Biomedical subjects

T J Shors

Publications and source records attributed to T J Shors.

At least 37 records · Page 2Linked to original sources

PubMed1997

Long-term potentiation: what's learning got to do with it?

Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with "Hebbian" descriptions of memory formation. Other characteristics of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms. provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism.

Attention↗

PubMed1996

Inescapable stress enhances extracellular acetylcholine in the rat hippocampus and prefrontal cortex but not the nucleus accumbens or amygdala.

A number of experimental results has pointed to a cholinergic involvement in the stress response. Recently, analytical techniques have become available to measure acetylcholine release in vivo during exposure to various stressors. In these experiments, microdialysis was used to monitor acetylcholine output every 15 min in the dorsal hippocampus, amygdala, nucleus accumbens and prefrontal cortex before, during and after 1 h of restraint, including a 15-min session of intermittent tail-shock (1/min, 1 mA, 1-s duration) in rats. In response to the stressful event, acetylcholine release was significantly increased in the prefrontal cortex (186%; p < 0.01) and hippocampus (168%; P < 0.01) but not in the amygdala or nucleus accumbens. The sole effects observed in the amygdala and nucleus accumbens occurred upon release from the restrainer, at which point acetylcholine levels were significantly elevated in both areas (amygdala: 150%; P < 0.05; nucleus accumbens: 13%; P < 0.05). An enhanced acetylcholine release was also evident during this sample period in the hippocampus and prefrontal cortex. These data demonstrate an enhancement of cholinergic activity in response to stress in two acetylcholine projection systems (hippocampus and prefrontal cortex) but not in the intrinsic acetylcholine system of the nucleus accumbens or the extrinsic innervation of the amygdala. Moreover, the data showed that relief from stress was accompanied by a more ubiquitous acetylcholine response that extended to each site tested.

Acetylcholine↗

PubMed1996

Early acquisition, but not retention, of the classically conditioned eyeblink response is N-methyl-D-aspartate (NMDA) receptor dependent.

N-methyl-D-aspartate (NMDA) antagonists impair performance in some tasks, but whether they impair learning directly or through effects on sensorimotor performance remains controversial. Rats administered a competitive NMDA antagonist, CGP-39551, 24 hr before training could not acquire a classically conditioned eyeblink response. The associative deficit remained evident during training with a high-intensity conditioned stimulus, even though sensory reactivity was unaffected. The antagonist did not alter retention and thus did not affect motor performance of the task. These results extend and confirm studies that implicate NMDA-receptor activation in the acquisition of classically conditioned associations and specifically in tasks not dependent on the hippocampus for learning itself. Moreover, they substantiate recent claims that NMDA receptor activation (and by association, long-term potentiation) may be involved in early processes of procedural memory formation.

Animals↗

PubMed1996

Hippocampal responses to corticosterone and stress, one of which is the 35,000 M(r) protein, glycerol phosphate dehydrogenase.

Previously, the synthesis of a hippocampal 35,000 M(r) protein increased in response to glucocorticoid treatment and a variety of stressors. We now show by immunoprecipitation that this cytosolic protein is glycerol 3-phosphate dehydrogenase (E.C.1.1.1.8; GPDH). In addition, four polypeptides encoded by glucocorticoid-induced mRNAs co-migrated with hippocampal protein synthetic products on two-dimensional polyacrylamide gels, including 35,000 M(r) protein of approximately pl 6.3, that had previously been identified as GPDH by hybrid-selection with a GPDH cDNA clone. The 35,000 M(r) in vitro translation product was also immunoprecipitated with the GPDH antibody. Using radiolabeled hippocampal slices and two-dimensional gel analysis, a 35,000 M(r) polypeptide of approximately pl 6.4 increased five-fold after 30 min of intermittent tail-shock. This protein was found predominantly in the 20,000 x g pellet and did not immunoprecipitate with the GPDH antibody. However, a 35,000 M(r) polypeptide was also found in the cytosol as a minor component after stress, which did immunoprecipitate with the GPDH antibody. Therefore, there are at least two shock-induced 35,000 M(r) proteins, one of which is GPDH. These results establish that increases in GPDH mRNA prevalence and protein synthesis occur in response to both glucocorticoids and stress in the adult rat hippocampus. Based on the increased enzyme activity seen in the nervous system in response to glucocorticoids, dietary restriction, and nerve injury, the induction of GPDH may have functional consequences in cellular adaptation to stress.

Animals↗

PubMed1995

Stress-induced sensitization and facilitated learning require NMDA receptor activation.

Exposure to an inescapable stressor facilitates acquisition of a classically-conditioned eyeblink response in the freely-moving rat. Here, we tested the hypothesis that the facilitation is mediated via activation of the N-methyl-D-aspartate (NMDA) type of glutamate receptor. Rats were injected with the competitive NMDA antagonist CGP-37849 (5 mg kg-1) or vehicle 2 h prior to exposure to restraint and 90, 1 mA, 1 s tail shocks. In contrast to the dramatic facilitation exhibited in stressed rats injected with the vehicle, rats whose NMDA receptors were blocked during exposure to the stressor did not exhibit any facilitation 24 h later. The antagonist alone had no effect on learning. These results demonstrate that the stress-induced facilitation of classical conditioning is dependent on NMDA receptor activation and support the hypothesis that stress is inducing a phenomenon similar in mechanism to that of long-term potentiation (LTP).

2-Amino-5-phosphonovalerate↗

PubMed1995

Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely moving rat.

Centrally active drugs that enhance alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-gated currents by increasing the amplitude and duration of fast, excitatory synaptic responses in the hippocampus have recently been described. The effects of the compound 1-(1,3-benzodioxol-5-ylcarbonyl) perperidine (BDP) on associative and non-associative aspects of the classically conditioned eyeblink response in the freely moving rat were examined. Rats injected with BDP blinked significantly more to an acoustic stimulus of 85 dB than did vehicle controls, indicating that the drug enhances alpha responding to discrete auditory cues. Using a less intense stimulus of 80 dB, rats injected with BDP did not exhibit alpha responding or pseudo-conditioning, yet learned the conditioned response at a facilitated rate. These results suggest that increasing excitatory neurotransmission enhances the processing of sensory information and may contribute to subsequent contingency detection.

Acoustic Stimulation↗

PubMed1995

Contribution of stress and gender to exploratory preferences for familiar versus unfamiliar conspecifics.

An apparatus for measuring the exploratory preferences of rats for familiar and unfamiliar conspecifics in a novel environment was designed. The exploratory behavior of males and females was compared and contrasted to that elicited in response to an acute aversive event. Sprague-Dawley male and female rats were exposed to restraint and 60, 1 s, 1 mA tailshocks and returned to their home cage. Either 2 or 24 h later, they were placed in a novel environment with a familiar cage-mate and an unfamiliar conspecific of the same sex. Relative to unstressed controls and females, males stressed 2 h previously decreased the exploration of the unfamiliar conspecific, exhibiting a rapid decrease over the course of the trial. In response to the stressor, however both sexes, however, decreased the exploration of the familiar conspecific, decreased their overall activity, and returned preferentially to their starting quadrant. None of these stress-induced effects were evident 24 h later upon the first or second exposure to the apparatus. Thus, exposure to the stressor transiently increased perseveration and decreased activity in males and females, but only decreased the exploration of novel conspecifics in males. These results indicate that a number of behavioral responses to stressors are conserved across gender, but those relating to novelty are more pronounced in males.

Animals↗

PubMed1994

Effect of stress and long-term potentiation (LTP) on subsequent LTP and the theta burst response in the dentate gyrus.

Exposure to an aversive and stressful event is reported to have similar effects on hippocampal plasticity and behavior as does exposure to high-frequency stimulation of the hippocampus. Here we directly compared the effects of exposure to a stressor vs. a previous induction of LTP on a subsequent induction of LTP and the extracellular response to a tetanus patterned after endogenous theta rhythms. Stimulating the dentate gyrus via the perforant path, Sprague-Dawley rats (n = 65) were tetanized 2 h after exposure to a stressor consisting of restraint and 60, 1, s, 1 mA tail shocks. Unstressed controls were tetanized once and then again 2 h later. Exposure to the stressor impaired LTP of the EPSP 2 h later, as did a previous induction of LTP. In addition, exposure to the stressor altered the extracellular response to subsequent theta burst stimulation (10, 40 ms bursts at 100 Hz, each separated by 200 ms), as did a previous induction of LTP. Whereas unstressed rats exposed to the first tetanus exhibited a marked decline in the amplitude across successive bursts, stressed rats exhibited no such decline, a response pattern similar to that observed in unstressed rats exposed to a second tetanus. The similarity between the effects of stress and tetanic stimulation on hippocampal plasticity support the hypothesis that stress and LTP are converging on similar neuronal mechanisms.

Animals↗

PubMed1994

Exposure to inescapable stress persistently facilitates associative and nonassociative learning in rats.

The present study examined the proactive effects of inescapable stress on aversive Pavlovian conditioning. Stressed rats were restrained and exposed to 90 1-mA tailshocks. Twenty-four hours later, all rats were exposed to 10 conditioned stimuli (CS; 350 ms of white noise at 85 dB). Rats then received either paired training in which the CS coterminated with a 100-ms, 0.7-mA periorbital shock or the same stimuli presented in an explicitly unpaired fashion. After the unpaired exposures, these rats were also exposed to paired training. Previously stressed rats exhibited persistent sensitization to the white-noise stimulus. Stressed rats exposed to unpaired stimuli, and no longer exhibiting a sensitized response, acquired the eyeblink conditioned response at a facilitated rate when these stimuli were presented in a paired fashion. These results also demonstrate that the effect of stress on classical conditioning is long-lasting, in excess of 48 hr.

Acoustic Stimulation↗

PubMed1993

Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus.

Vasopressin receptors are present in both the developing and mature dentate gyrus of the rat brain and are of the V1 vasopressor type. Because vasopressin has been shown to influence memory function when injected into the dentate gyrus, the influence of this peptide on an electrophysiological model of learning and memory using the field excitatory postsynaptic potential (EPSP) of the dentate gyrus was investigated. Results of these studies showed that nanomolar concentrations of [Arg8]-vasopressin induced a prolonged increase in the amplitude and slope of the evoked population response in the presence of 1.5 mM calcium. Moreover, the expression of the vasopressin-induced potentiation of the EPSP persisted following removal of vasopressin from the perfusion medium. The vasopressin-induced sustained increase has been termed long-term vasopressin potentiation (LTVP). The closely related neuropeptide oxytocin had no effect upon the EPSP of the dentate gyrus. Preincubation of hippocampal slices in a selective V1 antagonist blocked the expression of LTVP. The ability of the V1 antagonist to block LTVP demonstrates that the potentiation induced by vasopressin is receptor-specific. In the presence of 2.5 mM calcium, the effect of vasopressin was opposite to that observed in 1.5 mM calcium. Under the conditions of 2.5 calcium, vasopressin induced a prolonged depression in the amplitude and slope of the EPSP. Expression of both potentiation and depression appeared within 5 minutes of application and persisted for the length of the observation, 60 minutes. These experiments demonstrate that vasopressin can induce long-lasting changes in the excitability of dentate gyrus neurons that are both calcium-dependent and receptor-specific.

Animals↗

PubMed1992

Stress-induced facilitation of classical conditioning.

Stress has been shown to impair subsequent learning. To determine whether stress would impair classical conditioning, rats were exposed to inescapable, low-intensity tail shock and subsequently classically conditioned under freely moving conditions with a brief periorbital shock unconditioned stimulus and a white noise conditioned stimulus. Unexpectedly stressed rats exhibited significantly more conditioned eyeblink responses and the magnitude of their individual responses was also enhanced. These results stand in contrast to the learning deficits typically observed and suggest that stress can enhance the acquisition of discrete conditioned responses.

Acoustic Stimulation↗

PubMed1992

Long-term potentiation is associated with increased [3H]AMPA binding in rat hippocampus.

The location and nature of the changes underlying long-term potentiation (LTP) remain controversial issues. In this study, we tested the possibility that changes in binding properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA/quisqualate and N-methyl-D-aspartate (NMDA) subtype of glutamate receptors are associated with LTP. LTP was elicited in vivo by stimulation of the perforant pathway in anesthetized rats. One hour following stimulation the animals were sacrificed. We performed quantitative ligand binding autoradiography on frozen brain sections using [3H]AMPA and [3H]N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([3H]TCP) to label the AMPA/quisqualate and the NMDA receptors, respectively. No changes in [3H]TCP binding were detected in any of the treatment groups. However, increases in [3H]AMPA binding were observed only in animals that exhibited LTP. These increases were bilateral and present in several subfields of the hippocampus and cortical areas. Administration of the NMDA receptor antagonist, ketamine, prior to tetanic stimulation prevented both the increase in binding and the induction of LTP. These results suggest that changes in the characteristics of AMPA/quisqualate receptors are a biochemical correlate of LTP.

Analysis of Variance↗

PubMed1992

Acute stress impairs (or induces) synaptic long-term potentiation (LTP) but does not affect paired-pulse facilitation in the stratum radiatum of rat hippocampus.

Rats were exposed to restraint coupled with 60, 1-sec, 1-mA, 60-Hz tail shocks. One hippocampus was immediately dissected for in vitro measurement of paired-pulse facilitation and LTP of the excitatory postsynaptic potential (EPSP) recording from the stratum radiatum of field CA1. There was no change in paired-pulse facilitation, suggesting that acute exposure to the stressor does not result in a decrease in presynaptic neurotransmitter release. There was, however, a significant decrease in the percent LTP produced by theta burst stimulation relative to naive controls. These results are consistent with the hypothesis that the stress-induced impairment of LTP is a result of changes in the postsynaptic glutamate receptors, specifically the AMPA type.

Animals↗

PubMed1992

Control of interocular suppression as a function of differential image blur.

This experiment studied normal adults, normal children, and corrected strabismics with alternating fixation, evaluating their ability to detect information presented to one eye under viewing conditions which might affect their eye preference. An apparatus was used which allowed unconstrained, binocular viewing of a video monitor, but in which the image seen by one eye was blurred while that seen by the other eye was in sharp focus. Under these viewing conditions, subjects were asked to identify a sharply focused letter which was shown briefly to the eye which was seeing the blurred background image or to the one which was watching the well-focused image. The question was whether there would be general suppression of the eye that was shown a degraded background, causing a reduction in its ability to process other information being presented. The results indicate no performance penalty for children, a mild decrement in recognition accuracy for normal adults, and a severe deficit in the ability of corrected strabismics to attend to the eye which views a blurred image. These results suggest that the loss of binocular vision that accompanies childhood strabismus is not a result of an inherent sensitivity to blurring, insofar as such vulnerability is reflected by these acute testing conditions.

Adolescent↗

PubMed1991

Increased synthesis of two polypeptides in area CA1 of the hippocampus in response to repetitive electrical stimulation.

Changes in the pattern of newly synthesized polypeptides were investigated in the in vitro hippocampal slice following exposure to repetitive stimulation with and without the induction of long-term potentiation. Using [35S]methionine labeling of polypeptides and two-dimensional gel electrophoresis, we detected an increase in the rate of synthesis of two polypeptides (48 kDa and 89 kDa) in CA1 in response to repetitive stimulation of the Schaffer collaterals. The synthesis of the 48 kDa polypeptide (pI approximately 6.6) increased 240% in response to high-frequency stimulation (100 Hz) relative to the same protein from unstimulated slices (n = 14), and increased 220% in response to low-frequency stimulation (1 Hz) (n = 5). Blockade of the N-methyl-D-aspartate (NMDA) receptor induced the protein 180%, with no further increase following tetanic stimulation. An 89 kDa doublet (pI approximately 6.8) increased 150% following high-frequency and 140% following low-frequency stimulation. Blockade of the NMDA receptor increased this protein as well (180% of the unstimulated control) and no further increase was observed following high-frequency stimulation. Based on physicochemical and electrophysiological properties, these proteins are not identifiable as any of those previously associated with long-term potentiation or repetitive electrical stimulation.

2-Amino-5-phosphonovalerate↗

PubMed1991

Selective increase of AMPA binding to the AMPA/quisqualate receptor in the hippocampus in response to acute stress.

The binding properties of ligands specific for two subclasses of glutamate receptors were studied by quantitative autoradiography after one hour of acute immobilization/shock stress. [3H]N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine (TCP) and [3H]alpha-amino-3-methylisoxazole-4-propionic acid (AMPA) were used to visualize the N-methyl-D-aspartate receptor and the AMPA/quisqualate receptor types, respectively. While no change was observed in the binding properties of the [3H]TCP, [3H]AMPA binding was significantly increased in several areas of the hippocampus of acutely stressed rats relative to naive controls.

Animals↗

PubMed1991

A negative correlation between the induction of long-term potentiation and activation of immediate early genes.

In the present study we examined the relationship between the induction of long-term potentiation (LTP) in the dentate gyrus of anesthetized rats and activation of immediate early genes (IEGs; c-fos and zif/268) using several different high-frequency stimulation paradigms. Stimulation parameters that effectively induced LTP were not associated with IEG activation. Conversely, stimulation parameters that failed to induce LTP consistently resulted in IEG activation. These results suggest that there is a negative correlation between IEG activation and LTP, and that activation of IEGs is neither necessary nor sufficient for the induction of LTP.

Animals↗

PubMed1991

Activation of immediate early genes after acute stress.

We used in-situ hybridization to study the effect of acute stress on induction of the immediate early genes (IEGs), c-fos and zif/268, in the rat brain. After one hour of restraint plus intermittent tail shock, messenger RNA (mRNA) levels for both genes were significantly increased bilaterally in the neocortex, particularly in layers IV, V and VI, and in the CA1 region of the hippocampus. This regionally-specific response suggests that IEGs may have a role in the mediation of acute stress responses in the central nervous system.

Acute Disease↗