Regulation of Cognitive Processing by Hippocampal Cholinergic Tone

Abstract

Cholinergic dysfunction has been associated with cognitive abnormalities in a variety of neurodegenerative and neuropsychiatric diseases. Here we tested how information processing is regulated by cholinergic tone in genetically modified mice targeting the vesicular acetylcholine transporter (VAChT), a protein required for acetylcholine release. We measured long-term potentiation of Schaffer collateral-CA1 synapses in vivo and assessed information processing by using a mouse touchscreen version of paired associates learning task (PAL). Acquisition of information in the mouse PAL task correlated to levels of hippocampal VAChT, suggesting a critical role for cholinergic tone. Accordingly, synaptic plasticity in the hippocampus in vivo was disturbed, but not completely abolished, by decreased hippocampal cholinergic signaling. Disrupted forebrain cholinergic signaling also affected working memory, a result reproduced by selectively decreasing VAChT in the hippocampus. In contrast, spatial memory was relatively preserved, whereas reversal spatial memory was sensitive to decreased hippocampal cholinergic signaling. This work provides a refined roadmap of how synaptically secreted acetylcholine influences distinct behaviors and suggests that distinct forms of cognitive processing may be regulated in different ways by cholinergic activity.

Cholinergic Regulation of hnRNPA2/B1 Translation by M1 Muscarinic Receptors

“…All animals with targeted elimination of VAChT were generated using the VAChT flox/flox mouse described by Martins-Silva et al (2011). To eliminate VAChT from the forebrain, VAChT flox/flox mice were crossed with C57BL/6J-Tg(Nkx2-1-cre)2Sand/J mice (Xu et al, 2008) to generate VAChT Nkx2.1-Cre-flox/flox (Al-Onaizi et al, 2016). To eliminate VAChT from the striatum, the VAChT flox/flox mice were crossed with D2-Cre mice (Drd2, line ER44) to generate VAChT D2-Cre-flox/flox .…”

“…Injection of AAV virus was described previously (Al-Onaizi et al, 2016). Briefly, mice were anesthetized with ketamine (100 mg/kg) and xylazine (25 mg/kg), and 1 l (titer of ϳ1013 Gene Copies/ml) of AAV8-GFP-Cre or control virus (AAV8-GFP, Vector BioLabs) was injected into the medial septum (0.98 anteroposterior, 0.1 laterolateral, and 4.1 dorsoventral) of VAChT flox/flox mice.…”

Decreased vesicular acetylcholine transporter related to memory deficits in epilepsy: A [18F] VAT positron emission tomography brain imaging study

“…In Alzheimer's disease patients, level of VAChT declined in prefrontal cortex and temporal cortex . In genetically modified mice targeting VAChT, information acquisition correlated to level of hippocampal VAChT and selective decreasing hippocampal VAChT resulted in synaptic plasticity disturbance and working memory impairment . Overexpression of VAChT enhances dendritic complexity of adult‐born hippocampal neurons and improves acquisition of spatial memory during aging …”

“…27 In genetically modified mice targeting VAChT, information acquisition correlated to level of hippocampal VAChT and selective decreasing hippocampal VAChT resulted in synaptic plasticity disturbance and working memory impairment. 28 Overexpression of VAChT enhances dendritic complexity of adult-born hippocampal neurons and improves acquisition of spatial memory during aging. 29 In our study, decline of VAChT in the epilepsy group and a positive correlation between VAChT level and memory function were found in most sectors of cholinergic pathway, which indicates a crucial role of cholinergic dysfunction in epilepsy-associated cognitive deficits.…”

Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress

“…Changes in VAChT expression and function have a direct influence on the amount of ACh released from nerve terminals (17,18,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Notably, decreased VAChT expression affects cholinergic signaling (17,18,20,23,25,26,30,31,36,37,(38)(39)(40)(41)(42)(43)(44)(45)(46)(47), suggesting that VAChT is the unique transporter for ACh. Importantly, VAChT deletion disturbs ACh storage and release but does not kill cholinergic neurons (25,26,38).…”