The serotonin-free brain: behavioral consequences of Tph2 deficiency in animal models

Mosienko, Valentina; Bäder, Michael; Alenina, Natalia

doi:10.1016/b978-0-444-64125-0.00035-9

Cited by 9 publications

(8 citation statements)

References 59 publications

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“…Reduced scores of aggression have been found in male knockout mice lacking the long form of the dopamine D2 receptor [ 21 , 22 ], the α-isoform of the oestrogen receptor [ 23 , 24 ], the arginine vasopressin V1b receptor [ 25 ] or dopamine β-hydroxylase [ 22 , 26 ]. Elevated aggression was shown in mice lacking tryptophan hydroxylase 2 (Tph2) [ 27 , 28 ], serotonin (5-HT) 1B receptor [ 29 ], dopamine transporter (DAT) [ 30 ], nitric oxide synthase (NOS) [ 31 ] and monoamine oxidase A (MAOA) [ 32 ].…”

Section: Animal Models Of Excessive Aggressionmentioning

confidence: 99%

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

Gorlova

Svirin

Павлов

et al. 2023

IJMS

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Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.

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Section: Animal Models Of Excessive Aggressionmentioning

confidence: 99%

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

Gorlova

Svirin

Павлов

et al. 2023

IJMS

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“…They are fertile and females have milk, but they do not care for their offspring, and therefore half of their offspring dies [11,12]. Disorders of the wakefulness-sleep cycle in these mutants are limited, judging by the results of registration of locomotor activity, to a slight increase in sleep and suppression of wakefulness in daylight (daytime), which seems to correspond with the above hypothesis [13].…”

Section: Serotonin and Sleepmentioning

confidence: 70%

Serotonin, Sleep and Depression: A Hypothesis

Kovalzon¹

2022

Serotonin and the CNS - New Developments in Pharmacology and Therapeutics

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For most cases of endogenous depression (major depression), the hypothesis of monoamine deficiency, despite a number of limitations it faces, is still considered the most acceptable explanation. The main difficulty faced by this hypothesis is the reason for the decrease in the level of cerebral monoamines (primarily serotonin) during depression. It is assumed either increased activity of the MAO enzyme, which metabolizes serotonin, or a mutation with the loss of function of the gene of the Tph-2 enzyme, which synthesizes serotonin, as possible causes. In this review, a third cause is proposed, which can explain a number of cases of «spontaneous» onset of depressive symptoms in apparently healthy people, as well as links the hypotheses of “monoamine deficiency” and “disturbances in circadian rhythms.” It is assumed that the formation of endogenous depression is due to a combination of two factors: a reduced “basal” level of cerebral serotonin and excessively long pre-morning periods of REM sleep, during which the release of cerebral monoamines stops altogether. As a possible way to of non-drug treatment of depression, not deprivation, but fragmentation of this phase of sleep is suggested, that is much easier for patients to tolerate.

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“…No association was found between 6 gene SNPs and AIHH-induced respiratory motor plasticity in the humans studied here. Tryptophan hydroxylase-2 ( TPH 2 ) is the rate limiting enzyme for serotonin synthesis [36]; presence of a “G” allele in exon 7 of the TPH 2 gene is associated with reduced serotonin bioavailability [35, 48]. An apparent (but.…”

Section: Discussionmentioning

confidence: 99%

“…Based on known roles of molecules in AIH-induced phrenic motor plasticity and a minimum population penetrance of 10% [3,23,24], we screened for 9 SNPs in genomic DNA extracted from the subject's saliva. Seven candidate genes (Figure 1; Table 1) included autosomal SNPs in: apolipoprotein (APOE4, SNP IDs: rs429358 [T>C] and rs7412 [T>C]), prevalence: APOE4 homozygous ~11%, [17,25,26], APOE3/4 heterozygous ~15-25% [27,28]; brain-derived neurotrophic factor (BDNFval/met, SNP ID: rs6265 [C>T], prevalence ~30-50% [14,[29][30][31]); neurotrophic receptor tyrosine kinase 2 (NTRK2, SNP ID: rs1212171 [C>T], prevalence ~50% [32][33][34]); tryptophan hydroxylase 2 (TPH2, SNP ID: rs7305115, [A>G], prevalence 38-58% [35,36]); 5-hydroxytryptamine receptor 2A (HTR2A, SNP ID: rs6313 [A>G], prevalence ~42% [37]); and, paired-like homeobox 2B (PHOX2B, SNP ID: rs16853571 [A>C], prevalence ~6-14% [38]).…”

Section: Candidate Gene and Single-nucleotide Polymorphism Selectionmentioning

confidence: 99%

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia

Nair

Welch

Marciante

et al. 2023

Preprint

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Rationale: Acute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability. Objectives: Identify individual factors (e.g., genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH). Methods: Associations of individual factors with the magnitude of AIHH (15, 1-min O2=9.5%, CO2=5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P0.1) were evaluated in 17 healthy individuals (age=27±5 years) compared to Sham. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (BDNF, HTR2A, TPH2, MAOA, NTRK2) and neuronal plasticity (apolipoprotein E, APOE) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)ApoE knock-in rats were performed to test causality. Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met (all p>0.05). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P0.1 within the limited age range studied (p=0.007). In hApoE4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3 controls (p<0.05). Conclusions: APOE4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.

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The serotonin-free brain: behavioral consequences of Tph2 deficiency in animal models

Cited by 9 publications

References 59 publications

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

Serotonin, Sleep and Depression: A Hypothesis

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia

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