TYPE Editorial PUBLISHED 26 October 2022 DOI 10.3389/fncir.2022.1028154 Editorial: Neuromodulatory OPEN ACCESS ascending systems: Their influence at the microscopic EDITED AND REVIEWED BY Nicoletta Berardi, University of Florence, Italy *CORRESPONDENCE Daniel Zaldivar and macroscopic levels daniel.zaldivarperez@nih.gov RECEIVED 25 August 2022 ACCEPTED 13 October 2022 Giuditta Gambino1 , Rebecca Bhik-Ghanie2 , Giuseppe Giglia1 , PUBLISHED 26 October 2022 M. Victoria Puig3 , Juan Ramirez-Villegas4 and Daniel Zaldivar2* CITATION 1 Gambino G, Bhik-Ghanie R, Giglia G, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Puig MV, Ramirez-Villegas J and Palermo, Italy, 2 National Institute of Mental Health (NIH), Bethesda, MD, United States, 3 Catalan Zaldivar D (2022) Editorial: Institute of Nanoscience and Nanotechnology (IN2), Universitat Autònoma de Barcelona (UAB), Neuromodulatory ascending systems: Barcelona, Spain, 4 Institute of Science and Technology Austria, Klosterneuburg, Austria Their influence at the microscopic and macroscopic levels. Front. Neural Circuits 16:1028154. KEYWORDS doi: 10.3389/fncir.2022.1028154 neuromodulation, networks, neuroanatomy, circuits, brain disorders COPYRIGHT © 2022 Gambino, Bhik-Ghanie, Giglia, Puig, Ramirez-Villegas and Zaldivar. This is an open-access article distributed under the terms of the Creative Commons Attribution License Editorial on the Research Topic (CC BY). The use, distribution or Neuromodulatory ascending systems: Their influence at the reproduction in other forums is microscopic and macroscopic levels permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic Brain activity and behavior are constantly changing (Puig et al., 2014; Disney, 2021). practice. No use, distribution or Recent studies in both animal models and humans have revealed that such variations reproduction is permitted which does are not random in nature but controlled through slow-acting neuromodulatory systems not comply with these terms. which influence our ability to process the influx of information, make decisions and take appropriate actions. Traditional anatomical, electrophysiological, stimulation, and lesion studies have revealed several important groups of pathways which are typically localized in brainstem/hypothalamic centers (McCormick et al., 2020). These so-called neuromodulatory ascending systems are known as the basal forebrain cholinergic system (ACh), noradrenergic brain stem, serotonergic brainstem, dopaminergic system (DA), endocannabinoids, oxytocin, nitric oxide-, and others less investigated (Puig and Gulledge, 2011; Gambino et al., 2020; Tong et al., 2021). All of these systems are known to broadly project to different brain areas, affect interneuronal communication, change synaptic efficacy, and influence cognitive processes. Hence, to understand the functioning of a given brain network, it is not only sufficient to know its elements, but one needs to understand how these elements are interlinked and dynamically interact (Zaldivar et al., 2022). In recent years, great progress has been made towards characterizing the role of neuromodulation and it is, therefore, more than timely that Frontiers Research Topic has chosen to devote a special topic on this subject. This brief editorial attempts to provide an overview about the publications in this special issue and should serve as an introduction to those unfamiliar with the topic. Frontiers in Neural Circuits 01 frontiersin.org Gambino et al. 10.3389/fncir.2022.1028154 Neurotransmitters and neuromodulators often share Dyachuk, who found that in some crustaceans the synthesis similar molecular elements, with main differences depending of dopamine, serotonin and acetylcholine takes place in the on the structure and function of their respective receptors. optic nerve. Markedly, authors identified that axons expressing Neurotransmitters are released by presynaptic neurons, enzymes for the synthesis of these neuromodulators were they directly and immediately influence their postsynaptic close to the neurosecretory cells which can further influence targets. The fast influence of many neurotransmitters comes animals’ behavior. about because their receptors are harnessed to ion-channels Understanding how disturbances in neuromodulatory that open almost instantaneously in the presence of the pathways might yield to brain disorders is of high importance for neurotransmitter ligand to modulate ion conductance. neuroscience research. Although we have learned a great deal of Neuromodulators tend to act much more slowly and endure information about the anatomical abnormalities associated with for a longer duration, since their receptors are coupled to cell brain disorders we are still far from understanding how these physiology via second messenger pathways. Ultimately, the abnormalities may be causally linked. Zhao et al. provided an influence of neuromodulation tightly depends on receptor in depth review about the Autism Spectrum Disorder (ASD) location, distribution and density. Indeed, these aspects were and the role that disturbances in neuromodulatory ascending essential in the study of Ogata et al., where authors evaluated pathways might play in the development of ASD. Zhao et al. how the uneven balance of dopamine receptors affects the proposed that other less investigated neuromodulatory systems role of medium spiny neurons in the direct and indirect might enhance our understanding about the origin, progression, motor pathways (Albin et al., 1989; Kravitz et al., 2010). This and treatment of this disorder. Authors emphasized in animal prompts speculation that axons of these two pathways might models and in clinical studies using treatments targeting the independently coordinate their responses to shape motor- or oxytocinergic and serotoninergic systems have shown to exert limbic-related information processing in the striatum. beneficial influence (Wichers et al., 2019). The cholinergic system is one of the most widely investigated The key problems in the field of neuromodulation are neuromodulatory systems as it is involved in multiple aspects not different from critical questions that have long been of sensory processing (Runfeldt et al., 2014; Minces et al., posed by the systems neuroscience community. Among others, 2017; Zaldivar et al., 2018), learning and memory (Atherton how does neuromodulatory ascending pathway inputs provide et al., 2015; Ramirez-Villegas et al., 2021), and it has been neurons with the flexibility to adjust neural activity? How causally linked to different types of dementia (Baxter and Chiba, do neuromodulators orchestrate the activity to give rise to 1999). However, to what extent does the role of ACh result the large repertoire of behaviors in the animal kingdom? from the local influence on neural circuits (Zaldivar et al., To succeed in this endeavor, we need a combination of 2018) or from the interactions between multiple and remote technological advances, a better understanding of anatomy circuits instantiated by ACh itself (Runfeldt et al., 2014)? In the and physiology and well-crafted experimental designs. In attempt to infer this differential role of cholinergic modulation, accordance with these questions, the present research topic has Tsolias and Medalla found that two areas of the prefrontal contributed to determining the multifaceted role of ascending cortex—commonly associated with arousal and motivation neuromodulatory pathways in neural networks and behavioral during executive functions—have distinct regional and laminar dynamics from basic to more complex experimental models. receptor distribution and density. This clear difference in ratio of muscarinic receptors type 1 and 2 in these areas is surprising since both regions were assumed to share similarities in their Author contributions anatomy and function. It is not far-fetched to hypothesize that these findings suggest that cholinergic neuromodulatory control All authors listed have made a substantial, direct, might optimize the bottom-up and top-down signals at different and intellectual contribution to the work and approved it processing stages to facilitate the transfer of information and for publication. during similar time scales. Most neural circuits in the animal kingdom must be sufficiently flexible to allow behavioral adaptation in response to Funding their unique ecological and social landscape. Neuromodulators lead to the assemblage of information between neural circuits This work was supported by a DFG grant ZA990/1 to DZ. so that they can be orchestrated to support behaviors in the species’ repertoires. However, such flexibility is not only given by the diversity of neuromodulators, neurons and receptors, but Acknowledgments it is also attained by the neuron’s capability to be influenced by more than one neuromodulator (Marder et al., 2014). This work was supported by the MSCA EU proposal This is clearly highlighted by the findings from Kotsyuba and 841301 – DREAM, European Commission; Horizon Frontiers in Neural Circuits 02 frontiersin.org Gambino et al. 10.3389/fncir.2022.1028154 2020 – Research and Innovation Framework Programme Publisher’s note to JFRV. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated Conflict of interest organizations, or those of the publisher, the editors and the reviewers. 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