Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models DOI Creative Commons
Saige K. Power, Sridevi Venkatesan,

Sarah Qu

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Dec. 3, 2024

Abstract Background Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence compensation in Alzheimer’s disease (AD) focusing on the cholinergic innervation of layer 6 prefrontal cortex. Cholinergic pathways are vulnerable neuropathology AD and its preclinical models, their modulation deep cortex is essential attention executive function. Methods We functionally interrogated pyramidal neurons two models: a compound transgenic mouse model that permits optogenetically-triggered release endogenous acetylcholine rat closely recapitulates human trajectory AD. then tested impact therapeutic interventions further amplify compensated responses preserve typical kinetic profile signaling. Results In found compensatory upregulation functional above non-transgenic controls after onset pathology. To identify locus this enhanced signal, dissected key pre- post-synaptic components with pharmacological strategies. identified significant selective increase nicotinic receptor signalling cortical neurons. probe additional intervention adapted circuit, nicotinic-selective pro-cognitive treatments. Inhibition acetylcholinesterase but greatly distorted kinetics. Positive allosteric receptors, by contrast, retained rapid Conclusions demonstrate occurs within models. Promisingly, signal can be while preserving signature. Taken together, our work suggests mechanisms harnessed positive modulation, highlighting new direction cognitive treatment neuropathology.

Language: Английский

M2 receptors are required for spatiotemporal sequence learning in mouse primary visual cortex DOI

Susrita Sarkar,

Catalina Martinez Reyes,

Cambria M. Jensen

et al.

Journal of Neurophysiology, Journal Year: 2024, Volume and Issue: 131(6), P. 1213 - 1225

Published: April 17, 2024

Acetylcholine is a neurotransmitter that plays variety of roles in the central nervous system. It was previously shown blocking muscarinic receptors with nonselective antagonist prevents form experience-dependent plasticity termed "spatiotemporal sequence learning" mouse primary visual cortex (V1). Muscarinic signaling complex process involving combined activities five different G protein-coupled receptors, M1-M5, all which are expressed murine brain but differ from each other functionally and anatomical localization. Here we present electrophysiological evidence M2, not M1, required for spatiotemporal learning V1. We show male mice M2 highly neuropil V1, especially thalamorecipient layer 4, colocalizes soma subset somatostatin-expressing neurons deep layers. also expression higher monocular region V1 than it binocular amount potentiation similar both regions after stimulation does prevent plasticity. This work establishes new functional role M2-type processing temporal information demonstrates circuits modified by experience manner to circuits.

Language: Английский

Citations

6
Cortical acetylcholine dynamics are predicted by cholinergic axon activity and behavior state DOI Creative Commons
Erin Neyhart, Na Zhou, Brandon R. Munn

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(10), P. 114808 - 114808

Published: Oct. 1, 2024

Highlights•Bulk ACh release around cortical cholinergic axons can be observed in vivo•ACh levels scale with locomotion speed and pupil size•Sensor deconvolution allows evaluation of precise temporal dynamics•ACh activity predicted from axon behavioral variablesSummaryAcetylcholine (ACh) is thought to play a role driving the rapid, spontaneous brain-state transitions that occur during wakefulness; however, spatiotemporal properties these state changes are still unclear. We perform simultaneous imaging GRAB-ACh sensors, GCaMP-expressing basal forebrain axons, behavior address this question. high correlation between periods dilation. fluorescence could accurately axonal alone, local decreased at farther distances an axon. Deconvolution traces allowed us account for sensor kinetics emphasized rapid clearance small transients. trained model predict size running speed, which generalized well unseen data. These results contribute growing understanding timing spatial characteristics fast transitions.Graphical abstract

Language: Английский

Citations

4
Revealing hidden knowledge in amnestic mice DOI Open Access
Andrea Santi, Sharlen Moore,

Kelly Fogelson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Alzheimer's disease (AD) is a form of dementia in which memory and cognitive decline thought to arise from underlying neurodegeneration. These impairments, however, are transient when they first appear can fluctuate across progression. Here, we investigate the neural mechanisms fluctuations performance amnestic mice. We trained APP/PS1+ mice on an auditory go/no-go task that dissociated learning contingencies (knowledge) its more variable expression under reinforcement (performance). exhibited significant deficits compared control Using large-scale two-photon imaging 6,216 excitatory neurons 8 mice, found cortical networks were suppressed, less selective sensory cues, aberrant higher-order encoding reward prediction A small sub-population neurons, displayed opposite phenotype, reflecting potential compensatory mechanism. Volumetric analysis demonstrated concentrated near Aβ plaques. Strikingly, these reversed almost instantaneously probe (non-reinforced) trials performed as well providing evidence for intact stimulus-action knowledge despite ongoing performance. biologically-plausible model recapitulated results showed synaptic weights sensory-to-decision preserved (i.e. knowledge) poor was due inadequate contextual scaling impaired performance). Our suggest phenotype transient, contextual, endogenously reversible, with circuits retaining associations. Thus, commonly observed mouse models, potentially at early stages humans, relate drivers rather than degeneration traces.

Language: Английский

Citations

0
Saponin components in Polygala tenuifolia as potential candidate drugs for treating dementia DOI Creative Commons
Songzhe Li, Zhitao Hou, Ting Ye

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 10, 2024

This study aims to elucidate the intervention effects of saponin components from

Language: Английский

Citations

3
Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models DOI Creative Commons
Saige K. Power, Sridevi Venkatesan,

Sarah Qu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 13, 2023

Abstract Background Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence compensation in Alzheimer’s disease (AD) focusing on the cholinergic innervation of layer 6 prefrontal cortex. Cholinergic pathways are vulnerable neuropathology AD and its preclinical models, their modulation deep cortex is essential attention executive function. Methods We functionally interrogate pyramidal neurons two models: a compound transgenic mouse that permits optogenetically-triggered release endogenous acetylcholine rat closely recapitulates human trajectory AD. then tested impact therapeutic interventions further amplify compensated responses preserve typical kinetic profile signaling. Results In find potentially-compensatory upregulation functional above non-transgenic controls after onset pathology. To identify locus this enhanced signal, dissect key pre– post-synaptic components with pharmacological strategies. significant selective increase nicotinic receptor signalling cortical neurons. probe additional intervention adapted circuit, test nicotinic-selective pro-cognitive treatments. The inhibition acetylcholinesterase enhances but greatly distorts kinetics. Positive allosteric receptors, by contrast, retains rapid Conclusions demonstrate occurs within models. Promisingly, signal can be while preserving signature. Taken together, our work suggests compensatory mechanisms harnessed positive modulation, highlighting new direction cognitive treatment neuropathology.

Language: Английский

Citations

3
Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models DOI Creative Commons
Saige K. Power, Sridevi Venkatesan,

Sarah Qu

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Dec. 3, 2024

Abstract Background Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence compensation in Alzheimer’s disease (AD) focusing on the cholinergic innervation of layer 6 prefrontal cortex. Cholinergic pathways are vulnerable neuropathology AD and its preclinical models, their modulation deep cortex is essential attention executive function. Methods We functionally interrogated pyramidal neurons two models: a compound transgenic mouse model that permits optogenetically-triggered release endogenous acetylcholine rat closely recapitulates human trajectory AD. then tested impact therapeutic interventions further amplify compensated responses preserve typical kinetic profile signaling. Results In found compensatory upregulation functional above non-transgenic controls after onset pathology. To identify locus this enhanced signal, dissected key pre- post-synaptic components with pharmacological strategies. identified significant selective increase nicotinic receptor signalling cortical neurons. probe additional intervention adapted circuit, nicotinic-selective pro-cognitive treatments. Inhibition acetylcholinesterase but greatly distorted kinetics. Positive allosteric receptors, by contrast, retained rapid Conclusions demonstrate occurs within models. Promisingly, signal can be while preserving signature. Taken together, our work suggests mechanisms harnessed positive modulation, highlighting new direction cognitive treatment neuropathology.

Language: Английский

Citations

0