Cellular circadian clocks in mood disorders. 2012

Michael J McCarthy, and David K Welsh
Department of Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.

Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.

UI MeSH Term Description Entries
D008027 Light That portion of the electromagnetic spectrum in the visible, ultraviolet, and infrared range. Light, Visible,Photoradiation,Radiation, Visible,Visible Radiation,Photoradiations,Radiations, Visible,Visible Light,Visible Radiations
D010487 Periaqueductal Gray Central gray matter surrounding the CEREBRAL AQUEDUCT in the MESENCEPHALON. Physiologically it is probably involved in RAGE reactions, the LORDOSIS REFLEX; FEEDING responses, bladder tonus, and pain. Mesencephalic Central Gray,Midbrain Central Gray,Central Gray Substance of Midbrain,Central Periaqueductal Gray,Griseum Centrale,Griseum Centrale Mesencephali,Periaqueductal Gray Matter,Substantia Grisea Centralis,Substantia Grisea Centralis Mesencephali,Central Gray, Mesencephalic,Central Gray, Midbrain,Gray Matter, Periaqueductal,Gray, Central Periaqueductal,Griseum Centrale Mesencephalus,Periaqueductal Grays, Central
D003865 Depressive Disorder, Major Disorder in which five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Symptoms include: depressed mood most of the day, nearly every daily; markedly diminished interest or pleasure in activities most of the day, nearly every day; significant weight loss when not dieting or weight gain; Insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate, or indecisiveness, nearly every day; or recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt. (DSM-5) Depression, Involutional,Major Depressive Disorder,Melancholia, Involutional,Paraphrenia, Involutional,Psychosis, Involutional,Depressive Disorders, Major,Involutional Depression,Involutional Melancholia,Involutional Paraphrenia,Involutional Paraphrenias,Involutional Psychoses,Involutional Psychosis,Major Depressive Disorders,Paraphrenias, Involutional,Psychoses, Involutional
D006179 Gyrus Cinguli One of the convolutions on the medial surface of the CEREBRAL HEMISPHERES. It surrounds the rostral part of the brain and CORPUS CALLOSUM and forms part of the LIMBIC SYSTEM. Anterior Cingulate Gyrus,Brodmann Area 23,Brodmann Area 24,Brodmann Area 26,Brodmann Area 29,Brodmann Area 30,Brodmann Area 31,Brodmann Area 32,Brodmann Area 33,Brodmann's Area 23,Brodmann's Area 24,Brodmann's Area 26,Brodmann's Area 29,Brodmann's Area 30,Brodmann's Area 31,Brodmann's Area 32,Brodmann's Area 33,Cingulate Gyrus,Gyrus Cinguli Anterior,Retrosplenial Complex,Retrosplenial Cortex,Anterior Cingulate,Anterior Cingulate Cortex,Cingular Gyrus,Cingulate Area,Cingulate Body,Cingulate Cortex,Cingulate Region,Gyrus, Cingulate,Posterior Cingulate,Posterior Cingulate Cortex,Posterior Cingulate Gyri,Posterior Cingulate Gyrus,Posterior Cingulate Region,Superior Mesial Regions,24, Brodmann Area,Anterior Cingulate Cortices,Anterior Cingulates,Anterior, Gyrus Cinguli,Anteriors, Gyrus Cinguli,Area 23, Brodmann,Area 23, Brodmann's,Area 24, Brodmann,Area 24, Brodmann's,Area 26, Brodmann,Area 26, Brodmann's,Area 29, Brodmann,Area 29, Brodmann's,Area 30, Brodmann,Area 30, Brodmann's,Area 31, Brodmann,Area 31, Brodmann's,Area 32, Brodmann,Area 32, Brodmann's,Area 33, Brodmann,Area 33, Brodmann's,Area, Cingulate,Body, Cingulate,Brodmanns Area 23,Brodmanns Area 24,Brodmanns Area 26,Brodmanns Area 29,Brodmanns Area 30,Brodmanns Area 31,Brodmanns Area 32,Brodmanns Area 33,Cingulate Areas,Cingulate Bodies,Cingulate Cortex, Anterior,Cingulate Cortex, Posterior,Cingulate Gyrus, Anterior,Cingulate Gyrus, Posterior,Cingulate Region, Posterior,Cingulate Regions,Cingulate, Anterior,Cingulate, Posterior,Cinguli Anterior, Gyrus,Cinguli Anteriors, Gyrus,Complex, Retrosplenial,Cortex, Anterior Cingulate,Cortex, Cingulate,Cortex, Posterior Cingulate,Cortex, Retrosplenial,Gyrus Cinguli Anteriors,Gyrus, Anterior Cingulate,Gyrus, Cingular,Gyrus, Posterior Cingulate,Posterior Cingulate Cortices,Posterior Cingulate Regions,Posterior Cingulates,Region, Cingulate,Region, Posterior Cingulate,Retrosplenial Complices,Retrosplenial Cortices,Superior Mesial Region
D006624 Hippocampus A curved elevation of GRAY MATTER extending the entire length of the floor of the TEMPORAL HORN of the LATERAL VENTRICLE (see also TEMPORAL LOBE). The hippocampus proper, subiculum, and DENTATE GYRUS constitute the hippocampal formation. Sometimes authors include the ENTORHINAL CORTEX in the hippocampal formation. Ammon Horn,Cornu Ammonis,Hippocampal Formation,Subiculum,Ammon's Horn,Hippocampus Proper,Ammons Horn,Formation, Hippocampal,Formations, Hippocampal,Hippocampal Formations,Hippocampus Propers,Horn, Ammon,Horn, Ammon's,Proper, Hippocampus,Propers, Hippocampus,Subiculums
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000679 Amygdala Almond-shaped group of basal nuclei anterior to the INFERIOR HORN OF THE LATERAL VENTRICLE of the TEMPORAL LOBE. The amygdala is part of the limbic system. Amygdaloid Body,Amygdaloid Nuclear Complex,Amygdaloid Nucleus,Archistriatum,Corpus Amygdaloideum,Intercalated Amygdaloid Nuclei,Massa Intercalata,Nucleus Amygdalae,Amygdalae, Nucleus,Amygdaloid Bodies,Amygdaloid Nuclear Complices,Amygdaloid Nuclei, Intercalated,Amygdaloid Nucleus, Intercalated,Amygdaloideum, Corpus,Amygdaloideums, Corpus,Archistriatums,Complex, Amygdaloid Nuclear,Complices, Amygdaloid Nuclear,Corpus Amygdaloideums,Intercalata, Massa,Intercalatas, Massa,Intercalated Amygdaloid Nucleus,Massa Intercalatas,Nuclear Complex, Amygdaloid,Nuclear Complices, Amygdaloid,Nuclei, Intercalated Amygdaloid,Nucleus, Amygdaloid,Nucleus, Intercalated Amygdaloid
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000928 Antidepressive Agents Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. Antidepressant,Antidepressant Drug,Antidepressant Medication,Antidepressants,Antidepressive Agent,Thymoanaleptic,Thymoanaleptics,Thymoleptic,Thymoleptics,Antidepressant Drugs,Agent, Antidepressive,Drug, Antidepressant,Medication, Antidepressant
D001714 Bipolar Disorder A major affective disorder marked by severe mood swings (manic or major depressive episodes) and a tendency to remission and recurrence. Affective Psychosis, Bipolar,Bipolar Disorder Type 1,Bipolar Disorder Type 2,Bipolar Mood Disorder,Depression, Bipolar,Manic Depression,Manic Disorder,Manic-Depressive Psychosis,Psychosis, Manic-Depressive,Type 1 Bipolar Disorder,Type 2 Bipolar Disorder,Psychoses, Manic-Depressive,Bipolar Affective Psychosis,Bipolar Depression,Bipolar Disorders,Bipolar Mood Disorders,Depression, Manic,Depressions, Manic,Disorder, Bipolar,Disorder, Bipolar Mood,Disorder, Manic,Manic Depressive Psychosis,Manic Disorders,Mood Disorder, Bipolar,Psychoses, Bipolar Affective,Psychoses, Manic Depressive,Psychosis, Bipolar Affective,Psychosis, Manic Depressive

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