Dataset Information

Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition.

ABSTRACT: OBJECTIVE:Although the assessment of expression of serotonin-related genes in experimental animals has become a common strategy to shed light on variations in brain serotonergic function, it remains largely unknown to what extent the manipulation of serotonin levels causes detectable changes in gene expression. We therefore chose to investigate how sub-acute depletion or elevation of brain serotonin influences the expression of a number of serotonin-related genes in six brain areas. METHODS:Male Wistar rats were administered a serotonin synthesis inhibitor, para-chlorophenylalanine (p-CPA), or a serotonin reuptake inhibitor, paroxetine, for 3 days and then sacrificed. The expression of a number of serotonin-related genes in the raphe nuclei, hypothalamus, amygdala, striatum, hippocampus and prefrontal cortex was investigated using real-time quantitative PCR (rt-qPCR). RESULTS:While most of the studied genes were uninfluenced by paroxetine treatment, we could observe a robust downregulation of tryptophan hydroxylase-2 in the brain region where the serotonergic cell bodies reside, that is, the raphe nuclei. p-CPA induced a significant increase in the expression of Htr1b and Htr2a in amygdala and of Htr2c in the striatum and a marked reduction in the expression of Htr6 in prefrontal cortex; it also enhanced the expression of the brain-derived neurotrophic factor (Bdnf) in raphe and hippocampus. CONCLUSION:With some notable exceptions, the expression of most of the studied genes is left unchanged by short-term modulation of extracellular levels of serotonin.

SUBMITTER: Naslund J

PROVIDER: S-EPMC7282867 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition.

Näslund Jakob J Studer Erik E Nilsson Staffan S Eriksson Elias E

Acta neuropsychiatrica 20200217

<h4>Objective</h4>Although the assessment of expression of serotonin-related genes in experimental animals has become a common strategy to shed light on variations in brain serotonergic function, it remains largely unknown to what extent the manipulation of serotonin levels causes detectable changes in gene expression. We therefore chose to investigate how sub-acute depletion or elevation of brain serotonin influences the expression of a number of serotonin-related genes in six brain areas.<h4>M ...[more]

PMID: 32063244

Similar Datasets

Project description:Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.

Project description:Selective serotonin reuptake inhibitors (SSRIs) were designed to treat depression by increasing serotonin levels throughout the brain via inhibition of clearance from the extracellular space. Although increases in serotonin levels are observed after acute SSRI exposure, 3-6 weeks of continuous use is required for relief from the symptoms of depression. Thus, it is now believed that plasticity in multiple brain systems that are downstream of serotonergic inputs contributes to the therapeutic efficacy of SSRIs. The onset of antidepressant effects also coincides with desensitization of somatodendritic serotonin autoreceptors in the dorsal raphe nucleus (DRN), suggesting that disrupting inhibitory feedback within the serotonin system may contribute to the therapeutic effects of SSRIs. Previously, we showed that chronic SSRI treatment caused a frequency-dependent facilitation of serotonin signaling that persisted in the absence of uptake inhibition. In this work, we use in vivo fast-scan cyclic voltammetry in mice to investigate a similar facilitation after a single treatment of the SSRI citalopram hydrobromide. Acute citalopram hydrobromide treatment resulted in frequency-dependent increases of evoked serotonin release in the substantia nigra pars reticulata. These increases were independent of changes in uptake velocity, but required SERT expression. Using microinjections, we show that the frequency-dependent enhancement in release is because of SERT inhibition in the DRN, demonstrating that SSRIs can enhance serotonin release by inhibiting uptake in a location distal to the terminal release site. The novel finding that SERT inhibition can disrupt modulatory mechanisms at the level of the DRN to facilitate serotonin release will help future studies investigate serotonin's role in depression and motivated behavior. In this work, stimulations of the dorsal raphe nucleus (DRN) evoke serotonin release that is recorded in the substantia nigra pars reticulata (SNpr) using in vivo fast-scan cyclic voltammetry. Systemic administration of a selective serotonin reuptake inhibitor (SSRI) causes both an increase in t1/2 and an increase in [5-HT]max in the SNpr. Local application of SSRI to the DRN recapitulates the increase in [5-HT]max observed in the SNpr without affecting uptake. Thus, SSRIs increase serotonin signaling via two distinct SERT-mediated mechanisms.

Project description:The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI). Mesenteric nerve recordings were conducted in mice after treatment with SSRI to ascertain if this class of drugs resulted in increased vagal excitability. Patch clamp recordings of enteric neurons were carried out to measure activity of primary afferent neurons in the gut in response to SSRI and to assess the importance of gut epithelium in transducing signal. The tail suspension test (TST) was used following 14d feeding of SSRI in vagotomised and surgical sham mice to measure depressive-like behaviour. Brain mRNA expression was examined via PCR and the intestinal microbiome was assessed. Mesenteric nerve recordings in BALB/c mice demonstrated that oral treatment with SSRI leads to a significant increase in vagal activity. This effect was not observed in mice treated with a representative noradrenaline-dopamine reuptake inhibitor. It is known that signals from the gut can be transmitted to the vagus via the enteric nervous system. Exposure of the gut to SSRI increased the excitability of intrinsic primary afferent neurons in the myenteric plexus, through an intestinal epithelium dependent mechanism, and alpha-diversity of gut microbiota was altered. Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test. This work suggests that vagus nerve dependent gut-brain signaling contributes to the effects of oral SSRI and further, highlights the potential for pharmacological approaches to treatment of mood disorders that focus on vagal stimulation and may not even require therapeutic agents to enter the circulation.

Project description:Besides its "classical" neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system, besides an external placental source, represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC), an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders. Little is known, however, about the exact role of 5-HT and its signaling molecules in the formation of the raphe-prefrontal network. Using explant essays, we here studied the role of the 5-HT transporter (5-HTT), an important modulator of the 5-HT signal, in rostral raphe-prefrontal network formation. We found that the chemotrophic nature of the interaction between the origin (rostral raphe cluster) and a target (mPFC) of the 5-HT projection system was affected in rats lacking the 5-HTT (5-HTT(-/-)). While 5-HTT deficiency did not affect the dorsal raphe 5-HT-positive outgrowing neurites, the median raphe 5-HT neurites switched from a strong repulsive to an attractive interaction when co-cultured with the mPFC. Furthermore, the fasciculation of the mPFC outgrowing neurites was dependent on the amount of 5-HTT. In the mPFC of 5-HTT(-/-) pups, we observed clear differences in 5-HT innervation and the identity of a class of projection neurons of the mPFC. In the absence of the 5-HTT, the 5-HT innervation in all subareas of the early postnatal mPFC increased dramatically and the number of Satb2-positive callosal projection neurons was decreased. Together, these results suggest a 5-HTT dependency during early development of these brain areas and in the formation of the raphe-prefrontal network. The tremendous complexity of the 5-HT projection system and its role in several neurodevelopmental disorders highlights the need for further research in this largely unexplored area.

Dataset Information

Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition.

Publications

Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets