Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation at the goal location

Jarzebowski, Przemyslaw; Tang, Clara Sze-Man; Paulsen, Ole; Hay, Y. Audrey

doi:10.1101/2020.05.14.096784

Cited by 5 publications

(11 citation statements)

References 58 publications

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“…Jarzebowski et al stimulated septal cholinergic neurons at the goal zone in an appetitive Y-maze task, which slowed spatial learning. This coincided with a significant reduction in sharp wave ripple (SWR) incidence in hippocampal CA1 at the goal zone in rewarded trials, where SWRs most often occurred 46 . SWRs are an important oscillatory pattern in the hippocampus that are closely linked with (spatial) learning and memory.…”

Section: Discussionmentioning

confidence: 84%

“…One of these studies observed that higher hippocampal cholinergic activity was correlated with lower consolidation capacities and suggested that the post-training electrical MSDB stimulation improved memory through non-cholinergic elements and that septohippocampal cholinergic activation is more likely to facilitate memory processes prior to consolidation 23 Our study represents the first study where selective cholinergic MSDB stimulation resulted in improved learning and (reference) memory. Very recently, two other studies have investigated the effect of selective cholinergic MSDB stimulation on memory 46,47 . Both of these studies used optogenetics to stimulate cholinergic MSDB neurons at a very specific time during the behavioural task.…”

Section: Selective Cholinergic Neuronal Msdb Stimulation During Train...mentioning

confidence: 99%

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Selective cholinergic stimulation of the medial septum-diagonal band of Broca via DREADDs improves spatial learning in healthy rats

Missault

Waegenaere

Kosten

et al. 2022

Preprint

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The septohippocampal pathway plays an important role in learning and memory. It projects from the medial septum-vertical limb of the diagonal band of Broca (MSDB) to the hippocampus and provides the latter with its main cholinergic innervation. To assess the importance of cholinergic selectivity and timing of MSDB stimulation in modulating learning and memory, we directly compared the effects of several MSDB stimulation strategies in healthy rats. We evaluated the effects of DREADD-mediated selective cholinergic neuronal MSDB stimulation and nonselective neuronal MSDB stimulation on spatial learning and memory in the appetitive radial arm maze and on resting-state brain networks using resting-state functional MRI. DREADDs were activated with the novel DREADD agonist J60. Selective cholinergic MSDB stimulation during, but not after, radial arm maze training improved spatial learning compared with J60-treated sham rats and had no effect on working memory or reversal learning. J60-treated sham rats had a worse working memory than saline-treated sham rats during the reversal phase of the radial arm maze task, suggesting an adverse effect of chronic use of J60. Nonselective MSDB stimulation during training resulted in a loss of appetite and exclusion from the radial arm maze training. Acute selective cholinergic and nonselective MSDB stimulation induced decreased functional connectivity (FC) in the default mode-like network. In addition, acute nonselective MSDB stimulation resulted in increased intrahippocampal FC, while selective cholinergic MSDB stimulation led to globally increased FC with the nucleus accumbens. While the combined effect of radial arm maze learning and the necessary chronic food restriction with or without chronic MSDB stimulation had no observable effect on resting-state networks, chronic food restriction alone globally increased FC in the brain.

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Section: Discussionmentioning

confidence: 84%

Section: Selective Cholinergic Neuronal Msdb Stimulation During Train...mentioning

confidence: 99%

Selective cholinergic stimulation of the medial septum-diagonal band of Broca via DREADDs improves spatial learning in healthy rats

Missault

Waegenaere

Kosten

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Cholinergic inputs from the medial septum are thought to play a key role in this process (Teles-Grilo Ruivo and Mellor, 2013). Typically, ACh levels in the rodent hippocampus are high during exploratory behaviour and decrease substantially during immobility or slow-wave sleep (Betterton et al, 2017; Fisahn et al, 1998; Jarzebowski et al, 2021; Zhang et al, 2021). Both these phases are required for the acquisition and consolidation of learnt behaviours (Buzsaki, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…This is typically followed by an offline state characterised by sharp-wave ripples (SWRs) during immobility and slow-wave sleep, a time when ACh is low or absent (Zhang et al, 2021). Indeed, ACh has been shown to directly inhibit SWRs, allowing an animal to switch between a high-ACh, online attentive processing state dominated by low-gamma oscillations and a low-ACh, offline memory consolidation state dominated by SWRs (Jarzebowski et al, 2021; Zhang et al, 2021). This switch in the dynamics of hippocampal function has been proposed as a two-stage process of memory trace formation (Buzsaki, 1989).…”

Section: Introductionmentioning

confidence: 99%

Cholinergic stimulation modulates the functional composition of CA3 cell types in the hippocampus

Puhl

Wefelmeyer

Burrone

2022

Preprint

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The functional heterogeneity of hippocampal CA3 pyramidal neurons has emerged as a key aspect of circuit function. Here, we explored the effects of long-term cholinergic activity on the functional heterogeneity of CA3 pyramidal neurons in organotypic slices. Application of agonists to either acetylcholine receptors (AChRs) generally, or muscarinic AChRs (mAChRs) specifically, induced robust increases in network activity in the low-gamma range. Prolonged AChR stimulation for 48 hrs uncovered a population of hyperadapting CA3 pyramidal neurons that typically fired a single, early action potential in response to current injection. Although these neurons were present in control networks, their proportions were dramatically increased following long-term cholinergic activity. Characterised by the presence of a strong M-current, the hyperadaptation phenotype was abolished by acute application of either M-channel antagonists or the re-application of AChR agonists. We conclude that long-term mAChR activation modulates the intrinsic excitability of a subset of CA3 pyramidal cells, uncovering a highly plastic cohort of neurons that are sensitive to chronic ACh modulation. Our findings provide evidence for the activity-dependent plasticity of functional heterogeneity in the hippocampus.

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“…Further, recent publications demonstrate that BFCN loss underpins the gait dysfunction in Parkinson's disease (PD), suggesting that therapeutically targeting the cholinergic system could also address certain motor aspects of neurodegenerative disease 4,[50][51] . Recent evidence also indicates that correcting the functional deficit in the cholinergic system, thus amplifying the physiologic release of acetylcholine is likely to be more effective than the conventional approach of compensating for BFCN dysfunction by delaying clearance of released acetylcholine with cholinesterase inhibitors 5 .…”

mentioning

confidence: 99%

Preclinical and Clinical Studies of p38α MAP kinase inhibition to Treat Basal Forebrain Cholinergic Dysfunction and Degeneration

Nixon

Jiang

Gomperts

et al. 2021

Preprint

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The endosome-associated protein Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α kinase is a Rab-5 activator, we hypothesized that inhibition of this kinase held potential as an approach to treat diseases associated with BFCN loss. Herein we report that treatment with an oral small molecule p38α kinase inhibitor reversed pathological disease progression in the basal forebrain in a mouse model that develops BFCN degeneration. Further, the preclinical results were successfully translated to the clinic, with improvement of clinical outcomes associated with cholinergic function in a clinical study in dementia with Lewy bodies (DLB), a disease in which BFCN dysfunction and degeneration is the primary driver of disease expression. The findings both advances a novel approach to treating DLB and validates the translational platform that provided the mechanistic rationale for advancing that approach.

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Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation at the goal location

Cited by 5 publications

References 58 publications

Selective cholinergic stimulation of the medial septum-diagonal band of Broca via DREADDs improves spatial learning in healthy rats

Selective cholinergic stimulation of the medial septum-diagonal band of Broca via DREADDs improves spatial learning in healthy rats

Cholinergic stimulation modulates the functional composition of CA3 cell types in the hippocampus

Preclinical and Clinical Studies of p38α MAP kinase inhibition to Treat Basal Forebrain Cholinergic Dysfunction and Degeneration

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