Plateau potentials evoked by climbing-fibre stimulation are restricted to the Purkinje cell dendrites of the cat

The present study investigated the duration of afterdepolarizations in Purkinje cell somata following climbing-fibre activation. Intracellular recordings revealed that, in cells with membrane potentials more negative than -50 mV and with normal spike-generating capabilities, climbing-fibre activation resulted in somatic responses with short afterdepolarizations. As the cell deteriorated and the resting membrane potential became more positive, the duration and form of the climbing-fibre response resembled the plateau potentials recorded from proximal dendrites. The absence of plateau potentials in undamaged Purkinje cell somata was confirmed by extracellular recording of test spike amplitudes following evoked climbing-fibre responses.     

Feedback control of Purkinje cell activity by the cerebello-olivary pathway

The pathway from the deep cerebellar nuclei to the inferior olive, the source of the climbing fibre input to the cerebellum, inhibits olivary transmission. As climbing fibre activity can depress the background firing of the Purkinje cells, it was suggested that nucleo-olivary (N-O) inhibition is a negative feedback mechanism for regulating Purkinje cell excitability. This suggestion was investigated, in a set-up with decerebrate ferrets, both by blocking and by stimulating cerebellar output while recording Purkinje cell activity. Blocking the N-O pathway was followed by an increased climbing fibre activity and a dramatic reduction in simple spike firing. Stimulation of the N-O fibres depressed climbing fibre responses and caused an increase in simple spike firing. These results are taken as support for the feedback hypothesis.     

Diagnosing depression in primary care: a Rasch analysis of the major depression inventory

Objective: This study aims to assess the measurement properties of the Major Depression Inventory (MDI) in a clinical sample of primary care patients.

Design: General practitioners (GPs) handed out the MDI to patients aged 18–65 years on clinical suspicion of depression.

Setting: Thirty-seven general practices in the Central Denmark Region participated in the study.

Patients: Data for 363 patients (65% females, mean age: 49.8 years, SD: 17.7) consulting their GP were included in the analysis.

Main outcome measures: The overall fit to the Rasch model, individual item and person fit, and adequacy of response categories were tested. Statistical tests for local dependency, unidimensionality, differential item functioning, and correct targeting of the scale were performed. The person separation reliability index was calculated. All analyses were performed using RUMM2030 software.

Results: Items 9 and 10 demonstrated misfit to the Rasch model, and all items demonstrated disordered response categories. After modifying the original six-point to a five-point scoring system, ordered response categories were achieved for all 10 items. The MDI items seemed well targeted to the population approached. Model fit was also achieved for core symptoms of depression (items 1–3) and after dichotomization of items according to diagnostic procedure.

Conclusion: Despite some minor problems with its measurement structure, the MDI seems to be a valid instrument for identification of depression among adults in primary care. The results support screening for depression based on core symptoms and dichotomization of items according to diagnostic procedure.

• Key points

• The Major Depression Inventory (MDI) is widely used for screening, diagnosis and monitoring of depression in general practice.

• This study demonstrates misfit of items 9 and 10 to the Rasch model and a need to modify the scoring system

• The findings support screening for depression based on core symptoms and dichotomization of items according to diagnostic procedure.

• Minor problems with measurement structure should be addressed in future revisions of the MDI.

     

Extinction of conditioned blink responses by cerebello-olivary pathway stimulation

Learning of classically conditioned eyeblink responses depends on mechanisms within the cerebellum. It has been suggested that climbing fibres from the inferior olive transmit the unconditioned stimulus signal to the cerebellum. We have previously shown that the pathway from the deep cerebellar nuclei to the inferior olive inhibits olivary activity. It is known that repeated presentation of the conditioned stimulus on its own leads to extinction of the conditioned response. If the unconditioned stimulus signal is transmitted to the cerebellum via the inferior olive - climbing fibre system then stimulation of the nucleo-olivary pathway just before the unconditioned stimulus in a trained animal should lead to extinction. The results from this investigation confirm this.     

Purkinje cell activity during classical conditioning with different conditional stimuli explains central tenet of Rescorla–Wagner model

A central tenet of Rescorla and Wagner’s model of associative learning is that the reinforcement value of a paired trial diminishes as the associative strength between the presented stimuli increases. Despite its fundamental importance to behavioral sciences, the neural mechanisms underlying the model have not been fully explored. Here, we present findings that, taken together, can explain why a stronger association leads to a reduced reinforcement value, within the context of eyeblink conditioning. Specifically, we show that learned pause responses in Purkinje cells, which trigger adaptively timed conditioned eyeblinks, suppress the unconditional stimulus (US) signal in a graded manner. Furthermore, by examining how Purkinje cells respond to two distinct conditional stimuli and to a compound stimulus, we provide evidence that could potentially help explain the somewhat counterintuitive overexpectation phenomenon, which was derived from the Rescorla–Wagner model.The Rescorla–Wagner model of associative learning is arguably the most influential theory of associative learning in recent history. The model successfully predicted several behavioral phenomena (1). Moreover, in contrast to the Hebbian model, it is a prime example of an error correction process in which behavioral changes result from violation of expectations (2). A central tenet of the model is that the reinforcement value of a paired trial depends on the existing associative strength between the presented stimuli (3, 4). Neural mechanisms for several phenomena related to the Rescorla–Wagner model have already been proposed (5–16). In this paper, we present evidence from our eyeblink setup that builds on and advances prior thinking regarding the physiological basis of the Rescorla–Wagner model.In eyeblink conditioning, repeated presentations of a neutral conditional stimulus (CS), such as a tone or a light stimulus, followed by a blink-eliciting unconditional stimulus (US), such as an air puff to the cornea or electrical stimulation of the periorbital skin, results in the acquisition of a conditioned blink response (CR). Previous studies have shown that eyeblink conditioning depends on the cerebellum (17, 18) and that the cerebellar cortex plays a crucial role (19). Specifically, conditioned blink responses appear to be triggered by pause responses in GABAergic Purkinje cells (20). These pause responses, which are acquired gradually during conditioning (21), disinhibit cells in the cerebellar nuclei (22), thus allowing them to activate muscles controlling the eyelid (23, 24). Disinhibition of the cerebellar nuclei also activates GABAergic cells that project to the inferior olive (15). Because the US signal enters the cerebellum via the inferior olive (18), we hypothesized that the nucleo-olivary inhibition that arises during learning, suppresses the US signal and therefore reduces the reinforcement value of a paired trial, as postulated in the Rescorla–Wagner model.A surprising consequence of the model is that if a subject has learned to respond to two different CSs, the reinforcement value of a trial where both CSs and the US are presented will be negative and will cause extinction. This counterintuitive prediction has been confirmed in several learning paradigms including fear conditioning (25, 26), appetitive conditioning (27, 28), and eyeblink conditioning (10). The phenomenon is known as “overexpectation” because the subject may be said to “expect” a US that is more intense than the one it actually receives. We hypothesized that, within the context of eyeblink conditioning, overexpectation occurs because the compound CS results in stronger simple spike suppression in the Purkinje cells and, consequently, a stronger nucleo-olivary inhibition of the US signal, to the extent that the reinforcement value becomes negative.     

Recognition and activation of ryanodine receptors by purines

Ryanodine receptor (RyR) is a tetrameric, high molecular weight protein that functions as a calcium release channel. It plays a key role in phenomena such as signal transduction, excitation-contraction and excitation-secretion coupling. Hyperthermia maligna, central core disease and myocardial infarction have been related with RyR dysfunction. RyR is present as three isoforms in vertebrates: RyR 1 mainly localized in skeletal muscle, RyR 2 in cardiac muscle, and RyR 3 in nervous system. RyR is regulated by a number of physiological and pharmacological factors. Main physiological modulators: calcium, kinases and phosphatases, redox state and energy charge. Main pharmacological regulators: caffeine, dantrolene, ruthenium red, heavy metals and ryanodine. Purines have to do with both, physiological and pharmacological regulation of the RyR activity. So far, the mechanisms of RyR activation by ATP and caffeine have been described in detail using [3H]-ryanodine binding assays and unitary channel activity recorded in planar lipid bilayers. However, some questions remain to be addressed and are at present aim of active scrutiny: How many sites for purines are present in the RyR? Is the same site recognized by nucleotides and methylxanthines? What differences exist among the interaction between RyR and purine bases, nucleosides and nucleotides? Are the phosphate groups important for the recognition of nucleotides? Is the sugar moiety important for the recognition of nucleosides? The review article will examine the most recent specialized literature about the mechanism of activation of RyR by purines with emphasis on reports with approaches of structure-function and structure-activation.     

Successful biventricular cardiac resynchronization therapy in a failing Fontan patient: Implications of ventriculo‐ventricular interdependency in single ventricle physiology

We describe a Fontan patient with severe heart failure who was successfully treated with biventricular cardiac resynchronization therapy (CRT). Our case shows that strain imaging might play a crucial role in guiding placement of pacing leads and in characterizing the electromechanical substrate associated with a favorable CRT response. Furthermore, we demonstrate for the first time that ventriculo‐ventricular interdependency seems an important mechanical concept, which can be utilized to augment cardiac performance in failing Fontan patients with a functional hypoplastic ventricle.     

Cerebellar control of the inferior olive

A subpopulation of neurones in the cerebellar nuclei projects to the inferior olive, the source of the climbing fibre input to the cerebellum. This nucleo-olivary projection follows the zonal and, probably also, the microzonal arrangement of the cerebellum so that closed loops are formed between the neurones in the olive, the cerebellar cortex and the nuclei. The nucleo-olivary pathway is GABAergic, but several investigators argue that its main effect is to regulate electrotonic coupling between cells in the inferior olive rather than inhibit the olive. However, there is now strong evidence that the nucleo-olivary fibres do inhibit the olive. Three functions have been suggested for this inhibition: (i) feedback control of background activity in Purkinje cells, (ii) feedback control of learning, and (iii) gating of olivary input in general. Evidence is consistent with (i) and (ii). Activity in the nucleo-olivary pathway suppresses both synaptic transmission and background activity in the olive. When learned blink responses develop, the blink related part of the olive is inhibited while blinks are produced. When the nucleo-olivary pathway is interrupted, there is a corresponding increase in complex spike discharge in Purkinje cells followed by a strong suppression of simple spike firing. Stimulation of the pathway has the opposite results. It is concluded that the nucleo-olivary fibres are inhibitory and that they form a number of independent feedback loops, each one specific for a microcomplex, that regulate cerebellar learning as well as spontaneous activity in the olivo-cerebellar circuit.     

Inhibition of the inferior olive during conditioned responses in the decerebrate ferret

Output from the interpositus nucleus can inhibit the inferior olive, probably via the GABA-ergic nucleo-olivary pathway. It has been suggested that the function of this inhibition might be to regulate synaptic plasticity resulting from parallel fibre/climbing fibre interaction in cerebellar Purkinje cells, by providing negative feedback information to the olive. Thus, when a learned response, generated by the interpositus nucleus, reaches a sufficient amplitude, the olive would be inhibited and further learning blocked. This suggestion was tested in a classical conditioning paradigm. Decerebrate ferrets were trained using electrical skin stimulation of the forelimb as the conditioned stimulus (CS) and periorbital stimulation as the unconditioned stimulus (US). Climbing fibre responses evoked in Purkinje cells by the US were recorded as surface field potentials in the part of the c3 zone controlling eyeblink. It was found that the CS did not inhibit the olive at the beginning of training, but when conditioned responses were large, the olive was inhibited by the CS in some animals. After a number of unpaired CS presentations, which caused extinction of the conditioned response, the inhibition disappeared. The size of individual conditioned responses correlated negatively with the size of the climbing fibre responses evoked by the US. Climbing fibre responses evoked by direct stimulation of the olive were also inhibited. It was concluded that cerebellar output during performance of a conditioned response inhibits the inferior olive. The results thus support the hypothesis of a cerebellar locus of conditioning and are consistent with the proposed role of cerebello-olivary inhibition.     

Simple and Complex Spike Firing Patterns in Purkinje Cells During Classical Conditioning

Classical blink conditioning is known to depend critically on the cerebellum and the relevant circuitry is gradually being unravelled. Several lines of evidence support the theory that the conditioned stimulus is transmitted by mossy fibers to the cerebellar cortex whereas the unconditioned stimulus is transmitted by climbing fibers. This view has been dramatically confirmed by recent Purkinje cell recordings during training with a classical conditioning paradigm. We have tracked the activity of single Purkinje cells with microelectrodes for several hours in decerebrate ferrets during learning, extinction, and relearning. Paired peripheral forelimb and periocular stimulation, as well as paired direct stimulation of cerebellar afferent pathways (mossy and climbing fibers) causes acquisition of a pause response in Purkinje cell simple spike firing. This conditioned Purkinje cell response has temporal properties that match those of the behavioral response. Its latency varies with the interstimulus interval and it responds to manipulations of the conditioned stimulus in the same way that the blink does. Complex spike firing largely mirrors the simple spike behavior. We have previously suggested that cerebellar learning is subject to a negative feedback control via the inhibitory nucleo-olivary pathway. As the Purkinje cell learns to respond to the conditioned stimulus with a suppression of simple spikes, disinhibition of anterior interpositus neurons would be expected to cause inhibition of the inferior olive. Observations of complex spike firing in the Purkinje cells during conditioning and extinction confirm this prediction. Before training, complex spikes are unaffected or facilitated by the conditioned stimulus, but as the simple spike pause response develops, spontaneous and stimulus-evoked complex spikes are also strongly suppressed by the conditioned stimulus. After extinction of the simple spike pause response, the complex spikes reappear.