Perinatal hypoxia ischemia (H/I) remains a leading global cause of infant mortality and lifelong disability. An emerging literature in rodents suggests that both the magnitude of injury and its response to therapeutic intervention is shaped by precipitating events such as inflammation. The need for preventative and protective therapies is paramount, as complex and unknown factors limit the efficacy of current treatments. Eyeblink conditioning is a Pavlovian learning task in which a discrete stimulus (e.g., a tone) is paired with an unconditioned stimulus, such as an air puff to the eye to elicit a blink. The unconditioned stimulus alone elicits the blink reflex. As repeated pairings of the tone and unconditioned stimulus progress, the organism begins to blink in response to the tone, which is now the conditioned stimulus. Successful acquisition and expression of the conditioned eyeblink requires plasticity within the cerebellum, manifesting as a well-timed blink just prior to the unconditioned stimulus. Associative modulation of the eyeblink reflex is an extremely flexible model system of learning and memory; the neural circuits necessary for the acquisition are known, and highly conserved across species. Eyeblink conditioning yields measurements of rate of learning, memory retention, reflex latency and magnitude. These measures are sensitive indices of learning ability and interval timing that can detect learning disability and rapid stimulus processing deficits. The eyeblink reflex is an extremely sensitive measure of early cerebellar pathology with high prognostic validity, readily measured in infants as early as five months of age. The second postnatal week is a critical period of cerebellum development in the rat. At this time the synaptic connections critical for associative and motor learning are maturing within the cerebellum, and are linking with cortical and limbic circuits that support higher order cognitive function. Simple changes in stimulus parameters increase task difficulty, and recruit limbic and cortical circuits for acquisition. Delay eyeblink conditioning, in which the conditioned stimulus overlaps and co-terminates with the unconditioned stimulus, relies on circuitry within the cerebellum, whereas trace conditioning, in which a brief gap between the conditioned stimulus and unconditioned stimulus is present, requires the cerebellum, hippocampus and prefrontal cortices for consistent, adaptive conditioned responses. The experiments proposed here will use eyeblink conditioning to test cerebellar integrity following hypoxia ischemia with or without prior inflammation. The dichotomy in the necessary and sufficient circuitry involved in delay versus trace conditioning permits assessment of cerebellar and cortico-cerebellar circuits with the same Pavlovian preparation. The comparisons across tasks will provide insight into the severity of damage to intra-cerebellar circuitry as well as cortical circuitry.
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