Elevation of p11 in lateral habenula mediates depression-like behavior

Js, Seo; Zhong, Ping; A, Liu; Zhang, Yan; Greengard, Paul

doi:10.1038/mp.2017.96

Cited by 65 publications

(71 citation statements)

References 48 publications

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“…(b) Open field test was performed for 5 min as previously described (Gould et al, ). (c) Force swim test was performed in glass cylinders (height 30 cm, diameter: 16 cm) containing water at 24°C and depth of 14 cm as previously described (Seo, Zhong, Liu, Yan, & Greengard, ).…”

Section: Methodsmentioning

confidence: 99%

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

Farfara

Feierman

Richards

et al. 2019

Glia

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The cross‐talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein‐kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood–brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild‐type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long‐term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro‐inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive‐like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.

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Section: Methodsmentioning

confidence: 99%

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

Farfara

Feierman

Richards

et al. 2019

Glia

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“…Surprisingly, we find that stress causes the LHb to respond to rewards as if they were punishment. This switch is tightly linked temporally with onset of anhedonic behavior, suggesting that this aberrant LHb responsivity contributes to anhedonia (29)(30)(31)(32)(33)(34)(35). These changes were also accompanied by a larger (i.e., "more negative") LHb signal to reward omission.…”

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confidence: 91%

Stress transforms lateral habenula reward responses into punishment signals

Shabel

Wang

Monk

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal activity in the lateral habenula (LHb), a brain region implicated in depression [C. D. Proulx, O. Hikosaka, R. Malinow, Nat. Neurosci. 17, 1146-1152], decreases during reward and increases during punishment or reward omission [M. Matsumoto, O. Hikosaka, Nature 447, 1111-1115]. While stress is a major risk factor for depression and strongly impacts the LHb, its effect on LHb reward signals is unknown. Here we image LHb neuronal activity in behaving mice and find that acute stress transforms LHb reward responses into punishment-like neural signals; punishmentlike responses to reward omission also increase. These neural changes matched the onset of anhedonic behavior and were specific to LHb neurons that distinguished reward and its omission. Thus, stress distorts LHb responsivity to positive and negative feedback, which could bias individuals toward negative expectations, a key aspect of the proposed pathogenesis of depression [A. T. Beck, Depression: Clinical, Experimental, and Theoretical Aspects, sixth Ed (1967)]. habenula | stress | reward | anhedonia | prediction error L ateral habenula (LHb) neurons encode numerous stimuli including rewards, their omission, and punishment (1-7). In particular, the LHb provides reward prediction error (RPE) (2) signals-the difference between expected and actual reward value-a computation thought to be essential for an animal to learn from its environment (8-10). In this way, LHb activity, which is aversive (1, 11-13), can provide "teaching" signals to an animal: increased LHb activity (i.e., if actual reward value is less than expected) discourages repeating a behavior in the future (11,12,14), while decreased LHb activity is thought to reinforce a behavior.Human and nonhuman animal studies indicate that stressinduced changes in LHb activity may contribute to depression by suppressing reward-based behavior (1,(15)(16)(17)(18). While stress decreases reward sensitivity (19,20), is a major risk factor for depression (21, 22), forms the basis for most animal models of depression (23-25), and causes plasticity in the LHb (26-31), its effects on LHb reward and RPE signals are not known. Here, we use calcium-imaging techniques to monitor RPE from individual LHb neurons in awake, behaving mice in the absence and presence of intermittent tail shock stress. Surprisingly, we find that stress causes the LHb to respond to rewards as if they were punishment. This switch is tightly linked temporally with onset of anhedonic behavior, suggesting that this aberrant LHb responsivity contributes to anhedonia (29)(30)(31)(32)(33)(34)(35). These changes were also accompanied by a larger (i.e., "more negative") LHb signal to reward omission. Our results indicate that stress causes a negative shift in LHb signaling of reward and its omission. While potentially adaptive in some conditions (e.g., suppressing reward-seeking behavior during threat), repeated occurrence of such effects could contribute to the pathogenesis of depression. ResultsRPE Encoding in a Subpopulation of LHb Neurons. W...

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“…anhedonia, social withdrawal), which are thought to reflect some of the core symptoms seen in depressed humans (Berton et al, 2012;Monteggia et al, 2018;Nestler and Hyman, 2010;Willner et al, 1992). Although patients with depression show a highly diverse set of combination of symptoms (Carragher et al, 2009;ten Have et al, 2016;Musil et al, 2018;Willner et al, 2013), scientists often considered CS-exposed animals as a homogeneous population in their search for a pathological mechanism (Agudelo et al, 2014;Cui et al, 2018;Frisbee et al, 2015;Li et al, 2013;Moreines et al, 2017;Ramirez et al, 2015;Schweizer et al, 2009;Seo et al, 2018;. However, simply dividing animals into "stressed" and "non-stressed" groups may not account for the diversity of behavioral phenotypes that arise in response to CS exposure.…”

Section: Introductionmentioning

confidence: 99%

Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

Cerniauskas

Winterer

Jong

et al. 2019

Neuron

124

118

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CHAPTER 1: INTRODUCTION Heterogeneity of major depressive disorder Depression, or major depressive disorder, is a mental disorder that dramatically affects a person's health and life. It is characterized by persistent low mood, inability to feel pleasure in previously enjoyable activities, feeling of low-esteem, fatigue, sleep disturbances, appetite changes, pain without a clear cause, and thoughts of suicide. It has become the leading cause of disability worldwide with over 300 million people affected. The prevalence of major depressive disorder increased by 18% from 2005 to 2015 (World Health Organization, 2017). Depression is also a chronic disease, as half of a people who experienced a single episode are likely to have recurrent episodes with higher frequency and severity (Akil et al., 2018). Even though major depressive disorder is diagnosed as a single entity, it is a really heterogeneous disorder characterized by patients having widely varied symptoms, with little to even no overlap of symptomatologies in some cases (Akil et al., 2018). This heterogeneity of depression hinders both research and treatment of this highly prevalent disorder (Fried, 2017). Antidepressants available on the market today were developed based on a theory called monoamine hypothesis of depression, which was established on several key observations made in 1950s. The hypothesis states that the underlying biological reason for depression is depletion of dopamine, serotonin, and/or norepinephrine levels in the central nervous system. It has been demonstrated that increasing the levels of the aforementioned monoamine neurotransmitters in the brain, either by blockage of their reuptake or inhibition of their degradation, alleviates the depression symptoms in patients (Delgado, 2000; Hirschfeld, 2000). Despite the relative effectiveness of currently available antidepressant medications, they are still lacking and possess a variety of drawbacks. Less than half of the patients achieve full remission after the first treatment with antidepressants (Rush, 2007). That leads to trial-and-error approach, where multiple trials of different treatment are needed until the patient is matched with optimal medication. Even then, for patients that do respond to treatment, it takes weeks or months until the depressive symptoms are alleviated (Berton and Nestler, 2006). Some patients also exhibit resistance to antidepressants, which can develop spontaneously in patients previously responsive to treatment or as a result of worsening illness over the course of time (Thase and Schwartz, 2015). Moreover, treatment with antidepressants has numerous side effects, such as fatigue, sleep disturbances, weight and appetite, and sexual dysfunction (Fergusson, 2001). Therefore, there is still an unmet need for more effective, faster, and safer treatment for major depressive disorder. A different approach to depression treatment would be to conceptualize this disease as a circuit dysfunction instead of a neurotransmitter dysfunction. It is possible that the heterogene...

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Elevation of p11 in lateral habenula mediates depression-like behavior

Cited by 65 publications

References 48 publications

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

Stress transforms lateral habenula reward responses into punishment signals

Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

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