Dopaminemediated Learning Aging and pd

Sequential learning, involved with the processing of a variety of cognitive functions, such as linguistic expression, semantic sequencing, working memory, and procedural memory, is an important aspect of cognitive processing [88]. Sequential learning is impaired in PD patients, suggesting that altered dopamine neurotransmission may be responsible for serial reaction time learning deficits associated with this disease [89-90]. In animal studies, following neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated unilateral lesions in the striatum to deplete dopamine unilaterally in the striatum, show loss in learning sequential tasks [91-92]. Recent study using molecular imaging supports the notion that striatal dopamine is critical for motor sequential learning [88].

In aging, the deficiency of dopamine in the prefrontal cortex results in the deficit in working memory, whereas, in acute stress, excessive dopamine neurotransmission leads to impairment in working memory. These impairments can be attenuated by D1 receptor agonist and antagonist treatment, respectively [93-94]. Age-related loss of dopamine synthesis has been reported in the striatum as well as in the extrastriatal regions except midbrain in the postmortem brain [95]. Age-related loss of D2 and D3 receptors has been observed in the striatal and several extrastriatal regions in normal human brain [96]. Age-related decline in brain performance, including learning, is due to deterioration of synaptic contact and changes in neurotransmitters/neuromodulators concentrations [93-94,97].

In PD, there is a decline in some forms of memory while leaving others relatively intact [98-99]. These patients suffer from impaired working memory and have problems in organizing and using new materials as well as applying strategies. Evidence indicates that these problems are probably due to dysregulation in prefrontal cortex as a result of decreased subcortical input into the frontal cortex [100-101]. In the prefrontal cortex, D1 and D5 receptors play an essential role in mediating working memory functions, whereas less is known about the importance of other dopamine receptor subtypes (D2, D3, D4) in the prefrontal cortex [94]. D1-like antagonists that inhibit D1 and D5 receptors (but not D2 receptors) suppress prefrontal cortex, disrupting working memory, whereas prefrontal infusion of low levels of D1 agonists (but not D2 agonists) improves working memory. Interestingly, D4 receptors, are also abundantly expressed in the prefrontal cortex, and seem to be involved with working memory of rats [102]. Moreover, patients with schizophrenia show a variety of impairments in cognitive and executive functions subserved by the prefrontal cortex, which may be due to alterations in mesocortical dopamine activity in the prefrontal cortex, impairement in prefrontal calcium signaling, and altered D1 receptor signaling within prefrontal cortex [103-104]. Collectively, dopamine dysregulation disrupts synaptic plasticity that leads to deficits in working memory.

0 0

Post a comment