Abstract
It has been well established that the cerebellum and its associated circuitry constitute the essential neuronal system for both delay and trace classical eyeblink conditioning (DEC and TEC). However, whether the cerebellum is sufficient to independently modulate the DEC, and TEC with a shorter trace interval remained controversial. Here, we used direct optogenetic stimulation of mossy fibers in the middle cerebellar peduncle (MCP) as a conditioned stimulus (CS) replacement for the peripheral CS (eg, a tone CS or a light CS) paired with a periorbital shock unconditioned stimulus (US) to examine the ability of the cerebellum to learn the DEC and the TEC with various trace intervals. Moreover, neural inputs to the pontine nucleus (PN) were pharmacological blocked to limit the associative motor learning inside the cerebellum. We show that all rats quickly acquired the DEC, indicating that direct optogenetic stimulation of mossy fibers in the left MCP is a very effective and sufficient CS to establish DEC and to limit the motor learning process inside the cerebellum. However, only five out of seven rats acquired the TEC with a 150-ms trace interval, three out of nine rats acquired the TEC with a 350-ms trace interval, and none of the rats acquired the TEC with a 500-ms trace interval. Moreover, pharmacological blocking glutamatergic and GABAergic inputs to the PN from the extra-cerebellar and cerebellar regions has no significant effect on the DEC and TEC learning with the optogenetic CS. These results indicate that the cerebellum has the ability to independently support both the simple DEC, and the TEC with a trace interval of 150 or 350 ms, but not the TEC with a trace interval of 500 ms. The present results are of great importance in our understanding of the mechanisms and ability of the cerebellum in associative motor learning and memory.
Highlights
A prerequisite to understand the neural mechanisms by which an organism acquires and retains information is the identification of the neural substrates of the learning and memory1
in the eyeblink conditioning (EBC), the conditioned stimulus (CS) signals are conveyed to the cerebellum via mossy fiber inputs, and electrical stimulation of mossy fibers has been shown to substitute for a peripheral CS to support EBC in rabbits[25,64,66,94,95,96]
We examined the ability of the cerebellum to independently learn the delay eyeblink conditioning (DEC) and trace eyeblink conditioning (TEC) with various trace intervals using pharmacological and optogenetic approaches in awake, freely moving rats
Summary
A prerequisite to understand the neural mechanisms by which an organism acquires and retains information is the identification of the neural substrates of the learning and memory. Cerebellar cortex lesions studies showed inconsistent results[44,45,46,47,48,49], studies of cerebellar Purkinje cells have revealed inhibitory or excitatory patterns of cellular activity that related to CS or US presentation, conditioned response (CR) generation, and the timing of the CR14,50–56 These data, together with data from a number of other studies, has provided clear evidence that the cerebellum is necessary for the simple DEC. Our recent study indicates that muscimol inactivation of the anterior cingulate cortex one day after learning had no significant effects on retrieval of the TEC with 350-ms trace interval in guinea pigs when louder CS (100-dB) was used, indicating that the cerebellum is capable of supporting the TEC with a relative shorter trace interval when sufficient CS and US signals into the cerebellum are provided In these lesion and inactivation studies, other extra-cerebellar regions, excepting hippocampus and mPFC, remained intact and might be involved in modulation of the TEC. The maximal trace interval for TEC to be established without involvement of extra-cerebellar regions remains unknown
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