioned response, although the amplitude-time course of the learned response could be affected. These results, together with results of other studies, demonstrate that the medial dentate and/or lateral interpositus nuclei are active during learning and performance of the conditioned eyeblink response, are capable of producing this learned response, and are essential for the learning and retention of the conditioned eyeblink response. Therefore, the medial dentate and/or lateral interpositus nuclei are a part of the essential neuronal circuit involved in the learning and production of the classically conditioned eyeblink response in the rabbit.

Acoustic Stimulation↗
PubMed1983

Neuronal responses of the rabbit brainstem during performance of the classically conditioned nictitating membrane (NM)/eyelid response.

Through the use of a chronic microdrive recording system, neuronal unit activity was recorded throughout the brainstem of the rabbit during performance of the classically conditioned nictitating membrane (NM) extension/eyeblink response using an acoustical conditioned stimulus (CS) and a corneal airpuff unconditioned stimulus (UCS). Regions which exhibited neuronal responses near the onset of the learned response were found to be relatively localized to: the abducens, accessory abducens, and facial nuclei (the motoneurons known to innervate the muscles responsible for expression of the conditioned response); the sensory nuclei of the fifth (probably representing somatosensory or proprioceptive feedback from the conditioned response); the superior colliculus; the periaqueductal gray; various reticular regions and the brainstem nuclei directly connected with the cerebellum (pontine nuclei, tegmental reticular nucleus (Bechterew), red nucleus, and perhaps the inferior olive). Stimulus (tone-airpuff) evoked responses were found within all classical auditory nuclei of the brainstem; the superior colliculus; the periaqueductal gray; pontine nuclei; fifth sensory nuclei, and various reticular regions. Recent lesion studies have shown the ipsilateral cerebellum to be essential for the learning and retention of this response. Collectively these results indicate that the cerebellum and its related brainstem nuclei are critically involved in the control and production of the classically conditioned NM/eyeblink response and may contain essential long term neuronal changes--the 'memory trace'--which serves to encode this learned response.

Acoustic Stimulation↗
PubMed1982

Locus coeruleus lesions and resistance to extinction of a classically conditioned response: involvement of the neocortex and hippocampus.

Bilateral electrolytic lesions of the locus coeruleus were made in rabbits prior to classical conditioning of the nictitating membrane (NM) response. After recovery, the animals received one session of unpaired training followed by 3 days of paired acquisition training and 4 days of unpaired training (extinction). At the end of extinction norepinephrine (NE) and dopamine (DA) levels were measured in several brain regions. Each lesioned animal was placed into one of two groups according to whether or not the animal exhibited a significant depletion of cortical/hippocampal NE. A third group was formed by non-lesioned controls. There were no significant differences between the 3 groups during acquisition; however, during days 3 and 4 of unpaired extinction the group with cortical/hippocampal NE depletion showed significantly larger NM responses on the conditioned stimulus-alone trials than either of the two control groups. This extinction deficit appeared mainly in the unconditioned stimulus-period component of the tone-alone conditioned responses. The magnitude of the extinction deficit was highly correlated with the depletion of NE in both cortical and hippocampal samples but not with the depletion of NE in the hypothalamus/mid-thalamus, or cerebellum.

Animals↗
PubMed1982

Concomitant classical conditioning of the rabbit nictitating membrane and eyelid responses: correlations and implications.

Simultaneous recordings of muscle unit activity from the muscles of the left and right eyelids (M. obicularis oculi) and recordings of the movement of the left nictitating membrane (NM) were taken during classical conditioning in the rabbit using a tone CS paired with an airpuff UCS to the left cornea. The unconditioned eyelid responses were found to be bilateral. The conditioned eyelid responses were also bilateral in most animals. Both the conditioned and unconditioned eyelid responses were larger on the left side. The conditioned responses of the left and right eyelids and the left NM were found to increase in magnitude and decrease in latency from the onset of the CS over training trials in almost the exactly same manner (correlations as high as .99). Behaviorally, the three responses could occur independently, suggesting that the cranial nuclei which control them (left abducens/accessory abducens, left facial nucleus, right facial nucleus) are not strongly coupled. Thus, for the learned response, it is suggested that the three nuclei are controlled by a common central system. This finding has implications for the nature of the engram--the essential neuronal circuitry encoding the learned response.

Abducens Nerve↗
PubMed1982

Initial localization of the memory trace for a basic form of learning.

Electrophysiological recording of neuronal unit activity during paired training trials from various regions of the ipsilateral cerebellum in rabbits well trained in the classically conditioned eyelid/nictitating membrane response have revealed both stimulus-evoked responses and responses that form an amplitude/temporal model of the learned behavioral response. Ablation of the ipsilateral, lateral cerebellum completely and permanently abolished the behavioral conditioned response in well-trained animals but had no effect at all on the unconditioned reflex response. In marked contrast, conditioned responses were easily trained in the eye contralateral to the cerebellar lesion. We suggest that at least part of the essential neuronal plasticity that codes the learned response may be localized to the cerebellum.

Animals↗