Dopamine error signal to actively cope with lack of expected reward

目標に向けて努力し続けられる脳の仕組みを解明 --期待外れを乗り越えるためのドーパミン機能--. 京都大学プレスリリース. 2023-03-13.Dope defense against disappointment: Neurons in rats increase dopamine immediately after setbacks. 京都大学プレスリリース. 2023-06-20.To obtain more of a particular uncertain reward, animals must learn to actively overcome the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively overcome unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward

Alpha and beta adrenoceptors activate interleukin-6 transcription through different pathways in cultured astrocytes from rat spinal cord

In brain astrocytes, noradrenaline (NA) has been shown to up-regulate IL-6 production via 13-adrenoceptors (ARs). However, the underlying intracellular mechanisms for this regulation are not clear, and it remains unknown whether ?-ARs are involved. In this study, we investigated the AR-mediated regulation of IL-6 mRNA levels in the cultured astrocytes from rat spinal cord. NA, the ?1-agonist phenylephrine, and the 13-agonist isoproterenol increased IL-6 mRNA levels. The phenylephrine-induced IL-6 increase was accompanied by an increase in ERK phosphorylation, and these effects were blocked by inhibitors of PKC and ERK. The isoproterenol-induced IL-6 increase was accompanied by an increase in CREB phosphorylation, and these effects were blocked by a PKA inhibitor. Our results indicate that IL-6 increases by ?1- and 13-ARs are mediated via the PKC/ERK and cAMP/PKA/CREB pathways, respectively. Moreover, conditioned medium collected from astrocytes treated with the ?2-AR agonist dexmedetomidine, increased IL-6 mRNA in other astrocytes. In this study, we elucidate that ?1- and ?2-ARs, in addition to 13-ARs, promote IL-6 transcription through different pathways in spinal cord astrocytes

The alpha(2A)-adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine

Xylazine, the classical alpha(2)-adrenoceptor (alpha(2)-AR) agonist, is still used as an analgesic and sedative in veterinary medicine, despite its low potency and affinity for alpha(2)-ARs. Previous pharmacological studies suggested that the alpha(2A)-AR subtype plays a role in mediating the clinical effects of xylazine; however, these studies were hampered by the poor subtype-selectivity of the antagonists used and a lack of knowledge of their bioavailability in vivo. Here, we attempted to elucidate the role of the alpha(2A)-AR subtype in mediating the clinical effects of xylazine by comparing the analgesic and sedative effects of this drug in wild-type mice with those in alpha(2A)-AR functional knockout mice using the hot-plate and open field tests, respectively. Hippocampal noradrenaline turnover in both mice was also measured to evaluate the contribution of alpha(2A)-AR subtype to the inhibitory effect of xylazine on presynaptic noradrenaline release. In wild-type mice, xylazine (10 or 30 mg/kg) increased the hot-plate latency. Furthermore, xylazine (3 or 10 mg/kg) inhibited the open field locomotor activity and decreased hippocampal noradrenaline turnover. By contrast, all of these effects were abolished in alpha(2A)-AR functional knockout mice. These results indicate that the alpha(2A)-AR subtype is mainly responsible for the clinical effects of xylazine

Bidirectional modulation of TNF-alpha transcription via alpha- and beta-adrenoceptors in cultured astrocytes from rat spinal cord

Noradrenaline (NA) suppresses TNF-alpha production via beta-adrenoceptors (ARs) in brain astrocytes. However, the downstream pathways from beta-ARs, and the involvement of alpha-ARs, remains unknown. In this study, we investigated the AR-mediated regulation of TNF-alpha mRNA levels in cultured astrocytes from rat spinal cord. NA, the aragonist phenylephrine, and the beta-agonist isoproterenol decreased the TNF-alpha mRNA level, while the alpha(2)-agonist dexmedetomidine increased it. The isoproterenol-induced TNF-alpha mRNA decrease was accompanied by a decrease in ERK phosphorylation. An adenylyl cyclase activator and an ERK inhibitor mimicked these effects. These results indicate that the transcriptional regulation of TNF-alpha by beta-ARs is mediated via cAMP pathways followed by the ERK pathway inhibition. The dexmedetomidine-induced TNF-alpha mRNA increase was accompanied by phosphorylation of JNK and ERK, which was blocked by a JNK inhibitor. Furthermore, the LPS-induced increase in the TNF-alpha mRNA level was accompanied by NF-kappa B nuclear translocation, and both these effects were blocked by phenylephrine. An NF-kappa B inhibitor suppressed the LPS-induced increase in the TNF-alpha mRNA level. These results suggest that alpha(1)-ARs suppress the LPS-induced increase in the TNF-alpha mRNA level via inhibition of NF-kappa B nuclear translocation. Taken together, our study reveals that both alpha- and beta-ARs are involved in the transcriptional regulation of TNF-alpha in astrocytes. (C) 2020 Elsevier Inc. All rights reserved

Dopamine regulates astrocytic IL-6 expression and process formation via dopamine receptors and adrenoceptors

Dopamine levels in the central nervous system change under pathological conditions such as Parkinson's disease, Huntington's disease, and addiction. Under those pathological conditions, astrocytes become reactive astrocytes characterized by morphological changes and the release of inflammatory cytokines involved in pathogenesis. However, it remains unclear whether dopamine regulates astrocytic morphology and functions. Elucidating these issues will help us to understand the pathogenesis of neurodegenerative diseases caused by abnormal dopamine signaling. In this study, we investigated the effects of dopamine on IL-6 expression and process formation in rat primary cultured astrocytes and acute hippocampal slices. Dopamine increased IL-6 expression in a concentration-dependent manner, and this was accompanied by CREB phosphorylation. The effects of a low dopamine concentration (1 mu M) were inhibited by a D1-like receptor antagonist, whereas the effects of a high dopamine concentration (100 mu M) were inhibited by a beta-antagonist and enhanced by a D2-like receptor antagonist. Furthermore, dopamine (100 mu M) promoted process formation, which was inhibited by a beta-antag-onist and enhanced by both an alpha-antagonist and a D2-like receptor antagonist. In acute hippocampal slices, both a D1-like receptor agonist and beta-agonist changed astrocytic morphology. Together, these results indicate that dopamine promotes IL-6 expression and process formation via D1-like receptors and beta-adrenoceptors. Further-more, bidirectional regulation exists; namely, the effects of D1-like receptors and beta-adrenoceptors were nega-tively regulated by D2-like receptors and alpha(2)-adrenoceptors

IL-1 beta augments H2S-induced increase in intracellular Ca2+ through polysulfides generated from H2S/NO interaction

H2S has excitatory and inhibitory effects on Ca2+ signals via transient receptor potential ankyrin 1 (TRPA1) and ATP-sensitive K+ channels, respectively. H2S converts intracellularly to polysulfides, which are more potent agonists for TRPA1 than H2S. Under inflammatory conditions, changes in the expression and activity of these H2S target channels and/or the conversion of H2S to polysulfides may modulate H2S effects. Effects of proinflammatory cytokines on H2S-induced Ca2+ signals and polysulfide production in RIN14B cells were examined using fluorescence imaging with fura-2 and SSP4, respectively. Na2S, a H2S donor, induced 1) the inhibition of spontaneous Ca2+ signals, 2) inhibition followed by [Ca2+](i) increase, and 3) rapid [Ca2+](i) increase without inhibition in 50% (23/46), 22% (10/46), and 17% (8/46) of cells tested, respectively. IL-1 beta augmented H2S-induced [Ca2+](i) increases, which were inhibited by TRPA1 and voltage-dependent L-type Ca2+ channel blockers. However, IL-1 beta treatment did not affect [Ca2+](i) increases evoked by a TRPA1 agonist or high concentration of KCl. Na2S increased intracellular polysulfide levels, which were enhanced by IL-1 beta treatment. A NOS inhibitor suppressed the increased polysulfide production and [Ca2+](i) increase in IL-1 beta-treated cells. These results suggest that IL-1 beta augments H2S-induced [Ca2+](i) increases via the conversion of H2S to polysulfides through NO synthesis, but not via changes in the activity and expression of target channels. Polysulfides may play an important role in the effects of H2S during inflammation

Opposing functions of alpha- and beta-adrenoceptors in the formation of processes by cultured astrocytes

Astrocytes are glial cells with numerous fine processes which are important for the functions of the central nervous system. The activation of beta-adrenoceptors induces process formation of astrocytes via cyclic AMP (cAMP) signaling. However, the role of alpha-adrenoceptors in the astrocyte morphology has not been elucidated. Here, we examined it by using cultured astrocytes from neonatal rat spinal cords and cortices. Exposure of these cells to noradrenaline and the beta-adrenoceptor agonist isoproterenol increased intracellular cAMP levels and induced the formation of processes. Noradrenaline-induced process formation was enhanced with the alpha(1)-adrenoceptor antagonist prazosin and alpha(2)-adrenoceptor antagonist atipamezole. Atipamezole also enhanced noradrenaline-induced cAMP elevation. Isoproterenol-induced process formation was not inhibited by the alpha(1)-adrenoceptor agonist phenylephrine but was inhibited by the alpha(2)-adrenoceptor agonist dexmedetomidine. Dexmedetomidine also inhibited process formation induced by the adenylate cyclase activator forskolin and the membrane-permeable cAMP analog dibutyryl-cAMP. Moreover, dexmedetomidine inhibited cAMP-independent process formation induced by adenosine or the Rho-associated kinase inhibitor Y27632. In the presence of propranolol, noradrenaline inhibited Y27632-induced process formation, which was abolished by prazosin or atipamezole. These results demonstrate that alpha-adrenoceptors inhibit both cAMP-dependent and -independent astrocytic process formation. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society