Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

/pdf/the-mammalian-circadian-timing-system-organization-and-54vfplckht.pdf

The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.

/pdf/major-depressive-disorder-rkewp1bncd.pdf

Major depressive disorder.

Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.

/pdf/animal-models-of-neuropsychiatric-disorders-1w7jb15e05.pdf

Animal models of neuropsychiatric disorders

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

/pdf/the-genetics-of-mammalian-circadian-order-and-disorder-bpbner8gua.pdf

The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease

Sleep and circadian rhythm disruption are frequently observed in patients with psychiatric disorders and neurodegenerative disease. The abnormal sleep that is experienced by these patients is largely assumed to be the product of medication or some other influence that is not well defined. However, normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Disruption of sleep alters sleep-wake timing, destabilizes physiology and promotes a range of pathologies (from cognitive to metabolic defects) that are rarely considered to be associated with abnormal sleep. We propose that brain disorders and abnormal sleep have a common mechanistic origin and that many co-morbid pathologies that are found in brain disease arise from a destabilization of sleep mechanisms. The stabilization of sleep may be a means by which to reduce the symptoms of--and permit early intervention of--psychiatric and neurodegenerative disease.

Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease

Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood.

https://www.pnas.org/content/pnas/104/15/6406.full.pdf

Mania-like behavior induced by disruption of CLOCK.

Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of κ-opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressive-like behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective κ-opioid agonist, would produce depressive-like effects in the forced swim test (FST) and intracranial self-stimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125–2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressive-like effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain κ-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.

http://www.sagewisdom.org/carlezonetal.pdf

Depressive-Like Effects of the κ-Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats

The transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) plays an important role in regulating mood. In rodents, increased CREB activity within the NAc produces depression-like signs including anhedonia, whereas disruption of CREB activity by expression of a dominant-negative CREB (mCREB, which acts as a CREB antagonist) has antidepressant-like effects. We examined how disruption of CREB activity affects brain reward processes using intracranial self-stimulation (ICSS) and inducible bitransgenic mice with enriched expression of mCREB in forebrain regions including the NAc. Mutant mice or littermate controls were prepared with lateral hypothalamic stimulating electrodes, and trained in the ICSS procedure to determine the frequency at which the stimulation becomes rewarding (threshold). Inducible expression of mCREB did not affect baseline sensitivity to brain stimulation itself. However, mCREB-expressing mice were more sensitive to the rewarding (threshold-lowering) effects of cocaine. Interestingly, mCREB mice were insensitive to the depressive-like (threshold-elevating) effects of the kappa-opioid receptor agonist U50,488. These behavioral differences were accompanied by decreased mRNA expression of G-protein receptor kinase-3 (GRK3), a protein involved in opioid receptor desensitization, within the NAc of mCREB mice. Disruption of CREB or GRK3 activity within the NAc specifically by viral-mediated gene transfer enhanced the rewarding impact of brain stimulation in rats, establishing the contribution of functional changes within this region. Together with previous findings, these studies raise the possibility that disruption of CREB in the NAc influences motivation by simultaneously facilitating reward and reducing depressive-like states such as anhedonia and dysphoria.

https://www.jneurosci.org/content/jneuro/29/6/1855.full.pdf

Altered Sensitivity to Rewarding and Aversive Drugs in Mice with Inducible Disruption of cAMP Response Element-Binding Protein Function within the Nucleus Accumbens

Several preclinical studies indicate that selective kappa-opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism. We compared the in vitro receptor binding selectivity of salvA and four analogs containing an ethyl ether (EE), isopropylamine (IPA), N-methylacetamide (NMA), or N-methylpropionamide (NMP) at C-2. All compounds showed high binding affinity for the KOR (K(i) = 0.11-6.3 nM), although only salvA, EE, and NMA exhibited KOR selectivity. In a liver microsomal assay, salvA was least stable, whereas NMA and IPA displayed slower metabolic transformations. Intraperitoneal (i.p.) administration of salvA, NMA, and NMP dose-dependently elevated brain reward thresholds in the intracranial self-administration (ICSS) test, consistent with prodepressive-like KOR agonist effects. NMA and NMP were equipotent to salvA but displayed longer lasting effects (6- and 10-fold, respectively). A dose of salvA with prominent effects in the ICSS test after i.p. administration (2.0 mg/kg) was inactive after oral administration, whereas the same oral dose of NMA elevated ICSS thresholds. These studies suggest that, although salvA and NMA are similar in potency and selectivity as KOR agonists in vitro, NMA has improved stability and longer lasting actions that might make it more useful for studies of KOR agonist effects in animals and humans.

https://jpet.aspetjournals.org/content/jpet/early/2007/10/19/jpet.107.129023.full.pdf

Jennifer A. DiNieri

Papers

Mania-like behavior induced by disruption of CLOCK.

Depressive-Like Effects of the κ-Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats

Altered Sensitivity to Rewarding and Aversive Drugs in Mice with Inducible Disruption of cAMP Response Element-Binding Protein Function within the Nucleus Accumbens

N-Methylacetamide Analog of Salvinorin A: A Highly Potent and Selective κ-Opioid Receptor Agonist with Oral Efficacy