Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

?CaMKII in lateral habenula mediates core symptoms of depression.

ABSTRACT: The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the ? form of calcium/calmodulin-dependent protein kinase type II (?CaM???) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing ?-, but not ?-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of ?CaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify ?CaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.

SUBMITTER: Li K

PROVIDER: S-EPMC3932364 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

βCaMKII in lateral habenula mediates core symptoms of depression.

Li Kun K Zhou Tao T Liao Lujian L Yang Zhongfei Z Wong Catherine C Henn Fritz F Malinow Roberto R Yates John R JR Hu Hailan H

Science (New York, N.Y.) 20130801 6149

The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the β form of calcium/calmodulin-dependent protein kinase type II (βCaMΚΙΙ) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing β-, but not α-, CaMKII in t ...[more]

PMID: 23990563

Similar Datasets

Elevation of p11 in lateral habenula mediates depression-like behavior.

Project description:The lateral habenula (LHb) is a key brain region involved in the pathophysiology of depression. It is activated by stimuli associated with negative experiences and is involved in encoding aversive signals. Hyperactivity of LHb is found in both rodent models of depression and human patients with depression. However, little is known about the underlying molecular mechanisms. Here we show that in LHb neurons, p11, a multifunctional protein implicated in depression, is significantly upregulated by chronic restraint stress. Knockdown of p11 expression in LHb alleviates the stress-induced depression-like behaviors. Moreover, chronic restraint stress induces bursting action potentials in LHb neurons, which are abolished by p11 knockdown. Overexpression of p11 in dopamine D2 receptor-containing LHb neurons of control mice induces depression-like behaviors. These results have identified p11 in LHb as a key molecular determinant regulating negative emotions, which may help to understand the molecular and cellular basis of depression.

| S-EPMC5690885 | biostudies-literature

Case Report: Lateral Habenula Deep Brain Stimulation for Treatment-Resistant Depression.

Project description:Treatment-resistant depression (TRD) is a chronic and severe psychiatric illness associated with limited therapeutic options. Deep brain stimulation (DBS) is a promising therapy for TRD patients. However, its safety and efficacy are still unclear. Here we reported the safety and efficacy of lateral habenula (LHb) DBS for a TRD patient who had failed medical, psychological, electroconvulsive, and ketamine therapy. The DBS system is compatible with 3T magnetic resonance imaging along with local field potential (LFP) streaming. Two DBS electrodes were implanted at the bilateral LHb without any complication. The patient showed acute stimulation effects and achieved long-term improvements in his depression, anxiety, and sleep with left LHb 160 Hz frequency stimulation, accompanying the change of LFPs. These results provided clinical evidence toward the safety and efficacy and electrophysiological basis of LHb DBS for TRD.

| S-EPMC7838359 | biostudies-literature

NMDA receptor-dependent long-term depression in the lateral habenula: implications in physiology and depression.

Project description:Abnormally increased neuronal activity in the lateral habenula (LHb) is closely associated with depressive-like behavior. Despite the emphasis on the pathological importance of NMDA receptor (NMDAR)-dependent long-term depression (LTD) and the involvement of calcium permeable AMPA receptor (CP-AMPAR) as major Ca2+ source, the functions of NMDAR and CP-AMPAR on LTD modulation in the LHb still have not been fully investigated. Here, we found that NMDAR-dependent LTD by low frequency stimulation was induced in both synaptic and extrasynaptic regions in the LHb. In addition, CP-AMPAR was necessary for the activation of NMDAR in the induction phase of NMDAR-dependent LTD. The acute stress, which induced depressive behavior, had a blocked effect on synaptic NMDAR-dependent LTD but left extrasynaptic NMDAR-dependent LTD intact. These findings show that NMDAR-dependent LTD in LHb plays an important role in regulating neuronal activity, which is probable to be excessively increased by repeated stress, via maintaining homeostasis in both synaptic and extrasynaptic regions of the LHb. Moreover, NMDAR and CP-AMPAR may serve as a depression-related modulator and be regarded as a promising therapeutic target for treatment of psychopathology such as depression.

| S-EPMC7578045 | biostudies-literature

Molecular profiling of the lateral habenula in a rat model of depression.

Project description:ObjectiveThis study systematically investigated the effect of chronic mild stress and response to antidepressant treatment in the lateral habenula at the whole genome level.MethodsRat whole genome expression chips (Affymetrix) were used to detect gene expression regulations in the lateral habenula of rats subjected to chronic mild stress (mild stressors exchanged twice a day for 8 weeks). Some rats received antidepressant treatment during fifth to eights week of CMS. The lateral habenula gene expression profile was studied through the gene ontology and signal pathway analyses using bioinformatics. Real-time quantitative polymerase chain reaction (RT-PCR) was used to verify the microarray results and determine the expression of the Fcrla, Eif3k, Sec3l1, Ubr5, Abca8a, Ankrd49, Cyp2j10, Frs3, Syn2, and Znf503 genes in the lateral habenula tissue.ResultsIn particular we found that stress and antidepressant treatment affected intracellular cascades like growth factor receptor signaling, G-protein-coupled receptor signaling, and Wnt signaling - processes involved in the neuroplastic changes observed during the progression of depression and antidepressant treatment.ConclusionThe present study suggests an important role of the lateral habenula in the development of depression-like conditions and correlates to previous studies demonstrating a significant role of the lateral habenula in depressive-like conditions and antidepressant treatment.

| S-EPMC3855087 | biostudies-literature

Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula.

Project description:Addictive substances mediate positive and negative states promoting persistent drug use. However, substrates for aversive effects of drugs remain elusive. We found that, in mouse lateral habenula (LHb) neurons targeting the rostromedial tegmental nucleus, cocaine enhanced glutamatergic transmission, reduced K(+) currents and increased excitability. GluA1 trafficking in LHb was instrumental for these cocaine-evoked modifications and drug-driven aversive behaviors. Altogether, our results suggest that long-lasting adaptations in LHb shape negative symptoms after drug taking.

| S-EPMC4357267 | biostudies-literature

Stress undermines reward-guided cognitive performance through synaptic depression in the lateral habenula.

Project description:Weighing alternatives during reward pursuit is a vital cognitive computation that, when disrupted by stress, yields aspects of neuropsychiatric disorders. To examine the neural mechanisms underlying these phenomena, we employed a behavioral task in which mice were confronted by a reward and its omission (i.e., error). The experience of error outcomes engaged neuronal dynamics within the lateral habenula (LHb), a subcortical structure that supports appetitive behaviors and is susceptible to stress. A high incidence of errors predicted low strength of habenular excitatory synapses. Accordingly, stressful experiences increased error choices while decreasing glutamatergic neurotransmission onto LHb neurons. This synaptic adaptation required a reduction in postsynaptic AMPA receptors (AMPARs), irrespective of the anatomical source of glutamate. Bidirectional control of habenular AMPAR transmission recapitulated and averted stress-driven cognitive deficits. Thus, a subcortical synaptic mechanism vulnerable to stress underlies behavioral efficiency during cognitive performance.

| S-EPMC7980092 | biostudies-literature

Downregulation of M-channels in lateral habenula mediates hyperalgesia during alcohol withdrawal in rats.

Project description:Hyperalgesia often occurs in alcoholics, especially during abstinence, yet the underlying mechanisms remain elusive. The lateral habenula (LHb) has been implicated in the pathophysiology of pain and alcohol use disorders. Suppression of m-type potassium channels (M-channels) has been found to contribute to the hyperactivity of LHb neurons of rats withdrawn from chronic alcohol administration. Here, we provided evidence that LHb M-channels may contribute to hyperalgesia. Compared to alcohol naïve counterparts, in male Long-Evans rats at 24-hours withdrawal from alcohol administration under the intermittent access paradigm for eight weeks, hyperalgesia was evident (as measured by paw withdrawal latencies in the Hargreaves Test), which was accompanied with higher basal activities of LHb neurons in brain slices, and lower M-channel protein expression. Inhibition of LHb neurons by chemogenetics, or pharmacological activation of M-channels, as well as overexpression of M-channels' subunit KCNQ3, relieved hyperalgesia and decreased relapse-like alcohol consumption. In contrast, chemogenetic activation of LHb neurons induced hyperalgesia in alcohol-naive rats. These data reveal a central role for the LHb in hyperalgesia during alcohol withdrawal, which may be due in part to the suppression of M-channels and, thus, highlights M-channels in the LHb as a potential therapeutic target for hyperalgesia in alcoholics.

| S-EPMC6389965 | biostudies-literature

Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression.

Project description:Hyperconnectivity of the default-mode network (DMN) is one of the most widely replicated neuroimaging findings in major depressive disorder (MDD). Further, there is growing evidence for a central role of the lateral habenula (LHb) in the pathophysiology of MDD. There is preliminary neuroimaging evidence linking LHb and the DMN, but no causal relationship has been shown to date. We combined optogenetics and functional magnetic resonance imaging (fMRI), to establish a causal relationship, using an animal model of treatment-resistant depression, namely Negative Cognitive State rats. First, an inhibitory light-sensitive ion channel was introduced into the LHb by viral transduction. Subsequently, laser stimulation was performed during fMRI acquisition on a 9.4 Tesla animal scanner. Neural activity and connectivity were assessed, before, during and after laser stimulation. We observed a connectivity decrease in the DMN following laser-induced LHb perturbation. Our data indicate a causal link between LHb downregulation and reduction in DMN connectivity. These findings may advance our mechanistic understanding of LHb inhibition, which had previously been identified as a promising therapeutic principle, especially for treatment-resistant depression.

| S-EPMC5913319 | biostudies-literature

Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats.

Project description:Depression is a well-known risk factor for developing relapse drinking, but the neuronal mechanisms underlying the interactions between depression and alcohol use disorders remain elusive. Accumulating evidence has associated depression with hyperactivity of the lateral habenula (LHb), an epithalamic structure in the brain that encodes aversive signals. Glutamate receptors contribute substantially to the excitability of LHb neurons. Glutamatergic synapses in LHb neurons largely express GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that can be modulated by Ca2+/calmodulin-dependent protein II (CaMKII). In the current study, we tested the hypothesis that withdrawal from repeated cycles of ethanol drinking triggers an increase in LHb AMPAR and CaMKII activity concomitant with depression-like symptoms, and their inhibitions bring a reduction in depressive-like behaviors and alcohol consumption. Western blotting revealed a higher level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (GluA1-Ser831) in the LHb of ethanol-withdrawn rats than that of age-matched naïve counterparts. In ethanol-withdrawn rats, pharmacological inhibition of LHb AMPAR activity significantly mitigated the depressive-like behavior and ethanol drinking and seeking behaviors, but affected neither sucrose intake nor locomotor activity; and inhibition of LHb CaMKII activity, or chemogenetic inhibition of LHb activity produced similar effects. Conversely, activation of LHb AMPARs induced depressive-like behaviors in ethanol-naïve rats. These results demonstrate that CaMKII-AMPAR signaling in the LHb exemplifies a molecular basis for depressive-like symptoms during ethanol withdrawal and that inhibition of this signaling pathway may offer a new therapeutic approach to address the comorbidity of alcohol abuse and depression.

| S-EPMC5634930 | biostudies-literature

Orexinergic innervations at GABAergic neurons of the lateral habenula mediates the anesthetic potency of sevoflurane.

Project description:AimsThe circuitry mechanism associated with anesthesia-induced unconsciousness is still largely unknown. It has been reported that orexinergic neurons of the lateral hypothalamus (LHA) facilitate the emergence from anesthesia through their neuronal projections to the arousal-promoting brain areas. However, the lateral habenula (LHb), as one of the orexin downstream targets, is known for its anesthesia-promoting effect. Therefore, the current study aimed to explore whether and how the orexinergic projections from the LHA to the LHb have a regulatory effect on unconsciousness induced by general anesthesia.MethodsWe applied optogenetic, chemogenetic, or pharmacological approaches to regulate the orexinergicLHA-LHb pathway. Fiber photometry was used to assess neuronal activity. Loss or recovery of the righting reflex was used to evaluate the induction or emergence time of general anesthesia. The burst-suppression ratio and electroencephalography spectra were used to measure the anesthetic depth.ResultsWe found that activation of the orexinergicLHA-LHb pathway promoted emergence and reduced anesthetic depth during sevoflurane anesthesia. Surprisingly, the arousal-promoting effect of the orexinergicLHA-LHb pathway was mediated by excitation of glutamate decarboxylase (GAD2)-expressing neurons, but not glutamatergic neurons in the LHb.ConclusionThe orexinergicLHA-LHb pathway facilitates emergence from sevoflurane anesthesia, and this effect was mediated by OxR2 in GAD2-expressing GABA neurons.

| S-EPMC10068468 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data