Schizophrenia is a substantially heritable disorder associated with disrupted neural transmission, as well as dysfunction of brain systems involved in higher cognitive processes. Among the several putative candidate genes for schizophrenia, the gene encoding dystrobrevin-binding-protein-1 (aka dysbindin) is associated with cognitive impairments, including memory and attention deficits, in both schizophrenia patients and non-schizophrenic individuals. The mechanism underlying these deficits is thought to be based in changes in glutamatergic and dopaminergic function within corticostriatal networks, circuitry known to be critical for schizophrenia. Recent support for this hypothesis derives from the study of mice with a null mutation in the dysbindin gene that exhibit memory dysfunction and abnormalities in excitatory neurotransmission in prefrontal and hippocampal networks. At a cellular level, dysbindin is thought to mediate pre-synaptic glutamatergic transmission. Here, we investigated whether loss of dysbindin expression also affects postsynaptic NMDA receptor function. We show that decreases in dysbindin are associated with specific decreases in NMDA-evoked currents in prefrontal pyramidal neurons, as well as decreases in expression of the obligatory NMDA receptor subunit (NR1). Furthermore, the degree of NR1 expression directly correlates with performance on a spatial working memory task, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression. These data show a significant down-regulation of NMDA receptors due to dysbindin deficiency and illuminate molecular mechanisms mediating the association between dysbindin insufficiency and cognitive impairments associated with schizophrenia, encouraging study of the dysbindin/NR1 expression association in humans with and at risk for the disease.

It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus (US). However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction as an active learning process distinct from acquisition. Experimental data in eyeblink conditioning suggest that plastic changes specific to extinction may play an important role in this process. Both cerebellar and hippocampal systems may be involved in extinction of these memories. The nature of this phenomenon and identification of the neural substrates necessary for extinction of originally learned responses is the topic of this review.

It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus. However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction to be an active learning process distinct from acquisition. Accordingly, this current understanding of extinction has guided neural studies that have tried to identify possible brain structures that could support this new learning. However, whether extinction engages the same brain sites necessary for acquisition is not yet clear. This poses an overriding problem for understanding brain mechanisms necessary for extinction because such analysis cannot be done without first identifying brain sites and pathways involved in this phenomenon. Equally elusive is the validity of a behavioral theory of extinction that can account for the properties of extinction. In this study, we looked at the involvement of the interpositus and the red nucleus in extinction. Results show that, although inactivation of both nuclei blocks response expression, only inactivation of the interpositus has a detrimental effect on extinction. Moreover, this detrimental effect was completely removed when inactivation of the interpositus was paired with electrical stimulation of the red nucleus. These findings speak to the important role of cerebellar structures in the extinction of discrete motor responses and provide important insight as to the validity of a particular theory of extinction.

Climbing fiber input to the cerebellum is believed to serve as a teaching signal during associative, cerebellum-dependent forms of motor learning. However, it is not understood how this neural pathway coordinates changes in cerebellar circuitry during learning. Here, we use pharmacological manipulations to prolong the postcomplex spike pause, a component of the climbing fiber signal in Purkinje neurons, and show that these manipulations enhance the rate of learning in classical eyelid conditioning. Our findings elucidate an unappreciated aspect of the climbing fiber teaching signal, and are consistent with a model in which convergent postcomplex spike pauses drive learning-related plasticity in the deep cerebellar nucleus. They also suggest a physiological mechanism that could modulate motor learning rates.associative learning | pavlovian | ZD 7288 | 1-EBIO | rebound

Rabbits (Oryctolagus cuniculus) were presented with 7 daily sessions of tone-alone training after conditioning. Before the beginning of each of the first 4 extinction sessions, an artificial tear solution or tetracaine hydrochloride was administered to the cornea of rabbits in the control group (n = 6) and experimental group (n = 7), respectively. There were no between-group differences in the percentage of conditioned responses between both groups. However, the amplitude of the conditioned response was notably reduced in the tetracaine group (M = 0.40, SEM +/- 0.216) relative to the control group (M = 1.32, SEM +/- 0.639) early in extinction. Results seem to suggest that although motor output has been found to play an important role in extinction, corneal sensory feedback is not necessary.