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R. CARMONA and B. ROZOVSKII (Eds.). Providence, RI: American Mathematical Society, 1999. ISBN 0-8218-0806-0. xi + 334 pp. $49. The field of stochastic partial differential equations (SPDEs) is an interdisciplinary [...]

Juvenile rodents and other altricial mammals react with calming, immobility, and postural modifications to parental pickup, a set of behaviors referred to as the transport response. 1 , 2 , 3 , 4 , 5 Here, we investigate sensory mechanisms underlying the rat transport response. Grasping rat pups in anterior neck positions evokes strong immobility and folding up of feet, whereas more posterior grasping has lesser effects on immobility and foot position. Transport responses are enhanced by slow (1 Hz), and even more so by fast (4 Hz), gentle shaking and translation, features consistent with parental transport. With lateral grasping, the forepaw below the grasping position points downward and the forepaw lateral to the grasping position points upward and medially. Such forepaw adjustments put the pup's center of gravity below the grasping point, optimizing pup transportability. Tactile stimuli on the back, belly, tail, whisker, dorsal forepaws, and dorsal hind-paws do not significantly affect behavior of anterior-neck-held pups. Instead, ground contact, or paw stimulation consistent with ground contact, disrupts transport responses. We identify afferents mediating transport response by examining membrane labeling with FM 1-43 6 following anterior neck grasping. We observe a dense innervation of the anterior-neck-skin region (∼30 terminals/mm 2 ). We find an age-related decrease of cytochrome oxidase reactivity in the rat somatosensory cortical neck representation, a possible correlate to developmental decrease in pup transport response. We conclude that anterior neck grasping and loss of ground contact trigger calming and postural adjustments for parental transport in rat pups, responses putatively driven from the densely innervated anterior neck skin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype. Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs., (© 2024. The Author(s).)

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism., Competing Interests: Competing interests statement:The authors declare no competing interest.

Echo chambers, i.e. clusters of users exposed to news and opinions in line with their previous beliefs, were observed in many online debates on social platforms. We propose a completely unbiased entropy-based method for detecting echo chambers. The method is completely agnostic to the nature of the data. In the Italian Twitter debate about the Covid-19 vaccination, we find a limited presence of users in echo chambers (about 0.35% of all users). Nevertheless, their impact on the formation of a common discourse is strong, as users in echo chambers are responsible for nearly a third of the retweets in the original dataset. Moreover, in the case study observed, echo chambers appear to be a receptacle for disinformative content., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma-aminobutyric acid type A receptors (GABA A receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABA A receptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter., Competing Interests: Competing interests statement:The authors declare no competing interest.

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. Similar change in transmitter identity was found in the postmortem brains of individuals with posttraumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors mediated the switch, and prompt antidepressant treatment blocked the cotransmitter switch and generalized fear. Our results provide important insight into the mechanisms involved in fear generalization.

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities., Competing Interests: JC is employee of RBI and founder of the Luxi Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. MAG-G was coordinator of the research topic collection “Women in neuroscience of Bioelectronic Medicine”, and SCT, MET and SVC were editors of the same research topic collection. This had no impact on the peer review process and the final decision., (Copyright © 2024 González-González, Conde, Latorre, Thébault, Pratelli, Spitzer, Verkhratsky, Tremblay, Akcora, Hernández-Reynoso, Ecker, Coates, Vincent and Ma.)

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Bow-tie structures were introduced to describe the World Wide Web (WWW): in the direct network in which the nodes are the websites and the edges are the hyperlinks connecting them, the greatest number of nodes takes part to a bow-tie, i.e. a Weakly Connected Component (WCC) composed of 3 main sectors: IN, OUT and SCC. SCC is the main Strongly Connected Component of WCC, i.e. the greatest subgraph in which each node is reachable by any other one. The IN and OUT sectors are the set of nodes not included in SCC that, respectively, can access and are accessible to nodes in SCC. In the WWW, the greatest part of the websites can be found in the SCC, while the search engines belong to IN and the authorities, as Wikipedia, are in OUT. In the analysis of Twitter debate, the recent literature focused on discursive communities, i.e. clusters of accounts interacting among themselves via retweets. In the present work, we studied discursive communities in 8 different thematic Twitter datasets in various languages. Surprisingly, we observed that almost all discursive communities therein display a bow-tie structure during political or societal debates. Instead, they are absent when the argument of the discussion is different as sport events, as in the case of Euro2020 Turkish and Italian datasets. We furthermore analysed the quality of the content created in the various sectors of the different discursive communities, using the domain annotation from the fact-checking website Newsguard: we observe that, when the discursive community is affected by m/disinformation, the content with the lowest quality is the one produced and shared in SCC and, in particular, a strong incidence of low- or non-reputable messages is present in the flow of retweets between the SCC and the OUT sectors. In this sense, in discursive communities affected by m/disinformation, the greatest part of the accounts has access to a great variety of contents, but whose quality is, in general, quite low; such a situation perfectly describes the phenomenon of infodemic, i.e. the access to "an excessive amount of information about a problem, which makes it difficult to identify a solution", according to WHO., (© 2022. The Author(s).)

Background: Patterns of coordinated variations of gray matter (GM) morphology across individuals are promising indicators of disease. However, it remains unclear if they can help characterize first-episode psychosis (FEP) and symptoms' severity., Methods: Sixty-seven FEP and 67 matched healthy controls (HC) were assessed with structural MRI to evaluate the existence of distributed GM structural covariance patterns associated to brain areas belonging to salience network. Voxel-based morphometry (VBM) and structural covariance differences, investigated with salience network seed-based Partial Least Square, were applied to explore differences between groups. GM density associations with Raven's intelligent quotient (IQ) and Positive and Negative Syndrome Scale (PANSS) scores were investigated., Results: Univariate VBM results gave trend without significant GM differences across groups. GM and IQ correlated positively in both groups: in FEP, mostly in hippocampus, insula, and fronto-temporal structures, while in HC mostly in amygdala, thalamus and fronto-temporal regions. GM and PANSS scores correlated negatively in FEP, with widespread clusters located in limbic regions. Multivariate analysis showed strong and opposite structural GM covariance with salience network for FEP and HC. Moreover, structural covariance of the salience network in FEP correlated negatively with severity of clinical symptoms., Conclusion: Our study provides evidence supporting the insular dysfunction model of psychosis. Reduced structural GM covariance of the salience network, with its association to symptom's severity, appears a promising morphometry feature for FEP detection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic has impacted on every human activity and, because of the urgency of finding the proper responses to such an unprecedented emergency, it generated a diffused societal debate. The online version of this discussion was not exempted by the presence of misinformation campaigns, but, differently from what already witnessed in other debates, the COVID-19 -intentional or not- flow of false information put at severe risk the public health, possibly reducing the efficacy of government countermeasures. In this manuscript, we study the effective impact of misinformation in the Italian societal debate on Twitter during the pandemic, focusing on the various discursive communities. In order to extract such communities, we start by focusing on verified users, i.e., accounts whose identity is officially certified by Twitter. We start by considering each couple of verified users and count how many unverified ones interacted with both of them via tweets or retweets: if this number is statically significant, i.e. so great that it cannot be explained only by their activity on the online social network, we can consider the two verified accounts as similar and put a link connecting them in a monopartite network of verified users. The discursive communities can then be found by running a community detection algorithm on this network. We observe that, despite being a mostly scientific subject, the COVID-19 discussion shows a clear division in what results to be different political groups. We filter the network of retweets from random noise and check the presence of messages displaying URLs. By using the well known browser extension NewsGuard, we assess the trustworthiness of the most recurrent news sites, among those tweeted by the political groups. The impact of low reputable posts reaches the 22.1% in the right and center-right wing community and its contribution is even stronger in absolute numbers, due to the activity of this group: 96% of all non reputable URLs shared by political groups come from this community., Supplementary Information: The online version contains supplementary material available at 10.1140/epjds/s13688-021-00289-4., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2021.)

Neurotransmitter switching is a form of brain plasticity in which an environmental stimulus causes neurons to replace one neurotransmitter with another, often resulting in changes in behavior. This raises the possibility of applying a specific environmental stimulus to induce a switch that can enhance a desirable behavior or ameliorate symptoms of a specific pathology. For example, a stimulus inducing an increase in the number of neurons expressing dopamine could treat Parkinson's disease, or one affecting the number expressing serotonin could alleviate depression. This may already be producing successful treatment outcomes without our knowing that transmitter switching is involved, with improvement of motor function through physical activity and cure of seasonal depression with phototherapy. This review presents prospects for future investigation of neurotransmitter switching, considering opportunities and challenges for future research and describing how the investigation of transmitter switching is likely to evolve with new tools, thus reshaping our understanding of both normal brain function and mental illness., (Copyright © 2020 the authors.)

Serotonin (5-HT)-releasing fibers show substantial structural plasticity in response to genetically induced changes in 5-HT content. However, whether 5-HT fibers appear malleable also following clinically relevant variations in 5-HT levels that may occur throughout an individual's life has not been investigated. Here, using confocal imaging and 3D modeling analysis in Tph2 GFP knock-in mice, we show that chronic administration of the antidepressant fluoxetine dramatically affects the morphology of 5-HT fibers innervating the dorsal and ventral hippocampus resulting in a reduced density of fibers. Importantly, GFP fluorescence levels appeared unaffected in the somata of both dorsal and median raphe 5-HT neurons, arguing against potential fluoxetine-mediated down-regulation of the Tph2 promoter driving GFP expression in the Tph2 GFP mouse model. In keeping with this notion, mice bearing the pan-serotonergic driver Pet1-Cre partnered with a Cre-responsive tdTomato allele also showed similar morphological alterations in hippocampal 5-HT circuitry following chronic fluoxetine treatment. Moreover 5-HT fibers innervating the cortex showed proper density and no overt morphological disorganization, indicating that the reported fluoxetine-induced rearrangements were hippocampus specific. On the whole, these data suggest that 5-HT fibers are shaped in response to subtle changes of 5-HT homeostasis and may provide a structural basis by which antidepressants exert their therapeutic effect.

Serotonin (5-hydroxytriptamine; 5-HT) is a fascinating neurotransmitter that thanks to an extensive axonal network is released throughout the entire central nervous system (CNS) and exerts its action on the modulation of a countless number of physiological, behavioral and cognitive processes. In addition, cumulating evidences have linked alteration in 5-HT neurotransmission with the onset of psychiatric and neurodevelopmental disorders, such as depression, autisms and schizophrenia. Nevertheless only 5% of the total body content of serotonin exerts its action in the CNS, while the rest is synthetized and stored in peripheral tissues where it acts as an autacoid. In 2003 it became evident that two distinct isoforms of tryptophan hydroxylase (Tph), the rate-limiting enzyme for the synthesis of serotonin, are selectively expressed in peripheral tissues and in the CNS, with Tph2 as the brain specific isoform. In the present review we describe how the discovery of Tph2 has improved our understanding on the role of serotonergic neurotransmission. We mainly focus on the analysis of animal models generated by genetic manipulation of Tph2, in which the synthesis of brain serotonin was either reduced or disrupted. The consequences of an altered serotonergic neurotransmission on brain development, as well as on physiological and behavioral processes will be assessed. Finally, we report on several association studies that have linked single nucleotide polymorphisms (SNPs) in the human TPH2 gene with behavioral disturbances and neuropsychiatric disorders., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Serotonin (5-HT)-synthetizing neurons, which are confined in the raphe nuclei of the rhombencephalon, provide a pervasive innervation of the central nervous system (CNS) and are involved in the modulation of a plethora of functions in both developing and adult brain. Classical studies have described the post-natal development of serotonergic axons as a linear process of terminal field innervation. However, technical limitations have hampered a fine morphological characterization. With the advent of genetic mouse models, the possibility to label specific neuronal populations allowed the rigorous measurement of their axonal morphological features as well as their developmental dynamics. Here, we used the Tph2 GFP knock-in mouse line, in which GFP expression allows punctual identification of serotonergic neurons and axons, for confocal microscope imaging and we performed 3-dimensional reconstruction in order to morphologically characterize the development of serotonergic fibers in specified brain targets from birth to adulthood. Our analysis highlighted region-specific developmental patterns of serotonergic fiber density ranging from a linear and progressive colonization of the target (Caudate/Putamen, Basolateral Amygdala, Geniculate Nucleus and Substantia Nigra) to a transient increase in fiber density (medial Prefrontal Cortex, Globus Pallidus, Somatosensory Cortex and Hippocampus) occurring with a region-specific timing. Despite a common pattern of early post-natal morphological maturation in which a progressive rearrangement from a dot-shaped to a regular and smooth fiber morphology was observed, starting from post-natal day 28 serotonergic fibers acquire the region specific morphological features present in the adult. In conclusion, we provided novel, target-specific insights on the morphology and temporal dynamics of the developing serotonergic fibers.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2 GFP , in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene. Tph2 GFP mES cells selectively express GFP upon in vitro differentiation toward the serotonergic fate, they synthesize serotonin, possess excitable membranes, and show the typical morphological, morphometrical, and molecular features of in vivo serotonergic neurons. Thanks to the vital reporter GFP, we highlighted by time-lapse video microscopy several dynamic processes such as cell migration and axonal outgrowth in living cultures. Finally, we demonstrated that predifferentiated Tph2 GFP cells are able to terminally differentiate, integrate, and innervate the host brain when grafted in vivo. On the whole, the present study introduces the Tph2 GFP mES cell line as a useful tool allowing accurate developmental and dynamic studies and representing a reliable platform for the study of serotonergic neurons in health and disease.

Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2 fl ° x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.