Depression-like Behavior Induced By Nesfatin-1 In Rats: Involvement Of Activation Of The HPAAxis

Nesfatin-1, discovered in 2006 by Oh-I as an 82-amino-acid peptide derived from the precursor protein nucleobindin2 (NUCB2), has been identified to play an important role in the regulation of food intake and energy metabolism. Recently, it has also been found that Nesfatin-1 might be associated with the pathogenesis of depression. Intracerebroventricular administration of Nesfatin-1 can induce the hyperactivity of HPA axis, which might be among the most potent factors that trigger depressive episodes, indicating that Nesfatin-1 could result in depression-like behavior through evoking the HPA axis. The results of clinical studies have also shown an increase of plasma NUCB2/Nesfatin-1 in depressed patients and anxious patients. However, these studies could not provide the exact effect of stress on the activation of Nesfatin-1. nor could they detail the cause-effect relationship between depression and Nesfatin-1.Objective:To reveal the Nesfatin-1-operative mechanism that triggers depression-like behavior, which should throw light in understanding the neurobiological mechanism of depression and developing new kinds of antidepressant targeting at Nesfatin-1.Methods:1. Effect of acute stress on the plasma concentration and hypothalamic mRNA expression of Nesfatin-1Twelve Sprague-Dawley rats were randomly divided into 2 groups including a control and an AS group. Control rats were kept in home cages without AS (Acute stress), and AS rats were subjected to water avoid stress (WAS). The plasma concentration and hypothalamic mRNA expression of Nesfatin-1 were measured with an enzyme-linked immunosorbent assay (ELISA) and real-time fluorescent quantitative PCR (qRT-PCR), respectively.2. Effect of chronic stress on the plasma concentration and hypothalamic mRNA expression of Nesfatin-1Sixteen Sprague-Dawley rats were randomly divided into 2 groups including a control and a chronic unpredictable mild stress (CUMS) group. Rats in the control group were housed 4 per cage. Rats in the CUMS group were individually housed and stressed according to the CUMS procedure. The plasma concentration and hypothalamic mRNA expression of Nesfatin-1 were measured with an ELISA and qRT-PCR, respectively.3. Effect of single-dose administration of Nesfatin-1 on the depression-like behavior and activity of the HPAaxis.Twenty-four SD rats were randomly divided into four groups including control and Nesfatin-1 (10,20,40 μg/kg) groups. Approximately 30 min after the i.p. injection of sterile saline solution or Nesfatin-1 at the corresponding dose, a 5-min forced swimming test (FST) was conducted by placing each rat in a cylinder (height:60 cm; diameter:25cm) containing water at 22 ± 2℃ and a depth of 30 cm. The plasma concentration of corticosterone (CORT) was measured with an ELISA and the hypothalamic mRNA of CRH was measured with qRT-PCR.4. Effect of chronic administration of Nesfatin-1 on the depression-like behavior and activity of the HPA axis.Forty SD rats were divided into 4 groups matching based on the bodyweight and the result of the first open field test (OFT). The groups included a control and Nesfatin-1 (10,20,40 μg/kg) groups. All the rats received a daily injection of sterile saline solution or Nesfatin-1 at the corresponding dose. The animals were continuously treated between 0800 and 1000 h for 3weeks before the behavioral test. The plasma concentrations of CORT, interleukin-6 (IL-6) and C-reactive protein (CRP) were measured with an ELISA and the hypothalamic mRNA of CRH, Nesfatin-1, synaptotagmin I and synapsin I was measured with qRT-PCR.Results:1. In the present study, we demonstrated the effect of AS on the abundance of Nesfatin-1 and the possible role of the HPA axis. The results showed that both acute stress and chronic stress could result in the hyperactivity of the HPA axis, and CUMS could induce depression-like behavior in rats. Moreover, AS could increase the plasma concentration and hypothalamic mRNA expression of Nesfatin-1, which was positively correlated with the HPA axis activity.2. Both acute and chronic administration of Nesfatin-1 increased immobility in the FST, and resulted in the hyperactivity of HPA axis, as indicated by the increase of plasma CORT concentration and hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Moreover, after chronic Nesfatin-1 administration, the rats exhibited decreased activity and exploratory behavior in the OFT and increased mRNA expression of synapsin I and synaptotagmin I in the hypothalamus. Furthermore, chronic administration of Nesfatin-1 elevated plasma concentrations of IL-6 and CRP, which were positively correlated with despair behavior, plasma CORT level, and the hypothalamic mRNA expression of synapsin I and synaptotagmin I.Conclusion:1. Acute stress, but not chronic stress, increased the plasma concentration and hypothalamic mRNA expression of NUCB2/Nesfatin-1 in rats.2. Exogenous Nesfatin-1 could induce the immune-inflammatory activation, which might be a central hug linking the depression-like behavior and the imbalanced mRNA expression of synaptic vesicle proteins in the hypothalamus.