Biology subjects

Coulson, E. J.

Publications and source records attributed to Coulson, E. J..

4 recordsLinked to original sources

bioRxiv2024

Cholinergic basal forebrain neurons regulate vascular dynamics and cerebrospinal fluid flux

Waste from the brain is cleared via a cerebrospinal fluid (CSF) exchange pathway, the dysfunction of which is suggested to underlie the pathogenesis of many brain conditions. Coherent cerebrovascular oscillation that couples with pulsatile CSF inflow is suggested to drive the fluid flux. However, how this coupling is regulated, whether it mediates waste clearance, and why fluid flux is impaired in disease status remain unclear. Here we show that vascular-CSF coupling correlates with cortical cholinergic activity in non-demented aged humans. The causal role of basal forebrain cholinergic neurons that project to the cortex is then verified by specific lesioning in mice, revealing correlated changes in vascular-CSF coupling, arterial pulsation and glymphatic flux, which can be altered by an acetylcholinesterase inhibitor. These results suggest a neurovascular mechanism by which CSF/glymphatic flux is modulated by cholinergic neuronal activity, thereby providing a conceptual basis for the development of diagnostics and treatments for glymphatic dysfunction.

neuroscience↗

bioRxiv2022

Stimulation of the muscarinic receptor M4 activates quiescent neural precursor cells and ameliorates medial septum cholinergic lesion-induced impairments in adult hippocampal neurogenesis

Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis and hippocampus-dependent cognitive and mood-related functions. However, the contribution of basal forebrain medial septum (MS) and diagonal band of Broca (DBB) cholinergic neurons that innervate the hippocampus and the identity of the cholinergic receptor(s) that regulate the production and maturation of new neurons are not completely understood. Using a targeted, selective ablation approach, we show that MS/DBB cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. We demonstrate that the muscarinic acetycholine receptor subtype M4 (M4 mAChR) is expressed on a population of quiescent neural precursor cells (NPCs) and that its pharmacological stimulation via intra-hippocampal or systemic administration of M4-selective modulators leads to their activation, thereby enhancing neurogenesis in vivo. Furthermore, we show that the activation of M4 mAChR-expressing quiescent NPCs ameliorates the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis. In contrast, the impairment in the morphological maturation of adult-born neurons due to MS/DBB cholinergic neuron loss is further exacerbated by the systemic administration of an M4-selective allosteric potentiator. These findings reveal novel and stage-specific roles of cholinergic signaling in regulating adult hippocampal neurogenesis. They also uncouple the positive role of selective M4 potentiators in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic dysfunction. Significance statementCholinergic signaling plays an important role in the regulation of adult hippocampal neurogenesis and cognitive function, with impairments in these processes reported as early pathogenic events in age-related dementia. Here, we uncover the presence of cholinergic-responsive hippocampal precursor cells that are are directly activated by selective stimulation of the muscarinic receptor subtype M4. Furthermore, M4-mediated stimulation rescues the decrease in the level of hippocampal neurogenesis following the sepal-hippocampal cholinergic neuron loss. We also reveal that septal-hippocampal cholinergic dysfunction impairs the structural maturation of hippocampal adult-born neurons, an effect which is further exacerbated by M4 receptor modulators. These findings reveal stage-specific roles of cholinergic signaling in regulating functionally relevant adult hippocampal neurogenesis.

neuroscience↗

bioRxiv2020

Cholinergic basal forebrain degeneration due to obstructive sleep apnoeaincreases Alzheimer's pathology in mice

Epidemiological studies indicate that obstructive sleep apnoea is a strong risk factor for the development of Alzheimers disease but the mechanisms of the risk remain unclear. We developed a method of modelling obstructive sleep apnoea in mice that replicates key features of human obstructive sleep apnoea: altered breathing during sleep, sleep disruption, moderate intermittent hypoxemia and cognitive impairment. When we induced obstructive sleep apnoea in a familial Alzheimers disease model, the mice displayed exacerbation of cognitive impairment and pathological features of Alzheimers disease, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the neurodegeneration was mediated by the oxygen-sensitive p75 neurotrophin receptor and hypoxia inducible factor 1 alpha activity. Furthermore, restoring blood oxygen levels during sleep to prevent intermittent hypoxia prevented the pathological changes induced by the OSA. These findings provide a signalling mechanism by which obstructive sleep apnoea induces cholinergic basal forebrain degeneration and could thereby increase the risk of developing Alzheimers disease, as well as providing a rationale for testing a range of possible prophylactic treatment options for people with obstructive sleep apnoea and hypoxia including increased compliance of continuous positive airway pressure therapy.

neuroscience↗

bioRxiv2020

A validated quantitative method for the assessment of neuroprotective barrier impairment in neurodegenerative disease models

The blood brain barrier (BBB) and blood spinal cord barrier (BSCB) are highly specialised structures that limit molecule entry from the blood and maintain homeostasis within the central nervous system (CNS). BBB and BSCB breakdown are associated with multiple neurodegenerative diseases. Given the key role of neuroprotective barrier impairment in neurodegeneration, it is important to identify an effective quantitative method to assess barrier integrity in animal models. In the present study, we developed and validated a quantitative method for assessing BBB and BSCB integrity using sodium fluorescein, a compound that outperformed other fluorescent dyes. We demonstrated using this method that multiple CNS regions progressively increase in permeability in models of Huntingtons disease and amyotrophic lateral sclerosis, while biphasic disruption occurred in a mouse model of Alzheimers disease with disease progression. Collectively, we report a quantitative fluorometric marker with validated reproducible experimental methods, that allows the effective assessment of BBB and BSCB integrity in animal models. This method could be useful to further the understanding of the contribution of these neuroprotective barriers to neurodegeneration processes.

neuroscience↗