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The cholinergic system in the brain plays crucial roles in regulating sensory and motor functions as well as cognitive behaviors by modulating neuronal activity. Understanding the organization of the cholinergic system requires a complete map of cholinergic neurons and their axon arborizations throughout the entire brain at the level of single neurons. Here, we report a comprehensive whole-brain atlas of the cholinergic system originating from various cortical and subcortical regions of the mouse brain. Using genetically labeled cholinergic neurons together with whole-brain reconstruction of optical images at 2-μm resolution, we obtained quantification of the number and soma volume of cholinergic neurons in 22 brain areas. Furthermore, by reconstructing the complete axonal arbors of fluorescently labeled single neurons from a subregion of the basal forebrain at 1-μm resolution, we found that their projections to the forebrain and midbrain showed neuronal subgroups with distinct projection specificity and diverse arbor distribution within the same projection area. These results suggest the existence of distinct subtypes of cholinergic neurons that serve different regulatory functions in the brain and illustrate the usefulness of complete reconstruction of neuronal distribution and axon projections at the mesoscopic level.

Basal forebrain cholinergic neurons mature in adolescence coinciding with development of adult cognitive function. Preclinical studies using the rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55) reveal persistent increases of brain neuroimmune genes that are associated with cognitive dysfunction. Adolescent intermittent ethanol exposure also reduces basal forebrain expression of choline acetyltransferase (ChAT), an enzyme critical for acetylcholine synthesis in cholinergic neurons similar to findings in the post-mortem human alcoholic basal forebrain. We report here that AIE decreases basal forebrain ChAT+IR neurons in both adult female and male Wistar rats following early or late adolescent ethanol exposure. In addition, we find reductions in ChAT+IR somal size as well as the expression of the high-affinity nerve growth factor (NGF) receptor tropomyosin receptor kinase A (TrkA) and the low-affinity NGF receptor p75NTR, both of which are expressed on cholinergic neurons. The decrease in cholinergic neuron marker expression was accompanied by increased phosphorylation of NF-κB p65 (pNF-κB p65) consistent with increased neuroimmune signaling. Voluntary wheel running from P24 to P80 prevented AIE-induced cholinergic neuron shrinkage and loss of cholinergic neuron markers (i.e., ChAT, TrkA, and p75NTR) as well as the increase of pNF-κB p65 in the adult basal forebrain. Administration of the anti-inflammatory drug indomethacin (4.0 mg/kg, i.p prior to each ethanol exposure) during AIE also prevented the loss of basal forebrain cholinergic markers and the concomitant increase of pNF-κB p65. In contrast, treatment with the proinflammatory immune activator lipopolysaccharide (1.0 mg/kg, i.p. on P70) caused a loss of cholinergic neuron markers that was paralleled by increased pNF-κB p65 in the basal forebrain. These novel findings are consistent with AIE causing lasting activation of the neuroimmune system that contributes to the persistent loss of basal forebrain cholinergic neurons in adulthood.

Background Dysfunctional basal forebrain (BF) connectivity contributes to primary insomnia (PI). This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) modulates BF functional connectivity (FC) in patients with PI and whether baseline FC predicts taVNS treatment response. Methods Seventy patients with PI were randomized to real or sham taVNS for 4 weeks. Clinical assessments—including Pittsburgh Sleep Quality Index (PSQI], Insomnia Severity Index (ISI] and Zung’s Self-Rating Anxiety (SAS], and Depression Scale (SDS)—and resting-state fMRI data were collected at baseline and after treatment. FC of the bilateral BF subregions (Ch_123, Ch_4) was analyzed, and pre-to-post intervention changes in FC and clinical scores were compared between groups. Baseline FC was used to predict treatment response using a support vector regression (SVR) model, validated on an independent dataset. Results Sixty-seven patients completed the study (33 real taVNS, 34 sham taVNS). Changes in clinical outcomes showed that real taVNS significantly reduce PSQI, ISI, and SAS scores compared to sham. FC analysis revealed reduced connectivity between bilateral BF and areas involved in visual (superior occipital gyrus, SOG; middle occipital gyrus, MOG; fusiform gyrus, FFG), somatosensory (supplementary motor area, SMA) cortex and medial prefrontal cortex (mPFC) after taVNS treatment. Reduced FC between bilateral BF and left MOG correlated positively with ISI improvement ( r  = 0.490, p  = 0.008, Bonferroni correction). The SVR model effectively predicted treatment response based on BF-visual circuit connectivity ( r  = 0.520, p  = 0.0014, 5000 permutation test) and generalized well to an independent dataset ( r  = 0.443, p  = 0.0354, 5000 permutation test). Conclusions Our findings suggest that taVNS may alleviate symptoms of primary insomnia through modulation of basal forebrain connectivity with visual, sensorimotor, and medial prefrontal cortical regions. Preliminary investigations indicate that baseline functional connectivity in the BF-visual circuit could represent a candidate biomarker for taVNS response, potentially informing personalized treatment strategies. Trial registration The study was registered with the China Clinical Trial Registry (Clinical Trial No. ChiCTR1900022535).

Brain waste is cleared via a cerebrospinal fluid (CSF) pathway, the glymphatic system, whose dysfunction may underlie many brain conditions. Previous studies show coherent vascular oscillation, measured by blood oxygenation level-dependent (BOLD) fMRI, couples with CSF inflow to drive fluid flux. Yet, how this coupling is regulated, whether it mediates waste clearance, and why it is impaired remain unclear. Here we demonstrate that cholinergic neurons modulate BOLD-CSF coupling and glymphatic function. We find BOLD-CSF coupling correlates cortical cholinergic activity in aged humans. Lesioning basal forebrain cholinergic neurons in female mice impairs glymphatic efflux and associated changes in BOLD-CSF coupling, arterial pulsation and glymphatic influx. An acetylcholinesterase inhibitor alters these dynamics, primarily through peripheral mechanisms. Our results suggest cholinergic loss impairs glymphatic function by a neurovascular mechanism, potentially contributing to pathological waste accumulation. This may provide a basis for developing diagnostics and treatments for glymphatic dysfunction. The authors find cholinergic neurons regulate glymphatic waste clearance via neurovascular mechanisms, with their loss impairing this process. This finding suggests targets for diagnostics and treatment.

Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/− 4) at baseline to 12.9 (SD +/− 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.

Acetylcholinesterase inhibitors are approved drugs currently used for the treatment of Alzheimer’s disease (AD) dementia. Basal forebrain cholinergic system (BFCS) atrophy is reported to precede both entorhinal cortex atrophy and memory impairment in AD, challenging the traditional model of the temporal sequence of topographical pathology associated with AD. We studied the effect of one-year Donepezil treatment on the rate of BFCS atrophy in prodromal AD patients using a double-blind, randomized, placebo-controlled trial of Donepezil (10 mg/day). Reduced annual BFCS rates of atrophy were found in the Donepezil group compared to the Placebo treated arm. Secondary analyses on BFCS subregions demonstrated the largest treatment effects in the Nucleus Basalis of Meynert (NbM) and the medial septum/diagonal band (Ch1/2). Donepezil administered at a prodromal stage of AD seems to substantially reduce the rate of atrophy of the BFCS nuclei with highest concentration of cholinergic neurons projecting to the cortex (NbM), hippocampus and entorhinal cortex (Ch1/2).

The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimer’s disease and vascular cognitive impairment. Most of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its sub-region the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39–77 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusion-based tracking of NBM white matter projections, and computed white matter hypointensities (WM-hypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous post-mortem and DTI tractography studies. We found that high WM-hypo load was associated with older age, male sex, and lower performance in attention and memory. A high WM-hypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WM-hypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to re-evaluate the cholinergic hypothesis of cognitive aging. [Display omitted] •Cholinergic pathways can be modelled in vivo with multimodal MRI.•Integrity of cholinergic pathways and age are strong contributors to cognition.•New opportunities emerge to re-evaluate the cholinergic hypothesis of aging.

The endosome-associated GTPase 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 is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB. The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.

We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined the level of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer’s Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF 10 ) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF 10  = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF 10  = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF 10  = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.

Theta oscillations of the mammalian amygdala are associated with processing, encoding and retrieval of aversive memories. In the hippocampus, the power of the network theta oscillation is modulated by basal forebrain (BF) GABAergic projections. Here, we combine anatomical and computational approaches to investigate if similar BF projections to the amygdaloid complex provide an analogous modulation of local network activity. We used retrograde tracing with fluorescent immunohistochemistry to identify cholinergic and non-cholinergic parvalbumin- or calbindin-immunoreactive BF neuronal subgroups targeting the input (lateral and basolateral nuclei) and output (central nucleus and the central bed nucleus of the stria terminalis) regions of the amygdaloid complex. We observed a dense non-cholinergic, putative GABAergic projection from the ventral pallidum (VP) and the substantia innominata (SI) to the basolateral amygdala (BLA). The VP/SI axonal projections to the BLA were confirmed using viral anterograde tracing and transsynaptic labeling. We tested the potential function of this VP/SI-BLA pathway in a 1000-cell biophysically realistic network model, which incorporated principal neurons and three major interneuron groups of the BLA, together with extrinsic glutamatergic, cholinergic, and VP/SI GABAergic inputs. We observed in silico that theta-modulation of VP/SI GABAergic projections enhanced theta oscillations in the BLA via their selective innervation of the parvalbumin-expressing local interneurons. Ablation of parvalbumin-, but not somatostatin- or calretinin-expressing, interneurons reduced theta power in the BLA model. These results suggest that long-range BF GABAergic projections may modulate network activity at their target regions through the formation of a common interneuron-type and oscillatory phase-specific disinhibitory motif.