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

Yang, Limin; Hu, Bing; Xia, Ying-Hong; Zhang, Beilin; Zhao, Hua

doi:10.1016/j.bbr.2007.10.022

Cited by 200 publications

(153 citation statements)

References 47 publications

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“…This nucleus has recently attracted a surge of interest as a neural substrate for the underlying pathophysiology of depression because studies have reported increased activity in the habenula in major depression (Morris et al, 1999;Roiser et al, 2009) and in a helpless rat model for depression (Li et al, 2011). These findings, together with the antidepressant effects of LHb lesions in rats (Yang et al, 2008) or deep brain stimulation (DBS) of the habenular circuit in rats (Li et al, 2011) and humans (Sartorius et al, 2010), support the hypothesis that hyperactivation of the habenula plays a role in the pathophysiology of depression.…”

Section: Introductionmentioning

confidence: 82%

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Cui¹,

Mizukami

Yanagisawa³

et al. 2014

J. Neurosci.

114

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The lateral habenula (LHb) regulates the activity of monoaminergic neurons in the brainstem. This area has recently attracted a surge of interest in psychiatry because studies have reported the pathological activation of the habenula in patients with major depression and in animal models. The LHb plays a significant role in the pathophysiology of depression; however, how habenular neurons are activated to cause various depression symptoms, such as reduced motivation and sleep disturbance, remain unclear. We hypothesized that dysfunctional astrocytes may cause LHb hyperactivity due to the defective uptake activity of extracellular glutamate, which induces depressivelike behaviors. We examined the activity of neurons in habenular pathways and performed behavioral and sleep analyses in mice with pharmacological and genetic inhibition of the activity of the glial glutamate transporter GLT-1 in the LHb. The habenula-specific inhibition of GLT-1 increased the neuronal firing rate and the level of c-Fos expression in the LHb. Mice with reduced GLT-1 activity in the habenula exhibited a depressive-like phenotype in the tail suspension and novelty-suppressed feeding tests. These animals also displayed increased susceptibility to chronic stress, displaying more frequent avoidant behavior without affecting locomotor activity in the openfield test. Intriguingly, the mice showed disinhibition of rapid eye movement sleep, which is a characteristic sleep pattern in patients with depression. These results provide evidence that disrupting glutamate clearance in habenular astrocytes increases neuronal excitability and depressive-like phenotypes in behaviors and sleep.

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Section: Introductionmentioning

confidence: 82%

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Cui¹,

Mizukami

Yanagisawa³

et al. 2014

J. Neurosci.

114

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“…Tissue concentrations of glutamate and GABA were measured using HPLC with electrochemical detection (ECD-300, Eicom Corporation, Japan) as previously described (Yang et al 2008;Kang et al 2009a). Tissue NE concentration was measured using HPLC with electrochemical detection (HTEC-500, Eicom Corporation, Japan) as previously described (Barber et al 2003;Yang et al 2008;Kang et al 2009a).…”

Section: Measurement Of Pvn Tissue Levels Of Glutamate Gaba and Ne mentioning

confidence: 99%

“…Tissue NE concentration was measured using HPLC with electrochemical detection (HTEC-500, Eicom Corporation, Japan) as previously described (Barber et al 2003;Yang et al 2008;Kang et al 2009a). Plasma NE was measured using HPLC as previously described (Guggilam et al 2007(Guggilam et al , 2008.…”

Section: Measurement Of Pvn Tissue Levels Of Glutamate Gaba and Ne mentioning

confidence: 99%

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

Kang

Wang

Yang

et al. 2010

Tohoku J. Exp. Med.

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Proinflammatory cytokines, including tumor necrosis factor (TNF)-α , augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-α in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-α blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-α in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.

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“…A recent pilot study also assessed the safety and efficacy of DBS to the supero-lateral branch of the medial forebrain bundle in seven patients with highly refractory depression (Schlaepfer et al, 2013) with promising results. The choice of these targets is based on various sources of evidence pointing to their involvement in depressive symptoms including functional neuroimaging studies (Kennedy et al, 2007;Lakhan and Callaway, 2010;Mayberg et al, 1999), observations of reduced depressive symptoms following ablative procedures performed on MDD and obsessive compulsive disorder patients (Greenberg et al, 2003) and lesion studies in animal models (Yang et al, 2008). Although the small number of cases published to date preclude a conclusion as to which of these locations are best suited as DBS targets, the observation that successful treatment has been achieved using various targets is compatible with the hypothesis that MDD is a network disorder.…”

Section: Introductionmentioning

confidence: 99%

EEG Power Asymmetry and Functional Connectivity as a Marker of Treatment Effectiveness in DBS Surgery for Depression

Quraan

Protzner

Daskalakis

et al. 2013

Neuropsychopharmacol

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Recently, deep brain stimulation (DBS) has been evaluated as an experimental therapy for treatment-resistant depression. Although there have been encouraging results in open-label trials, about half of the patients fail to achieve meaningful benefit. Although progress has been made in understanding the neurobiology of MDD, the ability to characterize differences in brain dynamics between those who do and do not benefit from DBS is lacking. In this study, we investigated EEG resting-state data recorded from 12 patients that have undergone DBS surgery. Of those, six patients were classified as responders to DBS, defined as an improvement of 50% or more on the 17-item Hamilton Rating Scale for Depression (HAMD-17). We compared hemispheric frontal theta and parietal alpha power asymmetry and synchronization asymmetry between responders and non-responders. Hemispheric power asymmetry showed statistically significant differences between responders and non-responders with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry was characterized by an increase in frontal theta in the right hemisphere relative to the left combined with an increase in parietal alpha in the left hemisphere relative to the right in non-responders compared with responders. Hemispheric mean synchronization asymmetry showed a statistically significant difference between responders and non-responders in the theta band, with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry resulted from an increase in frontal synchronization in the right hemisphere relative to the left combined with an increase in parietal synchronization in the left hemisphere relative to the right in non-responders compared with responders. Connectivity diagrams revealed long-range differences in frontal/central-parietal connectivity between the two groups in the theta band. This pattern was observed irrespective of whether EEG data were collected with active DBS or with the DBS stimulation turned off, suggesting stable functional and possibly structural modifications that may be attributed to plasticity.

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

Cited by 200 publications

References 47 publications

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

EEG Power Asymmetry and Functional Connectivity as a Marker of Treatment Effectiveness in DBS Surgery for Depression

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