Role of the Lateral Habenula in Pain-Associated Depression

Abstract

Patients with chronic pain have significantly higher incidences of depression and anxiety than the average person. However, the mechanism underlying this link has not been elucidated in terms of how chronic pain causes significant mood changes and further develops into severe anxiety or depression. The serotonergic system in the raphe nuclei is an important component in both pain processing and the pathogenesis of depression. Since the lateral habenular nucleus (LHb) controls the raphe nuclei, it may participate in the regulation of pain-associated depression. Thus, the aim of the current study was to investigate the role of the LHb in this pathophysiological process. We used chronic constriction injury (CCI) of the sciatic nerve in rats as a model for neuropathic pain and assessed the changes potentially related to the mood disorders. The forced swim test (FST) and sucrose preference test (SPT) were performed to determine the behavioral changes 28 days after pain surgery. Expression of β calmodulin-dependent protein kinase type II (βCaMKII) in the LHb, cytochrome-c oxidase (COX) activity in the LHb and dorsal raphe nucleus (DRN) and serotonin (5-HT) levels in the DRN were measured. We found an increasing in LHb activity and βCaMKII expression, and a decrease in neuronal activity in the DRN and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratios in the CCI rats. These effects were accompanied by the depression-like behaviors. Lesions in the LHb improved the pain threshold and depression-like behavior in the rats. These results suggest that the LHb may play a role in pain-associated depression by affecting the activity of 5-HT neurons in the DRN. Furthermore, we showed that increases in the LHb-DRN pathway activity were a common neurobiological mechanisms for pain and depression, which may explain the coexistence of pain and depression.

The lateral habenula is critically involved in histamine-induced itch sensation

“…Among brain regions engaging the processing of pain information, the lateral habenula (LHb) is known to be activated by aversive stimuli and induces avoidance behavior [9,10]. Many studies have reported that the LHb in rodent and human is activated by noxious stimuli [11][12][13][14][15]. The lateral hypothalamic region (LHA) is directly innervated by sensory stimuli transmitted via spinothalamic tract, and directly projects to LHb.…”

Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving

“…Monosynaptic viral vector tracing and electrophysiological studies have shown a variety of pathways from LHb to DR and median raphe, including glutamatergic projections to 5-HT neurons and GABAergic neurons, and that the LHb innervation of GABAergic DR neurons provides feedforward inhibition to 5-HT neurons (Pollack-Dorocic et al, 2014; Ogawa eta l., 2014; Zhou et al, 2017). These mechanisms by which the LHb regulates the serotoninergic DR and median raphe have been proposed to be involved in comorbidity of a variety of disorders with depression (Li et al, 2017; Wang et al, 2017; Zhang et al, 2016) and defensive behavior (Pobbe and Zangrossi, 2010). …”

Reward Circuitry Plasticity in Pain Perception and Modulation

“…Furthermore, the connections between the Hb and raphe nuclei are especially important since the serotonergic system plays a role in both depression and pain ( Stamford, 1995 ; Gao et al, 2008 ). In animal models, lesions in the LHb produces a reduction in depressive-like behaviors by elevating the levels of serotonin in the dorsal raphe nucleus ( Yang et al, 2008 ), which strongly suggests the participation of the LHb in the control of pain-related depression ( Li et al, 2017 ). Supporting this notion, an increase in the LHb activity along with a reduced activity in the dorsal raphe nucleus has been found in an experimental model of neuropathic pain.…”

“…Supporting this notion, an increase in the LHb activity along with a reduced activity in the dorsal raphe nucleus has been found in an experimental model of neuropathic pain. This model has also resulted in pain and depressive-like behaviors, which have been reversed by LHb lesions ( Li et al, 2017 ).…”