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Human Brain Mapping Feb 2024Attention network theory proposes three distinct types of attention-alerting, orienting, and control-that are supported by separate brain networks and modulated by...
Attention network theory proposes three distinct types of attention-alerting, orienting, and control-that are supported by separate brain networks and modulated by different neurotransmitters, that is, norepinephrine, acetylcholine, and dopamine. Here, we explore the extent of cortical, genetic, and molecular dissociation of these three attention systems using multimodal neuroimaging. We evaluated the spatial overlap between fMRI activation maps from the attention network test (ANT) and cortex-wide gene expression data from the Allen Human Brain Atlas. The goal was to identify genes associated with each of the attention networks in order to determine whether specific groups of genes were co-expressed with the corresponding attention networks. Furthermore, we analyzed publicly available PET-maps of neurotransmitter receptors and transporters to investigate their spatial overlap with the attention networks. Our analyses revealed a substantial number of genes (3871 for alerting, 6905 for orienting, 2556 for control) whose cortex-wide expression co-varied with the activation maps, prioritizing several molecular functions such as the regulation of protein biosynthesis, phosphorylation, and receptor binding. Contrary to the hypothesized associations, the ANT activation maps neither aligned with the distribution of norepinephrine, acetylcholine, and dopamine receptor and transporter molecules, nor with transcriptomic profiles that would suggest clearly separable networks. Independence of the attention networks appeared additionally constrained by a high level of spatial dependency between the network maps. Future work may need to reconceptualize the attention networks in terms of their segregation and reevaluate the presumed independence at the neural and neurochemical level.
Topics: Humans; Orientation; Acetylcholine; Brain; Magnetic Resonance Imaging; Norepinephrine
PubMed: 38401136
DOI: 10.1002/hbm.26588 -
ELife Dec 2023Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung, and intestine. Extensive human genetic studies...
Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung, and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in that allowed for rapid identification, validation, and prioritization of COPD risk genes that were selected based on risk loci identified in human genome-wide association studies (GWAS). Using intestinal barrier dysfunction in flies as a readout, our results validate the impact of candidate gene perturbations on epithelial barrier function in 56% of the cases, resulting in a prioritized target gene list. We further report the functional characterization in flies of one family of these genes, encoding for nicotinic acetylcholine receptor (nAchR) subunits. We find that nAchR signaling in enterocytes of the fly gut promotes epithelial barrier function and epithelial homeostasis by regulating the production of the peritrophic matrix. Our findings identify COPD-associated genes critical for epithelial barrier maintenance, and provide insight into the role of epithelial nAchR signaling for homeostasis.
Topics: Animals; Humans; Receptors, Nicotinic; Genome-Wide Association Study; Drosophila melanogaster; Pulmonary Disease, Chronic Obstructive; Lung
PubMed: 38063293
DOI: 10.7554/eLife.86381 -
Nutrients Sep 2023Choline plays many important roles, including the synthesis of acetylcholine, and may affect muscle responses to exercise. We previously observed correlations between... (Randomized Controlled Trial)
Randomized Controlled Trial
Choline plays many important roles, including the synthesis of acetylcholine, and may affect muscle responses to exercise. We previously observed correlations between low choline intake and reduced gains in strength and lean mass following a 12-week resistance exercise training (RET) program for older adults. To further explore these findings, we conducted a randomized controlled trial. Three groups of 50-to-69-year-old healthy adults underwent a 12-week RET program (3x/week, 3 sets, 8-12 reps, 70% of maximum strength (1RM)) and submitted >48 diet logs (>4x/week for 12 weeks). Participants' diets were supplemented with 0.7 mg/kg lean/d (low, n = 13), 2.8 mg/kg lean/d (med, n = 11), or 7.5 mg/kg lean/d (high, n = 13) of choline from egg yolk and protein powder. The ANCOVA tests showed that low choline intake, compared with med or high choline intakes, resulted in significantly diminished gains in composite strength (leg press + chest press 1RM; low, 19.4 ± 8.2%; med, 46.8 ± 8.9%; high, 47.4 ± 8.1%; = 0.034) and thigh-muscle quality (leg press 1RM/thigh lean mass; low, 12.3 ± 9.6%; med/high, 46.4 ± 7.0%; = 0.010) after controlling for lean mass, protein, betaine, and vitamin B. These data suggest that low choline intake may negatively affect strength gains with RET in older adults.
Topics: Humans; Aged; Middle Aged; Choline; Resistance Training; Acetylcholine; Betaine; Correlation of Data
PubMed: 37764658
DOI: 10.3390/nu15183874 -
Neuron Jun 2024A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal...
A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various brain states. Although these neuromodulators fluctuated in parallel during NREM packets, transitions from NREM to REM were characterized by a surge of ACh but a continued decrease of OXT. OXT signaling lagged behind ACh. High ACh was correlated with population synchrony and gamma oscillations during active waking, whereas minimum ACh predicts sharp-wave ripples (SPW-Rs). Optogenetic control of ACh and OXT neurons confirmed the active role of these neuromodulators in the observed correlations. Synchronous hippocampal activity consistently reduced OXT activity, whereas inactivation of the lateral septum-hypothalamus path attenuated this effect. Our findings demonstrate how cooperative actions of these neuromodulators allow target circuits to perform specific functions.
Topics: Oxytocin; Acetylcholine; Hippocampus; Animals; Male; Optogenetics; Neurons; Gamma Rhythm; Neurotransmitter Agents; Mice; Rats; Wakefulness
PubMed: 38537642
DOI: 10.1016/j.neuron.2024.02.021 -
Biochemical Pharmacology Nov 2023Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous...
Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous research has revealed that IBD patients often have a deficiency of choline and its metabolites, including acetylcholine (ACh) and phosphatidylcholine (PC), within the colon. However, a comprehensive study linking these three substances and their mechanistic implications in IBD remains lacking. This study aimed to investigate the efficacy and underlying mechanism of cytidine diphosphate (CDP)-choline (citicoline), an intermediate product of choline metabolism, in a mouse model of IBD induced by dextran sulfate sodium salt (DSS). The results demonstrated that CDP-choline effectively alleviated colonic inflammation and deficiencies in choline, ACh, and PC by increasing the raw material. Further detection showed that CDP-choline also increased the ACh content by altering the expression of high-affinity choline transporter (ChT1) and acetylcholinesterase (AChE) in DSS-induced mice colon. Moreover, CDP-choline increased the expression of alpha7 nicotinic acetylcholine receptor (α7 nAChR) and activated the cholinergic anti-inflammatory pathway (CAP), leading to reduced colon macrophage activation and proinflammatory M1 polarization in IBD mice, thus reducing the levels of TNF-α and IL-6. In addition, CDP-choline reduced intestinal ecological imbalance and increased the content of hexanoic acid in short-chain fatty acids (SCFAs) in mice. In conclusion, this study elucidates the ability of CDP-choline to mitigate DSS-induced colon inflammation by addressing choline and its metabolites deficiencies, activating the CAP, and regulating the composition of the intestinal microbiome and SCFAs content, providing a potential prophylactic and therapeutic approach for IBD.
Topics: Humans; Mice; Animals; Cytidine Diphosphate Choline; Gastrointestinal Microbiome; Acetylcholinesterase; Choline; Colitis; Inflammation; Acetylcholine; Inflammatory Bowel Diseases; Nicotinic Antagonists; Colon; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37827341
DOI: 10.1016/j.bcp.2023.115845 -
Cell Reports Oct 2023The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform...
The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats.
Topics: Mice; Animals; Acoustic Stimulation; Learning; Basolateral Nuclear Complex; Amygdala; Acetylcholine; Cholinergic Agents
PubMed: 37742187
DOI: 10.1016/j.celrep.2023.113167 -
Archives of Biochemistry and Biophysics Nov 2023Membrane cholesterol oxidation is a hallmark of redox and metabolic imbalance, and it may accompany neurodegenerative disorders. Using microelectrode recordings of...
Membrane cholesterol oxidation is a hallmark of redox and metabolic imbalance, and it may accompany neurodegenerative disorders. Using microelectrode recordings of postsynaptic responses as well as fluorescent dyes for monitoring synaptic vesicle cycling and membrane properties, the action of enzymatic cholesterol oxidation on neuromuscular transmission was studied in the mice diaphragms. Cholesterol oxidase (ChO) at low concentration disturbed lipid-ordering specifically in the synaptic membranes, but it did not change markedly spontaneous exocytosis and evoked release in response to single stimuli. At low external Ca conditions, analysis of single exocytotic events revealed a decrease in minimal synaptic delay and the probability of exocytosis upon plasmalemmal cholesterol oxidation. At moderate- and high-frequency activity, ChO treatment enhanced both neurotransmitter and FM-dye release. Furthermore, it precluded a change in exocytotic mode from full-fusion to kiss-and-run during high-frequency stimulation. Accumulation of extracellular acetylcholine (without stimulation) dependent on vesamicol-sensitive transporters was suppressed by ChO. The effects of plasmalemmal cholesterol oxidation on both neurotransmitter/dye release at intense activity and external acetylcholine levels were reversed when synaptic vesicle membranes were also exposed to ChO (i.e., the enzyme treatment was combined with induction of exo-endocytotic cycling). Thus, we suggest that plasmalemmal cholesterol oxidation affects exocytotic machinery functioning, enhances synaptic vesicle recruitment to the exocytosis and decreases extracellular neurotransmitter levels at rest, whereas ChO acting on synaptic vesicle membranes suppresses the participation of the vesicles in the subsequent exocytosis and increases the neurotransmitter leakage. The mechanisms underlying ChO action can be related to the lipid raft disruption.
Topics: Mice; Animals; Cholesterol Oxidase; Acetylcholine; Synaptic Transmission; Neuromuscular Junction; Cholesterol; Neurotransmitter Agents
PubMed: 37955112
DOI: 10.1016/j.abb.2023.109803 -
Molecular Psychiatry Dec 2023The brain's ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes...
The brain's ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes instead to the emergence of pathological traits which are common in addiction and depression. However, the mechanisms and neural dynamics at the single-cell resolution underlying the encoding of associative learning remain elusive. Here, employing a Pavlovian discrimination task in mice we investigate how neuronal populations in the lateral habenula (LHb), a subcortical nucleus whose excitation underlies negative affect, encode the association between conditioned stimuli and a punishment (unconditioned stimulus). Large population single-unit recordings in the LHb reveal both excitatory and inhibitory responses to aversive stimuli. Additionally, local optical inhibition prevents the formation of cue discrimination during associative learning, demonstrating a critical role of LHb activity in this process. Accordingly, longitudinal in vivo two-photon imaging tracking LHb calcium neuronal dynamics during conditioning reveals an upward or downward shift of individual neurons' CS-evoked responses. While recordings in acute slices indicate strengthening of synaptic excitation after conditioning, support vector machine algorithms suggest that postsynaptic dynamics to punishment-predictive cues represent behavioral cue discrimination. To examine the presynaptic signaling in LHb participating in learning we monitored neurotransmitter dynamics with genetically-encoded indicators in behaving mice. While glutamate, GABA, and serotonin release in LHb remain stable across associative learning, we observe enhanced acetylcholine signaling developing throughout conditioning. In summary, converging presynaptic and postsynaptic mechanisms in the LHb underlie the transformation of neutral cues in valued signals supporting cue discrimination during learning.
Topics: Male; Animals; Mice, Inbred C57BL; Association Learning; Habenula; Neuronal Plasticity; Punishment; Neurons; Cues; Acetylcholine; Synapses
PubMed: 37414924
DOI: 10.1038/s41380-023-02155-3 -
The Journal of Physiology Jun 2024Play is a suite of apparently non-functional, pleasurable behaviours observed in human and non-human animals. Although the phenomenon has been studied extensively, no... (Review)
Review
Play is a suite of apparently non-functional, pleasurable behaviours observed in human and non-human animals. Although the phenomenon has been studied extensively, no adaptationist behavioural theory of how play evolved can be supported by the available evidence. However, the advancement of the extended evolutionary synthesis and developments in systems biology offer alternative avenues for non-adaptationist physiological hypotheses. I therefore propose a hypothesis of play, based upon a complex ACh activity that is under agential control of the organism, whereby play initiates ACh-mediated feedforward and feedback processes which act to: (i) regulate metabolic processes; (ii) form new ACh receptors via ACh mRNA activity; (iii) mediate attention, memory consolidation and learning; and (iv) mediate social behaviours, reproduction and embryonic development. However, play occurs across taxa, but does not occur across all taxonomic groups or within all species of a taxonomic group. Thus, to support the validity of the proposed hypothesis, I further propose potential explanations for this anomaly, which include sampling and observer biases, altricial versus precocial juvenile development, and the influence of habitat niche and environmental conditions on behaviour. The proposed hypothesis thus offers new avenues for study in both the biological and social sciences, in addition to having potential applications in applied sciences, such as animal welfare and biomedical research. Crucially, it is hoped that this hypothesis will promote further study of a valid and behaviourally significant, yet currently enigmatic, biological phenomenon.
Topics: Animals; Humans; Play and Playthings; Behavior, Animal; Biological Evolution; Acetylcholine; Social Behavior; Adaptation, Physiological
PubMed: 37656171
DOI: 10.1113/JP284413 -
Molecular Psychiatry Dec 2023Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems...
Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
Topics: Animals; Hippocampus; Neurogenesis; Aging; Memory, Short-Term; Male; Cholinergic Neurons; Acetylcholine; Neurons; Mice; Mice, Inbred C57BL; Memory Disorders; Dentate Gyrus
PubMed: 37479778
DOI: 10.1038/s41380-023-02167-z