Cholinergic basal forebrain and hippocampal structure influence visuospatial memory in Parkinson’s disease

Berlot, Rok; Pirtošek, Zvezdan; Brezovar, Simon; Koritnik, Blaž; Teipel, Stefan J.; Grothe, Michel J.; Ray, Nicola

doi:10.1007/s11682-021-00481-0

Cited by 9 publications

(7 citation statements)

References 56 publications

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“…We therefore used immunostaining with an antibody to c-Fos to compare activity at T 0 with the effects of CLP and CLP + xanomeline on activity in several brain regions. Baseline expression of c-Fos was most pronounced in the hippocampus, a finding consistent with previous reports (Berlot et al 2022 ). At 48 h post-CLP c-Fos expression in this region was significantly lower than at T 0 (Fig.…”

Section: Resultssupporting

confidence: 92%

“…In particular, recent studies have demonstrated decreased activity in the basal forebrain cholinergic system of mice subjected to cecal ligation and puncture (CLP, the most commonly used animal model of sepsis (Zaghloul et al 2017 ; Yin et al 2023 ; Zhai et al 2017 ; Osuchowski et al 2018 ). This system, which is involved in altered executive functions in neurodegenerative disorders (Berlot et al 2022 ; Dwomoh et al 2022 ; Scarpa et al 2020 ), also contributes to immune dysfunction (Bricher Choque et al 2021 ; Zhai et al 2017 ; Lehner et al 2019 ; Munyaka et al 2014 ), one of the defining characteristics of sepsis (Singer et al 2016 ). In particular, Zhai et al used optogenetic stimulation to activate basal forebrain neurons that express choline acetyltransferase (ChAT, the enzyme that catalyzes the rate-limiting step in ACh biosynthesis) at very early time points post-CLP (Zhai et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Abraham,

Nedeljkovic-Kurepa,

Fernandes

et al. 2024

Mol Med

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Background The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. Methods In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline. Results At 48 h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα+ and ILβ+ neutrophils and ILβ+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline—treated and untreated post-CLP mice. Conclusion Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Abraham,

Nedeljkovic-Kurepa,

Fernandes

et al. 2024

Mol Med

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“…Additionally, hippocampal cholinergic innervation is also strongly depleted in PD dementia [ 76 ]. Now, considering the second major function of the memory-centered limbic system, the processing of spatial information, it has been found that PD related hippocampal alterations are associated with impaired spatial working memory, which can be explained by the essential role of the hippocampus and its connections in object-place memory [ 95 ].…”

Section: Discussionmentioning

confidence: 99%

“…In face of this detrimental symptom, extensive research has addressed pathological changes in the hippocampus. Morphological studies have reported reduced hippocampal volume in PD patients, whereby atrophy has inconsistently been reported in early-PD but becomes more pronounced with increasing disease duration and is strongly linked to cognitive decline including memory, spatial working memory, and language impairments [ 29 , 31 , 36 , 37 , 54 , 60 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. The severity of volume loss has also been found to be predictive of conversion to dementia [ 53 , 98 , 99 ].…”

Section: Regions Of the Limbic Systemmentioning

confidence: 99%

Imaging the Limbic System in Parkinson’s Disease—A Review of Limbic Pathology and Clinical Symptoms

et al. 2022

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The limbic system describes a complex of brain structures central for memory, learning, as well as goal directed and emotional behavior. In addition to pathological studies, recent findings using in vivo structural and functional imaging of the brain pinpoint the vulnerability of limbic structures to neurodegeneration in Parkinson’s disease (PD) throughout the disease course. Accordingly, dysfunction of the limbic system is critically related to the symptom complex which characterizes PD, including neuropsychiatric, vegetative, and motor symptoms, and their heterogeneity in patients with PD. The aim of this systematic review was to put the spotlight on neuroimaging of the limbic system in PD and to give an overview of the most important structures affected by the disease, their function, disease related alterations, and corresponding clinical manifestations. PubMed was searched in order to identify the most recent studies that investigate the limbic system in PD with the help of neuroimaging methods. First, PD related neuropathological changes and corresponding clinical symptoms of each limbic system region are reviewed, and, finally, a network integration of the limbic system within the complex of PD pathology is discussed.

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“…In particular, recent studies have demonstrated decreased activity in the basal forebrain cholinergic system of mice subjected to cecal ligation and puncture (CLP, the most commonly used animal model of sepsis ( 2 , 5 – 7 ). This system, which is involved in altered executive functions in neurodegenerative disorders ( 8 – 10 ), also contributes to immune dysfunction ( 4 , 6 , 11 , 12 ), one of the defining characteristics of sepsis ( 1 ). In particular, Zhai et al used optogenetic stimulation to activate basal forebrain neurons that express choline acetyltransferase (ChAT, the enzyme that catalyzes the rate-limiting step in Ach biosynthesis) at very early time points post-CLP ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

M1 Cholinergic Signaling Modulates Cytokine Levels and Splenocyte Sub-Phenotypes Following Cecal Ligation and Puncture

Abraham,

Nedeljkovic-Kurepa,

Fernandes

et al. 2023

Preprint

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Background: The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1/M4 muscarinic acetylcholine (ACh) receptor (M1/M4AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1/M4AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. Methods: Basal forebrain cholinergic activity (immunostaining), serum cytokine/chemokine levels (ELISA) and splenocyte subtypes (flow cytometry) were examined at baseline and following CLP in male C57BL/6 male mice. Rersults: At 48hrs. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFa+ and ILb+ neutrophils and ILb+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline, a central-acting M1AChR agonist, activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. The effects of CLP on percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline - treated and untreated post-CLP mice. Conclusion: Our findings indicate that M1/M4AChR-mediated responses modulate CLP-induced alterations in the distribution of some, but not all, leukocyte phenotypes and certain cytokines and chemokines.

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Cholinergic basal forebrain and hippocampal structure influence visuospatial memory in Parkinson’s disease

Cited by 9 publications

References 56 publications

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Imaging the Limbic System in Parkinson’s Disease—A Review of Limbic Pathology and Clinical Symptoms

M1 Cholinergic Signaling Modulates Cytokine Levels and Splenocyte Sub-Phenotypes Following Cecal Ligation and Puncture

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