RESUMO
BACKGROUND: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. OBJECTIVE: To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn. METHODS: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions. RESULTS: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. CONCLUSIONS: This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.
Assuntos
Doença de Alzheimer , Demência , Doença de Parkinson , Humanos , Masculino , Camundongos , Animais , alfa-Sinucleína/metabolismo , Doença de Parkinson/patologia , Córtex Pré-Frontal/patologiaRESUMO
Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. To investigate the consequences of α-syn pathology in the cortex, we injected human α-syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.
RESUMO
Dopamine in the prefrontal cortex can be disrupted in human disorders that affect cognitive function such as Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia. Dopamine has a powerful effect on prefrontal circuits via the D1-type dopamine receptor (D1DR). It has been proposed that prefrontal dopamine has "inverted U-shaped" dynamics, with optimal dopamine and D1DR signaling required for peak cognitive function. However, the quantitative relationship between prefrontal dopamine and cognitive function is not clear. Here, we conducted a meta-analysis of published manipulations of prefrontal dopamine and the effects on working memory, a high-level executive function in humans, primates, and rodents that involves maintaining and manipulating information over seconds to minutes. We reviewed 646 articles and found that 75 studies met criteria for inclusion. Our quantification of effect sizes for dopamine, D1DRs, and behavior revealed a negative quadratic slope. This is consistent with the proposed inverted U-shape of prefrontal dopamine and D1DRs and working memory performance, explaining 10% of the variance. Of note, the inverted quadratic fit was much stronger for prefrontal D1DRs alone, explaining 26% of the variance, compared to prefrontal dopamine alone, explaining 10% of the variance. Taken together, these data, derived from a variety of manipulations and systems, demonstrate that optimal prefrontal dopamine signaling is linked with higher cognitive function. Our results provide insight into the fundamental dynamics of prefrontal dopamine, which could be useful for pharmacological interventions targeting prefrontal dopaminergic circuits, and into the pathophysiology of human brain disease. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Assuntos
Dopamina , Esquizofrenia , Animais , Dopamina/farmacologia , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/metabolismoRESUMO
One hallmark feature of Parkinson's disease (PD) is Lewy body pathology associated with misfolded alpha-synuclein. Previous studies have shown that striatal injection of alpha-synuclein preformed fibrils (PFF) can induce misfolding and aggregation of native alpha-synuclein in a prion-like manner, leading to cell death and motor dysfunction in mouse models. Here, we tested whether alpha-synuclein PFFs injected into the medial prefrontal cortex results in deficits in interval timing, a cognitive task which is disrupted in human PD patients and in rodent models of PD. We injected PFF or monomers of human alpha-synuclein into the medial prefrontal cortex of mice pre-injected with adeno-associated virus (AAV) coding for overexpression of human alpha-synuclein or control protein. Despite notable medial prefrontal cortical synucleinopathy, we did not observe consistent deficits in fixed-interval timing. These results suggest that cortical alpha-synuclein does not reliably disrupt fixed-interval timing.