Optogenetic activation of serotonergic terminals facilitates GABAergic inhibitory input to orexin/hypocretin neurons

Chowdhury, Srikanta; Yamanaka, Akihiro

doi:10.1038/srep36039

Cited by 35 publications

(23 citation statements)

References 56 publications

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“…Then, 300 μL supernatant (plasma) was stored in a vial and kept at -80 °C until analysis. Once the blood collection was finished, some of the rats were perfused transcardially and immediately with ice-cold formalin (40 g/L) solution, and the brain and stomach were quickly removed and post-fixed by immersing in 40 g/L formalin solution at 4 °C overnight for immunohistochemistry (IHC) measurements[ 45 ]. Others of the rats were sacrificed by rapid decapitation and the hippocampus and gastric fundus (by another operator) were then isolated carefully, wrapped in foil and dropped in liquid nitrogen immediately and stored at -80 °C for ELISA or Western blot (WB) measurements[ 46 ].…”

Section: Methodsmentioning

confidence: 99%

“…The ELISA assays of MPO activity and the levels of 5-HT, GABA, BDNF and nesfatin-1 were analyzed as described by the instructions of the ELISA kits and the methods described previously[ 32 , 41 - 44 ]. The IHC and WB tests of the levels of 5-HT1AR in the hippocampal CA1 subfield or the mucosa of the gastric fundus were also performed using the methods reported previously[ 45 , 46 ].…”

Section: Methodsmentioning

confidence: 99%

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Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress

Fu-chun

Zhang

Chen

et al. 2017

WJG

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AIMTo establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress.METHODSAnimal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.RESULTSSequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group).CONCLUSIONSequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress

Fu-chun

Zhang

Chen

et al. 2017

WJG

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“…OF and orexin-EGFP ( OE ) (Yamanaka et al, 2003) mice of both sexes, aged 2-5 months, were used for electrophysiological recordings. Brain slice preparations and subsequent electrophysiological recording were modified from a previously published protocol (Chowdhury and Yamanaka, 2016). Briefly, mice were deeply anesthetized using isoflurane (Wako) and decapitated at around 11:00 AM.…”

Section: Methodsmentioning

confidence: 99%

“…These inputs include GABAergic neurons in the preoptic area, serotonergic neurons in the dorsal and median raphe nuclei, central amygdala, basal forebrain cholinergic neurons, the bed nucleus of the stria terminalis, supraventricular zone, and the dorsomedial, lateral and posterior hypothalamus (Sakurai et al, 2005; Yoshida et al, 2006). Recently, we reported that serotonergic neurons in the raphe nucleus inhibit orexin neurons both directly and indirectly (Chowdhury and Yamanaka, 2016). Orexin neurons are also found to respond to multiple humoral factors and neuropeptides (Inutsuka and Yamanaka, 2013; Sakurai, 2014).…”

Section: Introductionmentioning

confidence: 99%

Dissociating orexin-dependent and -independent functions of orexin neurons using novel orexin-Flp knock-in mice

Chowdhury

Hung

Izawa

et al. 2019

Preprint

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1Uninterrupted arousal is important for survival during threatening situations. Activation of 2 orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons 3 produce and release orexin as well as several co-transmitters including dynorphin and 4 glutamate. Thus, it is important to disambiguate orexin peptide-dependent and 5 -independent physiological functions of orexin neurons. To attain this, we generated a 6 novel orexin-flippase (Flp) knock-in (KI) mouse line. Crossing with Flp-reporter or 7 Cre-expressing mice showed gene expression exclusively in orexin neurons. 8Histological studies confirmed that orexin was completely knock-out (KO) in KI/KI 9 homozygous mice. Orexin neurons without orexin showed altered electrophysiological 10 properties, as well as received decreased glutamatergic inputs. Selective chemogenetic 11 activation revealed that both orexin and co-transmitters functioned to increase 12 wakefulness, however, orexin was indispensable to promote sustained arousal.13 Surprisingly, activation of orexin neurons without orexin caused a significant increase in 14 the total time spent in cataplexy. Taken together, orexin is essential to maintain basic 15 membrane properties and input-output computation of orexin neurons, as well as to exert 16 awake-sustaining aptitude of orexin neurons. 17 18 19 sleep/wakefulness, cataplexy 20 23 2011; Tsunematsu et al., 2011). In addition to these, employing transgenic mice, we 24 reported that chemogenetic activation of orexin neurons increased locomotion, feeding 25 behavior and metabolism (Inutsuka et al., 2014). Thus, orexin neurons are thought to 26 4 interact with the neuroregulatory, autonomic and neuroendocrine systems, and perform 1 critical roles in the regulation of sleep/wakefulness and energy homeostasis.2 The physiological activity of orexin neurons is modulated by multiple neural 3 inputs and humoral factors. These inputs include GABAergic neurons in the preoptic 4 area, serotonergic neurons in the dorsal and median raphe nuclei, central amygdala, 5 basal forebrain cholinergic neurons, the bed nucleus of the stria terminalis, 6 supraventricular zone, and the dorsomedial, lateral and posterior hypothalamus (Sakurai 7 et al., 2005; Yoshida et al., 2006). Recently, we reported that serotonergic neurons in the 8 raphe nucleus inhibit orexin neurons both directly and indirectly (Chowdhury and 9 Yamanaka, 2016). Orexin neurons are also found to respond to multiple humoral factors 10 and neuropeptides (Inutsuka and Yamanaka, 2013; Sakurai, 2014). Most interestingly, 11 orexin neurons form a positive-feedback circuitry among themselves in the LHA by 12 activating other orexin neurons through OX2R to maintain the wake-active network at 13 optimum level and/or for a sustained period (Yamanaka et al., 2010a).14 However, orexin neurons contain other neurotransmitters including glutamate 15 (Rosin et al., 2003), dynorphin (Chou et al., 2001) and galanin (Hakansson et al., 1999). 16Therefore, to better understand the physiology and pathophy...

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“…Serotonin and noradrenaline hyperpolarize all orexin neurons through two receptors coupled to inhibitory Gi proteins (5HT1A and alpha 2A receptors, respectively) and subsequently activate protein-coupled inwardly rectifying potassium channels. Recent optogenetic methods allowed to confirm that the activation of serotoninergic neuron terminal inhibits orexin neurons either directly (via 5-HT1A receptor) or indirectly (via facilitation of GABAergic-inhibitory inputs) [25]. Dopamine also hyperpolarizes orexin neurons possibly by an indirect action through alpha 2A receptor [26], and glycine inhibits the activity of orexin neurons either directly and indirectly [27].…”

Section: Orexinergic Neurons Their Receptors and Physio-pharmacologmentioning

confidence: 99%

Hypothalamic Control of Sleep-Wake Circadian Cycle

Cruz¹,

Laranjo²,

Rocha³

2018

Hypothalamus in Health and Diseases

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Sleep-wake cycle is probably the most truthful signature of life. These unavoidable interchangeable states are together the matrix for all that occurs in physiology, and its rhythms are regulated by homeostatic and circadian processes involving different neuronal structures and distinct neural substrates. Hypothalamic regulation of sleep-wake cycle becomes of relevance as several neuropeptide-producing neurons involved in sleep and wakefulness regulation are located there. In this chapter, we provide a review of the hypothalamic regulation of sleep-wake cycle, focusing on the hypocretin system and melanin-concentrating hormone (MCH)-producing neurons located in the lateral hypothalamic area (LHA).

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Optogenetic activation of serotonergic terminals facilitates GABAergic inhibitory input to orexin/hypocretin neurons

Cited by 35 publications

References 56 publications

Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress

Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress

Dissociating orexin-dependent and -independent functions of orexin neurons using novel orexin-Flp knock-in mice

Hypothalamic Control of Sleep-Wake Circadian Cycle

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