scholarly journals Pain, Anxiety- and Depression-Like Behaviors in Alcohol-Preferring and -NonPreferring Rats

2020 ◽  
pp. 1-8
Author(s):  
Jiang-Hong Ye ◽  
Emily Bian ◽  
Jiang-Hong Ye ◽  
Jing Li ◽  
Michal Gajewski ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Critical Role ◽  
Alcohol Exposure ◽  
Anxiety And Depression ◽  
Mechanical Stimuli ◽  
Lateral Habenula ◽  
Pain Anxiety ◽  
Calcium Calmodulin Dependent ◽  
Neuronal Mechanisms ◽  
Dependent Protein

Introduction: Psychiatric disorders such as anxiety, hyperalgesia, and depression have been associated with excessive alcohol drinking, but the neuronal mechanisms involved are only partially understood. Alcoholism more often occurs in individuals with a family history, indicating that genes may play a critical role. Chronic alcohol exposure alters calcium/calmodulin-dependent protein kinase II (CaMKII) signaling in the lateral habenula (LHb), and the LHb is implicated in mediating aversive behaviors, including those related to alcohol. We compared the CaMKII signaling in the LHb and the aberrant behaviors in the selectively bred alcohol-preferring (P) and alcohol-non-preferring (NP) lines of rats. Materials and Methods: The responses to mechanical (Von Frey) and thermal (Hargreaves) nociception tests, anxiety- (elevated plus maze, Marble burying) and depressive-like behaviors (forced swimming) were examined in the alcohol-naïve P and NP rats, as well as in P rats after 4-8 weeks of alcohol consumption; their LHb tissues were also collected for Western blot analysis of CaMKII expression. Results: Compared to NP rats, the P rats had a higher sensitivity to mechanical stimuli, and displayed depressive- and anxiety-like behaviors, as well as a higher level of CaMKII in the LHb. Alcohol consumption alleviated all these behaviors, except for anxiety, and decreased CaMKII levels in the LHb of P rats. Conclusions: The results show that selective breeding for different oral alcohol preference has produced differences in nociception, anxiety, and depression, as well as CaMKII expression in the LHb of P and NP rats. P rats may deal with pain and depression by self-medicating with alcohol.

scholarly journals Hypothalamic neuronal circuits regulating hunger-induced taste modification

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ou Fu ◽  
Yuu Iwai ◽  
Masataka Narukawa ◽  
Ayako W. Ishikawa ◽  
Kentaro K. Ishii ◽  
...  
Keyword(s):  
Lateral Hypothalamus ◽  
Critical Role ◽  
Taste Preference ◽  
Lateral Septum ◽  
Gustatory System ◽  
Lateral Habenula ◽  
Mechanistic Insight ◽  
Aversive Taste ◽  
Neuronal Mechanisms ◽  
Internal States

Abstract The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting.

scholarly journals MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

2018 ◽  
Vol 11 (549) ◽  
pp. eaar3721 ◽  
Author(s):  
Bishuang Cai ◽  
Canan Kasikara ◽  
Amanda C. Doran ◽  
Rajasekhar Ramakrishnan ◽  
Raymond B. Birge ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Calmodulin Dependent ◽  
Mitogen Activated Protein ◽  
Dependent Protein ◽  
Inflammation Resolution

Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs: lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. We now show that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca2+ concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This, in turn, reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX–derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression.

scholarly journals The Emerging Role of LHb CaMKII in the Comorbidity of Depressive and Alcohol Use Disorders

2020 ◽  
Vol 21 (21) ◽  
pp. 8123
Author(s):  
Chaya Shor ◽  
Wanhong Zuo ◽  
Jean D. Eloy ◽  
Jiang-Hong Ye
Keyword(s):  
Alcohol Use ◽  
Depressive Disorders ◽  
Alcohol Use Disorders ◽  
Lateral Habenula ◽  
Calcium Calmodulin Dependent ◽  
Targeted Treatments ◽  
Serotonin Neurons ◽  
Significant Public Health ◽  
Core Components ◽  
Dependent Protein

Depressive disorders and alcohol use disorders are widespread among the general population and are significant public health and economic burdens. Alcohol use disorders often co-occur with other psychiatric conditions and this dual diagnosis is called comorbidity. Depressive disorders invariably contribute to the development and worsening of alcohol use disorders, and vice versa. The mechanisms underlying these disorders and their comorbidities remain unclear. Recently, interest in the lateral habenula, a small epithalamic brain structure, has increased because it becomes hyperactive in depression and alcohol use disorders, and can inhibit dopamine and serotonin neurons in the midbrain reward center, the hypofunction of which is believed to be a critical contributor to the etiology of depressive disorders and alcohol use disorders as well as their comorbidities. Additionally, calcium/calmodulin-dependent protein kinase II (CaMKII) in the lateral habenula has emerged as a critical player in the etiology of these comorbidities. This review analyzes the interplay of CaMKII signaling in the lateral habenula associated with depressive disorders and alcohol use disorders, in addition to the often-comorbid nature of these disorders. Although most of the CaMKII signaling pathway’s core components have been discovered, much remains to be learned about the biochemical events that propagate and link between depression and alcohol abuse. As the field rapidly advances, it is expected that further understanding of the pathology involved will allow for targeted treatments.

scholarly journals Role of HIF-1α in Alcohol-Mediated Multiple Organ Dysfunction

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 170 ◽  
Author(s):  
Niya Morris ◽  
Samantha Yeligar
Keyword(s):  
Alcohol Consumption ◽  
Organ Dysfunction ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Alcohol Exposure ◽  
Experimental Models ◽  
Multiple Organ ◽  
Organ Injury ◽  
Excessive Alcohol Consumption ◽  
Multiple Organ Injury

Excess alcohol consumption is a global crisis contributing to over 3 million alcohol-related deaths per year worldwide and economic costs exceeding $200 billion dollars, which include productivity losses, healthcare, and other effects (e.g., property damages). Both clinical and experimental models have shown that excessive alcohol consumption results in multiple organ injury. Although alcohol metabolism occurs primarily in the liver, alcohol exposure can lead to pathophysiological conditions in multiple organs and tissues, including the brain, lungs, adipose, liver, and intestines. Understanding the mechanisms by which alcohol-mediated organ dysfunction occurs could help to identify new therapeutic approaches to mitigate the detrimental effects of alcohol misuse. Hypoxia-inducible factor (HIF)-1 is a transcription factor comprised of HIF-1α and HIF-1β subunits that play a critical role in alcohol-mediated organ dysfunction. This review provides a comprehensive analysis of recent studies examining the relationship between HIF-1α and alcohol consumption as it relates to multiple organ injury and potential therapies to mitigate alcohol’s effects.

scholarly journals βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression

Science ◽  
2013 ◽  
Vol 341 (6149) ◽  
pp. 1016-1020 ◽  
Author(s):  
Kun Li ◽  
Tao Zhou ◽  
Lujian Liao ◽  
Zhongfei Yang ◽  
Catherine Wong ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
Lateral Habenula ◽  
Proteomic Screen ◽  
Symptoms Of Depression ◽  
Calcium Calmodulin Dependent ◽  
Molecular Determinant ◽  
Animal Models Of Depression ◽  
Dependent Protein ◽  
Neuron Function ◽  
Core Symptoms

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 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 βCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify βCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.

scholarly journals Calcium/calmodulin-dependent protein kinase IIdelta associates with the ryanodine receptor complex and regulates channel function in rabbit heart

2004 ◽  
Vol 377 (2) ◽  
pp. 357-366 ◽  
Author(s):  
Susan CURRIE ◽  
Christopher M. LOUGHREY ◽  
Margaret-Anne CRAIG ◽  
Godfrey L. SMITH
Keyword(s):  
Protein Kinase ◽  
Sarcoplasmic Reticulum ◽  
Critical Role ◽  
Phosphorylation Site ◽  
Specific Inhibitor ◽  
Ventricular Myocardium ◽  
Inhibitory Peptide ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein

Cardiac ryanodine receptors (RyR2s) play a critical role in excitation–contraction coupling by providing a pathway for the release of Ca2+ from the sarcoplasmic reticulum into the cytosol. RyR2s exist as macromolecular complexes that are regulated via binding of Ca2+ and protein phosphorylation/dephosphorylation. The present study examined the association of endogenous CaMKII (calcium/calmodulin-dependent protein kinase II) with the RyR2 complex and whether this enzyme could modulate RyR2 function in isolated rabbit ventricular myocardium. Endogenous phosphorylation of RyR2 was verified using phosphorylation site-specific antibodies. Co-immunoprecipitation studies established that RyR2 was physically associated with CaMKIIδ. Quantitative assessment of RyR2 protein was performed by [3H]ryanodine binding to RyR2 immunoprecipitates. Parallel kinase assays allowed the endogenous CaMKII activity associated with these immunoprecipitates to be expressed relative to the amount of RyR2. The activity of RyR2 in isolated cardiac myocytes was measured in two ways: (i) RyR2-mediated Ca2+ release (Ca2+ sparks) using confocal microscopy and (ii) Ca2+-sensitive [3H]ryanodine binding. These studies were performed in the presence and absence of AIP (autocamtide-2-related inhibitory peptide), a highly specific inhibitor of CaMKII. At 1 µM AIP Ca2+ spark duration, frequency and width were decreased significantly. Similarly, 1 µM AIP decreased [3H]ryanodine binding. At 5 µM AIP, a more profound inhibition of Ca2+ sparks and a decrease in [3H]ryanodine binding was observed. Separate measurements showed that AIP (1–5 µM) did not affect sarcoplasmic reticulum Ca2+-ATPase-mediated Ca2+ uptake. These results suggest the existence of an endogenous CaMKIIδ that associates directly with RyR2 and specifically modulates RyR2 activity.

scholarly journals The Calcium Component of Gonadotropin-Releasing Hormone-Stimulated Luteinizing Hormone Subunit Gene Transcription Is Mediated by Calcium/Calmodulin-Dependent Protein Kinase Type II

Endocrinology ◽  
2003 ◽  
Vol 144 (6) ◽  
pp. 2409-2416 ◽  
Author(s):  
Daniel J. Haisenleder ◽  
Heather A. Ferris ◽  
Margaret A. Shupnik
Keyword(s):  
Protein Kinase ◽  
Gene Transcription ◽  
Calcium Influx ◽  
Critical Role ◽  
Type Ii ◽  
Subunit Gene ◽  
Dependent Protein Kinase ◽  
Α Subunit ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein

Abstract Calcium influx plays a critical role in GnRH regulation of rat LH subunit gene transcription, but the site(s) of action are undefined. We investigated the potential of GnRH acting through calcium to activate calcium/calmodulin-dependent protein kinase type II (Ca/CaMK II) in mouse gonadotrope-derived LβT2 cells. GnRH stimulated Ca/CaMK II β subunit activity 3-fold 2 min after treatment and returned to control values by 45 min. The Ca/CaMK II response to GnRH was blocked by administration of the Ca/CaMK II-specific inhibitor, KN-93. The calcium channel activator Bay K 8644 stimulated a 3-fold increase in Ca/CaMK II activity, similar to GnRH. Blocking calcium influx with nimodipine or depleting intracellular calcium storage pools with thapsigargin each resulted in a partial suppression of GnRH-induced activation of Ca/CaMK II, and in combination, completely suppressed the Ca/CaMK II response to GnRH. KN-93 and nimodipine also suppressed α-subunit and LHβ promoter responses to GnRH by 40–60%. LHβ promoter constructs containing either proximal or proximal and distal GnRH-responsive regions were sensitive to inhibition. These data show for the first time that Ca/CaMK II activation plays an important role in the transmission of GnRH signals from the plasma membrane to the LH subunit genes.

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