Circadian rhythms and mood disorders: Time to see the light.

The importance of time is ever prevalent in our world, and disruptions to the normal light/dark and sleep/wake cycle have now become the norm rather than the exception for a large part of it. All mood disorders, including seasonal affective disorder (SAD), major depressive disorder (MDD), and bipolar disorder (BD), are strongly associated with abnormal sleep and circadian rhythms in a variety of physiological processes. Environmental disruptions to normal sleep/wake patterns, light/dark changes, and seasonal changes can precipitate episodes. Moreover, treatments that target the circadian system have proven to be therapeutic in certain cases. This review will summarize much of our current knowledge of how these disorders associate with specific circadian phenotypes, as well as the neuronal mechanisms that link the circadian clock with mood regulation. We also discuss what has been learned from therapies that target circadian rhythms and how we may use current knowledge to develop more individually designed treatments.

Sleep Deprivation Does Not Influence Photic Resetting of Circadian Activity Rhythms in Drosophila.

Previous investigations in humans and rodent animal models have assessed the interplay of sleep in the circadian system's phase responses to nighttime light exposure. The resulting data have been mixed, but generally support a modulatory role for sleep in circadian photic resetting (not an absolute requirement). Drosophila have been historically used to provide important insights in the sleep and circadian sciences. However, no experiments to date have evaluated how immediate sleep need or recent sleep history affects their pacemaker's phase readjustments to light. We did so in the current study by (1) forcing separate groups of animals to stay awake for 1 or 4 h after they were shown a broadspectrum pulse (15 min during the first half of the night, 950 lux), or (2) placing them on a restricted sleep schedule for a week before light presentation without any subsequent sleep disruption. Forced sleep restriction, whether acute or chronic, did not alter the size of light-induced phase shifts. These data are consistent with observations made in other diurnal animals and raise the possibility, more broadly, that phototherapies applied during sleep-such as may be necessary during the winter months-may still be efficacious in individuals experiencing sleep-continuity problems such as insomnia.

The Drosophila circadian phase response curve to light: Conservation across seasonally relevant photoperiods and anchorage to sunset.

Photic history, including the relative duration of day versus night in a 24-hour cycle, is known to influence subsequent circadian responses to light in mammals. Whether such modulation is present in Drosophila is currently unknown. To date, all photic phase-response curves (PRCs) generated from Drosophila have done so with animals housed under seasonally agnostic equatorial photoperiods with alternating 12-hour segments of light and darkness. However, the genus contains thousands of species, some of which populate high and low-latitude habitats (20-50° north or south of the Equator) where seasonal variations in the light-dark schedule are pronounced. Here, we address this disconnect by constructing the first high-resolution Drosophila seasonal atlas for light-induced circadian phase-resetting. Testing the light responses of over 4,000 Drosophila at 120 timepoints across 5 seasonally-relevant rectangular photoperiods (i.e., LD 8:16, 10:14, 12:12, 14:10, and 16:8; 24 hourly intervals surveyed in each), we determined that many aspects of the fly circadian PRC waveform are conserved with increasing daylength. Surprisingly though, irrespective of LD schedule, the start of the PRCs always remained anchored to the timing of subjective sunset, creating a differential overlap of the advance zone with the morning hours after subjective sunrise that was maximized under summer photoperiods and minimized under winter photoperiods. These data suggest that there may be differences in flies versus mammals as to how the photoperiod modulates the waveform and amplitude of the circadian PRC to light. On the other hand, they support the possibility that the lights-off transition determines the phase-positioning of photic PRCs across seasons and across species. More work is necessary to test this claim and whether it might factor into the timing of seasonal light responses in humans.

Intracerebral hemorrhage in the mouse altered sleep-wake patterns and activated microglia.

Sleep-wake disturbances are both a risk factor and reported morbidity for intracerebral hemorrhage (ICH). ICH begins with a ruptured blood vessel and blood leakage into the parenchyma. In response to initial damage, pathophysiological processes ensue that both exacerbate and repair damage. Inflammation is a hallmark process of ICH, which includes microglia activation and increased cytokine signaling. Due to the dual role of cytokines as inflammatory signaling proteins and sleep regulatory substances (SRSs), we hypothesized that ICH would activate microglia, increase SRSs, and alter sleep-wake patterns following an experimental model of ICH in the mouse. Male mice were randomized to receive an injection of collagenase (ICH; n = 8) or saline (sham; n = 11) in the striatum of the right hemisphere. Sleep-wake activity was recorded for 6 full days after ICH via noninvasive sleep cages. Blood and tissue were collected at 7 days after ICH to quantify pro-inflammatory cytokines/SRSs (IL-1ß, TNF-α, IL-6) and microglia deramification by skeleton analysis. There was an overall injury effect on sleep in mice subjected to ICH at the transition from dark (wake) to light (sleep) at 2, 3, 4, 5, and 6 days after ICH compared with shams. Further analysis confirmed that ICH mice had significantly earlier wake offsets at the dark/light transition and more robust circadian patterns of wake behavior than saline control mice. Spatiotemporal skeleton analysis indicated an increase in microglial cell number with a decrease in endpoints per cell (decreased ramification) for the ipsilateral ICH perihematomal region compared with saline control. There were no changes to plasma cytokine levels at 7 days after ICH when comparing each condition. This is the first known study to show changes in sleep-wake patterns after experimental ICH. Elucidation of mechanisms that link sleep, inflammation, and ICH offers new pharmacological opportunities and rehabilitative strategies to improve recovery in stroke patients.

Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.

Diazepam reverses increased anxiety-like behavior, social behavior deficit, and dopamine dysregulation following withdrawal from acute amphetamine.

Psychostimulants such as amphetamine (AMPH) increase dopamine (DA) release from ventral tegmental area (VTA) neurons, which is associated with their acute reinforcing actions. This positive state is followed by a negative affective state during the withdrawal period each time the drug is taken (i.e., opponent process theory). AMPH withdrawal is accompanied by symptoms of anxiety and depression, which are associated with DA system dysfunction in humans and animal models. Most studies have focused on the negative affective state after withdrawal from chronic drug administration; yet, this negative state appears even after a drug is taken for the first time in both humans and rodents. In rats, withdrawal from a single dose of AMPH (2 mg/kg) increases forced swim test immobility and decreases the number of spontaneously active VTA DA neurons up to 48 h post-withdrawal. In the current study, acute AMPH withdrawal was found to increase anxiety-like behavior in the elevated plus maze (EPM), reduce social cage time in the three-chambered social approach test (SAT), and attenuate VTA population activity. The effects of diazepam, a drug commonly used to treat anxiety disorders, were tested on anxiety-like and social behavior as well as VTA DA neuron activity following acute AMPH withdrawal. A single (5 mg/kg) dose of diazepam circumvented the neurobehavioral effects induced by acute AMPH withdrawal, as demonstrated by increased open arm time and social cage time as well as normalized VTA DA activity comparable to controls, suggesting that these neurobehavioral effects of acute AMPH withdrawal reflect an anxiety-like state.

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine.

Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18, 48 and 72 h after injection of amphetamine. The effects of inactivation of the basolateral amygdala (BLA) and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal, there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which returned to baseline after 72 h. Inactivation of the BLA after acute amphetamine prevented the decrease in DA neuron tonic activity. Injection of ketamine also prevented the decrease in DA population activity but had no effect on immobility measured in the modified FST. The data support a model in which the negative affective state following acute amphetamine withdrawal is associated with a decrease in DA neuron population activity, driven by hyperactivity of the BLA. Although ketamine reversed the hypodopaminergic state following withdrawal, the failure to reduce immobility in the modified FST indicates that different processes underlying negative emotional state may exist between depression and drug withdrawal.