An effect of serotonergic stimulation on learning rates for rewards apparent after long intertrial intervals

Serotonin has widespread, but computationally obscure, modulatory effects on learning and cognition. Here, we studied the impact of optogenetic stimulation of dorsal raphe serotonin neurons in mice performing a non-stationary, reward-driven decision-making task. Animals showed two distinct choice strategies. Choices after short inter-trial-intervals (ITIs) depended only on the last trial outcome and followed a win-stay-lose-switch pattern. In contrast, choices after long ITIs reflected outcome history over multiple trials, as described by reinforcement learning models. We found that optogenetic stimulation during a trial significantly boosted the rate of learning that occurred due to the outcome of that trial, but these effects were only exhibited on choices after long ITIs. This suggests that serotonin neurons modulate reinforcement learning rates, and that this influence is masked by alternate, unaffected, decision mechanisms. These results provide insight into the role of serotonin in treating psychiatric disorders, particularly its modulation of neural plasticity and learning.info:eu-repo/semantics/publishedVersio

The effects of acute tryptophan depletion on costly information sampling: impulsivity or aversive processing?

RATIONALE: The neurotransmitter serotonin (5-HT) has been implicated in both aversive processing and impulsivity. Reconciling these accounts, recent studies have demonstrated that 5-HT is important for punishment-induced behavioural inhibition. These studies focused on situations where actions lead directly to punishments. However, decision-making often involves making tradeoffs between small 'local' costs and larger 'global' losses. OBJECTIVE: We aimed to distinguish whether 5-HT promotes avoidance of local losses, global losses, or both, in contrast to an overall effect on reflection impulsivity. We further examined the influence of individual differences in sub-clinical depression, anxiety and impulsivity on global and local loss avoidance. METHODS: Healthy volunteers (N = 21) underwent an acute tryptophan depletion procedure in a double-blind, placebo-controlled crossover design. We measured global and local loss avoidance in a decision-making task where subjects could sample information at a small cost to avoid making incorrect decisions, which resulted in large losses. RESULTS: Tryptophan depletion removed the suppressive effects of small local costs on information sampling behaviour. Sub-clinical depressive symptoms produced effects on information sampling similar to (but independent from) those of tryptophan depletion. Dispositional anxiety was related to global loss avoidance. However, trait impulsivity was unrelated to information sampling. CONCLUSIONS: The current findings are consistent with recent theoretical work that characterises 5-HT as pruning a tree of potential decisions, eliminating options expected to lead to aversive outcomes. Our results extend this account by proposing that 5-HT promotes reflexive avoidance of relatively immediate aversive outcomes, potentially at the expense of more globally construed future losses

Euclid preparation: XIII. Forecasts for galaxy morphology with the Euclid Survey using deep generative models

We present a machine learning framework to simulate realistic galaxies for the Euclid Survey, producing more complex and realistic galaxies than the analytical simulations currently used in Euclid. The proposed method combines a control on galaxy shape parameters offered by analytic models with realistic surface brightness distributions learned from real Hubble Space Telescope observations by deep generative models. We simulate a galaxy field of 0.4 deg2 as it will be seen by the Euclid visible imager VIS, and we show that galaxy structural parameters are recovered to an accuracy similar to that for pure analytic Sérsic profiles. Based on these simulations, we estimate that the Euclid Wide Survey (EWS) will be able to resolve the internal morphological structure of galaxies down to a surface brightness of 22.5 mag arcsec-2, and the Euclid Deep Survey (EDS) down to 24.9 mag arcsec-2. This corresponds to approximately 250 million galaxies at the end of the mission and a 50% complete sample for stellar masses above 1010.6 M (resp. 109.6 M) at a redshift z ∼ 0.5 for the EWS (resp. EDS). The approach presented in this work can contribute to improving the preparation of future high-precision cosmological imaging surveys by allowing simulations to incorporate more realistic galaxies

Euclid preparation XIII. Forecasts for galaxy morphology with the Euclid Survey using deep generative models

We present a machine learning framework to simulate realistic galaxies for the Euclid Survey, producing more complex and realistic galaxies than the analytical simulations currently used in Euclid. The proposed method combines a control on galaxy shape parameters offered by analytic models with realistic surface brightness distributions learned from real Hubble Space Telescope observations by deep generative models. We simulate a galaxy field of 0.4 deg2 as it will be seen by the Euclid visible imager VIS, and we show that galaxy structural parameters are recovered to an accuracy similar to that for pure analytic Sérsic profiles. Based on these simulations, we estimate that the Euclid Wide Survey (EWS) will be able to resolve the internal morphological structure of galaxies down to a surface brightness of 22.5 mag arcsec−2, and the Euclid Deep Survey (EDS) down to 24.9 mag arcsec−2. This corresponds to approximately 250 million galaxies at the end of the mission and a 50% complete sample for stellar masses above 1010.6 M⊙ (resp. 109.6 M⊙) at a redshift z ∼ 0.5 for the EWS (resp. EDS). The approach presented in this work can contribute to improving the preparation of future high-precision cosmological imaging surveys by allowing simulations to incorporate more realistic galaxies

The striatal neurotensin receptor modulates striatal and pallidal glutamate and GABA release: functional evidence for a pallidal glutamate-GABA interaction via the pallidal-subthalamic nucleus loop.

In the present study, we used dual-probe microdialysis to investigate the effects of intrastriatal perfusion with neurotensin (NT) on striatal and pallidal glutamate and GABA release. The role of the pallidal GABAA receptor in the intrastriatal NT-induced increase in pallidal glutamate release was also investigated. Intrastriatal NT (100 and 300 nm) increased striatal glutamate and GABA (100 nm, 155 ± 9 and 141 ± 6%, respectively; 300 nm, 179 ± 8 and 166 ± 11%, respectively) release, as well as pallidal glutamate and GABA (100 nm, 144 ± 8 and 130 ± 5%; 300 nm, 169 ± 9 and 157 ± 8%, respectively) release. These effects were dose-dependently antagonized by the NT receptor antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.3.7)-decan-2-carboxylic acid (SR48692). Intrasubthalamic injection of the GABAA receptor antagonist (−)-bicuculline (10 pmol/100 nl, 30 sec) rapidly increased pallidal glutamate release, whereas the intrastriatal NT-induced increase in pallidal glutamate release was counteracted by intrapallidal perfusion with (−)-bicuculline, suggesting that an increase in striopallidal GABA-mediated inhibition of the GABAergic pallidal–subthalamic pathway results in an increased glutamatergic drive in the subthalamic–pallidal pathway. These results demonstrate a tonic pallidal GABA-mediated inhibition of excitatory subthalamic–pallidal neurons and strengthen the evidence for a functional role of NT in the regulation of glutamate and GABA transmission in the basal ganglia. The ability of intrastriatal SR48692 to counteract the NT-induced increase in both striatal and pallidal glutamate and GABA release suggests that blockade of the striatal NT receptor may represent a possible new therapeutic strategy in the treatment of those hypokinetic disorders implicated in disorders of the indirect pathway mediating motor inhibition

Direct and indirect interactions between cannabinoid CB1 receptor and group II metabotropic glutamate receptor signalling in layer V pyramidal neurons from the rat prefrontal cortex.

At proximal synapses from layer V pyramidal neurons from the rat prefrontal cortex, activation of group II metabotropic glutamate receptors (group II mGlu) by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCG IV) induced a long-lasting depression of excitatory postsynaptic currents. Paired-pulse experiments suggested that the depression was expressed presynaptically. Activation of type 1 cannabinoid receptors (CB1) by WIN 55,212-2 occluded the DCG IV-induced depression in a mutually occlusive manner. At the postsynaptic level, WIN 55,212-2 and DCG IV were also occlusive for the activation of extracellular signal-regulated kinase. The postsynaptic localization of active extracellular signal-regulated kinase was confirmed by immunocytochemistry after activation of CB1 receptors. However, phosphorylation of extracellular signal-regulated kinase in layer V pyramidal neurons was dependent on the activation of N-methyl-d-aspartate receptors, consequently to a release of glutamate in the local network. Group II mGlu were also shown to be involved in long-term changes in synaptic plasticity induced by high frequency stimulations. The group II mGlu antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE) favoured long-term depression. However, no interaction was found between MSOPPE, WIN 55,212-2 and the CB1 receptor antagonist SR 141716A on the modulation of long-term depression or long-term potentiation and the effects of these drugs were rather additive. We suggest that CB1 receptor and group II mGlu signalling may interact through a presynaptic mechanism in the induction of a DCG IV-induced depression. Postsynaptically, an indirect interaction occurs for activation of extracellular signal-regulated kinase. However, none of these interactions seem to play a role in synaptic plasticities induced with high frequency stimulations

Neurotensin enhances glutamate excitotoxicity in dopamine nerve cells of primary cultures of mesencephalic neurons.

The tridecapeptide neurotensin has been demonstrated to increase glutamate release in discrete rat brain regions, leading to the hypothesis of a possible involvement of the peptide in neurodegenerative pathologies. The role of neurotensin in modulating glutamate excitotoxicity and the possible neuroprotective action of the neurotensin receptor antagonist SR48692 were investigated in primary cultures of mesencephalic neurons by measuring [(3)H]dopamine uptake and tyrosine hydroxylase immunocytochemistry 24 hr after glutamate treatment. The exposure to glutamate (30 and 100 microM, 10 min) decreased [(3)H]dopamine uptake into mesencephalic neurons. Neurotensin (10 and 100 nM), added before glutamate (30 microM) exposure, significantly enhanced the glutamate-induced reduction of [(3)H]dopamine uptake. In addition, the peptide (10 nM) also significantly enhanced the effect of 100 microM glutamate. The effects of neurotensin were counteracted by the neurotensin receptor antagonist SR48692 (100 nM) and by the protein kinase C inhibitor calphostin C. The exposure to 100 microM, but not 30 microM, glutamate significantly reduced the number of tyrosine hydroxylase-immunoreactive cells, and neurotensin (10 nM) significantly enhanced this effect. SR48692 (100 nM) prevented the neurotensin-induced action. These findings support the view of a possible pathophysiological role of neurotensin in mesencephalic dopamine neuronal function. Furthermore, selective neurotensin antagonists in combination with conventional drug treatments could provide a novel therapeutic approach for the treatment of neurodegenerative disorders, such as Parkinson's disease

Electrophysiological, behavioural and biochemical evidence for activation of brain noradrenergic systems following neurokinin NK3 receptor stimulation. Neuroscience 74:403–414

Abstract--The objective of the present in vitro and in vivo experiments was to examine the involvement of neurokinin NK 3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK 3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC 50 =26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 g) and (MePhe 7 )neurokinin B (1-10 g), another NK 3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 g of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 g i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration-or dose-dependently reduced by SR 142801, the selective non-peptide NK 3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 g). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-256 g/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by stimulation of neurokinin NK 3 receptors