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Serotonin and cognitive flexibility
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... sérotonine 5HTT. Ce gène est notamment impliqué dans la flexibilité cognitive (Nilsson et al., 2019), ainsi que dans la régulation des émotions et de la cognition sociale (Canli & Lesch, 2007). Les allèles HTTLPR du gène SLC6A4, en version courte (S pour Short), sont associés à l'anxiété, la dépression, et à une de plus forte sensibilité au stress, alors que les versions longues (L) sont associées à une augmentation significative de la sévérité des symptômes de la schizophrénie (Goldberg et al., 2009). ...
... Une hypothèse alternative pourrait expliquer en partie cette absence de lien dans cette étude. Au chapitre 2.4., nous avons abordé le lien entre le gène SLC6A4 codant pour la protéine 5HTT impliquée dans le transport de la sérotonine, la flexibilité cognitive (Nilsson et al., 2019), la régulation des émotions, et la cognition sociale (Canli & Lesch, 2007). Chez l'humain, différentes versions des allèles de ce gène sont liées à une aggravation des troubles cliniques, par exemple chez le sujet schizophrène (Goldberg et al., 2009) ou TSA (Brune et al., 2006). ...
Cognitive flexibility is an executive function that allows us to switch from one cognitive operation to another. This ability is important for problem-solving in the physical and social worlds. The aim of this thesis was to investigate whether there is a link between individual cognitive flexibility abilities in baboons and their social position. This study was carried out with a group of Guinea baboons (Papio papio) from the “Cognition et comportement du Primate” (CCDP) platform housed at the Rousset sur Arc CNRS primatology center. This platform allows baboons to interact freely with a battery of operant conditioning systems (ALDM, Fagot & Paleressompoule, 2009) on which we present cognitive tests on touch screens. First, we exposed the baboons to an adaptation of the Wisconsin Card Sorting Test task (WCST: Berg, 1948) for two years. Analysis of the data shows an effect of age, with cognitive flexibility - as measured by the number of perseveration errors - being maximal in adults but less effective in the youngest and oldest baboons. Second, we studied supplanting behaviours in ALDM test systems to test whether these measures reflect hierarchical ranks. Comparison with data from direct observations allowed a validation of this hypothesis. Third, we analysed social networks and hierarchical ranks considering cognitive performance in the WSCT task. The baboons at the centre of the network (centrality index) are the most flexible in the WSCT task, while no effect appears with respect to hierarchical rank. Together, these data show the importance of executive control in the management of social problems in the Guinea baboon.
... Hominin evolution occurred in settings of strong climatic and environmental variability (Potts, 2013) and involved an increasing interdependence and reliance on intelligence, cooperation, and learning from others (Sterelny, 2012). This dynamic inevitably placed a higher strain on the serotonergic system given its involvement in facilitating stress relief and mental flexibility (Carhart-Harris and Nutt, 2017;Nilsson et al., 2019) by regulating perception, cognitive function, mood, memory, and social behavior (Berger et al., 2009;Friedman, 2018;Tricklebank and Daly, 2019). ...
Our hominin ancestors inevitably encountered and likely ingested psychedelic mushrooms throughout their evolutionary history. This assertion is supported by current understanding of: early hominins’ paleodiet and paleoecology; primate phylogeny of mycophagical and self-medicative behaviors; and the biogeography of psilocybin-containing fungi. These lines of evidence indicate mushrooms (including bioactive species) have been a relevant resource since the Pliocene, when hominins intensified exploitation of forest floor foods. Psilocybin and similar psychedelics that primarily target the serotonin 2A receptor subtype stimulate an active coping strategy response that may provide an enhanced capacity for adaptive changes through a flexible and associative mode of cognition. Such psychedelics also alter emotional processing, self-regulation, and social behavior, often having enduring effects on individual and group well-being and sociality. A homeostatic and drug instrumentalization perspective suggests that incidental inclusion of psychedelics in the diet of hominins, and their eventual addition to rituals and institutions of early humans could have conferred selective advantages. Hominin evolution occurred in an ever-changing, and at times quickly changing, environmental landscape and entailed advancement into a socio-cognitive niche, i.e., the development of a socially interdependent lifeway based on reasoning, cooperative communication, and social learning. In this context, psychedelics’ effects in enhancing sociality, imagination, eloquence, and suggestibility may have increased adaptability and fitness. We present interdisciplinary evidence for a model of psychedelic instrumentalization focused on four interrelated instrumentalization goals: management of psychological distress and treatment of health problems; enhanced social interaction and interpersonal relations; facilitation of collective ritual and religious activities; and enhanced group decision-making. The socio-cognitive niche was simultaneously a selection pressure and an adaptive response, and was partially constructed by hominins through their activities and their choices. Therefore, the evolutionary scenario put forward suggests that integration of psilocybin into ancient diet, communal practice, and proto-religious activity may have enhanced hominin response to the socio-cognitive niche, while also aiding in its creation. In particular, the interpersonal and prosocial effects of psilocybin may have mediated the expansion of social bonding mechanisms such as laughter, music, storytelling, and religion, imposing a systematic bias on the selective environment that favored selection for prosociality in our lineage.
: media-1vid110.1542/5839990273001PEDS-VA_2017-4161Video Abstract OBJECTIVES: To estimate the national prevalence of parent-reported autism spectrum disorder (ASD) diagnosis among US children aged 3 to 17 years as well as their treatment and health care experiences using the 2016 National Survey of Children's Health (NSCH).
Methods:
The 2016 NSCH is a nationally representative survey of 50 212 children focused on the health and well-being of children aged 0 to 17 years. The NSCH collected parent-reported information on whether children ever received an ASD diagnosis by a care provider, current ASD status, health care use, access and challenges, and methods of treatment. We calculated weighted prevalence estimates of ASD, compared health care experiences of children with ASD to other children, and examined factors associated with increased likelihood of medication and behavioral treatment.
Results:
Parents of an estimated 1.5 million US children aged 3 to 17 years (2.50%) reported that their child had ever received an ASD diagnosis and currently had the condition. Children with parent-reported ASD diagnosis were more likely to have greater health care needs and difficulties accessing health care than children with other emotional or behavioral disorders (attention-deficit/hyperactivity disorder, anxiety, behavioral or conduct problems, depression, developmental delay, Down syndrome, intellectual disability, learning disability, Tourette syndrome) and children without these conditions. Of children with current ASD, 27% were taking medication for ASD-related symptoms, whereas 64% received behavioral treatments in the last 12 months, with variations by sociodemographic characteristics and co-occurring conditions.
Conclusions:
The estimated prevalence of US children with a parent-reported ASD diagnosis is now 1 in 40, with rates of ASD-specific treatment usage varying by children's sociodemographic and co-occurring conditions.
Importance
Prenatal exposure to certain medications has been hypothesized to influence the risk of autism spectrum disorders (ASD). However, the underlying effects on the neurotransmitter systems have not been comprehensively assessed.
Objective
To investigate the association of early-life interference with different neurotransmitter systems by prenatal medication exposure on the risk of ASD in offspring.
Design, Setting, and Participants
This case-control study included children born from January 1, 1997, through December 31, 2007, and followed up for ASD until January 26, 2015, within a single Israeli health maintenance organization. Using publicly available data, 55 groups of medications affecting neurotransmitter systems and prescribed to pregnant women in this sample were identified. Children prenatally exposed to medications were compared with nonexposed children. Data were analyzed from March 1, 2017, through June 20, 2018.
Main Outcome and Measures
Hazard ratios (HRs) and 95% CIs of ASD risk associated with exposure to medication groups using Cox proportional hazards regression, adjusted for the relevant confounders (eg, birth year, maternal age, maternal history of psychiatric and neurologic disorders, or maternal number of all medical diagnoses 1 year before pregnancy).
Results
The analytic sample consisted of 96 249 individuals (1405 cases; 94 844 controls; mean [SD] age at the end of follow-up, 11.6 [3.1] years; 48.8% female), including 1405 with ASD and 94 844 controls. Of 34 groups of medications, 5 showed nominally statistically significant association with ASD in fully adjusted models. Evidence of confounding effects of the number of maternal diagnoses on the association between offspring exposure to medication and ASD was found. Adjusting for this factor, lower estimates of ASD risk among children exposed to cannabinoid receptor agonists (HR, 0.72; 95% CI, 0.55-0.95; P = .02), muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24-0.98; P = .04), opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45-0.99; P = .045), or α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19-0.96; P = .04) were observed. Exposure to antagonists of neuronal nicotinic acetylcholine receptor α was associated with higher estimates of ASD risk (HR, 12.94; 95% CI, 1.35-124.25; P = .03).
Conclusions and Relevance
Most of the medications affecting neurotransmitter systems in this sample had no association with the estimates of ASD risk. Replication and/or validation using experimental techniques are required.
Studies have investigated the risk of autism spectrum disorder (ASD) in children exposed in utero to antidepressant, with inconsistent results. Given the substantial public health implications on this topic, here, we presented an updated meta-analysis of the association between maternal antidepressant use during pregnancy and ASD. Cochrane Library, EMBASE, PsycINFO, and PubMed databases were systematically searched. A random effects model was used to pool the adjusted relative risk (RR) for cohort studies and the adjusted odds ratio (OR) for case-control studies as well as their corresponding 95% confidence intervals (CIs). Meta-analysis restricted to sibling studies was also conducted. Publication bias was systematically assessed. Fourteen studies were identified (eight cohort studies and six case-control studies). Pooled adjusted RR for cohort studies (n = 2,839,980) was 1.13 (0.93–1.39) showed a non-significant association; while two studies were potentially missing from the test of publication bias, filled estimates also showed a non-significant association (filled RR 0.97, 95% CI 0.79–1.19). Pooled OR was 1.51 (1.15–1.99) for case-control studies (n = 117,737) showed a significant association; two studies were potentially missing; however, the filled estimates suggested a non-significant association (filled OR 1.26, 95% CI 0.98–1.62). Analyses restricted to sibling studies also showed a non-significant association (RR 0.99, 95% CI 0.81–1.22). In summary, we did not evidence a significant association between maternal antidepressant use during pregnancy and ASD.
Electronic supplementary material
The online version of this article (10.1186/s13229-018-0207-7) contains supplementary material, which is available to authorized users.
An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.
Perinatal administration of serotonin (5HT) agonist 5-methoxytryptamine (5MT) induces developmental hyperserotonemia (DHS; elevated blood serotonin) and produces behavioral and neurochemical changes in rats relevant to Autism Spectrum Disorder (ASD), such as oxytocin dysregulation. Disruption of the oxytocin system may underlie many of the social deficits present in ASD individuals, thus we investigated the mechanism(s) underlying DHS-induced oxytocin dysregulation. The most parsimonious mechanism of 5HT action would be via alteration of 5HT receptors on oxytocin cells; 5HT is known to influence cell survival as well as influence oxytocin release via 5HT1A and 5HT2A receptors, which co-localize in oxytocin-expressing (OXT+) cells in the paraventricular nucleus (PVN) of the hypothalamus. We report that both male and female DHS rats have a lower percentage of OXT+ cells co-localized with excitatory 5HT2A receptors than control animals, while only DHS females have a higher percentage of OXT+ cells co-localized with inhibitory 5HT1A receptors compared to controls. Importantly, DHS also reduces the number of OXT+ cells in the PVN of adult male, but not female, rats. This pattern suggests that females, but not males, can regulate 5HT receptors in response to DHS in a manner that promotes oxytocin cell survival and functional efficiency. In addition, it has been previously reported that DHS alters normal juvenile play, especially in males, thus we also tested play partner preference among juvenile control and DHS males. Sex differences observed using the DHS model of ASD add to its validity, given the pronounced male sex bias in the prevalence of ASD, and emphasize the need for inclusion of both sexes in ASD research.
A variety of human and animal studies support the hypothesis that serotonin (5-hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5-HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, and review evidence implicating perinatal disruptions in 5-HT signaling in the pathophysiology of autism spectrum disorder. We discuss the importance, and relative dearth, of studies that explore the possible correlation to autism in the interactions between important intrinsic and extrinsic factors that may disrupt 5-HT homeostasis during development. In particular, we focus on exposure to 5-HT transport altering mechanisms such as selective serotonin-reuptake inhibitors or genetic polymorphisms in primary or auxiliary transporters of 5-HT, and how they relate to neurological stores of serotonin and its precursors. A deeper understanding of the many mechanisms by which 5-HT signaling can be disrupted, alone and in concert, may contribute to an improved understanding of the etiologies and heterogeneous nature of this disorder. We postulate that extreme bidirectional perturbations of these factors during development likely compound or synergize to facilitate enduring neurochemical changes resulting in insufficient or excessive 5-HT signaling, that could underlie the persistent behavioral characteristics of autism spectrum disorder.
Objective:
The cause of autistic spectrum disorder (i.e., autism and Asperger's syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors' knowledge.
Method:
The authors investigated cortical 5-HT2A receptor binding in eight adults with Asperger's syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150).
Results:
People with Asperger's syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication.
Conclusions:
The authors' findings suggest that adults with Asperger's syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.
The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of fourteen brains of human patients with Parkinson’s disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.
The continuing fascination with serotonin (5‐hydroxytryptamine, 5‐HT) as a nervous system chemical messenger began with its discovery in the brains of mammals in 1953. Among the many reasons for this decades‐long interest is that the small numbers of neurons that make 5‐HT influence the excitability of neural circuits in nearly every region of the brain and spinal cord. A further reason is that 5‐HT dysfunction has been linked to a range of psychiatric and neurological disorders many of which have a neurodevelopmental component. This has led to intense interest in understanding 5‐HT neuron development with the aim of determining whether early alterations in their generation lead to brain disease susceptibility. Here, we present an overview of the neuroanatomical organization of vertebrate 5‐HT neurons, their neurogenesis, and prodigious axonal architectures, which enables the expansive reach of 5‐HT neuromodulation in the central nervous system. We review recent findings that have revealed the molecular basis for the tremendous diversity of 5‐HT neuron subtypes, the impact of environmental factors on 5‐HT neuron development, and how 5‐HT axons are topographically organized through disparate signaling pathways. We summarize studies of the gene regulatory networks that control the differentiation, maturation, and maintenance of 5‐HT neurons. These studies show that the regulatory factors controlling acquisition of 5‐HT‐type transmitter identity continue to play critical roles in the functional maturation and the maintenance of 5‐HT neurons. New insights are presented into how continuously expressed 5‐HT regulatory factors control 5‐HT neurons at different stages of life and how the regulatory networks themselves are maintained. WIREs Dev Biol 2018, 7:e301. doi: 10.1002/wdev.301
This article is categorized under: Nervous System Development > Vertebrates: General Principles
Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
Gene Expression and Transcriptional Hierarchies > Cellular Differentiation
Nervous System Development > Secondary: Vertebrates: Regional Development
Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-HT<sub>1B/1D/5</sub> receptors. Since chronic blockade of sympatho-excitatory 5-HT<sub>2</sub> receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT<sub>2</sub> receptor antagonist) alters the pharmacological profile of the above sympatho-inhibition. Rats were pretreated during 2 weeks with sarpogrelate in drinking water (30 mg/kg.day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation (C<sub>7</sub>-T<sub>1</sub>) of the cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. I.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT receptor agonists 5-carboxamidotryptamine (5-CT; 5-HT<sub>1/5A</sub>), CP 93,129 (5-HT<sub>1B</sub>) or PNU 142633 (5-HT<sub>1D</sub>), but not by indorenate (5-HT<sub>1A</sub>) in both groups; whereas LY344864 (5-HT<sub>1F</sub>) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 μg/kg; 5-HT<sub>1B/1D/1F</sub> receptor antagonist) attenuated 5-CT- and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-HT<sub>5A</sub> receptor antagonist) abolished 5-CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-HT<sub>1B</sub>, 5-HT<sub>1D</sub> and 5-HT<sub>5A</sub> receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympatho-inhibition mediated by 5-HT<sub>1F</sub> receptors.