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M D Mauk

Publications and source records attributed to M D Mauk.

At least 37 records · Page 2Linked to original sources
PubMed1995

Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex.

We test the hypothesis that the cerebellar cortex is required for the extinction of conditioned eyelid responses in rabbits trained using standard Pavlovian delay procedures. Following 10 daily training sessions during which rabbits achieved asymptotic performance, lesions of the ipsilateral hemisphere of the cerebellar cortex were made by aspiration. The target of these lesions was the anterior lobe, as suggested by previous observations that this region is necessary for the learning-dependent timing of conditioned eyelid responses (Perrett et al., 1993). We report that anterior lobe damage, as indicated by disrupted response timing and confirmed by tissue analysis, produces severe deficits in conditioned response extinction. Postlesion responses show no significant decline over ten training sessions, whereas response timing and extinction are unaffected by lesions that do not include the anterior lobe. These conditioned responses that do not extinguish display stimulus specificity, excluding the possibility that they are unlearned responses unmasked by cerebellar cortex lesions. These observations suggest that Pavlovian eyelid conditioning is mediated by synaptic plasticity in at least two sites and the anterior lobe of the cerebellar cortex influences one of these sites during extinction. Based on these and previous data, we propose the hypothesis that eyelid conditioning can involve plasticity in both the cerebellar cortex and interpositus nucleus and that plasticity in the nucleus is controlled by input from Purkinje cell activity in the cortex. This hypothesis is consistent with observations that the cerebellar cortex may not always be required for the expression of conditioned responses, but it is necessary for response timing and for extinction.

Animals↗
PubMed1993

Calcium/calmodulin-dependent protein kinase II regulates hippocampal synaptic transmission.

Extracellular application of protein kinase inhibitors was used to examine the role of calcium/calmodulin-dependent protein kinase II (CaM-KII) in synaptic transmission in the CA1 region of rat hippocampus. Bath application of the broad spectrum, membrane permeable kinase inhibitor H7 (250 microM) decreased excitatory synaptic responses elicited in hippocampal slices. Whereas H7 inhibits several protein kinases and has non-specific effects, several synthetic peptides have been developed as specific inhibitors of CaM-KII. Using in situ phosphorylation in hippocampal slices, we demonstrate that extracellular application of synthetic peptide inhibitors of CaM-KII preferentially suppresses the phosphorylation of synapsin I at the CaM-KII specific site. This suppression was not reversed by the application of a calcium ionophore indicating the decrease in phosphorylation does not result only from blockade of presynaptic calcium influx. Thus, it appears the peptides gain access to intracellular compartments and retain their inhibitory properties. Further, we found that extracellular application of these peptide inhibitors decreased excitatory synaptic responses elicited in the CA1 region of hippocampal slices with relative potencies consistent with their ability to block CaM-KII activity in vitro. Peptide application did not alter the input resistance of postsynaptic cells nor responses elicited by glutamate iontophoresis. These results suggest that CaM-KII activity, possibly through phosphorylation of presynaptic synapsin I, is required for sustained synaptic transmission at mammalian synapses.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Glutamate iontophoresis induces long-term potentiation in the absence of evoked presynaptic activity.

Protocols that induce long-term potentiation (LTP) typically involve afferent stimulation. We tested the hypothesis that LTP induction does not require presynaptic activity. The significance of this hypothesis is underscored by results suggesting that LTP expression may involve activity-dependent presynaptic changes. An induction protocol using glutamate iontophoresis was developed that reliably induced LTP in hippocampal slices without afferent stimulation. Iontophoresis LTP was Ca2+ dependent, was blocked by MK-801, and occluded tetanus-induced LTP. Iontophoresis LTP was induced when excitatory postsynaptic potentials were completely blocked by adenosine plus tetrodotoxin. Our results suggest constraints on the involvement of presynaptic mechanisms and putative retrograde messengers in LTP induction and expression; namely, these processes must function without many forms of activity-dependent presynaptic processes.

Action Potentials↗
PubMed1993

Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses.

Among the many issues surrounding the involvement of the cerebellum in motor learning, the relative roles of the cerebellar cortex and cerebellar nuclei in Pavlovian conditioning have been particularly difficult to assess. While previous studies have investigated the effects of cerebellar cortex lesions on the acquisition and retention of conditioned movements, we have examined the effects of these lesions on the timing of Pavlovian eyelid responses. The rationale for this approach arises from previous studies indicating that this timing is a component of Pavlovian eyelid responses that is learned and that involves temporal discrimination. To permit within-animal comparisons, rabbits were trained to produce differently timed responses to high- and low-frequency auditory conditioned stimuli (CSs). Before the lesion the conditioned responses to both CSs were appropriately timed--each peaked near the time at which the unconditioned stimulus was presented for that CS. However, after the lesion both CSs could elicit similarly timed conditioned responses that peaked inappropriately at very short latencies. The changes in responses timing were sensitive to the size of the lesion, particularly its rostral-caudal extent. Similar results were obtained in animals trained with one CS, indicating that the disruption of response timing is not related to impaired auditory discrimination. Because response timing is learned and therefore requires synaptic plasticity, these data suggest that there are at least two sites of plasticity involved in the motor expression of Pavlovian eyelid responses. Plasticity at one site is necessary for the learned timing of conditioned responses, while plasticity at another site is revealed by the inappropriately timed responses observed following removal of the cerebellar cortex. This lesion-induced dissociation of the expression of motor responses and their learned timing supports a synthesis of competing views by suggesting that motor learning involves both the cerebellar cortex and cerebellar nuclei. We hypothesize that motor learning involves a decrease in strength of the granule cell-Purkinje cell synapses (e.g., Ito and Kano, 1982) in the cerebellar cortex and an increase in strength of the mossy fiber-cerebellar nuclei synapses (e.g., Racine et al., 1986). Finally, these data suggest that the cerebellar cortex may mediate the temporal discriminations that are necessary for the learned timing of conditioned responses.

Animals↗
PubMed1992

Learning-dependent timing of Pavlovian eyelid responses: differential conditioning using multiple interstimulus intervals.

This study demonstrates that individual animals can concurrently acquire differently timed conditioned eyelid responses using a differential conditioning procedure in which distinctive conditioned stimuli (CSs) are individually paired with an unconditioned stimulus, with each using a different interstimulus interval (ISI). This promotes robust conditioning, and the timing of the conditioned responses is appropriate for the respective ISIs, differs for each CS to the extent that the ISIs are dissimilar, and is apparent in individual trials. This procedure was used to demonstrate that response timing is not a function of associative strength. These data suggest response timing is mediated by an ability to make temporal discriminations during the CS. The within-animals comparisons made possible by this differential conditioning should facilitate lesion and unit recording analyses of the neural basis of response timing.

Animals↗
PubMed1989

An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation.

The phenomenon of long-term potentiation (LTP), a long lasting increase in the strength of synaptic transmission which is due to brief, repetitive activation of excitatory afferent fibres, is one of the most striking examples of synaptic plasticity in the mammalian brain. In the CA1 region of the hippocampus, the induction of LTP requires activation of NMDA (N-methyl-D-aspartate) receptors by synaptically released glutamate with concomitant postsynaptic membrane depolarization. This relieves the voltage-dependent magnesium block of the NMDA-receptor ion channel, allowing calcium to flow into the dendritic spine. Although calcium has been shown to be a necessary trigger for LTP (refs 11, 12), little is known about the immediate biochemical processes that are activated by calcium and are responsible for LTP. The most attractive candidates have been calcium/calmodulin-dependent protein kinase II (CaM-KII) (refs 13-16), protein kinase C (refs 17-19), and the calcium-dependent protease, calpain. Extracellular application of protein kinase inhibitors to the hippocampal slice preparation blocks the induction of LTP (refs 21-23) but it is unclear whether this is due to a pre- and/or postsynaptic action. We have found that intracellular injection into CA1 pyramidal cells of the protein kinase inhibitor H-7, or of the calmodulin antagonist calmidazolium, blocks LTP. Furthermore, LTP is blocked by the injection of synthetic peptides that are potent calmodulin antagonists and inhibit CaM-KII auto- and substrate phosphorylation. These findings demonstrate that in the postsynaptic cell both activation of calmodulin and kinase activity are required for the generation of LTP, and focus further attention on the potential role of CaM-KII in LTP.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1988

Buspirone, 8-OH-DPAT and ipsapirone: effects on hippocampal cerebellar and sciatic fiber excitability.

The effects of serotonin (5-hydroxytryptamine; 5-HT), and the novel anxiolytics buspirone, 8-OH-DPAT (8-hydroxy-2-[N,N-dipropylamino]-tetralin) and ipsapirone (TVXQ 7821, 2-[4-[4-[2-pyrimidinyl]-1-piperazinyl] butyl]-1,2-benzisothiazol-3[2H]one-1,1-dioxide-hydrochloride) on fiber excitability were studied in three axon systems; hippocampal Schaffer collateral fibers, cerebellar parallel fibers, and sciatic nerves. In the hippocampus, application of buspirone, 8-OH-DPAT and ipsapirone resulted in reversible, dose-dependent reductions in the amplitude and conduction velocity of action potentials recorded from presynaptic afferent fibers. Although these agents bind to 5-HT1A receptors, 5-HT application, even at very high (1 mM) concentrations, did not alter axonal responses. This suggests that buspirone, 8-OH-DPAT and ipsapirone exert an action independent of a serotonergic mechanism. Similar effects were observed on the cerebellar parallel fibers although the cerebellum does not have an appreciable number of 5-HT1A receptors. To examine the generalized effects of these agents on nerve excitability, rat sciatic compound action potentials were studied with sucrose gap recordings. Whereas 5-HT, 8-OH-DPAT and ipsapirone had no effects even at high concentrations (1 mM), application of buspirone led to reversible decrement of the responses without appreciable change in membrane potential. These results indicate that buspirone, 8-OH-DPAT and ipsapirone have actions on the excitability of hippocampal and cerebellar neurons independent of serotonergic mechanisms. Moreover, buspirone, but not 8-OH-DPAT or ipsapirone, produces decreased sciatic nerve excitability. NS 20393

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Buspirone attenuates synaptic activation of hippocampal pyramidal cells.

The actions of 5-hydroxytryptamine (5-HT) and buspirone, an anxiolytic agent that displays high and selective affinity for 5-HT1A receptor sites, on synaptic activation of hippocampal CA1 pyramidal cells were studied in vitro. Whereas 5-HT application leads to a rapid hyperpolarization and decreased input resistance in pyramidal cells, buspirone has no measurable effects on membrane potential and input resistance. However, unlike 5-HT, buspirone application leads to a gradual and reversible reduction in excitatory postsynaptic potentials (EPSPs) elicited by stimulation of afferents in the stratum radiatum. Concurrent with this attenuation of the EPSP, buspirone decreases the excitability of afferent fibers in the stratum radiatum as evidenced by conduction slowing, increased refractory period, and decreased ability to generate repetitive impulses. 5-HT has no measurable effect on the afferent fibers. The attenuation of the EPSPs and the decrease in afferent fiber excitability appear to be independent of 5-HT receptors as 5-HT neither shares nor antagonizes the effects of buspirone. Thus, both 5-HT and buspirone can contribute to reduced spike activity in pyramidal cells, but they do so via different mechanisms: 5-HT hyperpolarizes pyramidal cells whereas buspirone attenuates their synaptic activation, possibly via action on the presynaptic fibers in the stratum radiatum.

Afferent Pathways↗
PubMed1987

Retention of classically conditioned eyelid responses following acute decerebration.

We show that classically conditioned eyelid responses are retained in albino rabbits following decerebration. The presence of these responses represents retention rather than reacquisition in that they are present in the initial trials following decerebration. This excludes the possibility that the post-decerebration conditioned responses are mediated by pathways different from those involved in the intact animal. These data indicate that the conditioned response pathway, and sites of plasticity, for eyelid conditioning are spared by decerebration and are contained within the brainstem and cerebellum.

Animals↗
PubMed1987

Activity-evoked increases in extracellular potassium modulate presynaptic excitability in the CA1 region of the hippocampus.

1. The effects of stimulus-evoked potassium release on the excitability of presynaptic axons were studied in the rat hippocampal slice preparation. Extracellular stimulation and recording in the stratum radiatum of CA1 yielded a characteristic field potential corresponding to the compound action potential of nonmyelinated afferents and subsequent postsynaptic activation of pyramidal cells. 2. Repetitive stimulation (1 s; 2-100 Hz) produced biphasic changes in the excitability of the afferents. Initial responses showed increased conduction velocity and variably increased amplitude; subsequent responses showed progressively decreasing conduction velocity and amplitude tending toward conduction block. Decreases in excitability were maximal at the end of stimulation and were more pronounced with higher stimulation frequencies. 3. When synaptic transmission was abolished with superfusate containing elevated [Mg2+] (6 mM) and decreased [Ca2+] (0.25 mM), kynurenic acid (1 mM), or adenosine (100 microM), the ability of the fibers to follow repetitive stimulation was enhanced, as indicated by a reduction in amplitude decrement of the presynaptic volley. The decrease in conduction velocity at the end of stimulation was less than half that obtained with intact postsynaptic activity. 4. Concomitant with changes in the excitability of CA1 afferents, the concentration of extracellular potassium ( [K+]o) increased up to 7 mM, as recorded in the stratum radiatum with potassium ion-sensitive microelectrodes. When postsynaptic activity was blocked, activity-evoked rises in [K+]o were reduced to less than 25% of their former value. This suggests that activity-evoked increases in [K+]o derive predominantly from postsynaptic elements. 5. Superfusion of solutions containing elevated [K+] produced biphasic changes in the excitability of CA1 afferents that were qualitatively similar to those produced by repetitive stimulation. Elevated [K+]o below 6 mM produced increased excitability, whereas [K+]o above 6 mM yielded decreased excitability. 6. These results demonstrate that in the CA1 region of the hippocampus, significant rises in [K+]o occur with activity and derive predominantly from postsynaptic elements. The conduction properties of CA1 afferents are sensitive to the level of [K+]o, whether altered artificially or by activity. These effects may constitute a mechanism of postsynaptic modulation of presynaptic conduction operating within a broad range of afferent firing frequencies in the hippocampus.

Action Potentials↗
PubMed1986

Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus.

We show that conditioned eyelid responses develop when the unconditioned stimulus is electrical stimulation of the dorsal accessory nucleus of the inferior olive. When compared to conditioning using a standard unconditioned stimulus (air puff), the conditioning produced in this manner appears quite normal: the responses develop at a similar rate, are of comparable magnitude and topography, and demonstrate a steep interstimulus interval function; and response topography varies according to the interstimulus interval. These data indicate that activation of neurons in the dorsal accessory olive is a sufficient condition for a stimulus to be an effective unconditioned stimulus. Previous experiments indicate the dorsal accessory olive is necessary in that lesions have effects functionally equivalent to removal of the unconditioned stimulus. These data indicate that the dorsal accessory olive forms a portion of the pathway conveying information about the occurrence of an unconditioned stimulus to sites of synaptic plasticity responsible for conditioning.

Animals↗
PubMed1983

Abolition of conditioned heart-rate responses in rabbits following central administration of [N-MePhe3, D-Pro4] morphiceptin.

Rabbits were initially habituated to a tone and then give 15-20 paired trials where the tone was followed by periorbital shock resulting in conditioned heart-rate decelerations to tone onset and an acceleration of heart-rate following shock offset. The animals were matched for learning performance and divided into two groups. Each animal received a microinfusion into the region of the fourth ventricle of either the opiate [N-MePhe3,D-Pro4] morphiceptin, a highly selective mu receptor agonist, or a mixture of the morphiceptin analogue and the opiate antagonist naltrexone. Administration of the morphiceptin analogue eliminated the conditioned bradycardia to the tone but not the acceleration to the shock. Rabbits given the mixture continued to show conditioned heart-rate decelerations. Previous studies have shown that opiates abolish a recently learned conditioned nictitating membrane response. These effects are consistent with the hypothesis that the opiate effect on conditioning is due to an attenuation of conditioned fear.

Acoustic Stimulation↗
PubMed1982

Selective, naloxone-reversible morphine depression of learned behavioral and hippocampal responses.

Morphine administered intravenously causes immediate and complete abolition of a simple learned response (classically conditioned nictitating membrane extension in rabbit) and of the associated learning-induced increase in hippocampal neuron activity. Both effects are completely reversed by low doses of naloxone. Morphine has no effect at all on behavioral performance of the unconditioned reflex response.

Animals↗
PubMed1982

Opiates and classical conditioning: selective abolition of conditioned responses by activation of opiate receptors within the central nervous system.

It has previously been shown that opiates produce selective abolition of aversively motivated classically conditioned responses in the rabbit. The experiments reported here show that these effects are mediated by specific activation of opiate receptors within the central nervous system in that this central activation is both necessary and sufficient to produce opiate-induced abolition of conditioned responding. Further characterization suggests that selective activation through opiate-mu-receptor interactions within the periaqueductal gray/periventricular region of the fourth ventricle may be critical in mediating this abolition.

Avoidance Learning↗
PubMed1981

Tonic immobility produces hyperalgesia and antagonizes morphine analgesia.

Hyperalgesia was demonstrated during and immediately after termination of tonic immobility in the lizard Anolis carolinensis. Additionally, tonic immobility antagonized morphine-induced analgesia. In conjunction with other research, these data suggest that the response is accompanied by a reduced availability of serotonin, possibly at postsynaptic receptors of raphe neurons.

Analgesia↗
PubMed1981

Differential effects of neuropeptides on short-term memory in primates.

In a within-subject design, six rhesus monkeys (3 males and 3 females) received a 100 micrograms/kg injection of one of seven neuropeptides or a diluent control solution and were then tested for activity level, learning (discrimination reversal), short-term memory (delayed response), and for responsiveness to noxious stimuli. One daily injection was made with a different peptide for 10 consecutive days, including pre- and post tests on th first and last days with the diluent control. DSIP and D-Phe4-Met enkephalin seemed to produce some interference with short-term memory, while alpha-MSH showed some facilitation of it, as indicated by interactions of the peptides with the delay periods of 0, 15, or 30 sec. Sex differences were found in the learning task and the responsiveness to a noxious stimulus, suggesting the possibility of interactions between the peptides and endogenous hormones.

Animals↗