Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Barre, Annick; Berthoux, Coralie; Bundel, Dimitri De; Valjent, Emmanuel; Bockaert, Joël; Marin, Philippe; Bécamel, Carine

doi:10.1073/pnas.1525586113

Cited by 89 publications

(62 citation statements)

References 58 publications

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“…A high Bayesian learning rate is concordant with the enhanced neural plasticity observed in individuals in a psychedelic state (Barre et al, 2016;Berthoux, Barre, Bockaert, Marin, & Bécamel, 2018;Ly et al, 2018). While an impairment to highlevel cognition is found under psychedelics (Bayne & Carter, 2018), in line with the high Bayesian learning rate hypothesis, low-level learning (including extinction learning) and processing appears to be unaffected or enhanced in the psychedelic state (Carhart-Harris & Nutt, 2017;King, Martin, & Seymour, 1972;Romano et al, 2010).…”

Section: Evidence For the High Bayesian Learning Rate Hypothesissupporting

confidence: 59%

Dissolving the self

Deane

2020

PhiMiSci

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Psychedelic drugs such as psilocybin, LSD and DMT are known to induce powerful alterations in phenomenology. Perhaps of most philosophical and scientific interest is their capacity to disrupt and even “dissolve” one of the most primary features of normal experience: that of being a self. Such “peak” or “mystical” experiences are of increasing interest for their potentially transformative therapeutic value. While empirical research is underway, a theoretical conception of the mechanisms underpinning these experiences remains elusive. In the following paper, psychedelic-induced ego-dissolution is accounted for within an active inference framework, as a collapse in the “temporal thickness” of an agent’s deep temporal model, as a result of lowered precision on high-level priors. The argument here is composed of three moves: first, a view of the self-model is proposed as arising within a temporally deep generative model of an embodied organism navigating an affordance landscape in the service of allostasis. Next, a view of the action of psychedelics as lowering the precision of high-level priors within the generative model is unpacked in terms of a high Bayesian learning rate. Finally, the relaxation of high-level priors is argued to cause a “collapse” in the temporal thickness of the generative model, resulting in a collapse in the self-model and a loss of the ordinary sense of being a self. This account has implications for our understanding of ordinary self-consciousness and disruptions in self-consciousness present in psychosis, autism, depression, and dissociative disorders. The philosophical, theoretical and therapeutic implications of this account are touched upon.

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Section: Evidence For the High Bayesian Learning Rate Hypothesissupporting

confidence: 59%

Dissolving the self

Deane

2020

PhiMiSci

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“…Given that BP and RNA expression cor-related positively in right anterior insula but not in insula proisocortex, a likely reason for this noncorrespondence may be due to the presence of presynaptic 5HT 2A specifically within this region. Presynaptic 5HT 2A would contribute to BP but not necessarily to RNA levels, since the RNA coding for presynaptic receptors would normally reside in cell bodies in a distal part of the brain, such as, for example, the 5HT 2A -expressing thalamocortical inputs to the insula (43). Thus, depending on the overall balance between pre-and postsynaptic 5HT 2A , there will be more or less correspondence between BP and RNA in different brain areas.…”

Section: Discussionmentioning

confidence: 99%

Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates

Santangelo

Sawiak

Fryer

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variation in the serotonin transporter gene (SLC6A4) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT2A). Thus, we correlated 5HT2A binding potential (BP) and RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intruder after 5HT2A pharmacological antagonism, while CT/T/C individuals showed no effect. A voxel-based correlation analysis, independent of SLC6A4 genotype, revealed that 5HT2A BP in the adjacent right anterior insula and insula proisocortex was negatively correlated with trait anxiety scores. Moreover, 5HT2A BP in both regions was a good predictor of the size and direction of the acute emotional response to the human intruder threat after 5HT2A antagonism. Our findings suggest that genetic variation in the SLC6A4 repeat region may contribute to the trait anxious phenotype via neurochemical changes in brain areas implicated in interoceptive and emotional processing, with a critical role for the right insula 5HT2A in the regulation of affective responses to threat.

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“…substantia nigra (SN), ventral tegmental nuclei, pontine nuclei, hypothalamus, periaqueductal gray, ventral mesencephalon, and parabrachial regions (Sánchez-González et al, 2005;Jacob and Nienborg, 2018). Several observations indicate the participation of serotonin (Marek et al, 2001; Barre et al, 2016) and noradrenaline (Morrison and Foote, 1986;Jacob and Nienborg, 2018) in the early and complex visual processing as well as in the behavioral responses (inhibition/arousal) to visual inputs. These processes are obtained by modulating the activity of the sensory cortices, TRN, and selected thalamic nuclei, as well as distinct thalamocortical circuitry (Jacob and Nienborg, 2018).…”

Section: Neurotransmitters Involved In Visual Hallucinationsmentioning

confidence: 99%

The Pharmacology of Visual Hallucinations in Synucleinopathies

et al. 2019

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Visual Hallucinations in Synucleinopathies Russo et al. Visual Hallucinations in Synucleinopathies Russo et al. Verapamil Diltiazem Antimicrobial (Unclear mechanism) Carbapenems Trimethoprimsulfamethoxazole Voriconazole Posaconazole Therapeutic options for VH in synucleinopathies Category Drugs Novel antiserotonergic Pimavanserin Ondansetron Atypical antipsychotic Quetiapine Clozapine The lower part of the table shows instead suitable therapeutic options for VH in synucleinopathies.

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Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Cited by 89 publications

References 58 publications

Dissolving the self

Dissolving the self

Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates

The Pharmacology of Visual Hallucinations in Synucleinopathies

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