The dorsal raphe nucleus (DRN) is involved in organizing reward-related behaviours; however, it remains unclear how genetically defined neurons in the DRN of a freely behaving animal respond to various natural rewards. Here we addressed this question using fibre photometry and single-unit recording from serotonin (5-HT) neurons and GABA neurons in the DRN of behaving mice. Rewards including sucrose, food, sex and social interaction rapidly activate 5-HT neurons, but aversive stimuli including quinine and footshock do not. Both expected and unexpected rewards activate 5-HT neurons. After mice learn to wait for sucrose delivery, most 5-HT neurons fire tonically during waiting and then phasically on reward acquisition. Finally, GABA neurons are activated by aversive stimuli but inhibited when mice seek rewards. Thus, DRN 5-HT neurons positively encode a wide range of reward signals during anticipatory and consummatory phases of reward responses. Moreover, GABA neurons play a complementary role in reward processing.

The interactions between predator and prey represent some of the most dramatic events in nature and constitute a matter of life and death for both sides. The hypothalamus has been implicated in driving predation and evasion; however, the exact hypothalamic neural circuits underlying these behaviors remain poorly defined. Here, we demonstrate that inhibitory and excitatory projections from the mouse lateral hypothalamus (LH) to the periaqueductal gray (PAG) in the midbrain drive, respectively, predation and evasion. LH GABA neurons were activated during predation. Optogenetically stimulating PAG-projecting LH GABA neurons drove strong predatory attack, and inhibiting these cells reversibly blocked predation. In contrast, LH glutamate neurons were activated during evasion. Stimulating PAG-projecting LH glutamate neurons drove evasion and inhibiting them impeded predictive evasion. Therefore, the seemingly opposite behaviors of predation and evasion are tightly regulated by two dissociable modular command systems within a single neural projection from the LH to the PAG. VIDEO ABSTRACT.

The ability to predict reward promotes animal survival. Both dopamine neurons in the ventral tegmental area and serotonin neurons in the dorsal raphe nucleus (DRN) participate in reward processing. Although the learning effects on dopamine neurons have been extensively characterized, it remains largely unknown how the response of serotonin neurons evolves during learning. Moreover, although stress is known to strongly influence reward-related behavior, we know very little about how stress modulates neuronal reward responses. By monitoring Ca signals during the entire process of Pavlovian conditioning, we here show that learning differentially shapes the response patterns of serotonin neurons and dopamine neurons in mice of either sex. Serotonin neurons gradually develop a slow ramp-up response to the reward-predicting cue, and ultimately remain responsive to the reward, whereas dopamine neurons increase their response to the cue but reduce their response to the reward. For both neuron types, the responses to the cue and the reward depend on reward value, are reversible when the reward is omitted, and are rapidly reinstated by restoring the reward. We also found that stressors including head restraint and fearful context substantially reduce the response strength of both neuron types, to both the cue and the reward. These results reveal the dynamic nature of the reward responses, support the hypothesis that DRN serotonin neurons signal the current likelihood of receiving a net benefit, and suggest that the inhibitory effect of stress on the reward responses of serotonin neurons and dopamine neurons may contribute to stress-induced anhedonia. Both serotonin neurons in the dorsal raphe and dopamine neurons in the ventral tegmental area are intimately involved in reward processing. Using long-term fiber photometry of Ca signals from freely behaving mice, we here show that learning produces a ramp-up activation pattern in serotonin neurons that differs from that in dopamine neurons, indicating complementary roles for these two neuron types in reward processing. Moreover, stress treatment substantially reduces the reward responses of both serotonin neurons and dopamine neurons, suggesting a possible physiological basis for stress-induced anhedonia.

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The heart peptide hormone atrial natriuretic peptide (ANP) regulates blood pressure by stimulating guanylyl cyclase-A to produce cyclic guanosine monophosphate (cGMP). ANP and guanylyl cyclase-A are also expressed in many brain areas, but their physiological functions and downstream signaling pathways remain enigmatic. Here we investigated the physiological functions of ANP signaling in the neural pathway from the medial habenula (MHb) to the interpeduncular nucleus (IPN). Biochemical assays indicate that ANP increases cGMP accumulation in the IPN of mouse brain slices. Using optogenetic stimulation and electrophysiological recordings, we show that both ANP and brain natriuretic peptide profoundly block glutamate release from MHb neurons. Pharmacological applications reveal that this blockade is mediated by phosphodiesterase 2A (PDE2A) but not by cGMP-stimulated protein kinase-G or cGMPsensitive cyclic nucleotide-gated channels. In addition, focal infusion of ANP into the IPN enhances stress-induced analgesia, and the enhancement is prevented by PDE2A inhibitors. PDE2A is richly expressed in the axonal terminals of MHb neurons, and its activation by cGMP depletes cyclic adenosine monophosphates. The inhibitory effect of ANP on glutamate release is reversed by selectively activating protein kinase A. These results demonstrate strong presynaptic inhibition by natriuretic peptides in the brain and suggest important physiological and behavioral roles of PDE2A in modulating neurotransmitter release by negative crosstalk between cGMP-signaling and cyclic adenosine monophosphatesignaling pathways.presynaptic modulator | neurotransmission | ChannelRhodopsin 2 S ynaptic transmission is dynamically modulated by neuropeptides, which often act on receptors that belong to the G protein-coupled receptor (GPCR) family (1). In addition to GPCRs, a unique family of receptors known as membrane guanylyl cyclases (GCs) can be activated by neuropeptides such as natriuretic peptides to catalyze the intracellular production of cyclic guanosine monophosphate (cGMP) (2, 3). In animals across taxa, cGMP signals influence cellular physiology by acting on cGMP-stimulated protein kinase G (PKG), cyclic nucleotidegated (CNG) channels, or cGMP-sensitive phosphodiesterases (PDEs) (3, 4). In Caenorhabditis elegans, a membrane GC acts on the presynaptic terminals of olfactory neurons to induce a behavioral switch (5). Several membrane GCs and their associated peptide ligands are expressed in the mammalian brain. For example, GC-C is activated by the gut peptide hormones guanylin and uroguanylin to amplify postsynaptic responses of midbrain dopamine neurons (6). Another member of the membrane GC family, GC-A (also named NPR-A), is the receptor for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and its activation reduces blood pressure and volume in the cardiovascular system (7-9). Both natriuretic peptides and their receptors are expressed in several discrete brain areas (10-13), but it remains unclear how ANP affects behav...

BACKGROUND: To explore the protective effect of ozone-oxidative-preconditioning (OzoneOP) through the protein kinase C (PKC), ERK1/2, and heat shock protein70 (HSP70) signal transduction in rats during hepatic ischemic-reperfusion (IR) injury. METHODS: We constructed an IR model by occluding all vessels of the rats’ left and median liver lobes for 45 min, followed by reperfusion for 3 h. Afterwards, we constructed the OzoneOP model via intraperitoneal injection of 1 mg · kg -1 · d -1 of 50 mg · L -1 ozone for 5 days to investigate the significance of PKC, ERK1/2 and HSP70 signal transduction in OzoneOP. The PKC inhibitor chelerythrine chloride (CHE), activator phorobol12-myristate13-acetate (PMA) and MEK inhibitor PD98059 were utilized to analyze the phosphorylation of PKC and the expression levels of ERK1/2 and HSP70. After ischemia and reperfusion, alanine aminotransferase (ALT) and aspartase aminotransferase (AST) were detected in the abdominal aorta blood. Meanwhile, the expression of HSP70 protein and the activities of PKC and ERK1/2 in the left hepatic lobe were analyzed, and the ultrastructure of the hepatic was observed. RESULTS: Compared with the control group, the phosphorylation of PKC and ERK1/2 and the expression of HSP70 were higher in the OzoneOP-treated model ( P <0.05). Conversely, inhibiting PKC and ERK1/2 abolished the protection conferred by OzoneOP ( P <0.05). CONCLUSION: OzoneOP significantly increased the expression of HSP70 by activating PKC and ERK1/2 signaling pathways, thus significantly alleviating hepatic IR injury in rats. KEYWORDS: ERK1/2 MAPKs; HSP70; Liver ischemia-reperfusion; O zone - oxidative - preconditioning; PKC

Although biological pretreatment has the advantages of being environmentally friendly and having low-energy consumption, it usually requires a relatively long incubation time. In this study, a novel combined pretreatment with white-rot fungus and alkali at near room-temperature for saccharification of corn stalks was investigated to speed up the biological process. Biological pretreatment with Irpex lacteus or Echinodontium taxodii can improve enzymatic hydrolysis of corn stalk greatly, but the process requires a long time (60 days) to achieve a satisfactory sugar yield. The combination processes with the fungi were compared with the sole pretreatments. The results showed that the time of the biological process could be shortened to 15 days when the bio-treatment with I. lacteus was combined with alkali pretreatment. The efficiency of alkali pretreatment can be also enhanced significantly by biological treatment. 271.1mg/g of final glucose yield was obtained for the combination pretreatment, which was an improvement of 50.4% and 28.3% in comparison with the sole alkali pretreatment at the same and optimum reaction time, respectively. In conclusion, the combination of biological pretreatment with alkali processes not only speeded up the biological process, but also improved the sugar yield in comparison to the sole pretreatment and is favorable for the development of biological pretreatment.