Functional Convergence of Dopaminergic and Cholinergic Input Is Critical for Hippocampus-Dependent Working Memory

Abstract

Although Parkinson's disease is a movement disorder, in many patients cognitive dysfunction is an important clinical sign. It is not yet clear whether this is attributable solely to a decrease in dopamine levels, or whether other neurotransmitter systems might be involved as well. In the present study, the importance of the mesocorticolimbic dopamine pathway and a possible convergence with forebrain cholinergic projections to neocortex and hippocampus in the regulation of learning and memory abilities were investigated by using specific lesion paradigms in one or both systems. Lesioning of dopaminergic neurons in the ventral tegmental area resulted in an impaired performance in the reference memory task, whereas the execution of the working memory tasks appeared to be unaffected in the Morris water maze. Analysis of the swim paths revealed that the dopamine-depleted animals were capable of adapting a search strategy on a given testing day but failed to transfer this information to the next day, suggesting a deficit in information storage and/or recall. In contrast, cholinergic lesions alone were without effect in all test paradigms. However, when both dopamine and acetylcholine were depleted, animals were also impaired in the working memory task, indicating that a functional convergence of the inputs from these systems was critical for acquisition of spatial memory. Interestingly, such an additional acquisition deficit appeared only after hippocampal cholinergic depletion regardless of a concurrent disruption of basalocortical cholinergic afferents. Thus, further analyses of cholinergic alterations may prove useful in better understanding the cognitive symptoms in Parkinson's disease.

A descending dopamine pathway conserved from basal vertebrates to mammals

“…Alternatively, the LS-C41821 ChAT antibody was also used on rat tissue because of a better signal-to-noise ratio. Characterized by Crawford et al (66), the LS-C41821 ChAT antibody is routinely used to label cholinergic neurons in the rat brain (67,68). The labeling obtained with this antibody was very similar to that obtained with AB144P.…”

Combined immunohistochemical and retrograde tracing reveals little evidence of innervation of the rat dentate gyrus by midbrain dopamine neurons

“…This has implications for how we may interpret data from studies that look at the impact of mDA loss at the level of the hippocampus. For example, reduced neurogenesis (Suzuki et al, 2010) or deficits in cognitive function (Wisman et al, 2008) after 6OHDA lesioning may reflect mechanisms that are more indirect than loss of a direct mDA-hippocampus pathway -i.e., changes in hippocampal signaling at a broader systems level involving dopaminergic innervation of other nuclei that feed forward to the hippocampus. Both the nucleus accumbens and amygdala may be interesting targets to investigate further in this context.…”

“…Recent studies have reported that loss of midbrain dopamine (mDA) neurons in the rodent brain results in a reduction in hippocampal cell proliferation and neurogenesis (Suzuki et al, 2010),and can also impair cognitive function (Wisman et al, 2008). Interestingly, the rate of hippocampal neurogenesis has been shown to decline sharply with age (Ben Abdallah et al, 2010;Spalding et al, 2013)with a concomitant cognitive decline, and this is thought to be part of the pathophysiological basis of age-related dementia (Drapeau et al, 2003;Small et al, 2011;Seib et al, 2013).…”

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

“…The MWM was described in previous studies (Andringa et al, 2000;Wisman et al, 2008). Briefly, the pool dimensions were a diameter of 185 cm and a water depth of 30 cm, and the water temperature was 21° Celsius.…”