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Pain 106 (2003) 143­150 www.elsevier.com/locate/pain

An antinociceptive role of galanin in the arcuate nucleus of hypothalamus in intact rats and rats with inflammation

Yan-Gang Suna, Xing-Long Gua, Thomas Lundebergb, Long-Chuan Yua,*

Neurobiology Laboratory, College of Life Sciences, National Laboratory of Biomembrane and Membrane Biotechnology and Center for Brain and Cognitive Science, Peking University, Beijing 100871, China b Department of Physiology, and Pharmacology, and Department of Medical Rehabilitation, Karolinska Institutet, 171 77 Stockholm, Sweden Received 20 January 2003; received in revised form 21 July 2003; accepted 29 July 2003

a

Abstract In the arcuate nucleus of hypothalamus (ARC), galaninergic fibers form synaptic contacts with proopiomelanocortin neurons, which are involved in pain modulation. The present study assessed the role of exogenous and endogenous galanin in the modulation of nociception in the ARC of rats. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation was assessed by the hot-plate test and the Randall Selitto Test. Intra-ARC injection of galanin dose-dependently increased the HWLs in intact rats, indicating an antinociceptive role of exogenous galanin in the ARC. The antinociceptive effect of galanin was blocked by following intra-ARC injection of galantide, a putative galanin receptor antagonist, suggesting that the antinociceptive effect of galanin is mediated by galanin receptors. Moreover, intra-ARC injection of galanin increased the HWL in rats with inflammation. Intra-ARC administration of galantide alone reduced the HWLs in rats with inflammation, while there were no influences of galantide on the HWL in intact rats. Taken together, the results show that galanin has an antinociceptive role in the ARC of intact rats and rats with inflammation. q 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Keywords: Arcuate nucleus; Inflammation; Galanin; Galanin receptors; Antinociception; Hyperalgesia

1. Introduction The neuropeptide galanin was first isolated in 1983 in the laboratory of Mutt (Tatemoto et al., 1983). Galanin is proteolytically processed from a large precursor protein; it appears to be a unique sequence unrelated to any other known family of peptides. In most mammals, galanin consists of 29 amino acids, which is conserved in the Nterminal between species (Iismaa and Shine, 1999). Three galanin receptor subtypes have been cloned and all of them are G-protein coupled receptors (Branchek et al., 2000). There are wide distributions of galanin and galanin receptors in the central nervous system (Bedecs et al., 1995; Melander et al., 1986; Merchenthaler et al., 1993; Skofitsch and Jacobowitz, 1986). Galanin has been shown to be involved in a variety of physiological processes (Gundlach, 2002; Rajendren, 2002; Wiesenfeld-Hallin and Xu, 2001). Previous studies have demonstrated that galanin is upregulated after nerve injury or

* Corresponding author. Tel.: þ86-10-6276-2099; fax: þ 86-10-62751526. E-mail address: [email protected] (L.-C. Yu).

inflammation (Colvin et al., 1997; Ma and Bisby, 1997), suggesting an involvement of galanin in pain processing. The role of galanin in nociception has been investigated using behavioral (Liu and Hokfelt, 2000; Wang et al., 2000) and electrophysiological techniques (Flatters et al., 2002; Xu et al., 2000; Yu et al., 2001). We have demonstrated that galanin microinjected into the midbrain periaqueductal gray matter (PAG) of intact and mononeuropathic rats induced prolonged withdrawal latencies (Wang et al., 1999, 2000). A role of galanin in nociception during inflammation has been suggested, but the results have been contradictory (Heppelmann et al., 2000; Wiesenfeld-Hallin and Xu, 2001). It has been reported that galanin has an antinociceptive effect during inflammation in spinalized rats (Wiesenfeld-Hallin and Xu, 2001). On the other hand, a pronociceptive action is supported by Kerr and collaborators who reported that endogenous galanin is necessary for central sensitization (Kerr et al., 2001). They suggested that galanin plays a critical role in the development of the hyperalgesia seen following peripheral tissue injury. Even if there is controversy regarding the role of exogenous galanin in inflammation, it has been clearly

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demonstrated that endogenous galanin has an antinociceptive effect at the spinal level (Liu and Hokfelt, 2002). However, the role of endogenous galanin in nociception at the supraspinal level has not been investigated. It has been shown that there is a high concentration of galanin and of all three galanin receptor subtypes in the hypothalamus, especially in the arcuate nucleus (ARC) (Bouret et al., 2000; Merchenthaler et al., 1993). Studies have shown that the ARC plays an important role in the modulation of nociception (Bach, 1997; Zangen et al., 1998). In addition, galaninergic fibers form synaptic contacts with b-endorphinergic neurons in the ARC (Horvath et al., 1995), that express galanin receptors (Bouret et al., 2000). Based on the distribution of galanin and galanin receptors in the ARC and the role of the ARC in nociception, the present study was carried out to elucidate the role of exogenous and endogenous galanin in nociceptive modulation in the ARC of rats.

hindpaw. The contralateral paw was untreated. Three hours after injection of carrageenan, the hindpaw withdrawal latency (HWL) was measured by the hotplate test and the Randall Selitto Test. Then each animal received an intra-ARC injection of either vehicle or drug. After intra-ARC injection, the HWLs of each animal were assessed. 2.4. Nociceptive tests Rats were habituated to handling and the testing equipment for 5 days before surgery. The HWLs during noxious thermal and mechanical stimulation were tested as described before (Yu et al., 1996, 1999). Briefly, the HWL to noxious heat stimulation was tested by the hot-plate maintained at a temperature of 52 8C (51.8 ­52.4 8C). The time to hindpaw withdrawal was measured in seconds to be referred to as the HWL to thermal stimulation. The Randall Selitto Test (Ugo Basile, Type 7200, Italy) was used to assess the HWL to mechanical stimulation. A wedgeshaped pusher with a loading rate of 30 g/s was applied to the dorsal surface of the manually handled hind-paw and the latency required to initiate the struggle response was assessed and expressed in seconds. The average values obtained before intra-ARC injection were regarded as the basal HWLs in both tests. The measurements were performed on both hindpaws at each time point. The HWLs recorded during subsequent measurements (measured at 5, 10, 20, 30 and 60 min after intra-ARC injection) were expressed as percentage changes from the basal level for each rat. Each rat was tested with both types of stimulation. A cut-off limit of 15 s was set up to avoid tissue damage. 2.5. Chemicals Solutions for intra-ARC administration were prepared with sterilized saline, each with a volume of 1 ml containing: (1) 0.01, 0.1, 0.5 or 1 nmol of galanin (galanin, Tocris, UK); (2) 0.1, 0.5, 1, 2 nmol of galantide (Galanin (1 ­ 13)Substance P (5 ­ 11) amide, Bachem, Feinchemikalien AG, Switzerland). 2.6. Statistical analysis At the end of the experiments, the location of the tip of the injection needle was verified. The results are shown in Fig. 1. Only the results from nociceptive tests where the tips of the injection needle were within the ARC were used for statistical analysis. Data from nociceptive tests were presented as mean ^ SEM. Differences between groups were determined by two-way analysis of variance (ANOVA) for repeated measures or Student's t-test (two-tailed) where applicable. *P , 0:05; **P , 0:01 and ***P , 0:001 were considered as significant differences.

2. Materials and methods 2.1. Animal preparation All experiments were performed on freely moving male Wistar rats weighing 200 ­ 250 g (Experimental Animal Center of Peking University, Beijing, China). The rats were housed in cages with free access to food and water, and maintained in a climate-controlled room on a normal day/night cycle. All experiments were conducted according to the guidelines of the International Association for the Study of Pain (Zimmermann, 1983) and every effort was made to minimize both the animal suffering and the number of animals used. 2.2. Intra-ARC injection Rats were prepared surgically 2 ­3 days before experimental testing. The rats were anaesthetized by intraperitoneal pentobarbital (50 mg/kg) and mounted on a stereotaxic instrument. Sterilized stainless-steel guide cannulae (20 gauge) were positioned 2.8 mm dorsally to the ARC (AP: 2 4.0, L: 0.5, V: 9.8 mm; AP, anterior (þ ) or posterior (2 ) to Bregma; L, lateral to midline; V, ventral to the surface of skull) according to Paxinos and Watson (1998), and were fixed to the skull by dental acrylic. Stainless-steel stylettes were inserted into guide cannulae to keep them clean. On the day of experiment a stainless-steel needle (26 gauge) was directly inserted into the guide cannula, with 2.8 mm beyond the tip of the guide cannula. One microliter of solution was thereafter infused into ARC over 1 min, and the injection needle was left in the place for 30 s after each injection. 2.3. Carrageenan-induced inflammation Animals received a unilateral injection of carrageenan (2 mg in 0.1 ml saline, Sigma) into the left

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1 ml of 0.9% saline as a control ðn ¼ 7Þ: The nociceptive responses of rats were assessed at 10 min after the injection of galanin. As shown in Fig. 2, the HWLs to thermal and mechanical stimulation increased significantly in a dose-dependent manner after intra-ARC injection of galanin. 3.2. Involvement of galanin receptors in the galanininduced antinociceptive effect in the ARC Two groups of intact rats received intra-ARC injection of 1 nmol of galanin, followed 5 min later by intra-ARC injection of 1 nmol of galantide ðn ¼ 7Þ or 1 ml of 0.9% saline as a control ðn ¼ 13Þ: The HWLs were assessed at 20 min after the injection of galanin. The results are shown in Fig. 3. Compared with the control group, the galanin-induced increases in HWLs were significantly attenuated by subsequent intra-ARC injection of 1 nmol of galantide. Another group of rats ðn ¼ 8Þ received intra-ARC injection of 1 ml of saline, followed 5 min later by intra-ARC injection of 1 nmol of galantide. The HWLs were measured at 20 min after the injection of saline. There were no significant changes in HWLs after intra-ARC injection of galantide in intact rats, as shown in Fig. 3.

Fig. 1. Illustration of the location of the tip of the injection needle in the ARC.

3. Results 3.1. Antinociceptive effects of exogenous galanin in the ARC of intact rats Four groups of intact rats received intra-ARC injection of 0.1 ðn ¼ 8Þ; 0.5 ðn ¼ 8Þ or 1 nmol of galanin ðn ¼ 8Þ; or

Fig. 2. Effects of intra-ARC injection of 0.1, 0.5 or 1 nmol of galanin on HWLs to thermal (A) and mechanical stimulation (B) in intact rats. IntraARC administration of 1 ml of 0.9% saline served as the control group. The nociceptive responses of rats were assessed at 10 min after the injection. HWL: hindpaw withdrawal latency; ARC: the arcuate nucleus. Data are presented as mean ^ SEM. The statistical difference between groups was determined by Student's t-test (**P , 0:01; ***P , 0:001 versus the control group).

Fig. 3. Blockade of intra-ARC injection of galantide on the increased HWL induced by intra-ARC galanin in intact rats. HWLs to thermal (A) and mechanical (B) stimulation. The second injection was performed at 5 min after the initial injection, and the nociceptive responses of rats were assessed at 20 min after the initial injection. HWL: hindpaw withdrawal latency; ARC: the arcuate nucleus. Data are presented as mean ^ SEM. The statistical difference between groups was determined by Student's t-test (***P , 0:001 versus the control group).

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Fig. 4. Effects of intra-ARC injection of 0.01, 0.1 or 1 nmol of galanin on HWLs to thermal (A, B) and mechanical stimulation (C, D) in rats with inflammation. HWL of left hindpaw: A, C; HWL of right hindpaw: B, D. Intra-ARC administration of 1 ml of 0.9% saline served as the control group. One microliter of saline (W, n ¼ 8); 0.01 nmol (A, n ¼ 8); 0.1 nmol (X, n ¼ 8); 1 nmol of galanin (B, n ¼ 8). HWL: hindpaw withdrawal latency; ARC: the arcuate nucleus. Data are presented as mean ^ SEM. The statistical difference between groups was determined by two-way ANOVA (*P , 0:05; **P , 0:01; ***P , 0:001 versus the control group).

3.3. Antinociceptive effects of exogenous galanin in the ARC of rats with inflammation Rats with inflammation received intra-ARC injection of 0.01 ðn ¼ 8Þ; 0.1 ðn ¼ 8Þ or 1 nmol of galanin ðn ¼ 8Þ; or 1 ml of 0.9% saline as a control ðn ¼ 8Þ: The results are shown in Fig. 4. Compared with the control group, the HWLs to both thermal and mechanical stimulation increased significantly after intra-ARC injection of 0.01 nmol (Left HWL in thermal test: Fð1;14Þ ¼ 6:07; P , 0:05; right HWL in thermal test: Fð1;14Þ ¼ 13:17; P , 0:01: Left HWL in mechanical test: Fð1;14Þ ¼ 14:78; P , 0:01; right HWL in mechanical test: Fð1;14Þ ¼ 14:50; P , 0:01Þ; 0.1 nmol (Left HWL in thermal test: Fð1;14Þ ¼ 4:27; P ¼ 0:06; right HWL in thermal test: Fð1;14Þ ¼ 34:31; P , 0:001: Left HWL in mechanical test: Fð1;14Þ ¼ 16:72; P , 0:01; right HWL in mechanical test: Fð1;14Þ ¼ 22:27; P , 0:001Þ or 1 nmol of galanin (Left HWL in thermal test: Fð1;14Þ ¼ 105:42; P , 0:001; right HWL in thermal test: Fð1;14Þ ¼ 138:66; P , 0:001: Left HWL in mechanical test: Fð1;14Þ ¼ 259:49; P , 0:001; right HWL in mechanical test: Fð1;14Þ ¼ 341:78; P , 0:001). The results demonstrated that intra-ARC administration of galanin induced increases in HWLs in rats with inflammation, indicating that exogenous galanin plays an antinociceptive role in the ARC of rats with inflammation. 3.4. Antinociceptive effects of endogenous galanin in the ARC of rats with inflammation Four groups of rats with inflammation received intraARC injection of 0.1 ðn ¼ 7Þ; 0.5 ðn ¼ 6Þ or 2 nmol of

galantide ðn ¼ 8Þ; or 1 ml of 0.9% saline as a control ðn ¼ 8Þ: As shown in Fig. 5, the HWLs to thermal and mechanical stimulation decreased significantly after intra-ARC injection of 0.5 (Left HWL in thermal test: Fð1;12Þ ¼ 27:62; P , 0:001; right HWL in thermal test: Fð1;12Þ ¼ 25:67; P , 0:001: Left HWL in mechanical test: Fð1;12Þ ¼ 35:26; P , 0:001; right HWL in mechanical test: Fð1;12Þ ¼ 27:43; P , 0:001) or 2 nmol of galantide (Left HWL in thermal test: Fð1;14Þ ¼ 101:63; P , 0:001; right HWL in thermal test: Fð1;14Þ ¼ 156:96; P , 0:001: Left HWL in mechanical test: Fð1;14Þ ¼ 111:42; P , 0:001; right HWL in mechanical test: Fð1;14Þ ¼ 87:42; P , 0:001), but not 0.1 nmol of galantide (Left HWL in thermal test: Fð1;13Þ ¼ 1:79; P ¼ 0:20; right HWL in thermal test: Fð1;13Þ ¼ 0:10; P ¼ 0:75: Left HWL in mechanical test: Fð1;13Þ ¼ 3:88; P ¼ 0:07; right HWL in mechanical test: Fð1;13Þ ¼ 2:25; P ¼ 0:15) compared with the control group. The results suggest that endogenous galanin in the ARC plays an antinociceptive effect during carrageenan-induced inflammation. 3.5. Comparison of the effects induced by intra-ARC injection of galantide in intact rats and rats with inflammation Intact rats ðn ¼ 8Þ and rats with inflammation ðn ¼ 8Þ received intra-ARC injection of 1 nmol of galantide. The nociceptive responses to both thermal and mechanical stimulation were assessed at 30 min after injection of galantide. As shown in Fig. 6, there were no significant changes in HWLs to thermal and mechanical stimulation after intra-ARC administration of galantide in intact rats.

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Fig. 5. Effects of intra-ARC injection 0.1, 0.5 or 2 nmol of galantide on HWLs to thermal (A, B) and mechanical stimulation (C, D) in rats with inflammation. HWL of left hindpaw: A, C; HWL of right hindpaw: B, D. Intra-ARC administration of 1 ml of 0.9% saline served as the control group. One microliter of saline (W, n ¼ 8); 0.1 nmol (A, n ¼ 7); 0.5 nmol (X, n ¼ 6); 2 nmol of galantide (B, n ¼ 8). HWL: hindpaw withdrawal latency; ARC: the arcuate nucleus. Data are presented as mean ^ SEM. The statistical difference between groups was determined by two-way ANOVA (***P , 0:001 versus the control group).

Compared with the intact rats, the HWLs decreased significantly after injection of galantide in rats with inflammation.

4. Discussion 4.1. Antinociceptive effects of exogenous galanin in the ARC of intact rats and rats with inflammation The present study demonstrated that intra-ARC administration of galanin induced increases in HWLs to noxious stimulation, suggesting an antinociceptive role of exogenous galanin in the ARC of intact rats and rats with inflammation. The antinociceptive effect was blocked by the galanin receptor antagonist galantide which has high affinity to galanin receptors (Floren et al., 2000). That galanin receptors play a key role is supported by our previous finding demonstrating that the antinociceptive effect of galanin microinjected into the PAG is antagonized by galantide (Wang et al., 2000). Interestingly, proopiomelanocortin (POMC, the precursor of b-endorphin) containing neurons in the ARC express galanin receptors (Bouret et al., 2000), suggesting a possible link between galanin and the endogenous opioid systems. This is supported by a study demonstrating that the effect of galanin on POMC neurons was antagonized by galantide (Bouret et al., 2002). Therefore, we conclude that exogenous galanin has an antinociceptive effect that is mediated by galanin receptors in the ARC of rats. The effects of exogenous galanin in nociception have been extensively studied in the spinal cord (Kuraishi et al., 1991; Liu and Hokfelt, 2002; Yu et al., 1999), while only

few studies have focused on the effect of exogenous galanin at the supraspinal level. The present study, coupled with our previous studies that intra-PAG injection of galanin reduced the nociceptive responses in both intact (Wang et al., 1999) and mononeuropathic rats (Wang et al., 2000), supports an antinociceptive role of galanin at the supraspinal level.

Fig. 6. Effects of intra-ARC injection of 1 nmol of galantide on HWLs to thermal (A) and mechanical stimulation (B) in intact rats and rats with inflammation. The nociceptive responses of rats were assessed at 30 min after the injection. HWL: hindpaw withdrawal latency; ARC: the arcuate nucleus. Data are presented as mean ^ SEM. The statistical difference between groups was determined by Student's t-test (***P , 0:001; rats with inflammation versus intact rats).

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Three galanin receptors, GalR1, GalR2 and GalR3, have been characterized (Branchek et al., 2000). Due to the lack of selective galanin receptor subtype antagonists, it is difficult to identify which receptor subtype that mediates the antinociceptive effect of galanin in the ARC. Previously, Pooga and co-workers investigated the effect of intrathecal galanin with peptide nucleic acid (PNA) against the GalR1 receptor (Pooga et al., 1998). The PNA decreased galanin binding sites in the dorsal horn. As a result, the inhibitory effect of galanin was attenuated, while the excitatory effect of galanin rather enhanced (Pooga et al., 1998). They concluded that the inhibitory effect of galanin in the spinal cord was mainly mediated by the GalR1 receptor (Pooga et al., 1998). This is supported by the recent studies using a newly developed galanin receptor 2 (GalR2) agonist and the results of mice lacking GalR1 receptors (Blakeman et al., 2003; Liu et al., 2001). Both GalR1 and GalR2 receptors mRNA are present in the ARC (Bouret et al., 2000), and there is a wide distribution of GalR1 in the ARC (data not shown). Therefore, it is tempting to suggest that the antinociceptive effect of galanin in the ARC is mediated by the GalR1 receptor. 4.2. Antinociceptive effects of endogenous galanin in the ARC of rats with inflammation An antinociceptive role of endogenous galanin at the spinal level has been implicated (Liu and Hokfelt, 2002). In the present study, intra-ARC administration of galantide, the putative antagonist of galanin receptors, induced decreases in the HWLs to noxious stimulation in rats with inflammation, suggesting that endogenous galanin plays an antinociceptive role in the ARC. This is consistent with the antinociceptive role of endogenous galanin at the spinal level. Chronic intrathecal infusion of the galanin receptor antagonist M-35 increased autotomy, a behavior of self mutilation hypothetically related to neuropathic pain, in axotomized rats (Wiesenfeld-Hallin and Xu, 2001). Similarly, application of galanin antisense oligocleotide to the distal dump of the transected sciatic nerve effectively reduced the upregulation of galanin in sensory neurons and exaggerated autotomy (Ji et al., 1994). This is consistent with a finding showing that intrathecal injection of M-35 induced behavioral changes interpreted as signs of allodynia to mechanical stimulation in non-allodynic rats with sciatic nerve constriction injury (Liu and Hokfelt, 2000). 4.3. The antinociceptive mechanisms of galanin in the ARC The ARC contains most of the POMC neurons synthesizing b-endorphin in the brain (Bloom et al., 1978). In addition, galaninergic fibers form synaptic contacts with the b-endorphinergic neurons (Horvath et al., 1995), which project widely in the brain (Finley et al., 1981; Sim and Joseph, 1991). The major fiber bundles terminate in the PAG (Pilcher et al., 1988), which plays an important role

in the descending antinociceptive pathway (Behbehani, 1995; Sandkuhler, 1996). It has been proposed that galanin modulates nociception by regulating the excitability of the b-endorphinergic neurons in the ARC and thereby the release of b-endorphin in the PAG. Moreover, as most of the neurons in the ARC are projecting neurons, the galaninergic neurons may innervate throughout the entire neuraxis, including the spinal cord. It is possible that exogenous galanin may act through the galaninergic projecting neurons. The action mechanisms of galanin in the ARC are not clear and the existence of galanin receptors pre- and postsynaptically makes it even more complicated (Bouret et al., 2000; Kinney et al., 1998). It is possible that the antinociceptive effect of galanin in the ARC is mediated through other neuronal modulators as has been demonstrated in the nucleus accumbens where galanin increased dopamine and decreased acetylcholine extracellularly (Rada et al., 1998). It is also possible that galanin exerts its effects through the endogenous opioid system. This is supported by a study showing that naloxone inhibits food intake evoked by the intracerebroventricular administration of galanin (Barton et al., 1995; Dube et al., 1994). Recently, Bouret and collaborators reported that POMC neurons have a biphasic response pattern in response to galanin in vitro (Bouret et al., 2002). Taken together, this would suggest that galanin modulates the release of b-endorphin in the central nervous system. Vaughan and co-workers have demonstrated the existence of opioid-induced inhibition on GABAergic currents in the PAG (Vaughan et al., 1997). These effects were seen presynaptically and regulated by mopioid receptors. Moreover, a recent study indicated that opioid peptides negatively regulated the GABAergic terminals innervating POMC neurons in the ARC (Cowley et al., 2001). Both galanin and opioid receptors are Gprotein coupled receptors, suggesting that they may act in a similar way. Thus, we propose that part of the antinociceptive effect of galanin may be attributed to an effect on GABA-secreting nerve terminals. It is possible that galanin results in a reduced release of GABA onto POMC neurons resulting in an increased activity. A presynaptically galanin receptor-mediated inhibition of glutamate release in the ARC has also been suggested (Kinney et al., 1998).

5. Conclusion We demonstrated that administration of galanin to the ARC increased the HWLs in intact rats and rats with inflammation, indicating an antinociceptive effect of exogenous galanin in the ARC. The antinociceptive effect of galanin was blocked by the galanin receptor antagonist galantide, suggesting that the galanin-induced antinociception is mediated by galanin receptors in the ARC. Intra-ARC administration of galantide alone reduced the HWLs in rats with inflammation, while there was no effect of galantide on

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the HWLs in intact rats. The results suggest that there is a tonic release of galanin in the ARC during inflammation, which may play an important role in the nociceptive modulation. It is concluded that both exogenous and endogenous galanin plays an antinociceptive role in the ARC of rats.

Acknowledgements This study was supported by funds from the National Natural Science Foundation of China (NSFC) and the Karolinska Institute Foundation.

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