Long-term potentiation in the motor cortex.

Long-term potentiation (LTP) is a model for learning and memory processes. Tetanic stimulation of the sensory cortex produces LTP in motor cortical neurons, whereas tetanization of the ventrolateral nucleus of the thalamus, which also projects to the motor cortex, does not. However, after simultaneous high-frequency stimulation of both the sensory cortex and the ventrolateral nucleus of the thalamus, LTP of thalamic input to motor cortical neurons is induced. This associative LTP occurs only in neurons in the superficial layers of the motor cortex that receive monosynaptic input from both the sensory cortex and the ventrolateral nucleus of the thalamus. Associative LTP in the motor cortex may constitute a basis for the retention of motor skills.

Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety.

Anxiety is a common psychiatric illness often treated by benzodiazepines (BZs). BZs, such as Valium, bind to the alpha subunit of the pentameric GABA(A) receptor and increase inhibition in the CNS. There is considerable evidence for abnormal GABA(A) receptor function in anxiety, and a significant proportion of anxiety patients has a reduced sensitivity to BZs. Here, we show that serotonin(1A) (5-HT(1A)) receptor knock-out mice display BZ-resistant anxiety. Consistent with this finding, binding of both BZ and non-BZ GABA(A) receptor ligands were reduced and GABAergic inhibition was impaired in mutant mice. These changes were reflected by abnormal alpha subunit expression in the amygdala and hippocampus, two important limbic regions involved in fear and anxiety. These data suggest a pathological pathway, initiated by a 5-HT(1A) receptor deficit, leading to abnormalities in GABA(A) receptor composition and level, which in turn result in BZ-insensitivity and anxiety. This model mechanistically links together the 5-HT and GABA systems, which both have been implicated in anxiety. A related mechanism may underlie reduced BZ sensitivity in certain forms of anxiety.

Hippocampal homosynaptic long-term depression/depotentiation induced by adrenal steroids.

The effects of adrenal steroids on synaptic plasticity were investigated in the dentate gyrus of the hippocampus. Experiments were performed in either adrenalectomized or intact (non-adrenalectomized), anesthetized rats. High-frequency stimulation was applied to the medial perforant pathway at three different frequencies; 100, 200 or 400 Hz, either post- or pre- and post-administration of the specific Type-II adrenal steroid receptor agonist RU 28362. High-frequency stimulation prior to RU 28362 administration produced a frequency-dependent long-term potentiation of the population spike, with 100 Hz showing no long-term potentiation and 400 Hz the highest degree of potentiation. In contrast, following administration of RU 28362, high-frequency stimulation produced a long-term depression (in comparison to baseline). In the experiments in which high-frequency stimulation was applied both pre- and post-RU 28362 administration, the size of the population spike was initially potentiated and then depotentiated after the RU 28362 injection. This effect was also frequency dependent, although opposite to the long-term potentiation effect. That is, 400 Hz was the least effective frequency for inducing long-term depression/depotentiation, while 100 Hz was the most effective. Long-term depression/depotentiation was immediate following high-frequency stimulation and lasted for the extent of the recording session, in some cases longer than 1 h. Similar to the finding reported in the accompanying paper, induction of long-term potentiation was substantially suppressed by RU 28362. However, in a number of experiments long-term potentiation could still be induced after RU 28362 administration, even after long-term depression/depotentiation had been established. In these cases, stimulation at the higher frequencies was necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation.

Studies were performed in vivo on the dentate gyrus to investigate the possible involvement of Type I and Type II adrenal steroid receptors in the mediation of reported adrenal steroid effects on long-term potentiation, through the use of specific Type I and Type II receptor agonists and antagonists. In adrenalectomized rats, administration of aldosterone, a specific Type I agonist, produced a marked enhancement in long-term potentiation, in comparison to either the adrenalectomized or sham adrenalectomized controls. Administration of RU 28318, a Type I antagonist, which by itself had minimal effects, blocked the aldosterone enhancement. In contrast, administration of the specific Type II agonist, RU 28362, produced a marked decrement in the induction of long-term potentiation. The RU 28362 effect was blocked by a prior injection of the Type II antagonist, RU 38486. Neither adrenalectomy nor administration of any of the steroid agonists or antagonists had noticeable effects on neuronal excitability (as determined by the field potentials), nor on post-tetanic potentiation. These findings are consistent with other studies that have shown a biphasic effect of increasing levels of corticosterone on long-term or prime burst potentiation. Taken together, these studies suggest that Type I receptors, with a high affinity for corticosterone, and Type II receptors, having a lower affinity for corticosterone, form a two-level recognition system to modulate induced synaptic plasticity in opposite directions in the dentate gyrus and possibly also in Ammon's horn.

11beta-hydroxysteroid dehydrogenase functions reversibly as an oxidoreductase in the rat hippocampus in vivo.

The localization in the brain and metabolism of 3H-labeled corticosterone (B) and 11-dehydrocorticosterone (A) of high specific radioactivity was determined after stereotaxic injection into the hippocampus of anesthetized rats. [3H]B was cleared very rapidly with, on average, only about 7% being recovered after 5 min and 0.5% after 30 min. Most of this 3H-radioactivity was localized in the area surrounding the site of injection with little diffusion to adjacent areas. These findings make it possible to compare the short term metabolism of [3H]A and [3H]B in different lobes of the hippocampus in the same animal and establish their local equilibrium point in vivo. Under these conditions, about 5% conversion of each steroid to the other was observed in contrast to the situation in cultured hippocampal cells where 11beta-hydroxysteroid dehydrogenase (11-HSD) has been shown by others to act primarily as a reductase catalyzing the conversion of A to B. This method can also be used to study the effect of inhibitors such as 11alpha-hydroxyprogesterone, applied locally in the brain, on the metabolism of corticosteroids. The rate of conversion [3H]B or [3H]A to their dihydro- and tetrahydro-derivatives capable of modulating the GABAa receptor in the hippocampus was much lower than their interconversion. Thus, factors which influence the direction of the 11-HSD catalyzed reaction are important in regulating not only salt appetite and blood pressure but also the levels of neuroactive metabolites of corticosterone.

Neurobiological basis of motor learning in mammals.

Long-term potentiation (LTP) has been proposed as a model of learning and memory. There is still little evidence, however, linking LTP to cognitive processes. We have chosen to study motor learning, first, because it is relatively simpler than cognitive learning and second, because much of the circuitry involved in motor function is already known. In behavioral studies we determined that the sensory cortex is required for the acquisition of new motor skills. Once a skill is acquired, however, the sensory cortex is no longer necessary in the performance of that skill. In electrophysiological experiments we have shown that LTP can be induced in the motor cortex with stimulation of the sensory cortex (SCx) or associativly when stimulation was applied to both SCx and thalamus. We propose that motor learning involves the formation of loop circuits between the motor cortex and the periphery involving the SCx and the thalamus. At first these loop circuits are diffuse, producing contraction of unnecessary muscles, but become specific by producing LTP through practice.

Long-term potentiation in the cat somatosensory cortex.

Intracellular, in-vivo recordings were used to identify neurons in the cat somatosensory cortex in which long-term potentiation (LTP) was induced. Amplitudes of EPSPs produced by microstimulation in the motor cortex (area 4 gamma) were recorded before and after tetanic stimulation (200 Hz, 20 s). In 8/13 cells (62%), EPSP amplitudes increased significantly following the tetanic stimulation. LTP was induced exclusively in cells which produced monosynaptic EPSPs. Six of these cells were labeled by intracellular injections of biocytin. All the cells in which LTP was induced were pyramidal neurons, and were located exclusively in layers II or III of the somatosensory cortex; cells in deeper cortical layers were not potentiated. These data substantiate our previous findings demonstrating LTP in corticocortical pathways and suggest that these pathways play an important role in cortical synaptic plasticity.

Long-lasting facilitation of pyramidal tract input to spinal interneurons.

The purpose of this study was to determine whether long-term changes in synaptic efficacy can be induced in the pyramidal tract (PT). Tetanic stimulation of the PT induced long-term facilitation of PT input to spinal cord neurons. In contrast, tetanic stimulation of the pyramidal tract did not alter the efficacy of synaptic inputs of PT cells' intracortical axon collaterals to other cortical neurons. These findings suggest that the PT participates in motor learning by modulating the excitability of spinal cord neurons. The results also indicate that induction of LTP in the PT is dependent on postsynaptic mechanisms.

Type I adrenal steroid receptors prolong hippocampal long-term potentiation.

The effects of Type I adrenal steroid receptors in prolonging synaptic plasticity in the dentate gyrus of freely behaving rats was investigated. Rats were implanted with chronic, bilateral stimulating and recording electrodes in the perforant pathway and dentate gyrus, respectively, and adrenalectomized (ADX). After a 2-3 day recovery period, baseline recordings of field potentials were made followed by administration of aldosterone or vehicle. One hour later, high frequency stimulation (HFS; chosen to produce comparable long-term potentiation (LTP) in the aldosterone-treated and control groups) was applied unilaterally and recording was continued for 1 h and again performed at 3, 24 and 48 h. LTP in ADX controls decayed significantly within 3 h, and returned to baseline levels at 24 h. In contrast, the aldosterone-treated animals showed enhanced LTP at 3, 24 and 48 h. These findings demonstrate that aldosterone both enhances and prolongs hippocampal plasticity.

On-line acquisition, analysis and presentation of neurophysiological data based on a personal microcomputer system.

A microcomputer based system is described for the acquisition, averaging, displaying, analysis and storage of electrophysiological (EPSP and post-stimulus histogram) data. The system consists of commercially available hardware (IBM-PC AT compatible, 80286 or 80386 based microcomputer, Burr-Brown analog-to-digital (A/D) converter), a custom built interface module, and a combination of commercially available and custom built software packages. The software operates within a Microsoft Windows environment and is comprised of custom built data acquisition and review modules which are linked to Microsoft's Excel program. The system is capable of four channel A/D conversion of EPSP's at a sampling frequency of up to 10 KHz (50 KHz single channel), the averaging of data including the addition and subtraction of various channels, the graphical display of data, the extraction of various data parameters, and the transfer of data to an Excel spreadsheet. The spreadsheet allows for the development of mathematical formulas for statistical analysis of data and presentation of the results in graphical form. Finally, data can easily be output to a laser printer or plotter. A sample experiment, illustrating system operation, is presented.

Effects of mineralocorticoid and glucocorticoid receptors on long-term potentiation in the CA3 hippocampal field.

We have previously shown that the two types of adrenal steroid receptors, mineralocorticoid MR. and glucocorticoid GR. produce opposite effects on long-term potentiation LTP. in the dentate gyrus in vivo. and CA1 hippocampal field in vitro. More specifically, MR activation enhanced and prolonged LTP, whereas GR activation suppressed LTP in these areas and also produced a long-term depression LTD. of the synaptic response. In the present experiment we investigated acute effects of MR and GR activation on LTP induction in the mossy fiber and commissural associational input to the CA3 hippocampal field, since the mechanisms underlying LTP induction in these two pathways differ, the former being N-methyl-D-aspartate receptor NMDAR. independent while the latter being NMDAR-dependent. Rats were either adrenalectomized ADX or adrenally intact. ADX animals were acutely injected with either the specific MR agonist, aldosterone, the specific GR agonist RU 28362 or vehicle. One hour following the injection, the animals were prepared for electrophysiological recording stimulation. Field potential recordings were performed in the radiatum or laconosum moleculare layers of the CA3 field, with stimulation of either the mossy fibers or the commissural associational input from the contralateral hemisphere. We also replicated our previous findings by recording in the dentate gyrus with stimulation of the medial perforant pathway, in the same animals. As observed in our previous study in the dentate gyrus, we found an enhancement and a suppression of LTP with MR and GR activation, respectively. Similarly, for the commissural associational input to CA3, MR activation enhanced LTP, while GR activation reduced it. In contrast, for the mossy fiber input to CA3, neither MR nor GR activation significantly affected LTP induction. These results indicate that adrenal steroids may modulate LTP induction in the hippocampus via an interaction with glutamatergic NMDAR.

Long-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity.

In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulse of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity of the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occurring theta rhythm may play a modulatory role in the induction of LTP.

Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm.

Long-term potentiation (LTP), a long lasting enhancement of synaptic efficacy is considered a model for learning and memory. In anesthetized rats, theta-rhythm was induced in the dentate gyrus by midbrain stimulation. Short trains of pulses were applied to the perforant pathway either at the peak of theta-rhythm or its trough. Trains applied at the peak of theta-rhythm induced LTP while trains applied at the trough produced a decrease of synaptic efficacy or had no effect. Thus, theta-rhythm may play a modulating role in the induction of LTP, suggesting a possible mnemonic function for the rhythm during the behaviors in which it occurs.

Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices.

We previously demonstrated in the dentate gyrus (DG) of anesthetized and freely behaving rats that both acute as well as chronic administration of corticosterone produces a suppression in long-term potentiation (LTP). In subsequent studies we showed, again in the DG, that activation of the two types of adrenal steroid receptors (mineralocorticoid (MR) and glucocorticoid (GR)) produce biphasic effects on synaptic plasticity; activation of MR produces an enhancement while activation of GR produces a suppression in LTP. In a separate study, we further demonstrated in rats administered the specific GR agonist RU 28362 that high-frequency stimulation, which normally produces LTP, instead produced long-term depression (LTD) in these animals. In the present study we investigated the effects of MR and GR activation by adrenal steroids on synaptic plasticity of the hippocampal CA1 field, but we studied this ex vivo, in a slice preparation. The results indicate that, as in our studies in the DG, adrenal steroids produce biphasic effects: in ADX rats, aldosterone (a specific MR agonist) enhanced while RU 28362 suppressed synaptic plasticity. Unlike the in vivo preparation, however, rarely was LTD observed in the animals receiving RU 28362. Also, ADX itself did not produce noticeable effects on synaptic plasticity. The present results are in agreement with previous studies showing that elevations in corticosterone or an acute episode of experimentally induced stress in vivo causes a suppression in LTP in the hippocampal CA1 field, in vitro.

Differential glucose utilization in the parafascicular region during slow-wave sleep, the still-alert state and locomotion.

Regional cerebral glucose utilization (CGU), detectable by the uptake of 2-deoxy-[14C]glucose [( 14C]2DG), was examined during 3 behavioral states--slow-wave sleep (SWS), the still-alert state (SAL) and locomotion (LOC). Examination of the autoradiograms, generated by exposing the [14C]2DG incorporated brain sections to Kodak Royal X Pan film revealed a high level of uptake bilaterally and discretely in the parafascicular (PF) region during these behaviors. This pattern of [14C]2DG uptake does not correspond to any of the anatomical structures previously identified by histo- and cytochemical methods, including the [14C]2DG method. Further, optical density measurements of this region indicated that the [14C]2DG uptake was significantly lower during SWS than during SAL or LOC. The present finding is compatible with the interpretations of previous physiological and behavioral studies that there is an inhibition by cells at the PF relay to the dentate gyrus that is lowered during the SWS compared to the SAL state, thus allowing preferential brain-stem activation of the dentate gyrus.

Comparative extracellular current flow at dendrites and soma of dentate granule cells during long-term potentiation.

In the study of long-term potentiation (LTP) in the dentate gyrus, the magnitude of the initial slope of the evoked synaptic potential (ESP) in the region of the granule cell layer, is commonly used as a measure of synaptic efficacy at the site of the perforant path (PP) input. To investigate the viability of this assumption, in rats anesthetized with either chloropent or urethane, LTP was induced by tetanic stimulation of the PP and ESPs were measured simultaneously at both the soma and dendritic site of the PP input. Following LTP, the two responses were decoupled, the somal response being greater than the dendritic in rats anesthetized with chloropent, the opposite being true in urethanized animals. We conclude that in investigating changes in synaptic efficacy following LTP, measurements should be taken at the site of the PP input.

Central peripheral temperature gradient. Its value and limitations in the management of critically iii surgical patients.

Monitoring the central peripheral temperature gradient in critically ill surgical patients is a simple, sensitive, noninvasive and inexpensive method that can accurately reflect the state of peripheral circulation. It serves as an early warning sign, and its return to normal is a good measure of the efficacy o f therapy. Recognition of the cause of an abnormal gradient is essential to successful management since it can result from pain as well as hypovolemia. Warm-up patterns vary, and every patient should be treated individually. Forcing vasodilatation is usually unnecessary and amy be dangerous in hypothermic patients and in patients with hypovolemia if blood volume is not corrected simultaneously. Peripheral vascular disease, central hypothermia and the use of vasoactive drugs limit the usefulness of this method.

Interventional radiology of the biliary system and pancreas.

In recent years, newer techniques have become available to the clinician for the diagnosis and treatment of biliary and pancreatic disease. This article emphasizes interventional procedures through the liver, such as percutaneous transhepatic cholangiography, percutaneous transhepatic biliary drainage, and ancillary techniques. Also discussed are the nonsurgical management of bile duct calculi and the diagnosis and treatment of pancreatic tumors, abscesses, and pseudocysts.

Method of salvaging long-term dialysis catheters.

Hemodialysis is an important component of chronic renal replacement therapy, which is increasingly being provided with indwelling venous catheters. Catheter malfunction is commonly dealt with using Urokinase instillation or endovascular catheter stripping. We describe the application of a simple technique that allows the indwelling dialysis catheter to be replaced in a subcutaneous tunnel following manipulation for flow problems. Function was restored in all catheters without occurrence of tunnel infection or catheter-related sepsis. Preliminary results offer evidence of the efficacy of the technique in salvaging dialysis catheters, especially in patients with difficult vascular access.

Early splenectomy in chronic myelogenous leukemia: surgical aspects.

A retrospective study was conducted to analyze the surgical aspects of the splenectomy in chronic myelogenous leukemia. Twenty patients, Philadelphia chromosome-positive, were initially treated with busulfan until remission was reached. Elective splenectomy was then performed and chromosomal studies repeated at four- and six-month intervals yielding the indication for cyclic intensive chemotherapy. There ws no mortality, one episode of gram-negative sepsis with shock, and five instances of minimal complications. The spleen weights averaged 265 g, ranging from 60 to 800 g. All patients had normal coagulation profiles at the time of surgery, but four of them developed a postoperative thrombocytosis without related complications. A specific correlation was noted between postoperative thrombocytosis and splenomegaly (average weight 570 g). Eleven patients showed a high postoperative leukemoid reaction (average 40,500 cells/cu mm). The interval between diagnosis and splenectomy was shorter (average 7.5 months) in this group than for the patients who had a lower granulocytosis (average 19.5 months).