Diets high in antioxidant properties are known to reverse some deficits in neuronal and cognitive function that occur in aging animals. Antioxidants are also known to reduce levels of proinflammatory factors in the CNS. We report here that 6 weeks of a spinach-enriched diet ameliorates deficits in cerebellar-dependent delay classical eyeblink learning and reduces the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha) and TNFbeta in the cerebelli of eyeblink-trained animals. Eighteen-month-old Fischer 344 rats were given spinach-enriched lab chow or regular lab chow for 6 weeks. The rats were then given 6 d of 30 trials per day training using a 3 kHz tone conditioned stimulus and airpuff unconditioned stimulus. Rats were killed 3 weeks after eyeblink training. Cytokine expression was measured using RNase protection assay analysis in the eyeblink-trained animals and in a group of young control animals given regular lab chow diet. Old animals on the spinach-enriched lab chow diet learned delay eyeblink conditioning significantly faster than old animals on the regular diet. Cerebelli from older animals on the spinach-enriched diet had significantly less TNFalpha and TNFbeta than cerebelli from older animals on the control diet.

The pontine nuclei carry auditory conditioned stimulus information to the cerebellum during classical conditioning of the nictitating membrane response in rabbits. In well-trained animals learning-related as well as stimulus-evoked unit activity can be recorded throughout the pontine nuclei but particularly in the lateral and dorsolateral pons. Recent work in our laboratory has provided evidence that the learning-related unit activity in the pons is dependent on the interpositus nucleus and that the pons is not a site of essential plasticity for the learned response. In the present study we considered the question of whether learning-related unit activity might be projected from the interpositus nucleus to the pons through the red nucleus, a primary output target of the interpositus and a structure known to be essential for expression of the learned response. Multiple unit recordings were taken from lateral and dorsolateral pontine locations in well-trained rabbits before and during cooling of the red nucleus. Analysis of pooled data for all recording locations within the lateral and dorsolateral pons indicated that reversible inactivation of red nucleus abolished both stimulus-evoked and learning-related unit activity. However, we also found discrete recording locations where stimulus-evoked and learning-related 1Corresponding author. unit activity were attenuated but not abolished by red nucleus cooling.

The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks To date, no studies have shown a direct involvement of cerebellar noradrenergic activity nor localized the post-synaptic response to cerebellar ␤-noradrenergic receptor signaling. Using ipsilateral, localized infusions into cerebellar lobule HVI and interpositus (IP), we have established that blocking ␤-noradrenergic receptors with propranolol significantly impairs acquisition of conditioned responses. Furthermore, interrupting activation of cAMP-dependent PKA in the cerebellum using Rp-cAMPS completely prevents acquisition. However, neither blocking ␤-adrenergic receptors nor blocking PKA activation significantly interferes with performance of established conditioned responses when administered after the learned response is formed.The neurotransmitter norepinephrine (NE) is strongly implicated in cerebellar-dependent learning and memory in adaptation to a patterned rod runway task (Watson and McElligott 1983;Bickford 1995), in adaptation of the vestibulo-ocular reflex gain (VOR) (Pompeiano et al. 1991), and in cerebellar-dependent delay classical eyelid conditioning (Gould 1998;McCormick and Thompson 1982;Winsky and Harvey 1992;Cartford et al. 2002). The delay form of classical eyelid conditioning is a valuable model for studying NE because the functional anatomy is so well characterized and localization of learning in the cerebellum is strongly supported by the literature. Neurons within cerebellar lobule HVI and the interpositus nucleus (IP) in rabbits and rats show conditioning-related activity (Berthier and Moore 1986;Gould and Steinmetz 1994;Rogers et al. 2001). Classical conditioning of the eyelid response is disrupted by lesions of cerebellar lobule HVI (Yeo et al. 1985;Steinmetz and Sengelaub 1992;Nordholm et al. 1993;Perrett et al. 1993) and is abolished by lesions of cerebellar IP (Clark et al. 1992(Clark et al. , 1997Krupa et al. 1993;Clark and Lavond 1996;Rogers et al. 2001). However, Purkinje cell degeneration mutant (pcd) mice acquire the eyelid response (Chen et al. 1996), and both pcd mice as well as the jaundiced Gunn rat (also a mutant with loss of Purkinje cells) have normal to elevated levels of NE innervation and functional activity in cerebellar cortex and deep nuclei after degeneration of the Purkinje cell layer (Ghetti 1981;Kostrozewa and Harston 1986;Onozuka et al. 1990).Norepinephrine is known to modulate the action of other neurotransmitters in both the cerebellar cortex and the deep nuclei ) and can amplify afferent inputs to cerebellar Purkinje neurons. This effect is mediated through the ␤-noradrenergic receptor (Yeh and Woodward 1983;Woodward et al. 1991). Noradrenergic receptor activation signals a Gprotein-coupled signal transduction cascade in which adenyl cyclase (AC), cyclic-adenosine-monophosphat...

Norepinephrine (NE) is a central nervous system neuromodulator that enhances the actions of other neurotransmitters such as gamma-aminobutyric acid and glutamate. Based on the Marr-Albus theories, Gilbert suggested that NE influences consolidation of cerebellar learning. NE depletion or blockade of postsynaptic noradrenergic receptors decreases the rate of learning in several cerebellar-dependent learning tasks. Loss of cerebellar beta-adrenergic receptor function correlates with a loss of function in related learning tasks. Interventions that improve beta-adrenergic receptor function also improve performance in cerebellum-dependent learning tasks. Thus, the authors propose that NE has a central role in the modulation of learning within the cerebellum.