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Chronic social defeat stress induces anxiety-like behaviors via downregulation of serotonin transporter in the prefrontal serotonergic system in mice. 2024

Ryota Araki, and Ayami Kita, and Yukio Ago, and Takeshi Yabe
Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan. Electronic address: r-araki@pharm.setsunan.ac.jp.

The serotonergic (5-HTergic) system is closely involved in the pathophysiology of mood and anxiety disorders and the responsibility of this system may differ for each symptom. In this study, we examined the relationship between the dysfunction of the 5-HTergic system and abnormal behaviors in the social defeat stress model, an animal model of mood and anxiety disorders and in mice with knockdown of Slc6a4, the gene encoding SERT. Monoamine content, serotonin (5-HT) release, 5-HT uptake, 5-HT transporter (SERT) protein levels, and behaviors were investigated in mice subjected to chronic social defeat stress and in mice with knockdown of Slc6a4, in 5-HTergic neurons projecting to the prefrontal cortex (PFC). Furthermore, DNA methylation of Slc6a4 was examined in mice subjected to chronic social defeat stress. Increased turnover, increased extracellular basal levels, decreased release and decreased uptake of 5-HT, and decreased SERT protein levels were observed in the PFC of the stressed mice. The decreased 5-HT uptake correlated with anxiety-like behavior characterized by decreased time spent in the open arms of the elevated plus maze. DNA methylation was increased in the CpG island of Slc6a4 in 5-HTergic neurons projecting to the PFC of the stressed mice. Similar to the stressed mice, mice with Slc6a4 knockdown in 5-HTergic neurons projecting to the PFC also showed decreased release and uptake of 5-HT in the PFC and increased anxiety-like behavior. Chronic stress may induce anxiety due to dysfunction in the prefrontal 5-HTergic system via decreased SERT expression in the PFC.

UI MeSH Term Description Entries
D000083703 Social Defeat Conflict between members of the same species that generates emotional and psychological stress and increased social distance. Defeat, Social
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001007 Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with ANXIETY DISORDERS. Angst,Anxiousness,Hypervigilance,Nervousness,Social Anxiety,Anxieties, Social,Anxiety, Social,Social Anxieties
D012701 Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator. 5-HT,5-Hydroxytryptamine,3-(2-Aminoethyl)-1H-indol-5-ol,Enteramine,Hippophaine,Hydroxytryptamine,5 Hydroxytryptamine
D015536 Down-Regulation A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins. Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor
D017397 Prefrontal Cortex The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the MEDIODORSAL NUCLEUS OF THE THALAMUS. The prefrontal cortex receives afferent fibers from numerous structures of the DIENCEPHALON; MESENCEPHALON; and LIMBIC SYSTEM as well as cortical afferents of visual, auditory, and somatic origin. Anterior Prefrontal Cortex,Brodmann Area 10,Brodmann Area 11,Brodmann Area 12,Brodmann Area 47,Brodmann's Area 10,Brodmann's Area 11,Brodmann's Area 12,Brodmann's Area 47,Pars Orbitalis,Frontal Sulcus,Gyrus Frontalis Inferior,Gyrus Frontalis Superior,Gyrus Orbitalis,Gyrus Rectus,Inferior Frontal Gyrus,Lateral Orbitofrontal Cortex,Marginal Gyrus,Medial Frontal Gyrus,Olfactory Sulci,Orbital Area,Orbital Cortex,Orbital Gyri,Orbitofrontal Cortex,Orbitofrontal Gyri,Orbitofrontal Gyrus,Orbitofrontal Region,Rectal Gyrus,Rectus Gyrus,Straight Gyrus,Subcallosal Area,Superior Frontal Convolution,Superior Frontal Gyrus,Ventral Medial Prefrontal Cortex,Ventromedial Prefrontal Cortex,Anterior Prefrontal Cortices,Area 10, Brodmann,Area 10, Brodmann's,Area 11, Brodmann,Area 11, Brodmann's,Area 12, Brodmann,Area 12, Brodmann's,Area 47, Brodmann,Area 47, Brodmann's,Area, Orbital,Area, Subcallosal,Brodmanns Area 10,Brodmanns Area 11,Brodmanns Area 12,Brodmanns Area 47,Convolution, Superior Frontal,Convolutions, Superior Frontal,Cortex, Anterior Prefrontal,Cortex, Lateral Orbitofrontal,Cortex, Orbital,Cortex, Orbitofrontal,Cortex, Prefrontal,Cortex, Ventromedial Prefrontal,Cortices, Ventromedial Prefrontal,Frontal Convolution, Superior,Frontal Gyrus, Inferior,Frontal Gyrus, Medial,Frontal Gyrus, Superior,Frontalis Superior, Gyrus,Gyrus, Inferior Frontal,Gyrus, Marginal,Gyrus, Medial Frontal,Gyrus, Orbital,Gyrus, Orbitofrontal,Gyrus, Rectal,Gyrus, Rectus,Gyrus, Straight,Gyrus, Superior Frontal,Inferior, Gyrus Frontalis,Lateral Orbitofrontal Cortices,Olfactory Sulcus,Orbital Areas,Orbital Cortices,Orbital Gyrus,Orbitalis, Pars,Orbitofrontal Cortex, Lateral,Orbitofrontal Cortices,Orbitofrontal Cortices, Lateral,Orbitofrontal Regions,Prefrontal Cortex, Anterior,Prefrontal Cortex, Ventromedial,Prefrontal Cortices, Anterior,Region, Orbitofrontal,Subcallosal Areas,Sulcus, Frontal,Superior Frontal Convolutions,Superior, Gyrus Frontalis,Ventromedial Prefrontal Cortices
D050486 Serotonin Plasma Membrane Transport Proteins Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of serotonergic neurons. They are different than SEROTONIN RECEPTORS, which signal cellular responses to SEROTONIN. They remove SEROTONIN from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. Regulates signal amplitude and duration at serotonergic synapses and is the site of action of the SELECTIVE SEROTONIN REUPTAKE INHIBITORS. Neurotransmitter Transport Proteins, Serotonin-Specific,Neurotransmitter Transporters, Serotonin-Specific,Serotonin Plasma Membrane Transporter Proteins,5-Hydroxytryptamine Plasma Membrane Transport Protein,5HT Transporter,Platelet Serotonin Transporter,SERT Proteins,SLC6A4 Protein,Serotonectin,Serotonin Transporter,Serotonin Transporter, Platelets,Sodium-Dependent Serotonin Transporter,Solute Carrier Family 6, Member 4 Protein,5 Hydroxytryptamine Plasma Membrane Transport Protein,Neurotransmitter Transport Proteins, Serotonin Specific,Neurotransmitter Transporters, Serotonin Specific,Platelets Serotonin Transporter,Serotonin Transporter, Platelet,Serotonin Transporter, Sodium-Dependent,Serotonin-Specific Neurotransmitter Transporters,Sodium Dependent Serotonin Transporter,Transporter, Sodium-Dependent Serotonin
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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