Anders Rasmussen

Memory trace and timing mechanism localized to cerebellar Purkinje cells

Significance The standard view of neural signaling is that a neuron can influence its target cell by exciting or inhibiting it. An important aspect of the standard view is that learning consists of changing the efficacy of synapses, either strengthening (long-term potentiation) or weakening (long-term depression) them. In studying how cerebellar Purkinje cells change their responsiveness to a stimulus during learning of conditioned responses, we have found that these cells can learn the temporal relationship between two paired stimuli. The cells learn to respond at a particular time that reflects the time between the stimuli. This finding radically changes current views of both neural signaling and learning. The standard view of the mechanisms underlying learning is that they involve strengthening or weakening synaptic connections. Learned response timing is thought to combine such plasticity with temporally patterned inputs to the neuron. We show here that a cerebellar Purkinje cell in a ferret can learn to respond to a specific input with a temporal pattern of activity consisting of temporally specific increases and decreases in firing over hundreds of milliseconds without a temporally patterned input. Training Purkinje cells with direct stimulation of immediate afferents, the parallel fibers, and pharmacological blocking of interneurons shows that the timing mechanism is intrinsic to the cell itself. Purkinje cells can learn to respond not only with increased or decreased firing but also with an adaptively timed activity pattern.

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.

Number of spikes in climbing fibers determines the direction of cerebellar learning.

Cerebellar learning requires context information from mossy fibers and a teaching signal through the climbing fibers from the inferior olive. Although the inferior olive fires in bursts, virtually all studies have used a teaching signal consisting of a single pulse. Following a number of failed attempts to induce cerebellar learning in decerebrate ferrets with a nonburst signal, we tested the effect of varying the number of pulses in the climbing fiber teaching signal. The results show that training with a single pulse in a conditioning paradigm in vivo does not result in learning, but rather causes extinction of a previously learned response.

2013 Special Issue: Classical conditioning of motor responses: What is the learning mechanism?

According to a widely held assumption, the main mechanism underlying motor learning in the cerebellum, such as eyeblink conditioning, is long-term depression (LTD) of parallel fibre to Purkinje cell synapses. Here we review some recent physiological evidence from Purkinje cell recordings during conditioning with implications for models of conditioning. We argue that these data pose four major challenges to the LTD hypothesis of conditioning. (i) LTD cannot account for the pause in Purkinje cell firing that is believed to drive the conditioned blink. (ii) The temporal conditions conducive to LTD do not match those for eyeblink conditioning. (iii) LTD cannot readily account for the adaptive timing of the conditioned response. (iv) The data suggest that parallel fibre to Purkinje cell synapses are not depressed after learning a Purkinje cell CR. Models based on metabotropic glutamate receptors are also discussed and found to be incompatible with the recording data.

Bidirectional Plasticity of Purkinje Cells Matches Temporal Features of Learning

Many forms of learning require temporally ordered stimuli. In Pavlovian eyeblink conditioning, a conditioned stimulus (CS) must precede the unconditioned stimulus (US) by at least about 100 ms for learning to occur. Conditioned responses are learned and generated by the cerebellum. Recordings from the cerebellar cortex during conditioning have revealed CS-triggered pauses in the firing of Purkinje cells that likely drive the conditioned blinks. The predominant view of the learning mechanism in conditioning is that long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses underlies the Purkinje cell pauses. This raises a serious conceptual challenge because LTD is most effectively induced at short CS-US intervals, which do not support acquisition of eyeblinks. To resolve this discrepancy, we recorded Purkinje cells during conditioning with short or long CS-US intervals. Decerebrated ferrets trained with CS-US intervals ≥150 ms reliably developed Purkinje cell pauses, but training with an interval of 50 ms unexpectedly induced increases in CS-evoked spiking. This bidirectional modulation of Purkinje cell activity offers a basis for the requirement of a minimum CS-US interval for conditioning, but we argue that it cannot be fully explained by LTD, even when previous in vitro studies of stimulus-timing-dependent LTD are taken into account.

Activation of a Temporal Memory in Purkinje Cells by the mGluR7 Receptor.

Cerebellar Purkinje cells can learn to respond to a conditioned stimulus with an adaptively timed pause in firing. This response was usually ascribed to long-term depression of parallel fiber to Purkinje cell synapses but has recently been shown to be due to a previously unknown form of learning involving an intrinsic cellular timing mechanism. Here, we investigate how these responses are elicited. They are resistant to blockade of GABAergic inhibition, suggesting that they are caused by glutamate release rather than by a changed balance between GABA and glutamate. We show that the responses are abolished by antagonists of the mGlu7 receptor but not significantly affected by other glutamate antagonists. These results support the existence of a distinct learning mechanism, different from changes in synaptic strength. They also demonstrate in vivo post-synaptic inhibition mediated by glutamate and show that the mGlu7 receptor is involved in activating intrinsic temporal memory.

Changes in complex spike activity during classical conditioning

The cerebellar cortex is necessary for adaptively timed conditioned responses (CRs) in eyeblink conditioning. During conditioning, Purkinje cells acquire pause responses or “Purkinje cell CRs” to the conditioned stimuli (CS), resulting in disinhibition of the cerebellar nuclei (CN), allowing them to activate motor nuclei that control eyeblinks. This disinhibition also causes inhibition of the inferior olive (IO), via the nucleo-olivary pathway (N-O). Activation of the IO, which relays the unconditional stimulus (US) to the cortex, elicits characteristic complex spikes in Purkinje cells. Although Purkinje cell activity, as well as stimulation of the CN, is known to influence IO activity, much remains to be learned about the way that learned changes in simple spike firing affects the IO. In the present study, we analyzed changes in simple and complex spike firing, in extracellular Purkinje cell records, from the C3 zone, in decerebrate ferrets undergoing training in a conditioning paradigm. In agreement with the N-O feedback hypothesis, acquisition resulted in a gradual decrease in complex spike activity during the conditioned stimulus, with a delay that is consistent with the long N-O latency. Also supporting the feedback hypothesis, training with a short interstimulus interval (ISI), which does not lead to acquisition of a Purkinje cell CR, did not cause a suppression of complex spike activity. In contrast, observations that extinction did not lead to a recovery in complex spike activity and the irregular patterns of simple and complex spike activity after the conditioned stimulus are less conclusive.

Learned response sequences in cerebellar Purkinje cells

Significance Learning is thought to rely on the strengthening or weakening of synapses. However, we have previously shown that a neuron can also learn when to time its response so that the timing reflects the interval between two stimuli, without any temporal information in the input signal. Here, we report that a neuron can even learn a sequence of at least two, and probably more, accurately timed responses. A single cell is in a sense “programmable,” and can encode a temporal response pattern. This means that the nature of what a cell can learn is very different from the traditional view, and that the information storage capacity may be far greater. Associative learning in the cerebellum has previously focused on single movements. In eyeblink conditioning, for instance, a subject learns to blink at the right time in response to a conditional stimulus (CS), such as a tone that is repeatedly followed by an unconditional corneal stimulus (US). During conditioning, the CS and US are transmitted by mossy/parallel fibers and climbing fibers to cerebellar Purkinje cells that acquire a precisely timed pause response that drives the overt blink response. The timing of this conditional Purkinje cell response is determined by the CS–US interval and is independent of temporal patterns in the input signal. In addition to single movements, the cerebellum is also believed to be important for learning complex motor programs that require multiple precisely timed muscle contractions, such as, for example, playing the piano. In the present work, we studied Purkinje cells in decerebrate ferrets that were conditioned using electrical stimulation of mossy fiber and climbing fiber afferents as CS and US, while alternating between short and long interstimulus intervals. We found that Purkinje cells can learn double pause responses, separated by an intermediate excitation, where each pause corresponds to one interstimulus interval. The results show that individual cells can not only learn to time a single response but that they also learn an accurately timed sequential response pattern.

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

Significance The Rescorla–Wagner model of associative learning has guided research in behavioral and neural sciences for several decades. Although phenomena associated with the model have previously been linked to nucleo-olivary inhibition, many questions regarding the neural mechanisms underlying the model still remain. In this paper, we present evidence from our eyeblink conditioning setup, indicating that the variables used in Rescorla and Wagners model have physiological correlates. 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.

Physical attractiveness stereotype and memory.

Three experiments examined explicit and implicit memory for information that is congruent with the physical attractiveness stereotype (i.e. attractive-positive and unattractive-negative) and information that is incongruent with the physical attractiveness stereotype (i.e. attractive-negative and unattractive-positive). Measures of explicit recognition sensitivity and implicit discriminability revealed a memorial advantage for congruent compared to incongruent information, as evident from hit and false alarm rates and reaction times, respectively. Measures of explicit memory showed a recognition bias toward congruent compared to incongruent information, where participants tended to call congruent information old, independently of whether the information had been shown previously or not. This recognition bias was unrelated to reports of subjective confidence in retrieval. The present findings shed light on the cognitive mechanisms that might mediate discriminatory behavior towards physically attractive and physically unattractive individuals.