Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia.

Theoretical models suggest that symptoms of schizophrenia may be due to a dysfunctional modulatory system associated with the cerebellum. Although it has long been known that the cerebellum plays a critical role in associative learning and motor timing, recent evidence suggests that it also plays a role in nonmotor psychological processes. Indeed, cerebellar anomalies in schizophrenia have been linked to cognitive dysfunction and poor long-term outcome. To test the hypothesis that schizophrenia is associated with cerebellar dysfunction, cerebellar-dependent, delay eye-blink conditioning was examined in 62 individuals with schizophrenia and 62 age-matched non-psychiatric comparison subjects. The conditioned stimulus was a 400 ms tone, which co-terminated with a 50 ms unconditioned stimulus air puff. A subset of participants (25 with schizophrenia and 29 controls) also completed the Wechsler Abbreviated Scale of Intelligence. Participants with schizophrenia exhibited lower rates of eye-blink conditioning, including earlier (less adaptively timed) conditioned response latencies. Cognitive functioning was correlated with the rate of conditioned responsing in the non-psychiatric comparison subjects but not among those with schizophrenia, and the magnitude of these correlations significantly differed between groups. These findings are consistent with models of schizophrenia in which disruptions within the cortico-cerebellar-thalamic-cortical (CCTC) brain circuit are postulated to underlie the cognitive fragmentation that characterizes the disorder.

Eyeblink conditioning during an interstimulus interval switch in rabbits (Oryctolagus cuniculus) using picrotoxin to disrupt cerebellar cortical input to the interpositus nucleus.

The role of the cerebellar cortex in eyeblink classical conditioning remains unclear. Experimental manipulations that disrupt the normal function impair learning to various degrees, and task parameters may be important factors in determining the severity of impairment. This study examined the role of cerebellar cortex in eyeblink conditioning under conditioned stimulus?unconditioned stimulus intervals known to be optimal or nonoptimal for learning. Using infusions of picrotoxin to the interpositus nucleus of the rabbit cerebellum, the authors pharmacologically disrupted input from the cerebellar cortex while training with an interstimulus interval (ISI)-switch procedure. One group of rabbits (Oryctolagus cuniculus) was 1st trained with a 250-ms ISI (optimal) and then switched to a 750-ms ISI (nonoptimal). A 2nd group was trained in the opposite order. The most striking effect was that picrotoxin-treated rabbits initially trained with a 250-ms ISI learned comparably to controls, but those initially trained with a 750-ms ISI were severely impaired. These results suggest that functional input from cerebellar cortex becomes increasingly important for the interpositus nucleus to learn delay eyeblink conditioning as the ISI departs from an optimal interval.

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction.

OBJECTIVES: Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD. METHODS: Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls. RESULTS: Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses. CONCLUSIONS: These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.

Heart rate reactivity in HAD and LAD rats during Pavlovian fear conditioning.

Recently, we reported that High-Alcohol-Drinking (HAD) rats exhibited selective deficits in active avoidance learning under alcohol-naive conditions, and that administration of moderate doses of alcohol (0.5 and 1.0 g/kg) facilitated learning in these rats (Blankenship et al., 2000; Rorick et al., 2003b). We hypothesized that the deficits resulted from excessive fear in the aversive learning context and that the anxiolytic properties of alcohol may have contributed to the improved learning that was observed after alcohol administration. This hypothesis was supported by a recent study in which prolonged freezing in HAD rats was seen after a classical fear conditioning procedure (Rorick et al., 2003a). To provide additional evidence that HAD rats indeed exhibit behaviors consistent with the expression of increased fear in aversive learning contexts, we employed a Pavlovian fear conditioning task to measure heart rate in HAD and Low-Alcohol-Drinking (LAD) rats. In this study, HAD (HAD-1 and HAD-2) and LAD (LAD-1 and LAD-2) rats were assigned to one of three pre-exposure conditions: Context Only, Context/Tone, or Sequential (Context Only followed by Context/Tone) Pre-Exposure. Following pre-exposure, fear conditioning acquisition and extinction procedures were identical for all groups. Results indicated that although no baseline differences were observed between HAD and LAD rats, HAD rats receiving Context-Only pre-exposure exhibited excessive heart rate reactivity to the tone conditional stimulus during fear conditioning acquisition, compared to LAD rats receiving the same pre-exposure conditions. These findings support the hypothesis that HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts, as measured by autonomic conditioning.