High-frequency stimulation of the basolateral amygdala facilitates the induction of long-term potentiation in the dentate gyrus in vivo

We investigated the effect of high-frequency stimulation of the basolateral amygdala (BLA) on the induction of long-term potentiation (LTP) in the medial perforant path (PP)-dentate gyrus (DG) synapses of anesthetized rats. A conditioning stimulation (100 pulses at 100 Hz) of the ipsilateral BLA did not change the DG synaptic potential. However, when the BLA conditioning stimulation was applied at the same time as a weak tetanic stimulation of PP (20 pulses at 20 Hz) which alone did not induce LTP, robust DG LTP was induced. Simultaneous application of contralateral BLA stimulation and PP weak tetanus did not induce LTP. Moreover, the ipsilateral BLA stimulation enhanced the magnitude of LTP induced by a moderate tetanic stimulation of PP (30 pulses at 60 Hz), but did not further enhance the LTP induced by a strong tetanic stimulation of PP (100 pulses at 100 Hz). These results suggest that the ipsilateral BLA neurons modulate the induction of DG LTP in vivo.     

The NMDA receptor antagonist CPP impairs conditioned taste aversion and insular cortex long-term potentiation in vivo

It has been proposed that long-term potentiation (LTP) a form of activity-dependent modification of synaptic efficacy, may be a synaptic mechanism for certain types of learning. Recent studies on the insular cortex (IC) a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce an N-methyl-d-aspartate (NMDA) dependent LTP in the IC of adult rats in vivo. Here we present experimental data showing that intracortical administration of the NMDA receptor competitive antagonist CPP (-3(-2 carboxipiperazin-4-yl)-propyl-1-phosphonic acid) disrupts the acquisition of conditioned taste aversion, as well as, the IC-LTP induction in vivo. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying NMDA dependent neocortical LTP, constitute a possible mechanism for the learning related functions performed by the IC.     

Src activation in the induction of long-term potentiation in CA1 hippocampal neurons

Long-term potentiation (LTP) is an activity-dependent strengthening of synaptic efficacy that is considered to be a model of learning and memory. Protein tyrosine phosphorylation is necessary to induce LTP. Here, induction of LTP in CA1 pyramidal cells of rats was prevented by blocking the tyrosine kinase Src, and Src activity was increased by stimulation producing LTP. Directly activating Src in the postsynaptic neuron enhanced excitatory synaptic responses, occluding LTP. Src-induced enhancement of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor-mediated synaptic responses required raised intracellular Ca2+ and N-methyl-D-aspartate (NMDA) receptors. Thus, Src activation is necessary and sufficient for inducing LTP and may function by up-regulating NMDA receptors.     

A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation

The cadherins are a family of cell-cell adhesion molecules that mediate Ca2+-dependent homophilic interactions between cells and transduce signals by interacting with cytoplasmic proteins. In the hippocampus, immunostaining combined with confocal microscopy revealed that both neural- (N-) and epithelial- (E-) cadherin are present at synaptic sites, implying a role in synaptic function. Pretreatment of hippocampal slices with antibodies (Abs) raised against the extracellular domain of either N-cad or E-cad had no effect on basal synaptic properties but significantly reduced long-term potentiation (LTP). Infusion of antagonistic peptides containing the His-Ala-Val (HAV) consensus sequence for cadherin dimerization also attenuated LTP induction without affecting previously established LTP. Because the intense synaptic stimulation associated with LTP induction might transiently deplete extracellular Ca2+ and hence potentially destabilize cadherin-cadherin interactions, we examined whether slices could be protected from inhibition by N-cad Abs or HAV peptides by raising the extracellular Ca2+ concentration. Indeed, we found that high extracellular Ca2+ prevented the block of LTP by these agents. Taken together, these results indicate that cadherins are involved in synaptic plasticity, and the stability of cadherin-cadherin bonds may be regulated by synaptic stimulation.     

Picrotoxin-sensitive receptors mediate gamma-aminobutyric acid-induced modulation of synaptic plasticity in rat superior cervical ganglion

Activity-dependent changes of synaptic efficacy in the superior cervical ganglion (SCG) can be prevented by gamma-aminobutyric acid (GABA). We have studied the effects of picrotoxin (PTX) on GABA-mediated inhibition of long-term potentiation (LTP) of synaptic transmission in the rat SCG. Compound action potentials were recorded extracellularly in the postganglionic internal carotid nerve in response to preganglionic nerve stimulation. PTX (100 microM) antagonized the inhibition by exogenous GABA (250 microM) of LTP induced by strong tetanic stimulation (20 Hz, 20s, supramaximal stimulation, partial blockade of transmission by hexamethonium). Additionally, PTX alone (50 microM) facilitated the induction of LTP by a weak tetanus (20 Hz, 5 s, submaximal stimulation). These results further support previous data indicating that activation of GABAA-like receptors can prevent the occurrence of synaptic plasticity at this peripheral synapse.     

Modified hippocampal long-term potentiation in PKC gamma-mutant mice

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.     

Parallel augmentation of hippocampal long-term potentiation, theta rhythm, and contextual fear conditioning in water-deprived rats.

The influence of water deprivation on hippocampal long-term potentiation (LTP), theta rhythm, and contextual fear conditioning in 56 adult male rats was examined. In Exp 1, hippocampal EEG activity and perforant path LTP were assessed in pentobarbital-anesthetized rats. Water deprivation did not affect baseline cell excitability or low-frequency synaptic transmission in the dentate gyrus, but it increased the magnitude of perforant path LTP and elevated the proportion of theta rhythm in the EEG. In Exp 2, rats were classically conditioned to fear a novel context through the use of aversive footshocks. Water deprivation facilitated the rate of contextual fear conditioning but did not alter the asymptote of learning. Exp 3 demonstrated that the facilitation of contextual fear conditioning was not due to a change in unconditional shock sensitivity. These results suggest that water deprivation exerts an influence on contextual fear conditioning by modulating hippocampal LTP and theta rhythm and that these processes serve to encode contextual information during learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral-CA1 synapses in hippocampal slices in vitro

In this study, the effects of chronic morphine administration (20-30 days) on long-term potentiation (LTP) were investigated at the Schaffer collateral-CA1 pyramidal cell synapses of the rat hippocampal slices. Orthodromic population spike (OPS) amplitude and delay (peak latency) were measured as indices of increase in synaptic efficacy. The amounts of LTP of OPS delay and LTP of OPS amplitude were higher in slices from dependent rats. Perfusion of slices from control and dependent rats with morphine containing ACSF and delivering tetanic stimulation, showed that short-term presence of morphine could not mimic the LTP enhancing effects of chronic morphine administration, however, attenuated the amount of LTP of OPS amplitude in slices of dependent rats. This study supports the hypothesis that the susceptibility of CA1 synapses to plastic changes increases by chronic, not acute exposure to morphine and suggests that a withdrawal phenomenon might be an underlying mechanism for the observed augmented LTP of OPS amplitude in slices of dependent rats.     

Synaptically evoked glutamate transport currents may be used to detect the expression of long-term potentiation in cerebellar culture

Cerebellar long-term potentiation (LTP) is a use-dependent increase in the strength of the granule cell-Purkinje neuron synapse that occurs after brief stimulation of granule cell axons at 2-8 Hz. Previous work has shown that cerebellar LTP also may be seen when synaptic currents are evoked in granule cell-glial cell pairs in culture. This finding suggests a model in which cerebellar LTP is expressed presynaptically and therefore may be detected by either neuronal or glial postsynaptic cells. However, synaptic currents evoked in both granule cell-glial cell pairs and granule cell-Purkinje neuron pairs in culture are mediated primarily by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors, raising the possibility that cerebellar LTP might be expressed postsynaptically in both glial cells and Purkinje neurons in a similar manner. To address this question, glutamate transport currents were recorded in granule cell-glial cell pairs in culture by pharmacological isolation. These currents were increased by substitution of internal Cl with NO3 and were blocked by -pyrrolidine-2,4-dicarboxylate, both characteristics of the major cloned Bergmann glial cell glutamate transporter, EAAT1. After acquisition of baseline responses, LTP of isolated transport current was evoked by stimulation at 4 Hz (100 pulses) and could be blocked by removal of external Ca during this stimulation. The expression of LTP was associated with a decrease in the rate of synaptic failures and a decrease in the degree of paired-pulse facilitation. These findings, when taken together with the previous observation that both Purkinje neuron and glial AMPA/kainate responses can be used to detect cerebellar LTP, strongly suggest that the expression of cerebellar LTP is, at least in part, presynaptic. This strategy should also be useful in illuminating the locus of expression of other model systems of information storage such as hippocampal LTP/long-term depression.     

Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus

In addition to the regulation of neuronal survival and differentiation, neurotrophins may play a role in synapse development and plasticity. Application of brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) in CA1 synapses of neonatal hippocampus, which otherwise exhibit only short-term potentiation. This is attributable, at least in part, to an attenuation of the synaptic fatigue induced by high-frequency stimulation (HFS). However, the prevention of synaptic fatigue by BDNF could be mediated by an attenuation of synaptic vesicle depletion from presynaptic terminals and/or a reduction of the desensitization of postsynaptic receptors. Here we provide evidence supporting a presynaptic effect of BDNF. The effect of BDNF on synaptic fatigue depended on the stimulation frequency, not on the stimulus duration nor on the number of stimulation pulses. BDNF was only effective when the synapses were stimulated at frequencies >50 Hz. Treatment with BDNF also potentiated paired-pulse facilitation (PPF), a parameter reflecting changes in the properties of presynaptic terminals. This effect of BDNF was restricted only to PPF elicited with interpulse intervals 相似文献   

Proactive behavioral effects of theta-driving septal stimulation on conditioned suppression and punishment in the rat.

In 2 experiments, a treatment phase of septal stimulation preceded the acquisition of free operant leverpressing on a random-interval 64-sec reinforcement schedule. 32 male Sprague-Dawley rats were chronically implanted with a bilateral septal stimulating electrode and a unilateral bipolar hippocampal recording electrode. Ss received (a) low-frequency (7.7 Hz) stimulation, which drove the hippocampal theta rhythm; (b) random-pulse stimulation (average frequency 7.7 Hz), which produced only nonregular waveforms in the hippocampus; or (c) no stimulation. After 12 days of leverpress acquisition, Ss were presented while leverpressing with an auditory signal associated with a particular schedule of shock delivery: In Exp I, shocks occurred despite the S's response strategy; in Exp II, shocks were delivered only if the S pressed the lever. In both experiments, leverpressing was suppressed by the auditory stimulus. Theta-driving but not random-pulse septal stimulation proactively increased behavioral tolerance to the effects of electric shock. Results support the idea that proactive behavioral effects of septal stimulation are a consequence of the production of the hippocampal theta rhythm. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Extinction and retention of a classically conditioned flexor nerve response in acute spinal cat.

Conditioned adult male and female cats by pairing a mild electrical stimulus to the superficial peroneal sensory nerve (CS) with a stronger electrical stimulus to the ankle skin (UCS) of the same leg. Subsequent extinction was produced by presenting CS-alone trials. In Exp I (42 Ss), Ss given massed extinction trials showed response decrements to base levels, but Ss that received distributed extinction trials showed no decrements. In Exp II, .5-, 1-, 2-, 3-, or 4-hr intervals between acquisition and extinction produced no significant differences in the extinction data. In Exp III (20 Ss), Ss received extinction trials immediately or 30 min after acquisition trials, followed by 20 additional extinction trials 30 min later. Data indicated significant acquisition and extinction in the 10- and 20-acquisition trial groups. As in Exp II (35 Ss), varying the interval between acquisition and extinction did not produce any group differences in the extinction data. These results demonstrate that response increases produced by paired trials in the spinal preparation do not decay spontaneously over time and are not caused by sensitization effects. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Variations in learning reflect individual differences in sensory function and synaptic integration

With the invertebrate Hermissenda as subjects, variability in acquisition of a learned association between light and rotation was correlated with the magnitude of the unconditioned responses elicited by these stimuli. Moreover, learning was facilitated by increasing stimulus intensity. In the isolated nervous system, pairings of light and mechanical stimulation of the animal's vestibular hair cells resulted in an increase in the excitability of B photoreceptors (an in vitro index of learning) that was strongly correlated with the strength of the synaptic interaction between the hair cells and the photoreceptors and weakly correlated with the magnitude of the light response in the photoreceptors. Because these in vitro results are not attributable to motor or motivational variables, they suggest that the efficacy of synaptic integration between sensory systems and sensory transduction is the primary determinant of the variability in learning.     

Brain-derived neurotrophic factor alters the synaptic modification threshold in visual cortex

The effects of brain-derived neurotrophic factor (BDNF) were investigated on synaptic transmission and two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in visual cortex slices prepared from young (P21 -28) rats. The slices treated for 2-5 h in BDNF showed no difference from control slices when a 'strong' tetanus was used (theta-burst stimulation) to elicit a maximal level of LTP but displayed significantly greater synaptic potentiation in response to a 'weak' (20 Hz) tetanus. The BDNF-treated slices also showed significantly less LTD in response to a 1 Hz tetanus. Thus, BDNF treatment alters the relationship between stimulation frequency and synaptic plasticity in the visual cortex, shifting the modification threshold to the left. The effects of BDNF on LTP and LTD induction may be attributed to the significant enhancement of synaptic responses that was observed during conditioning stimulation. These data suggest that one role of BDNF during development of the visual cortex may be to modulate the properties of synaptic plasticity, enhancing synaptic strengthening and reducing synaptic weakening processes which contribute to the formation of specific synaptic connections.     

Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber-granule cell transmission in rat cerebellum

Long-term potentiation (LTP) is a form of synaptic plasticity that can be revealed at numerous hippocampal and neocortical synapses following high-frequency activation of N-methyl--aspartate (NMDA) receptors. However, it was not known whether LTP could be induced at the mossy fiber-granule cell relay of cerebellum. This is a particularly interesting issue because theories of the cerebellum do not consider or even explicitly negate the existence of mossy fiber-granule cell synaptic plasticity. Here we show that high-frequency mossy fiber stimulation paired with granule cell membrane depolarization (-40 mV) leads to LTP of granule cell excitatory postsynaptic currents (EPSCs). Pairing with a relatively hyperpolarized potential (-60 mV) or in the presence of NMDA receptor blockers [5-amino--phosphonovaleric acid (APV) and 7-chloro-kynurenic acid (7-Cl-Kyn)] prevented LTP, suggesting that the induction process involves a voltage-dependent NMDA receptor activation. Metabotropic glutamate receptors were also involved because blocking them with (+)-alpha-methyl-4-carboxyphenyl-glycine (MCPG) prevented potentiation. At the cytoplasmic level, EPSC potentiation required a Ca2+ increase and protein kinase C (PKC) activation. Potentiation was expressed through an increase in both the NMDA and non-NMDA receptor-mediated current and by an NMDA current slowdown, suggesting that complex mechanisms control synaptic efficacy during LTP. LTP at the mossy fiber-granule cell synapse provides the cerebellar network with a large reservoir for memory storage, which may be needed to optimize pattern recognition and, ultimately, cerebellar learning and computation.     

Conditions for the induction of long-term potentiation in layer II/III horizontal connections of the rat motor cortex

1. The present studies investigated conditions for the induction of long-term potentiation (LTP) in the local horizontal pathways of layers II/III in the primary motor cortex (MI) of the adult rat. Field potential and intracellular recordings demonstrated synaptic interactions across the superficial layers within MI that could be enhanced transiently by focal application of the gamma-aminobuturic acid-A receptor antagonist bicuculline methiodide (Bic) at the recording site. 2. Field potentials evoked in the superficial MI horizontal pathways increased in amplitude after tetanizing, theta burst stimulation (TBS), but only when Bic was applied transiently at the recording site immediately before TBS. In the absence of Bic, TBS failed to produce long-lasting increases in horizontally evoked field responses. By contrast, TBS delivery during focal Bic application increased field potential amplitudes by 25-35% when measured 25-30 min after stimulation. The amount of potentiation was greater when two converging horizontal inputs were stimulated together but was not increased with higher intensity stimulation. Persistent effects of Bic application alone were evident. However, these effects were small unless Bic application continued until evoked field potential amplitude increase exceeded 200% of baseline. 3. The synaptic nature of field potential increases were confirmed using intracellular recordings of layer II/III neurons located near field potential electrodes. 4. LTP also could be induced without Bic application by cotetanization of vertical pathways simultaneously with horizontal activation. Vertical conditioning alone at 2 Hz, which affects inhibitory efficacy, was shown to transiently relieve depression of successive responses that ordinarily occurs during a burst of three horizontal stimuli. These results suggest that LTP of horizontal pathways may be regulated by spatiotemporal interactions between horizontal and vertical pathways. 5. Horizontal LTP was blocked reversibly by bath application of the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid, thereby implicating NMDA-receptor activation in LTP induction for these pathways. 6. The results confirm and extend our previous finding that the potential for activity-dependent modification of synaptic connections exists within the intrinsic horizontal connections of the superficial cortical layers. Synaptic modification across horizontally connected neurons appears to be regulated both by the arrangement of intrinsic circuitry and by the availability of mechanisms for modification at individual synapses. The properties of horizontal connections indicate that they form a spatial substrate and provide an activity-dependent mechanism for plasticity of adult cortical representations.     

Stimulation on the positive phase of hippocampal theta rhythm induces long-term potentiation that can Be depotentiated by stimulation on the negative phase in area CA1 in vivo

Long-term potentiation (LTP) of synaptic transmission induced by high-frequency stimulation (HFS) is considered to be a model for learning processes; however, standard HFS protocols consisting of long trains of HFS are very different from the patterns of spike firing in freely behaving animals. We have investigated the ability of brief bursts of HFS triggered at different phases of background theta rhythm to mimic more natural activity patterns. We show that a single burst of five pulses at 200 Hz given on the positive phase of tail pinch-triggered theta rhythm reliably induced LTP in the stratum radiatum of the hippocampus of urethane-anesthetized rats. Three of these bursts saturated LTP, and 10 bursts occluded the induction of LTP by long trains of HFS. Burst stimulation on the negative phase or at zero phase of theta did not induce LTP or long-term depression. In addition, stimulation with 10 bursts on the negative phase of theta reversed previously established LTP. The results show that the phase of sensory-evoked theta rhythm powerfully regulates the ability of brief HFS bursts to elicit either LTP or depotentiation of synaptic transmission. Furthermore, because complex spike activity of approximately five pulses on the positive phase of theta rhythm can be observed in freely moving rats, LTP induced by the present theta-triggered stimulation protocol might model putative synaptic plastic changes during learning more closely than standard HFS-induced LTP.     

Epileptiform activity induced by low Mg2+ in cultured rat hippocampal slices

Organotypic cultured slices of the rat hippocampus undergo synaptic reorganization. Besides the establishment of reciprocal connections between area CA1 and the dentate gyrus (DG), collateral excitatory connections between granule cells are formed which are similar to those appearing in several epilepsy models and in the DG from patients with temporal lobe epilepsy. We studied the characteristics of epileptiform activity induced by low Mg2+ perfusion in cultured hippocampal slices using extra- and intracellular recordings. With low Mg2+ perfusion synchronous seizure like events (SLEs) were readily observed in the DG and areas CA3 and CA1. Also, the isolated DG was able to display seizure like activity. Intracellular recordings revealed long lasting depolarization shifts in granule cells of the DG and pyramidal cells of areas CA3 and CA1. The SLEs, lasting 2-3 s, could be recorded for at least 3 h in areas CA1 and CA3. However, approximately an hour after perfusion with low Mg2+, the epileptiform activity disappeared in the DG and responses to single pulse hilar stimulation progressively deteriorated. These responses returned to control values 1 week after reincubating the cultures. Interestingly, no deterioration of stimulus induced responses was observed in the isolated DG after exposure to low Mg2+.     

Element pretraining influences the content of appetitive serial compound conditioning in rats.

Examined the effects of prior pairings of conditioned stimulus/stimuli (CS)2 with the unconditioned stimulus/stimuli (UCS) on the nature of the associations formed in CS1?→?CS2?→?UCS serial compound conditioning, in 4 experiments with 72 male and 32 female albino rats. In Exps I and II, prior training of CS2 prevented the acquisition of stimulus–stimulus (S–S) associations between CS1 and stimulus features of CS2 but enhanced the acquisition of stimulus–response (S–R) associations between CS1 and the emotional conditioned response (CR) evoked by CS2. In Exps III and IV, the effects of CS2 pretraining were not due to CS2 training itself, but rather to its endowing CS2 with the ability to evoked a strong CR during the early stages of serial compound conditioning. In Exp III, suppression of the CR to a pretrained CS2 during serial compound conditioning permitted the establishment of S–S associations. In Exp IV, the induction of a CR in the presence of an untrained CS2 during serial compound conditioning prevented the acquisition of S–S associations. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synaptic transmission and hippocampal long-term potentiation in olfactory cyclic nucleotide-gated channel type 1 null mouse

Field potential recording was used to investigate properties of synaptic transmission and long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in both hippocampal slices of mutant mice in which the alpha-subunit of the olfactory cyclic nucleotide-gated channel (alpha3/OCNC)1 was rendered null and also in slices prepared from their wild-type (Wt) littermates. Several measures of basal synaptic transmission were unaltered in the OCNC1 knockout (KO), including maximum field excitatory postsynaptic potential (fEPSP) slope, maximum fEPSP and fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope and paired-pulse facilitation. When a high-frequency stimulation protocol was used to induce LTP, similar responses were seen in both groups [KO: 1 min, 299 +/- 50% (mean +/- SE), 60 min, 123 +/- 10%; Wt: 1 min, 287 +/- 63%; 60 min, 132 +/- 19%). However, on theta-burst stimulation, the initial amplitude of LTP was smaller (1 min after induction, 147 +/- 16% of baseline) and the response decayed faster in the OCNC1 KO (60 min, 127 +/- 18%) than in Wt (1 min, 200 +/- 14%; 60 min, 169 +/- 19%). Analysis of waveforms evoked by LTP-inducing tetanic stimuli revealed a similar difference between groups. The development of potentiation throughout the tetanic stimulus was similar in OCNC1 KO and Wt mice when high-frequency stimulation was used, but OCNC1 KO mice showed a significant decrease when compared with Wt mice receiving theta-burst stimulation. These results suggest that activation of cyclic nucleotide-gated channels may contribute to the induction of LTP by weaker, more physiological stimuli, possibly via Ca2+ influx.