Research report
Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus

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Abstract

The dorsal raphe nucleus (DRN)–serotonin (5-HT) system plays a key role in stress-related psychiatric disorders such as anxiety and depression. The habenular nucleus (Hb) is closely connected with the DRN both morphologically and functionally. Here, we used two types of depressive animal models by exposing rats to chronic mild stress (CMS) and by chronically administering the tricyclic antidepressant clomipramine (CLI) in the rat during the neonatal state of life to produce adult depressed rats. We investigated the effects of lateral habenular nucleus (LHb) lesions on the behavioral response and on the level of 5-HT in DRN in the depressed rats. Forced-swimming test (FST) showed that the immobility time decreased, and the climbing time increased after lesioning LHb of depressed rats. Microdialysis results indicated that the 5-HT level in DRN in depressed rats was lower than that of the control group. Lesion of the LHb was followed by an increased 5-HT turnover in the DRN. Our results suggested that the lesion of the LHb could improve the behavioral response of the depressed rats and the 5-HT level of the DRN increased by LHb lesions could be involved in the effects.

Introduction

Abnormalities in central serotonin (5-HT) neurotransmission are associated with anxiety and depression [1], [2]. Clinically effective antidepressant drugs are thought to exert therapeutic effects by facilitating 5-HT function [3], [4], [5] suggesting that 5-HT depletion plays a key role in the pathogenesis of depression. A large number of 5-HT cells were observed in the dorsal raphe nucleus (DRN) [6], [7], [8], and their terminals are widely distributed throughout the forebrain [9]. It was also found that the DRN receives neurotransmission from the forebrain [10], [11]. However, one important structure that connects directly to the DRN and influences its functions is the habenular (Hb) complex, in particular the lateral habenular nucleus (LHb) [12], [13], [14], [15]. The LHb has a relay function, conveying limbic forebrain input to the DRN structure [16], [17], [18] and exerts a functional inhibition on bioelectrical activity of DRN neurons [12], [19]. Some studies showed that the activity of DRN neurons was changed by stimulating the Hb electrically [12]. Anatomical studies suggested substance P (SP) was coexpressed with 50% of 5-HT neurons in the DRN of the human brain [20], [21] and it influenced 5-HT neuron function in DRN [13]. Thus, SP receptor antagonist was considered to have an antidepressant effect similar to those produced by clinically effective antidepressant drugs (such as the selective 5-HT reuptake inhibitors fluoxetine) by increasing 5-HT level of the DRN [22]. However, in vitro electrophysiological experiments showed that SP receptor antagonist did not directly influence the DRN firing. Moreover, SP receptor antagonist was found to induce increased DRN activity after it was microinjected into the LHb [22]. It has been reported that the SP receptors and fibers are distributed in the LHb and the fibers originate from SP-containing cells in the rostral entopeduncular nucleus (rEP) and in medial habenular nucleus (MHb) [23], [24]. This raises the possibility that SP or SP receptor antagonist influences DRN neuronal activity via an inhibitory effect from the LHb. In three types of depressant animal models, the metabolic rate of Hb was increased [25]. It was shown that the increased activity of Hb might contribute to the pathogenesis of depression. Although much data indicates that LHb may be an especially important region linked to depression. So far it is unclear whether the activities of the LHb influence the behavior of depressed rats and what possible mechanisms are involved in it.

Psychological stress has been implicated in mental disorders including anxiety and depression [26], [27], [28], [29]. Exposing the rat to chronic mild stress (CMS) induced depression behaviors. This model has been suggested as suitable for the experimental investigation of the pathogenesis of depression [30]. This was based on an earlier observation by Katz [31] and was verified by multiple scholars [32], [33], [34], [35]. A second model of depression using rats treated in the neonatal period with clomipramine (CLI) was used by Vogel et al. [36], [37], [38]. We used these two rat models of depression to study the role of LHb in influencing the behaviors of the depressed rat. We studied the effects on rat behaviors and 5-HT level in the DRN after ablation of LHb and microinjection of lidocaine into the LHb.

Section snippets

Animals

Male Wistar rats (175–250 g, Department of Experimental Animals, Jilin University, Changchun, China) were used in this study. They were housed in a standard cage with food and water available ad libitum and kept under normal laboratory conditions (temperature 22 ± 2 °C, 12-h day–night cycle, lights on at 8:00 a.m.). Forced-swimming test (FST) was performed between 8 a.m. and 12 p.m. The rats were randomly divided into two groups: the control group was given ordinary daily care without limit to food

The results of FST in depressed rats

After 21 days CMS, the immobile time of CMS rats were increased from 51.6 ± 8.2 to 110.5 ± 13.8 s (n = 32, t = 3.68, P < 0.001), the climbing time was decreased from 98.0 ± 7.7 to 27.9 ± 5.2 s (n = 32, t = 7.59, P < 0.001). The activities of rats were decreased significantly compared with those before stress (Fig. 1A).

The immobile time of CLI rats was longer than that of controls (160.1 ± 15.0 s vs. 51.6 ± 8.2 s, n = 19, t = 6.95, P < 0.001) and climbing time of CLI rats was shorter than that of controls (31.3 ± 4.8 s vs. 98.0 ± 7.7 

Discussion

The study showed that exposing the rat to CMS induced depressive behaviors as shown by increase of immobile time and decrease of the climbing time. This result was in agreement with others [32], [33], [34], [35]. In addition, the CLI model was also used in this study. Administering the tricyclic antidepressant CLI to neonatal rats (postnatal day 8–21) mimics in the adult rats some of the core symptoms of major depressive disorders in humans. We showed that the immobile time of CLI rats was

Acknowledgments

We should like to thank Prof. Jin Yuan-Zhe for providing the facilities with the Microdialysis system at Yanbian University and Dr. Jiang Hai-Ying and An Ying for their helpful advice and assistance. This research was supported by the National Natural Science Foundation of China (No. 30670670).

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