Assessing the commensurability of theories of consciousness: On the usefulness of common denominators in differentiating, integrating and testing hypotheses.

How deep is the current diversity in the panoply of theories to define consciousness, and to what extent do these theories share common denominators? Here we first examine to what extent different theories are commensurable (or comparable) along particular dimensions. We posit logical (and, when applicable, empirical) commensurability as a necessary condition for identifying common denominators among different theories. By consequence, dimensions for inclusion in a set of logically and empirically commensurable theories of consciousness can be proposed. Next, we compare a limited subset of neuroscience-based theories in terms of commensurability. This analysis does not yield a denominator that might serve to define a minimally unifying model of consciousness. Theories that seem to be akin by one denominator can be remote by another. We suggest a methodology of comparing different theories via multiple probing questions, allowing to discern overall (dis)similarities between theories. Despite very different background definitions of consciousness, we conclude that, if attention is paid to the search for a common methological approach to brain-consciousness relationships, it should be possible in principle to overcome the current Babylonian confusion of tongues and eventually integrate and merge different theories.

Functional (ir)relevance of posterior parietal cortex during audiovisual change detection.

The posterior parietal cortex (PPC) plays a key role in integrating sensory inputs from different modalities to support adaptive behavior. Neuronal activity in PPC reflects perceptual decision making across behavioral tasks, but the mechanistic involvement of PPC is unclear. In an audiovisual change detection task, we tested the hypothesis that PPC is required to arbitrate between the noisy inputs from the two different modalities and help decide in which modality a sensory change occurred. In trained male mice, we found extensive single-neuron and population-level encoding of task-relevant visual and auditory stimuli, trial history, as well as upcoming behavioral responses. However, despite these rich neural correlates, which would theoretically be sufficient to solve the task, optogenetic inactivation of PPC did not affect visual or auditory performance. Thus, in spite of neural correlates faithfully tracking sensory variables and predicting behavioral responses, PPC was not relevant for audiovisual change detection. This functional dissociation questions the role of sensory- and task-related activity in parietal associative circuits during audiovisual change detection. Furthermore, our results highlight the necessity to dissociate functional correlates from mechanistic involvement when exploring the neural basis of perception and behavior.SIGNIFICANCE STATEMENTThe Posterior Parietal Cortex (PPC) is active during many daily tasks, but capturing its function has remained challenging. Specifically, it is proposed to function as an integration hub for multisensory inputs. Here, we tested the hypothesis that, rather than classical cue integration, mouse PPC is involved in the segregation and discrimination of sensory modalities. Surprisingly, even though neural activity tracked current and past sensory stimuli and reflected the ongoing decision-making process, optogenetic inactivation did not affect task performance. Thus, we show an apparent redundancy of sensory and task-related activity in mouse PPC. These results narrow down the function of parietal circuits, as well as direct the search for those neural dynamics that causally drive perceptual decision making.

Diagnostic accuracy of clinical and laboratory characteristics in suspected non-surgical nosocomial central nervous system infections.

BACKGROUND: The diagnosis of meningitis in non-surgical hospitalized patients is often difficult and diagnostic accuracy of clinical, laboratory, and radiological characteristics is unknown. AIM: To assess diagnostic accuracy for individual clinical characteristics of patients suspected of non-surgical nosocomial central nervous system (CNS) infections. METHODS: In a prospective multi-centre cohort study in the Netherlands with adults suspected of CNS infections, consecutive patients who underwent a lumbar puncture for the suspicion of a non-surgical nosocomial CNS infection were included. All episodes were categorized into five final clinical diagnosis categories, as reference standard: CNS infection, CNS inflammatory disease, systemic infection, other neurological disease, or non-systemic, non-neurological disease. FINDINGS: Between 2012 and 2022, 114 out of 1275 (9%) patients included in the cohort had suspected non-surgical nosocomial CNS infection: 16 (14%) had a confirmed diagnosis, including four (25%) with bacterial meningitis, nine (56%) with viral CNS infections, two (13%) fungal meningitis, and one (6%) parasitic meningitis. Diagnostic accuracy of individual clinical characteristics was generally low. Elevated CSF leucocyte count had the highest sensitivity (81%; 95% confidence interval (CI): 54-96) and negative predictive value (NPV) (96%; 95% CI: 90-99). When combining the presence of abnormalities in neurological or CSF examination, sensitivity for diagnosing a CNS infection was 100% (95% CI: 79-100) and NPV 100% (95% CI: 78-100). CSF examination changed clinical management in 47% of patients. CONCLUSION: Diagnostic accuracy for individual clinical characteristics was low, with elevated CSF leucocyte count having the highest sensitivity and NPV.

Hyperglycaemia is associated with impaired pulsatile insulin secretion: effect of basal insulin therapy.

AIM: Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? METHODS: Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. RESULTS: Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031). CONCLUSIONS: Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous ß-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes.

[Unclear hepatopathy in a patient with atrial fibrillation]. / Unklare Hepatopathie bei einem Patienten mit Vorhofflimmern.

Although liver damage is a relatively rare adverse effect of oral anticoagulation with phenprocoumon, acute liver failure can be a serious treatment-associated complication. In this contribution, a patient with drug-induced liver failure during oral anticoagulation with phenprocoumon is presented. This case illustrates the need for close laboratory monitoring and suggests that phenrocoumon-induced liver damage should be considered along with other common complications of this treatment.

Experience-dependent alterations in conscious resting state activity following perceptuomotor learning.

In monkeys and rats, neural activity patterns during learning are reactivated during subsequent periods of rest or sleep. According to the reactivation-consolidation account, this process underlies the consolidation of memories. Brain imaging studies have extended these findings to humans during sleep, but not yet, during rest. Here, we show that learning-related reactivation also occurs in humans during rest. During functional MRI-scanning, participants trained on a perceptuomotor task flanked by rest periods. During training, we found robust activity in the superior parietal cortex. During post-training rest, this same area reactivated. We also found a link between parietal reactivation and learning. Activity in superior parietal cortex was associated with learning during training, and a control group that did not train on the perceptuomotor task did not show any difference between the pre- and post-training rest blocks in this region. These findings indicate that, during rest, reactivation also occurs in humans. This process may contribute to consolidation of perceptuomotor memories.

Expression of amphetamine sensitization is associated with recruitment of a reactive neuronal population in the nucleus accumbens core.

RATIONALE: Repeated exposure to psychostimulant drugs causes a long-lasting increase in the psychomotor and reinforcing effects of these drugs and an array of neuroadaptations. One such alteration is a hypersensitivity of striatal activity such that a low dose of amphetamine in sensitized animals produces dorsal striatal activation patterns similar to acute treatment with a high dose of amphetamine. OBJECTIVES: To extend previous findings of striatal hypersensitivity with behavioral observations and with cellular activity in the nucleus accumbens and prefrontal cortex in sensitized animals. MATERIALS AND METHODS: Rats treated acutely with 0, 1, 2.5, or 5 mg/kg i.p. amphetamine and sensitized rats challenged with 1 mg/kg i.p. amphetamine were scored for stereotypy, rearing, and grooming, and locomotor activity recorded. c-fos positive nuclei were quantified in the nucleus accumbens and prefrontal cortex after expression of sensitization with 1 mg/kg i.p. amphetamine. RESULTS: Intense stereotypy was seen in animals treated acutely with 5 mg/kg amphetamine, but not in the sensitized group treated with 1 mg/kg amphetamine. The c-fos response to amphetamine in the accumbens core was augmented in amphetamine-pretreated animals with a shift in the distribution of optical density, while no effect of sensitization was seen in the nucleus accumbens shell or prefrontal cortex. CONCLUSIONS: A lack of stereotypy in the sensitized group indicates a dissociation of behavioral responses to amphetamine and striatal immediate-early gene activation patterns. The increase in c-fos positive nuclei and shift in the distribution of optical density observed in the nucleus accumbens core suggests recruitment of a new population of neurons during expression of sensitization.

Augmented reinforcer value and accelerated habit formation after repeated amphetamine treatment.

Various processes might explain the progression from casual to compulsive drug use underlying the development of drug addiction. Two of these, accelerated stimulus-response (S-R) habit learning and augmented assignment of motivational value to reinforcers, could be mediated via neuroadaptations associated with long-lasting sensitization to psychostimulant drugs, i.e. augmented dopaminergic neurotransmission in the striatum. Here, we tested the hypothesis that both processes, which are often regarded as mutually exclusive alternatives, are present in amphetamine-sensitized rats. Amphetamine-sensitized rats showed increased responding for food under a random ratio schedule of reinforcement, indicating increased incentive motivational value of food. In addition, satiety-specific devaluation experiments under a random interval schedule of reinforcement showed that amphetamine-sensitized animals exhibit accelerated development of S-R habits. These data show that both habit formation and motivational value of reinforcers are augmented in amphetamine-sensitized rats, and suggest that the task demands determine which behavioral alteration is most prominently expressed.

The ventral striatum in off-line processing: ensemble reactivation during sleep and modulation by hippocampal ripples.

Previously it has been shown that the hippocampus and neocortex can spontaneously reactivate ensemble activity patterns during post-behavioral sleep and rest periods. Here we examined whether such reactivation also occurs in a subcortical structure, the ventral striatum, which receives a direct input from the hippocampal formation and has been implicated in guidance of consummatory and conditioned behaviors. During a reward-searching task on a T-maze, flanked by sleep and rest periods, parallel recordings were made from ventral striatal ensembles while EEG signals were derived from the hippocampus. Statistical measures indicated a significant amount of reactivation in the ventral striatum. In line with hippocampal data, reactivation was especially prominent during post-behavioral slow-wave sleep, but unlike the hippocampus, no decay in pattern recurrence was visible in the ventral striatum across the first 40 min of post-behavioral rest. We next studied the relationship between ensemble firing patterns in ventral striatum and hippocampal ripples-sharp waves, which have been implicated in pattern replay. Firing rates were significantly modulated in close temporal association with hippocampal ripples in 25% of the units, showing a marked transient enhancement in the average response profile. Strikingly, ripple-modulated neurons in ventral striatum showed a clear reactivation, whereas nonmodulated cells did not. These data suggest, first, the occurrence of pattern replay in a subcortical structure implied in the processing and prediction of reward and, second, a functional linkage between ventral striatal reactivation and a specific type of high-frequency population activity associated with hippocampal replay.

Anatomical evidence for direct connections between the shell and core subregions of the rat nucleus accumbens.

The nucleus accumbens is thought to subserve different aspects of adaptive and emotional behaviors. The anatomical substrates for such actions are multiple, parallel ventral striatopallidal output circuits originating in the nucleus accumbens shell and core subregions. Several indirect ways of interaction between the two subregions and their associated circuitry have been proposed, in particular through striato-pallido-thalamic and dopaminergic pathways. In this study, using anterograde neuroanatomical tracing with Phaseolus vulgaris-leucoagglutinin and biotinylated dextran amine as well as single-cell juxtacellular filling with neurobiotin, we investigated the intra-accumbens distribution of local axon collaterals for the identification of possible direct connections between the shell and core subregions. Our results show widespread intra-accumbens projection patterns, including reciprocal projections between specific parts of the shell and core. However, fibers originating in the core reach more distant areas of the shell, including the rostral pole (i.e. the calbindin-poor part of the shell anterior to the core) and striatal parts of the olfactory tubercle, than those arising in the shell and projecting to the core. The latter projections are more restricted to the border region between the shell and core. The density of the fiber labeling within both the shell and core was very similar. Moreover, specific intrinsic projections within shell and core were identified, including a relatively strong projection from the rostral pole to the rostral shell, reciprocal projections between the rostral and caudal shell, as well as projections within the core that have a caudal-to-rostral predominance. The results of the juxtacellular filling experiments show that medium-sized spiny projection neurons and medium-sized aspiny neurons (most likely fast-spiking) contribute to these intra-accumbens projections. While such neurons are GABAergic, the intrastriatal projection patterns indicate the existence of lateral inhibitory interactions within, as well as between, shell and core subregions of the nucleus accumbens.

A model of molecular circadian clocks: multiple mechanisms for phase shifting and a requirement for strong nonlinear interactions.

A fundamental question in the field of circadian rhythms concerns the biochemical and molecular nature of the oscillator. There is strong evidence that circadian oscillators are cell autonomous and rely on periodic gene expression. In Drosophila, Neurospora, Aplysia, and vertebrates, circadian oscillators are thought to be based on molecular autoregulatory loops composed of transcription, translation, and negative feedback by proteins on nuclear transcription. By studying a mathematical model of molecular clocks based on this general concept, the authors sought to determine which features such clocks must have to generate robust and stable oscillations and to allow entrainment by external stimuli such as light. The model produced circadian oscillations as an emergent property even though a time delay in protein synthesis and rate constants of the feedback loop were much shorter than 24 h. Along with the delay in protein production, strong nonlinear interactions in macromolecular synthesis and nuclear feedback appeared to be required for the model to show well-behaved oscillatory behavior. Realistic phase-shifting patterns induced by external stimuli could be achieved by multiple mechanisms-namely, up- and downward perturbations of protein or mRNA synthesis or degradation rates. The model makes testable predictions about interactions between clock elements and mechanisms of entrainment and may help to understand the functions of the intricate molecular interactions governing circadian rhythmogenesis.

A reexamination of the role of GABA in the mammalian suprachiasmatic nucleus.

Three independent electrophysiological approaches in hypothalamic slices were used to test the hypothesis that gamma-amino butyric acid (GABA)A receptor activation excites suprachiasmatic nucleus (SCN) neurons during the subjective day, consistent with a recent report. First, multiple-unit recordings during either the subjective day or night showed that GABA or muscimol inhibited firing activity of the SCN population in a dose-dependent manner. Second, cell-attached recordings during the subjective day demonstrated an inhibitory effect of bath- or microapplied GABA on action currents of single SCN neurons. Third, gramicidin perforated-patch recordings showed that bicuculline increased the spontaneous firing rate during the subjective day. Therefore, electrophysiological data obtained by three different experimental methods provide evidence that GABA is inhibitory rather than excitatory during the subjective day.

Reinforcement learning by Hebbian synapses with adaptive thresholds.

A central problem in learning theory is how the vertebrate brain processes reinforcing stimuli in order to master complex sensorimotor tasks. This problem belongs to the domain of supervised learning, in which errors in the response of a neural network serve as the basis for modification of synaptic connectivity in the network and thereby train it on a computational task. The model presented here shows how a reinforcing feedback can modify synapses in a neuronal network according to the principles of Hebbian learning. The reinforcing feedback steers synapses towards long-term potentiation or depression by critically influencing the rise in postsynaptic calcium, in accordance with findings on synaptic plasticity in mammalian brain. An important feature of the model is the dependence of modification thresholds on the previous history of reinforcing feedback processed by the network. The learning algorithm trained networks successfully on a task in which a population vector in the motor output was required to match a sensory stimulus vector presented shortly before. In another task, networks were trained to compute coordinate transformations by combining different visual inputs. The model continued to behave well when simplified units were replaced by single-compartment neurons equipped with several conductances and operating in continuous time. This novel form of reinforcement learning incorporates essential properties of Hebbian synaptic plasticity and thereby shows that supervised learning can be accomplished by a learning rule similar to those used in physiologically plausible models of unsupervised learning. The model can be crudely correlated to the anatomy and electrophysiology of the amygdala, prefrontal and cingulate cortex and has predictive implications for further experiments on synaptic plasticity and learning processes mediated by these areas.

Paired-pulse facilitation in the nucleus accumbens following stimulation of subicular inputs in the rat.

Anatomical tracing studies indicate that the nucleus accumbens receives inputs from limbic structures, and projects to the ventral pallidum. In order to get more fundamental insight into how information from the limbic areas is relayed via the nucleus accumbens, electrophysiological experiments were carried out in rats under halothane anaesthesia. Inputs originating in the subiculum were activated by electrical stimulation of the fornix fibres, and both field potentials and extracellular unit activity were recorded from the medial and lateral aspects of the nucleus accumbens. Evoked potentials consisted of two positive peaks (P1 at 10 ms and P2 at 25-30 ms). In between a negative-going wave (N1) was present. These initial components were followed by a complex negative wave (N2) with variable duration of 30-100 ms. The P2 and N2 components showed a conspicuous paired-pulse facilitation at stimulus intervals between 80 and at least 200 ms. When responses were recorded at increasing stimulus intensity, the second response emerged at lower threshold than the first response. The mechanisms underlying these phenomena were investigated by analysing the extracellularly recorded unit activity. Primarily, excitatory responses were found. Onset-latencies could be divided roughly into two clusters, one around 10 ms, representing monosynaptic inputs, and a second around 24-26 ms. Inhibitory responses were also found. Stimulation of the ventral pallidum was carried out in order to test whether the cells that could be driven by stimulation of the subicular inputs were projection cells. Latencies of antidromic action potentials ranged from 9 to 13 ms. A minority of the identified projection cells were activated by limbic inputs. The projection cells were found in the core region of the nucleus accumbens. Units that were inhibited by stimulation of the limbic inputs were found in the shell only, whereas excitatory responses were measured in both subdivisions of the nucleus accumbens. For the latter responses a significant enhancement, by a factor of four, was found using double pulse stimulation of the fornix at intervals of 100 ms. The basic electrophysiological properties are compared with those described in the literature, and speculations about the possible mechanisms responsible for the paired-pulse facilitation phenomena are put forward.

Responses of the nucleus accumbens following fornix/fimbria stimulation in the rat. Identification and long-term potentiation of mono- and polysynaptic pathways.

The nucleus accumbens occupies a strategic position as an interface between limbic cortex and midbrain structures involved in motor performance. The fornix-fimbria carries limbic inputs to the ventral striatum, namely by way of fibers originating in the CA1/subiculum and projecting to the nucleus accumbens. It also carries fibers arising in the septal area that project to the hippocampal formation, and projection fibers to other areas of the rostral forebrain from Ammon's horn. Electrical stimulation of this bundle causes characteristic field potentials both in the nucleus accumbens and in the subiculum. In rats, under halothane anesthesia, the responses evoked by fornix/fimbria stimulation in the nucleus accumbens consist of two main positive peaks (at 10 and 25 ms, referred to as P10 and P25, respectively). P10 represents monosynaptic activation. We hypothesized that P25 reflects the activation of a polysynaptic loop, i.e. a fornix-fimbria hippocampal loop in series with the fibers that arise in the subiculum and project to the nucleus accumbens. To test this hypothesis, we reversibly blocked the fibers projecting caudally to the hippocampus by a local anesthetic (lidocaine) and the glutamatergic transmission through the CA1/subiculum by a local injection of kynurenic acid. Both manipulations yielded a reversible depression of about 90% of the P25 component while P10 remained unaffected as expected. In concert a strong reduction (to 24-31%) of control values of the responses evoked in the subiculum was seen. The dynamics of the mono- and polysynaptic pathways differ markedly. The synaptic responses through both pathways are enhanced by paired-pulse stimulation, but the polysynaptic pathway is facilitated in a much stronger way. Following a tetanus (50 Hz, 2 s duration) applied to the fornix/fimbria, the P10 component of the nucleus accumbens responses showed an immediate increase by a factor of about 2 followed by a phase of gradual decrement with half-decay time of about 10 min, after which a persistent long-term potentiation of about 25% above control level was maintained for the rest of the experiment (max 90 min). The P25 component showed a transient 10-fold potentiation with return to control values after about 10 min. In contrast to the P25 elicited by a conditioning stimulus, the P25 component elicited by a second stimulus delivered at an interval of 100 ms (test stimulus) showed a persistent long-term potentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Circadian modulation of membrane properties in slices of rat suprachiasmatic nucleus.

Perforated patch clamp recordings of neurons in slices of the suprachiasmatic nucleus (SCN) were made in their subjective day and night phases. The spontaneous firing rate and input resistance were significantly higher during the subjective day as compared to the subjective night. In parallel, the membrane potential of neurons recorded at daytime was significantly more depolarized than at nighttime. The day-night differences in membrane potential and input resistance were maintained when spikes and GABA(A) receptor-mediated transmission were blocked by tetrodotoxin and bicuculline, suggesting a cell-autonomous regulation of the circadian modulation of membrane properties. In conclusion, these findings suggest that at least one hyperpolarizing ionic conductance would be open at night and closed during mid-day, when spontaneous firing reaches peak levels in the SCN.

C-fos activation patterns in rat prefrontal cortex during acquisition of a cued classical conditioning task.

The prefrontal cortex (PFC) is known to be involved in associative learning; however, its specific role in acquisition of cued classical conditioning has not yet been determined. Furthermore, the role of regional differences within the PFC in the acquisition of cued conditioning is not well described. These issues were addressed by exposing rats to either one or four sessions of a cued classical conditioning task, and subsequently examining c-fos immunoreactivity in various areas of the PFC. Differences in patterns of c-fos immunopositive nuclei were found when comparing the PFC areas examined. No significant differences were found between rats presented with a temporally contingent conditioned stimulus (CS) light and food (paired groups) and those presented with the same stimuli temporally non-contingently (unpaired groups). In lateral and orbital PFC, both the paired and unpaired groups showed more c-fos immunopositive nuclei than control groups exposed only to the behavioral setup (context exposed groups), and all groups showed a drop in c-fos immunopositive nuclei from session 1 to session 4. In dorsal medial PFC, no differences were seen between the paired, unpaired and context exposed groups. These groups did, however, differ from naive animals, an effect that was not seen in the ventral medial PFC. The results of this study do not support a role for the PFC in the acquisition of a cued classical conditioning task. The differences seen between paired, unpaired and context exposed groups in orbital and lateral PFC could be due to contextual conditioning or reward-related effects.

Muscarinic modulation of synaptic transmission in slices of the rat ventral striatum is dependent on the frequency of afferent stimulation.

Extracellular, intracellular and tight-seal patch-clamp recordings in ventral striatal slices were used to investigate whether the effectiveness of muscarinic neuromodulation of fast synaptic transmission may be dependent on the frequency of afferent stimulation. In all neurons tested, EPSPs were reversibly attenuated by muscarine or carbachol. This action was completely antagonized by atropine or pirenzepine. Several observations indicated a presynaptic site of action. In extracellular recordings, carbachol reduced the monosynaptic population spike but not the non-synaptic compound action potential. The acetylcholinesterase inhibitors eserine and pyridostigmine also induced an atropine-sensitive reduction of the EPSP. When the rate of afferent stimulation was increased, control EPSPs or EPSCs exhibited a decline in peak amplitude until reaching a steady-state value. Muscarinic modulation of steady-state EPSPs/EPSCs was significantly stronger in the range of lower frequencies (0.25-4 Hz) than at higher frequencies (8 and 12 Hz). The GABAA and GABAB-receptor/channel antagonists picrotoxin and 2-hydroxy-saclofen, the opiate receptor antagonist naloxone and atropine failed to alter the shape of the frequency-response curve. These results show that both exogenous and endogenous muscarinic receptor agonists are capable of activating a presynaptic mechanism by which fast excitatory inputs to the ventral striatum are depressed. The depressive effect is clearly stronger at lower rates of afferent stimulation than at high rates. This frequency-dependent attenuation of excitatory synaptic inputs exemplifies a new type of activity-dependent neuromodulation in central neural circuits.

Functional characterization of the H-current in SCN neurons in subjective day and night: a whole-cell patch-clamp study in acutely prepared brain slices.

Neurons of the rat suprachiasmatic nucleus (SCN) exhibit a circadian rhythm in spontaneous firing rate. In this whole-cell patch-clamp study in slices, we examined the possibility that H-current (IH) contributes to the spontaneous firing rate of SCN neurons. Most of our experiments were performed during the subjective day, because this is the time epoch during which one would expect the largest excitatory effect of IH if it were to fluctuate in a circadian rhythm. Current-clamp experiments showed that blockade of IH by Cs+ (1 mM) did not influence the spontaneous firing rate and resting membrane potential. Voltage-clamp experiments revealed that IH, when activated at the resting membrane potential, is probably too small in magnitude and too slow in activation to make a significant contribution to the spontaneous firing rate. Both results suggest that IH does not significantly contribute to the spontaneous firing of SCN neurons. In addition, we investigated whether the kinetics and voltage dependence of IH were modulated in a circadian manner. However, no substantial day-night differences in IH were found. We conclude that IH, as recorded in whole-cell mode, does not contribute significantly to spontaneous firing in most SCN neurons and that this current, is more likely to be involved in 'rescuing' SCN neurons from large and long-lasting hyperpolarizations by depolarizing the membrane.

Locally evoked potentials in slices of the rat nucleus accumbens: NMDA and non-NMDA receptor mediated components and modulation by GABA.

In a slice preparation of the rat nucleus accumbens (Acb), local electrical stimulation elicited a field potential composed of two negative peaks, followed by a positive wave. The early negative peak was identified as a non-synaptic compound action potential, the late negative peak as a monosynaptic population spike (PS) and the positive wave as a mixture of an excitatory and an inhibitory postsynaptic potential (PSP). Both the PS and the PSP exhibited a marked degree of paired-pulse facilitation. The quisqualate/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 2 microM) and the broadly acting glutamate receptor antagonist kynurenic acid (300 microM) reversibly abolished or reduced both the PS and PSP. In contrast, nicotinic, muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonists had no suppressive action. Washout of Mg2+ from the superfusion medium reversibly enhanced and prolonged the PSP and this effect was blocked by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5). The gamma-aminobutyric acid antagonist picrotoxin (60 microM) enhanced the PS and induced secondary spikes which were superimposed on a prolonged PSP. Most of this prolongation was abolished by D-AP-5. It is concluded that locally evoked synaptic responses in the Acb are mediated by glutamate or aspartate, and that NMDA receptor mediated activity evoked by low frequency stimulation is substantial in Mg2(+)-free medium or during reduced GABAA receptor activity, but not under normal conditions.