Effects of aging on cerebellar noradrenergic function and motor learning: nutritional interventions
Introduction
Aging is a complex phenomenon which effects all biological systems. One theory of aging, the free radical theory (Harman, 1956) proposes that the accumulation of free radical damage with time results in the eventual decline of the biological system and leads to death of the organism. This theory has wide support in the literature and is discussed in more detail later in this section. We propose to examine the role of oxidative stress in aging by studying a well defined neurobiological system in detail. Many of the functional and behavioral alterations that accompany the aging process are likely the result of underlying alterations in the central nervous system (CNS). In aging humans and animals there is a well-documented progressive decline in motor performance and coordination (Welford et al., 1969, Marshall and Berrios, 1979, Wallace et al., 1980, Janicke and Wrobel, 1984). There is evidence that elderly individuals have an impaired ability to learn new motor skills such as mirror tracking (Wright and Payne, 1985). Changes in the physiology of the cerebellum have been implicated to play a role in motor coordination (Chambers and Sprague, 1955) and in particular lesions of the noradrenergic input to the cerebellum cause problems in motor learning (Watson and McElligott, 1983, Watson and McElligott, 1984, Bickford et al., 1992). My laboratory has been studying the noradrenergic innervation of the cerebellum and its association to motor learning as a neurobiological model system with significant importance in aging (Bickford et al., 1992, Bickford, 1993).
Oxidative stress and reactive oxygen species (ROS) have been proposed as a major contributor to the aging process and to many neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (Harman, 1956, Ames and Shigenaga, 1992, Ames et al., 1993). In addition a mutation in the gene for SOD has been identified in familial amyotrophic lateral sclerosis (Deng et al., 1993, Rosen et al., 1993). The free radical theory of aging has gained significant support with the demonstration that life span of fruit flies can be increased by the over-expression of SOD and catalase (Orr and Sohal, 1994). A decline in the capacity of normal antioxidant defense mechanisms has been postulated as a causative factor in aging related declines in the function of biological systems (Harman, 1956, Leibovitz and Siegel, 1980, Ames et al., 1993). Lipid peroxidation of cellular membranes is a free radical induced chain reaction which may result in damage to protein (Davies, 1987), DNA (Ames et al., 1993) and membranes (Gutteridge and Stocks, 1976, van Kujik et al., 1987). There is an age-related increase in lipid peroxidation measured by malondialdehyde formation and phospholipid hydroperoxide (Zhang et al., 1994). This is related to an increase in hydroxyl radicals measured as the salycilate hydroxylation products 2,3 DHBA and 2,5 DHBA (Zhang et al., 1994). There are age-related increases in protein oxidation measured as carbonyl content (Starke-Reed and Oliver, 1989, Carney et al., 1991). Ames has estimated that there are 100 000 oxidative hits to DNA per cell per day in a rat and 10 000 hits to DNA per day per cell in humans. Because oxidative damage accumulates with age by the time a rat is 2 years old it has about 2 million DNA lesions per cell (Orr et al., 1992, Ames et al., 1993). Thus, there is evidence that products of oxidative stress accumulate with aging.
Consumption of fruits and vegetables has been acknowledged for some time as being beneficial to health. Much of the evidence supporting the protective role of fruits and vegetables comes from epidemiological literature. For example, it has been stated that in the Western nations from early times until the Industrial Revolution diets were composed primarily of fruit, beans and vegetables. Following the Industrial Revolution there have been significant increases in consumption of meat and decreases in plant food consumption, with corresponding increases in such common ‘killers’ as cancer, coronary artery disease and atherosclerotic related dementia and stroke that are known to increase with age. The traditional common diet of the Mediterranean region has been associated with a significant (17%) reduction in overall mortality in the elderly from these regions (Willett et al., 1995). The question has been raised as to the nature of the protective effects of specific nutrients found in fruits and vegetables, such as β-carotene, vitamin C, and vitamin E in the protection against these ‘age-related diseases’. However, investigators acknowledge that it is impossible to be confident that a particular factor is the effective agent. With few exceptions a single nutrient is not packaged into a single food, and it may be that the combinations of nutrients found in foods may have greater protective effects than each nutrient taken alone.
Given these considerations, we believed that it might be possible to counter the decreases in antioxidant protection that occur in aging, dietarily by increasing the intake of fruits and vegetables identified as being high in antioxidant activity (Cao et al., 1995, Cao et al., 1997). Such consumption has already been found to reduce cancer incidence (Willet, 1994a, Willet, 1994b) and ischemic heart disease (Hughes, 1995, Mayne, 1996).
The model system that was chosen to examine for the effect of the diets was the cerebellar noradrenergic system as it is known to show age-related changes in neurophysiology and these changes may underlie age-related deficits in motor learning. The noradrenergic input to cerebellar Purkinje neurons inhibits spontaneous discharge, but appears to augment the ‘signal to noise’ ratio for both excitatory and inhibitory neurotransmission, and thus has been previously characterized as a ‘modulatory’ input (Freedman et al., 1976). Specifically with regard to NE’s action on inhibitory neurotransmission within the cerebellum it has been shown that NE, applied iontophoretically or via activation of the locus coeruleus, will potentiate GABA-induced inhibitions of cerebellar Purkinje neurons via the β-adrenergic receptor. This effect of NE is altered in aged rats such only 30% of cells in aged rats demonstrate this effect whereas 70–80% of neurons recorded in young animals will show an increase in the response to GABA during application of isoproterenol (ISO) (see Fig. 1).
What is the functional significance of the decline in β-adrenergic neurotransmission in the cerebellum? As discussed above, NE selectively improves signal to noise ratio of evoked versus spontaneous activity, enhancing the sensitivity of cerebellar neurons to both excitatory and inhibitory afferent inputs. Therefore, one might expect NE to exert an important influence on information processing within the cerebellar cortex. The necessity of cerebellar norepinephrine for motor learning has been demonstrated in our laboratory and others. Depletion of cerebellar NE or blockade of β-adrenergic receptors impairs the ability of rats to improve performance on a runway task where the rats must learn to walk on varying patterns of pegs that protrude from the runway walls. Aged rats show impairments on this task that are correlated with the loss of β-adrenergic receptor sensitivity (Bickford et al., 1992, Bickford, 1993) (see Fig. 2).
Section snippets
Extracellular electrophysiology
Action potentials from Purkinje neurons are recorded with the 5 M NaCl-filled barrel of a 4- or 5-barrel micropipette, with input resistance ranging between 1 and 3 MΩ. The action potentials are monitored on an oscilloscope, separated from background activity and converted to constant voltage pulses with a window discriminator. They are then integrated over 1 s intervals by a ratemeter and displayed on a strip chart recorder. Neurotransmitter agonists are applied at the site of recording by
Effect of aging on cerebellar β-adrenergic receptor function
The effect of isoproterenol to ‘modulate’ or increase the GABA induced inhibition of spontaneous firing rate is reduced in aged rats. In Fig. 1A a typical example of the effect of isoproterenol on GABA induced inhibitions of firing rate are observed. The response to GABA alone is a 40% inhibition in firing rate, whereas when ISO is concurrently applied the GABA response is increased to a 98% inhibition of cell firing rate. In panel B it can be seen that this is not observed in Purkinje neurons
Discussion
This work has shown that there is an age-related loss of cerebellar β-adrenergic receptor function. There is also a loss of the ability of aged rats to learn new motor skills. The learning of motor skills is altered in rats that are depleted of NE, thus the age-related decline in motor learning skills may, in part, result from the loss of β-adrenergic receptor function in the cerebellar cortex. The free radical theory of aging predicts that age-related declines in function are the result of
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