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Basal forebrain control of wakefulness and cortical rhythms.

ABSTRACT: Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state.

SUBMITTER: Anaclet C

PROVIDER: S-EPMC4659943 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Basal forebrain control of wakefulness and cortical rhythms.

Anaclet Christelle C Pedersen Nigel P NP Ferrari Loris L LL Venner Anne A Bass Caroline E CE Arrigoni Elda E Fuller Patrick M PM

Nature communications 20151103

Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or ...[more]

PMID: 26524973

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Project description:Alzheimer's disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer's degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer's disease pathogenesis.

Dataset Information

Basal forebrain control of wakefulness and cortical rhythms.

Publications

Basal forebrain control of wakefulness and cortical rhythms.

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