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Increased extracellular free water (FW) is considered to provide better pathophysiological information than conventional diffusion tensor imaging (DTI) metrics. The cholinergic brain network is a key hub for cognitive function, and microstructural changes detected by free water imaging in this system may be associated with cognitive impairment in Alzheimer's disease (AD). However, the specific impact of FW changes in the cholinergic brain network on cognitive domains across the AD continuum and their diagnostic value remain unclear. Here, we investigated the basal forebrain cholinergic free water alterations based on free water-corrected diffusion tensor imaging in healthy controls (  = 36), amnestic mild cognitive impairment (aMCI;  = 31), the AD group (  = 33). The cholinergic basal forebrain subregions were divided into the Broca diagonal band (Ch1-3) and the Meynert basal nucleus (Ch4). The cognitive domains performance was measured using the Montreal Cognitive Assessment (MoCA). Additionally, we evaluated the diagnostic value of free water fraction (FWf) within the cholinergic system. FWf in the bilateral Ch1-3 and Ch4 regions increased with age, and was significantly higher in aMCI and AD (  < 0.001). In AD, the FWf within Ch4 was correlated with total MoCA score (  = -0.42,  = 0.015), especially with visual spatial/executive (  = -0.47,  = 0.006) and orientation deficits (  = -0.38,  = 0.029). No significant correlations were found in the aMCI group. ROC curve analysis showed that FWf within the cholinergic brain network had high diagnostic efficacy for AD versus HC (AUC = 0.958, 95% CI = 0.909-1.00), and moderate diagnostic efficacy for aMCI versus HC (AUC = 0.795, 95% CI = 0.685-0.905) and aMCI versus AD (AUC = 0.719, 95% CI = 0.589-0.850). FW imaging captures microstructural damage in the cholinergic brain network across the entire AD continuum. These changes occur early in aMCI but selectively affect domain-specific cognition in the later stages of AD, possibly through cholinergic network dysfunction. Our results highlight the potential of free water imaging as a biomarker for cognitive decline.

Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumour progression 1 , 2 . Synaptic inputs onto GBM cells identified so far are largely short range and glutamatergic 3 , 4 . The extent of GBM integration into the brain-wide neuronal circuitry remains unclear. Here we applied rabies virus-mediated and herpes simplex virus-mediated trans-monosynaptic tracing 5 , 6 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrate into diverse local and long-range neural circuits across the brain. Beyond glutamatergic inputs, we identified various neuromodulatory inputs, including synapses between basal forebrain cholinergic neurons and GBM cells. Acute acetylcholine stimulation induces long-lasting elevation of calcium oscillations and transcriptional reprogramming of GBM cells into a more motile state via the metabotropic CHRM3 receptor. CHRM3 activation promotes GBM cell motility, whereas its downregulation suppresses GBM cell motility and prolongs mouse survival. Together, these results reveal the striking capacity for human GBM cells to rapidly and robustly integrate into anatomically diverse neuronal networks of different neurotransmitter systems. Our findings further support a model in which rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumour fitness. A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease.

The cholinergic system is essential for memory. While degradation of cholinergic pathways characterizes memory-related disorders such as Alzheimer’s disease, the neurophysiological mechanisms linking the cholinergic system to human memory remain unknown. Here, combining intracranial brain recordings with pharmacological manipulation, we describe the neurophysiological effects of a cholinergic blocker, scopolamine, on the human hippocampal formation during episodic memory. We found that the memory impairment caused by scopolamine was coupled to disruptions of both the amplitude and phase alignment of theta oscillations (2–10 Hz) during encoding. Across individuals, the severity of theta phase disruption correlated with the magnitude of memory impairment. Further, cholinergic blockade disrupted connectivity within the hippocampal formation. Our results indicate that cholinergic circuits support memory by coordinating the temporal dynamics of theta oscillations across the hippocampal formation. These findings expand our mechanistic understanding of the neurophysiology of human memory and offer insights into potential treatments for memory-related disorders. Memory loss is a known result of cholinergic dysfunction, yet the neural basis for this effect remains unknown. Here, the authors demonstrate that the way cholinergic blockade disrupts memory is by impairing the amplitude and timing of theta oscillations.

•Nicotine promotes functional segregation in task, but not in resting-state.•In-task segregation correlates with visual-attentional performance.•A decrease in global coupling and local inhibition reproduces the effects of nicotine.•Modeling suggests mechanisms for the cholinergic influence on connectivity. Integration and segregation are two fundamental principles of brain organization. The brain manages the transitions and balance between different functional segregated or integrated states through neuromodulatory systems. Recently, computational and experimental studies suggest a pro-segregation effect of cholinergic neuromodulation. Here, we studied the effects of the cholinergic system on brain functional connectivity using both empirical fMRI data and computational modeling. First, we analyzed the effects of nicotine on functional connectivity and network topology in healthy subjects during resting-state conditions and during an attentional task. Then, we employed a whole-brain neural mass model interconnected using a human connectome to simulate the effects of nicotine and investigate causal mechanisms for these changes. The drug effect was modeled decreasing both the global coupling and local feedback inhibition parameters, consistent with the known cellular effects of acetylcholine. We found that nicotine incremented functional segregation in both empirical and simulated data, and the effects are context-dependent: observed during the task, but not in the resting state. In-task performance correlates with functional segregation, establishing a link between functional network topology and behavior. Furthermore, we found in the empirical data that the regional density of the nicotinic acetylcholine α4β2 correlates with the decrease in functional nodal strength by nicotine during the task. Our results confirm that cholinergic neuromodulation promotes functional segregation in a context-dependent fashion, and suggest that this segregation is suited for simple visual-attentional tasks.

The orbitofrontal cortex and amygdala are involved in emotion and in motivation, but the relationship between these functions performed by these brain structures is not clear. To address this, a unified theory of emotion and motivation is described in which motivational states are states in which instrumental goal-directed actions are performed to obtain rewards or avoid punishers, and emotional states are states that are elicited when the reward or punisher is or is not received. This greatly simplifies our understanding of emotion and motivation, for the same set of genes and associated brain systems can define the primary or unlearned rewards and punishers such as sweet taste or pain. Recent evidence on the connectivity of human brain systems involved in emotion and motivation indicates that the orbitofrontal cortex is involved in reward value and experienced emotion with outputs to cortical regions including those involved in language, and is a key brain region involved in depression and the associated changes in motivation. The amygdala has weak effective connectivity back to the cortex in humans, and is implicated in brainstem-mediated responses to stimuli such as freezing and autonomic activity, rather than in declarative emotion. The anterior cingulate cortex is involved in learning actions to obtain rewards, and with the orbitofrontal cortex and ventromedial prefrontal cortex in providing the goals for navigation and in reward-related effects on memory consolidation mediated partly via the cholinergic system.

Complex cognitive abilities are thought to arise from the ability of the brain to adaptively reconfigure its internal network structure as a function of task demands. Recent work has suggested that this inherent flexibility may in part be conferred by the widespread projections of the ascending arousal systems. While the different components of the ascending arousal system are often studied in isolation, there are anatomical connections between neuromodulatory hubs that we hypothesise are crucial for mediating key features of adaptive network dynamics, such as the balance between integration and segregation. To test this hypothesis, we estimated the strength of structural connectivity between key hubs of the noradrenergic and cholinergic arousal systems (the locus coeruleus [LC] and nucleus basalis of Meynert [nbM], respectively). We then asked whether the strength of structural LC and nbM inter-connectivity was related to individual differences in the emergent, dynamical signatures of functional integration measured from resting state fMRI data, such as network and attractor topography. We observed a significant positive relationship between the strength of white-matter connections between the LC and nbM and the extent of network-level integration following BOLD signal peaks in LC relative to nbM activity. In addition, individuals with denser white-matter streamlines interconnecting neuromodulatory hubs also demonstrated a heightened ability to shift to novel brain states. These results suggest that individuals with stronger structural connectivity between the noradrenergic and cholinergic systems have a greater capacity to mediate the flexible network dynamics required to support complex, adaptive behaviour. Furthermore, our results highlight the underlying static features of the neuromodulatory hubs can impose some constraints on the dynamic features of the brain.

Brain activity during the resting state is widely used to examine brain organization, cognition and alterations in disease states. While it is known that neuromodulation and the state of alertness impact resting-state activity, neural mechanisms behind such modulation of resting-state activity are unknown. In this work, we used a computational model to demonstrate that change in excitability and recurrent connections, due to cholinergic modulation, impacts resting-state activity. The results of such modulation in the model match closely with experimental work on direct cholinergic modulation of Default Mode Network (DMN) in rodents. We further extended our study to the human connectome derived from diffusion-weighted MRI. In human resting-state simulations, an increase in cholinergic input resulted in a brain-wide reduction of functional connectivity. Furthermore, selective cholinergic modulation of DMN closely captured experimentally observed transitions between the baseline resting state and states with suppressed DMN fluctuations associated with attention to external tasks. Our study thus provides insight into potential neural mechanisms for the effects of cholinergic neuromodulation on resting-state activity and its dynamics.

Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map of receptor organization across cortical regions is needed. In this study, we used in vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrated the receptor data with anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of receptor expression per neuron. This aligns with the cortical hierarchy from sensory cortex to higher cognitive areas. A second gradient, driven by serotonin 5-HT 1A receptors, peaks in the anterior cingulate, default mode and salience networks. We found a similar pattern of 5-HT 1A expression in the human brain. Thus, the macaque may be a promising translational model of serotonergic processing and disorders. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration in higher cognitive areas. Froudist-Walsh et al. reveal organizational principles of receptor densities in macaque cortex. Densities of multiple receptor types align with changes in dendritic properties, myelin and functional networks. Data are openly released to the community.

The local and long-range connectivity of cortical neurons are considered instrumental to the functional repertoire of the cortical region in which they reside. In cortical networks, distinct cell types build local circuit structures enabling computational operations. Computations in the medial prefrontal cortex (mPFC) are thought to be central to cognitive operation, including decision-making and memory. We used a retrograde trans-synaptic rabies virus system to generate brain-wide maps of the input to excitatory neurons as well as three inhibitory interneuron subtypes in the mPFC. On the global scale the input patterns were found to be mainly cell type independent, with quantitative differences in key brain regions, including the basal forebrain. Mapping of the local mPFC network revealed high connectivity between the different subtypes of interneurons. The connectivity mapping gives insight into the information that the mPFC processes and the structural architecture underlying the mPFC’s unique functions.The connectivity of a cortical region is instrumental to its function. The authors generated brain-wide maps of the afferent input to four distinct cell types in the mPFC to reveal the structural architecture that underlies the mPFC’s functions.