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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.

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.

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).

Here, the circuits underlying the motivational or rewarding component to aggression are deconstructed, showing that an inhibitory projection from the basal forebrain to the lateral habenula bi-directionally controls this aspect of aggression. Aggression as its own reward The brain areas responsible for initiating aggressive behaviour have been identified, but little is known about the systems responsible for establishing a motivational or rewarding component to aggression. Here, Scott Russo and colleagues deconstruct the circuits underlying reward processing as it relates to aggression. They show that an inhibitory projection from the basal forebrain to the lateral habenula controls this aspect of aggression bi-directionally. This work could pave the way for the identification of targets for therapeutics designed to treat aggression and aggression-related neuropsychiatric disorders Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders 1 and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli 2 . Nuclei within the ventromedial hypothalamus 3 , 4 , 5 , extended amygdala 6 and limbic 7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour 8 . Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF–lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF–lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF–lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF–lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep-wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep-wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the 'designer receptors exclusively activated by designer drugs (DREADD)' approach, and ChAT-IRES-Cre mice. Our results showed that activation of BF cholinergic neurons expressing hM3Dq receptors significantly and lastingly decreased the EEG delta power spectrum, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness in both light and dark phases, whereas inhibition of BF cholinergic neurons expressing hM4Di receptors significantly increased EEG delta power spectrum and slightly decreased wakefulness. Next, the projections of BF cholinergic neurons were traced by humanized Renilla green fluorescent protein (hrGFP). Abundant and highly dense hrGFP-positive fibers were observed in the secondary motor cortex and cingulate cortex, and sparse hrGFP-positive fibers were observed in the ventrolateral preoptic nucleus, a known sleep-related structure. Finally, we found that activation of BF cholinergic neurons significantly increased c-Fos expression in the secondary motor cortex and cingulate cortex, but decreased c-Fos expression in the ventrolateral preoptic nucleus. Taken together, these findings reveal that the primary function of BF cholinergic neurons is to inhibit EEG delta activity through the activation of cerebral cortex, rather than to induce behavioral wakefulness.

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.

INTRODUCTION The cholinergic basal forebrain system, particularly the nucleus basalis of Meynert (Ch4), is selectively vulnerable to amyloid beta (Aβ) and tau in Alzheimer's disease (AD). Their interplay may be a critical driver of AD progression, but remains poorly understood. METHODS Data from 779 older individuals in the Australian Imaging, Biomarker, and Lifestyle study were analyzed, all of whom underwent 18F‐NAV4694 Aβ and 18F‐MK6240 tau positron emission tomography and magnetic resonance imaging. RESULTS The co‐occurrence of Aβ and mesial‐temporal (MTL) tau pathologies was associated with reduced Ch4 volumes in cognitively unimpaired individuals. MTL tau burden was associated with Ch4 volumes exclusively in cognitively unimpaired individuals with established Aβ pathology, which was not observed for the hippocampus. This association persists in individuals with mild cognitive impairment, but was not apparent in AD dementia. DISCUSSION Findings underscore early Ch4 degeneration associated with Aβ and tau pathologies, supporting potential cognitive benefits of cholinergic therapies in early disease stages. HIGHLIGHTS Early‐stage tau pathology in the mesial‐temporal (MTL) region was assessed using 18F‐MK6240 positron emission tomography. Co‐occurring amyloid beta and MTL tau was linked to reduced nucleus basalis of Meynert (Ch4) volume in cognitively unimpaired individuals. Ch4 volume was associated with MTL tau burden exclusively in preclinical Alzheimer's disease (AD). No comparable association was observed between MTL tau and hippocampal volume. The MTL tau–Ch4 association persisted into the prodromal stage of AD.