Partial lesion of the nigrostriatal dopamine pathway in rats impairs egocentric learning but not spatial learning or behavioral flexibility.

Seip-Cammack, Katharine M.; Young, James J.; Young, Megan E.; Shapiro, Matthew L.

doi:10.1037/bne0000189

Cited by 10 publications

(7 citation statements)

References 78 publications

(106 reference statements)

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“…These regions are innervated by noradrenergic terminals originating from the locus ceruleus (LC) [27,28], dopaminergic terminals originating from the substantia nigra (pars compacta SNc), and the ventral tegmental area (VTA) [29][30][31]. Deficits in norepinephrine (NE) and dopamine (DA) signaling in these three key areas have been identified as contributors to deficits in domains of EF that lead to non-strategic, disadvantageous decisionmaking [29][30][31][32][33][34][35][36][37][38].…”

Section: What Neural Areas and Mechanisms Of Pd Are Probed By The Igt?mentioning

confidence: 99%

“…Thus, it is plausible that some level of nigrostriatal DA loss will diminish DA signaling in the PFC, thereby influencing components of EF and specifically decision-making [35,36]. In fact, PD animal model results support this possibility, as loss of DA to levels less than necessary for motor impairment adversely impact responsivity to salient cues or reversal learning [26,33]. Therefore, loss of nigrostriatal neurons in the prodromal or early stages of PD could play a pivotal role in facilitating EF deficits adversely affecting decision-making before dopamine replacement therapy has been initiated.…”

Section: What Neural Areas and Mechanisms Of Pd Are Probed By The Igt?mentioning

confidence: 99%

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Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

Salvatore

Soto

Alphonso

et al. 2021

JPD

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Up to 23% of newly diagnosed, non-demented, Parkinson’s disease (PD) patients experience deficits in executive functioning (EF). In fact, EF deficits may occur up to 39-months prior to the onset of motor decline. Optimal EF requires working memory, attention, cognitive flexibility, and response inhibition underlying appropriate decision-making. The capacity for making strategic decisions requires inhibiting imprudent decisions and are associated with noradrenergic and dopaminergic signaling in prefrontal and orbitofrontal cortex. Catecholaminergic dysfunction and the loss of noradrenergic and dopaminergic cell bodies early in PD progression in the aforementioned cortical areas likely contribute to EF deficits resulting in non-strategic decision-making. Thus, detecting these deficits early in the disease process could help identify a significant portion of individuals with PD pathology (14–60%) before frank motor impairment. A task to evaluate EF in the domain of non-strategic decision-making might be useful to indicate the moderate loss of catecholamines that occurs early in PD pathology prior to motor decline and cognitive impairment. In this review, we focus on the potential utility of the Iowa Gambling Task (IGT) for this purpose, given significant overlap between in loss of dopaminergic and noradrenergic cells bodies in early PD and the deficits in catecholamine function associated with decreased EF. As such, given the loss of catecholamines already well-underway after PD diagnosis, we evaluate the potential utility of the IGT to identify the risk of therapeutic non-compliance and a potential companion approach to detect PD in premotor stages.

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Section: What Neural Areas and Mechanisms Of Pd Are Probed By The Igt?mentioning

confidence: 99%

Section: What Neural Areas and Mechanisms Of Pd Are Probed By The Igt?mentioning

confidence: 99%

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

Salvatore

Soto

Alphonso

et al. 2021

JPD

View full text Add to dashboard Cite

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“…In laboratory animals, dopamine terminal region was a critical determinant of whether reversal learning was impacted by dopamine lesions. Lesions of the DLS did not impact reversal learning (Seip-Cammack et al, 2017) and is consistent with the observations that optogenetic stimulation of DLS dopamine terminals did not support reversal learning (van der Merwe et al, 2021). These reports may not be surprising, given the important role of DLS dopamine in supporting actions that are insensitive and inflexible to changes in outcome value and contingency (i.e., habitual behaviour).…”

Section: Dopamine and Reversal Learningsupporting

confidence: 87%

The Effects of Repeated Dopamine D2 Receptor Antagonism on D2 Receptor Expression and Behavioural Inflexibility

Highgate¹

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Background: Reversal learning has been shown to improve as a function of dopamine D2 receptor expression, and manipulations that downregulated D2 expression also impaired behavioural flexibility. The possibility remains that an upregulation may facilitate reversal learning. Further, D2 receptor expression and reversal learning were compromised following repeated methamphetamine exposure. It stands to reason that restoration of receptor expression following methamphetamine exposure might prevent this impairment from occurring. Objectives: Develop a procedure for measuring reversal learning and determine whether repeated D2 receptor antagonism increases D2 receptor expression and improves behavioural flexibility in rats. Further, the possibility that this treatment would ameliorate behavioural inflexibility produced by prior methamphetamine exposure was examined. Methods: A task was developed to measure reversal learning. I systematically replicated an existing procedure, but then developed a novel procedure that focused on identifying a reasonable criterion for visual discrimination. To do this, male Sprague Dawley rats completed 25 days of visual discrimination. Various criteria requiring different levels of accuracy and persistence were retrospectively applied to the data and a single criterion was selected from these. The procedure was then extended to include three reversal tasks. In the next study, male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D2 antagonist, eticlopride (0.0 or 0.3 mg/kg/day, IP, 14 days). Three days after treatment, whole-brain (minus olfactory bulbs and cerebellum) dopamine D2 receptor expression was measured using flow cytometry. Another cohort was exposed to the same regimen between the second and third reversal task to determine whether this treatment improved reversal learning. The final study was then conducted, the only difference from the previous study being that methamphetamine (0.0mg/kg or 2.0mg/kg, SC, 4 injections, 2 hours apart) was administered the day before eticlopride treatment commenced in order to produce behavioural inflexibility. Results: The criterion developed for the acquisition of visual discrimination was adopted for several reasons. First, the entire sample was able to meet the criterion. Second, the number of days to acquisition was equivalent irrespective of which visual cue served as the discriminative stimulus. Finally, accuracy was persistent both within and between test sessions. Importantly, therefore, these criteria eliminated confounds that might otherwise have been expected to impact reversal learning performance. The adjunct reversal tasks were typically completed within 2-5 test days, which was important since neuroadaptations can revert over time, and individual differences in performance were consistent across tasks. As expected, eticlopride treatment increased D2 receptor expression and improved reversal learning. Further, this improvement was predicted by baseline behavioural flexibility measures, such that, the improvement produced by repeated eticlopride treatment preferentially mpacted rats that were less behaviourally flexible prior to treatment. Methamphetamine treatment impaired reversal learning, but this impairment was prevented by repeated eticlopride treatment. Conclusions: Choice of criterion impacts behavioural performance in visual discrimination learning. D2 receptor expression is also a critical determinant of behavioural flexibility, irrespective of whether the discriminative stimulus is visual or spatial. Further, pre-existing, or experimentally produced behavioural inflexibility is sensitive to a treatment that upregulated D2 expression. Collectively, these findings support the critical role of D2 expression in reversal learning and suggest it is an effective target for facilitating behavioural flexibility.

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“…These deficits are present both in ON and OFF dopaminergic medication. Interestingly, patients with ICD seem to be less susceptible to making impulsive responses than patients without ICD in motor action tasks, suggesting that addictive behaviors in this subset of patients would not be related to increased impulsive action [ 91 ].…”

Section: Overview Of Neuropsychiatric and Cognitive Deficits In Pdmentioning

confidence: 99%

Neuropsychiatric and Cognitive Deficits in Parkinson’s Disease and Their Modeling in Rodents

et al. 2021

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Parkinson’s disease (PD) is associated with a large burden of non-motor symptoms including olfactory and autonomic dysfunction, as well as neuropsychiatric (depression, anxiety, apathy) and cognitive disorders (executive dysfunctions, memory and learning impairments). Some of these non-motor symptoms may precede the onset of motor symptoms by several years, and they significantly worsen during the course of the disease. The lack of systematic improvement of these non-motor features by dopamine replacement therapy underlines their multifactorial origin, with an involvement of monoaminergic and cholinergic systems, as well as alpha-synuclein pathology in frontal and limbic cortical circuits. Here we describe mood and neuropsychiatric disorders in PD and review their occurrence in rodent models of PD. Altogether, toxin-based rodent models of PD indicate a significant but non-exclusive contribution of mesencephalic dopaminergic loss in anxiety, apathy, and depressive-like behaviors, as well as in learning and memory deficits. Gene-based models display significant deficits in learning and memory, as well as executive functions, highlighting the contribution of alpha-synuclein pathology to these non-motor deficits. Collectively, neuropsychiatric and cognitive deficits are recapitulated to some extent in rodent models, providing partial but nevertheless useful options to understand the pathophysiology of non-motor symptoms and develop therapeutic options for these debilitating symptoms of PD.

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Partial lesion of the nigrostriatal dopamine pathway in rats impairs egocentric learning but not spatial learning or behavioral flexibility.

Cited by 10 publications

References 78 publications

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson’s Disease?

The Effects of Repeated Dopamine D2 Receptor Antagonism on D2 Receptor Expression and Behavioural Inflexibility

Neuropsychiatric and Cognitive Deficits in Parkinson’s Disease and Their Modeling in Rodents

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