βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression

Li, Kun; Zhou, Tao; Liao, Lujian; Yang, Zhipeng; Wong, Catherine C. L.; Henn, Fritz A.; Malinow, Roberto; Yates, John R.; Hu, Hailan

doi:10.1126/science.1240729

Cited by 366 publications

(343 citation statements)

References 52 publications

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“…In neurons they are a crucial transducer of One way to circumvent this problem could be the tailoring of CaMK-based pharmacotherapies to settings and time points where little normal learning is required and where drug memories can specifically activated and pharmacologically attenuated (see: Outstanding questions). Another future perspective would be the development of subtype specific ligands that can target major CaMKs more selectively and spare others that are primarily involved in other behaviours [120].…”

Section: Discussionmentioning

confidence: 99%

CaM Kinases: From Memories to Addiction

Müller

Quednow

Lourdusamy

et al. 2016

Trends in Pharmacological Sciences

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Drug addiction is a major psychiatric disorder with a neurobiological base that is still insufficiently understood. Initially, non-addicted, controlled drug consumption and drug instrumentalization are established. They comprise highly systematic behaviours acquired by learning and the establishment of drug memories. Ca 2+ /calmodulin-dependent protein kinases (CaMKs) are important Ca 2+ -sensors translating glutamatergic activation into synaptic plasticity during learning and memory formation. Here we review the role of CaMKs in the establishment of drugrelated behaviours in animal models and in humans. Converging evidence shows now that CaMKs are a crucial mechanism of how addictive drugs induce synaptic plasticity and establish various types of drug memories. Thereby, CaMKs are not only molecular relays for glutamatergic activity; they also directly control dopaminergic and serotonergic activity in the mesolimbic reward system. They can now be considered as major molecular pathways translating normal memory formation into establishment of drug memories and possibly transition to drug addiction. Keywords: Ca 2+/calmodulin-dependent protein kinase, drug dependence, addiction, psychostimulants, alcohol, opioids 3 Drug Use and AddictionDrug addiction is a major psychiatric disorder for which only limited therapies are currently available [1,2]. A striking criterion for drug abuse and addiction is that it severely threatens one's own and others well-being and health. As such, there is a persistent need to treat drug addiction effectively, and ideally reverse the behavioural repertoire of an affected individual back to normal.An important feature of drug addiction is that it develops from a behavioural repertoire, which is considered to be normal in many societies of the world: the controlled consumption and instrumentalization of psychoactive drugs [3,4].Establishing and maintaining controlled drug consumption is based on systematic learning and memory retrieval of distinct behaviours, related to drug seeking, preparation, and consumption in a specific context [5,6]. Thereby, information is encoded within different behavioural systems, which can be summarized as "drug memories" [5,[7][8][9] (Box 1). It is believed that an intensification of these memories together with a loss of impulse control (compulsivity) is responsible for the transition from controlled drug use to addiction [10][11][12]. Understanding how these drug memories are established and how they may take control over a normal behavioural repertoire should, therefore, allow to improve the prevention of addiction and to develop new and more effective treatments [13]. From Memories to Drug MemoriesIt was suggested that anatomical pathways, micro-morphological adaptations, as well as molecular mechanisms in the brain, overlap between normal learning and memory and drug memories [14][15][16]. A crucial player for memory formation in the brain is the glutamatergic system and its plasticity based on experience [17]. Addiction research considered glu...

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Section: Discussionmentioning

confidence: 99%

CaM Kinases: From Memories to Addiction

Müller

Quednow

Lourdusamy

et al. 2016

Trends in Pharmacological Sciences

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“…Notably, changes in both nodal strength and edge connection occurred in the thalamus, which plays a vital role in the pathophysiology of mood disorders (1). Due to limited spatial resolution here, we could not assess the potential effects involving the habenula (included in the thalamus node), a region heavily implicated in the depression circuit (57) and demonstrated in our recent work (58).…”

Section: Regional Regulation Of Small-world Networkmentioning

confidence: 97%

Large-Scale Persistent Network Reconfiguration Induced by Ketamine in Anesthetized Monkeys: Relevance to Mood Disorders

Yang

et al. 2016

Biological Psychiatry

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“…Indeed, lethargy and lack of motivation are core symptoms of major depressive disorder (American Psychiatric Association, 2013). The LHb, which activates and inactivates the RMTg and VTA, respectively (Hong et al, 2011), is overactive in rat models of depression (Caldecott-Hazard et al, 1988;Shumake et al, 2003;Li et al, 2013) and depressed human patients (Morris et al, 1999;Roiser et al, 2009). Inhibition of the LHb reverses depression-like behaviors in rats (Winter et al, 2011) and the LHb has been targeted with some success in deep brain stimulation to treat treatment-resistant depression in humans (Sartorius et al, 2010;Schneider et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

Lavezzi

Parsley

Zahm

2014

Neuropsychopharmacol

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The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the gamma-aminobutyric acid A (GABA A ) agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABA A receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways: (1) by disinhibitory stimulation of neurons in the lateral preoptic area and (2) by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired.

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βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression

Cited by 366 publications

References 52 publications

CaM Kinases: From Memories to Addiction

CaM Kinases: From Memories to Addiction

Large-Scale Persistent Network Reconfiguration Induced by Ketamine in Anesthetized Monkeys: Relevance to Mood Disorders

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

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