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Role of Serotonin in Brain Function
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Role of Serotonin in Brain Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 10809

Special Issue Editor

Dr. Anton S. Tsybko

E-Mail Website
Guest Editor
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
Interests: serotonin receptors; neurotrophic factors; behavior; neuropsychiatric diseases

Special Issue Information

Dear Colleagues,

This Special Issue aims to provide a modern view on serotonin as a polifunctional neurotransmitter that is equally important both for regulation of many physiological processes and higher brain functions, including cognition and emotional behavior. Recent advances in receptor-receptor interactions and mutual modulation between serotonin, other neurotransmitters, neurotrophic factors and immune system put the serotonin into the core for searching new strategies for treatment a wide range of neuropsychiatric diseases.

Here we focus on the current understanding and future research directions regarding the role of serotonin and its receptors as key players in normal physiology as well as pathobiology and treatment of different brain disorders. We warmly welcome original research and review articles relating to this hot topic. 

Sincerely,

Dr. Anton S. Tsybko
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • 5-hydroxytryptamine
  • 5-HT
  • 5-HT receptors
  • mood disorders
  • cognition and emotional behavior
  • neurodegeneration
  • animal models
  • physiological processes

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Published Papers (6 papers)

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Research

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27 pages, 6573 KiB  
Article
CDNF Exerts Anxiolytic, Antidepressant-like, and Procognitive Effects and Modulates Serotonin Turnover and Neuroplasticity-Related Genes
by Anton Tsybko, Dmitry Eremin, Tatiana Ilchibaeva, Nikita Khotskin and Vladimir Naumenko
Int. J. Mol. Sci. 2024, 25(19), 10343; https://doi.org/10.3390/ijms251910343 - 26 Sep 2024
Viewed by 955
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of [...] Read more.
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior. Full article
(This article belongs to the Special Issue Role of Serotonin in Brain Function)
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18 pages, 10188 KiB  
Article
Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses
by Philipp T. Neukam, Dirk K. Müller, Yacila I. Deza-Lougovski, Shakoor Pooseh, Stephanie H. Witt, Marcella Rietschel and Michael N. Smolka
Int. J. Mol. Sci. 2024, 25(12), 6666; https://doi.org/10.3390/ijms25126666 - 18 Jun 2024
Viewed by 916
Abstract
S/S carriers of 5-HTTLPR have been found to be more risk seeking for losses compared to L/L carriers. This finding may be the result of reduced top-down control from the frontal cortex due to altered signal pathways involving the amygdala and ventral striatum. [...] Read more.
S/S carriers of 5-HTTLPR have been found to be more risk seeking for losses compared to L/L carriers. This finding may be the result of reduced top-down control from the frontal cortex due to altered signal pathways involving the amygdala and ventral striatum. The serotonergic system is known to be involved in neurodevelopment and neuroplasticity. Therefore, the aim of this study was to investigate whether structural differences in white matter can explain the differences in risk-seeking behaviour. Lower structural connectivity in S/S compared to L/L carriers and a negative relationship between risk seeking for losses and connectivity were assumed. Diffusion-weighted imaging was used to compute diffusion parameters for the frontostriatal and uncinate tract in 175 genotyped individuals. The results showed no significant relationship between diffusion parameters and risk seeking for losses. Furthermore, we did not find significant differences in diffusion parameters of the S/S vs. L/L group. There were only group differences in the frontostriatal tract showing stronger structural connectivity in the S/L group, which is also reflected in the whole brain approach. Therefore, the data do not support the hypothesis that the association between 5-HTTLPR and risk seeking for losses is related to differences in white matter pathways implicated in decision-making. Full article
(This article belongs to the Special Issue Role of Serotonin in Brain Function)
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12 pages, 2168 KiB  
Article
Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms
by Giacomo Maddaloni, Noemi Barsotti, Sara Migliarini, Martina Giordano, Serena Nazzi, Marta Picchi, Francesco Errico, Alessandro Usiello and Massimo Pasqualetti
Int. J. Mol. Sci. 2024, 25(12), 6475; https://doi.org/10.3390/ijms25126475 - 12 Jun 2024
Cited by 2 | Viewed by 1904
Abstract
Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain—including those involving serotonin and dopamine—exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian [...] Read more.
Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain—including those involving serotonin and dopamine—exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors. Full article
(This article belongs to the Special Issue Role of Serotonin in Brain Function)
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14 pages, 2637 KiB  
Communication
In Vivo Serotonin 5-HT2A Receptor Availability and Its Relationship with Aggression Traits in Healthy Individuals: A Positron Emission Tomography Study with C-11 MDL100907
by Jeong-Hee Kim, Hang-Keun Kim, Young-Don Son and Jong-Hoon Kim
Int. J. Mol. Sci. 2023, 24(21), 15697; https://doi.org/10.3390/ijms242115697 - 28 Oct 2023
Viewed by 1733
Abstract
Serotonergic neurotransmission has been associated with aggression in several psychiatric disorders. Human aggression is a continuum of traits, ranging from normal to pathological phenomena. However, the individual differences in serotonergic neurotransmission and their relationships with aggression traits in healthy individuals remain unclear. In [...] Read more.
Serotonergic neurotransmission has been associated with aggression in several psychiatric disorders. Human aggression is a continuum of traits, ranging from normal to pathological phenomena. However, the individual differences in serotonergic neurotransmission and their relationships with aggression traits in healthy individuals remain unclear. In this study, we explored the relationship between 5-HT2A receptor availability in vivo and aggression traits in healthy participants. Thirty-three healthy participants underwent 3-Tesla magnetic resonance imaging and positron emission tomography (PET) with [11C]MDL100907, a selective radioligand for 5-HT2A receptors. To quantify 5-HT2A receptor availability, the binding potential (BPND) was derived using the basis function implementation of the simplified reference tissue model, with the cerebellum as the reference region. The participants’ aggression levels were assessed using the Buss–Perry Aggression Questionnaire. The voxel-based correlation analysis with age and sex as covariates revealed that the total aggression score was significantly positively correlated with [11C]MDL100907 BPND in the right middle temporal gyrus (MTG) pole, left fusiform gyrus (FUSI), right parahippocampal gyrus, and right hippocampus. The physical aggression subscale score had significant positive correlations with [11C]MDL100907 BPND in the left olfactory cortex, left orbital superior frontal gyrus (SFG), right anterior cingulate and paracingulate gyri, left orbitomedial SFG, left gyrus rectus, left MTG, left inferior temporal gyrus, and left angular gyrus. The verbal aggression subscale score showed significant positive correlations with [11C]MDL100907 BPND in the bilateral SFG, right medial SFG, left FUSI, and right MTG pole. Overall, our findings suggest the possibility of positive correlations between aggression traits and in vivo 5-HT2A receptor availability in healthy individuals. Future research should incorporate multimodal neuroimaging to investigate the downstream effects of 5-HT2A receptor-mediated signaling and integrate molecular and systems-level information in relation to aggression traits. Full article
(This article belongs to the Special Issue Role of Serotonin in Brain Function)
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15 pages, 3552 KiB  
Article
Cortical Correlates of Psychedelic-Induced Shaking Behavior Revealed by Voltage Imaging
by Tobias Buchborn, Taylor Lyons, Chenchen Song, Amanda Feilding and Thomas Knöpfel
Int. J. Mol. Sci. 2023, 24(11), 9463; https://doi.org/10.3390/ijms24119463 - 30 May 2023
Cited by 1 | Viewed by 3333
Abstract
(1) From mouse to man, shaking behavior (head twitches and/or wet dog shakes) is a reliable readout of psychedelic drug action. Shaking behavior like psychedelia is thought to be mediated by serotonin 2A receptors on cortical pyramidal cells. The involvement of pyramidal cells [...] Read more.
(1) From mouse to man, shaking behavior (head twitches and/or wet dog shakes) is a reliable readout of psychedelic drug action. Shaking behavior like psychedelia is thought to be mediated by serotonin 2A receptors on cortical pyramidal cells. The involvement of pyramidal cells in psychedelic-induced shaking behavior remains hypothetical, though, as experimental in vivo evidence is limited. (2) Here, we use cell type-specific voltage imaging in awake mice to address this issue. We intersectionally express the genetically encoded voltage indicator VSFP Butterfly 1.2 in layer 2/3 pyramidal neurons. We simultaneously capture cortical hemodynamics and cell type-specific voltage activity while mice display psychedelic shaking behavior. (3) Shaking behavior is preceded by high-frequency oscillations and overlaps with low-frequency oscillations in the motor cortex. Oscillations spectrally mirror the rhythmics of shaking behavior and reflect layer 2/3 pyramidal cell activity complemented by hemodynamics. (4) Our results reveal a clear cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior and open a promising methodological avenue relating a cross-mammalian psychedelic effect to cell-type specific brain dynamics. Full article
(This article belongs to the Special Issue Role of Serotonin in Brain Function)
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Review

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66 pages, 1069 KiB  
Review
The Role of the Serotonergic System in Time Perception: A Systematic Review
by Rauf Akhmirov, Dina Mitiureva, Maria Zaichenko, Kirill Smirnov and Olga Sysoeva
Int. J. Mol. Sci. 2024, 25(24), 13305; https://doi.org/10.3390/ijms252413305 - 11 Dec 2024
Cited by 1 | Viewed by 728
Abstract
Time perception is a fundamental cognitive function essential for adaptive behavior and shared across species. The neural mechanisms underlying time perception, particularly its neuromodulation, remain debated. In this review, we examined the role of the serotonergic system in time perception (at the scale [...] Read more.
Time perception is a fundamental cognitive function essential for adaptive behavior and shared across species. The neural mechanisms underlying time perception, particularly its neuromodulation, remain debated. In this review, we examined the role of the serotonergic system in time perception (at the scale of seconds and minutes), building a translational bridge between human and non-human animal studies. The literature search was conducted according to the PRISMA statement in PubMed, APA PsycINFO, and APA PsycARTICLES. Sixty papers were selected for full-text review, encompassing both human (n = 10) and animal studies (n = 50). Summarizing the reviewed literature, we revealed consistent evidence for the role of serotonin in timing behavior, highlighting its complex involvement across retrospective, immediate, and prospective timing paradigms. Increased serotonergic activation appears to accelerate internal time speed, which we interpret through the dual klepsydra model as accelerated discharge of the temporal accumulator. However, some findings challenge this framework. Additionally, we link impulsivity—associated with decreased serotonergic functioning in our review—to a slower internal time speed. Variability in prospective timing tasks underscores the need for further research into how serotonin modulates reward-based temporal decisions, using novel approaches to disentangle internal time speed, response inhibition, and other factors. Full article
(This article belongs to the Special Issue Role of Serotonin in Brain Function)
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