Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization.

Background: Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers.

Determinants of Optogenetic Cortical Spreading Depolarizations.

Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP).

Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

Cortical spreading depression, which plays an important role in multiple neurological disorders, has been studied primarily with experimental models that use highly invasive methods. We developed a relatively non-invasive optogenetic model to induce cortical spreading depression by transcranial stimulation of channelrhodopsin-2 ion channels expressed in cortical layer 5 neurons. Light-evoked cortical spreading depression in anesthetized and freely behaving mice was studied with intracortical DC-potentials, multi-unit activity and/or non-invasive laser Doppler flowmetry, and optical intrinsic signal imaging.

From migraine genes to mechanisms.

Migraine is a common multifactorial episodic brain disorder with strong genetic basis. Monogenic subtypes include rare familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, familial advanced sleep-phase syndrome (FASPS), and retinal vasculopathy with cerebral leukodystrophy. Functional studies of disease-causing mutations in cellular and/or transgenic models revealed enhanced (glutamatergic) neurotransmission and abnormal vascular function as key migraine mechanisms.

Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations.

Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia.

Migraine mutations impair hippocampal learning despite enhanced long-term potentiation.

To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the α1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo.

Regulation of circadian and acute activity levels by the murine suprachiasmatic nuclei.

The suprachiasmatic nuclei (SCN) coordinate the daily sleep-wake cycle by generating a circadian rhythm in electrical impulse frequency. While period and phase of the SCN rhythm have been considered as major output parameters, we propose that the waveform of the rhythm of the SCN also has significance. Using implanted micro-electrodes, we recorded SCN impulse frequency in freely moving mice and manipulated its circadian waveform by exposing mice to light-dark (LD) cycle durations ranging from 22 hours (LD 11:11) to 26 hours (LD 13:13).

Detrimental effects of constant light exposure and high-fat diet on circadian energy metabolism and insulin sensitivity.

Circadian rhythm disturbances are observed in, e.g., aging and neurodegenerative diseases and are associated with an increased incidence of obesity and diabetes.

The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity.

Disturbances in the circadian system are associated with the development of type 2 diabetes mellitus. Here, we studied the direct contribution of the suprachiasmatic nucleus (SCN), the central pacemaker in the circadian system, in the development of insulin resistance. Exclusive bilateral SCN lesions in male C57Bl/6J mice, as verified by immunochemistry, showed a small but significant increase in body weight (+17%), which was accounted for by an increase in fat mass.

Fractal patterns of neural activity exist within the suprachiasmatic nucleus and require extrinsic network interactions.

The mammalian central circadian pacemaker (the suprachiasmatic nucleus, SCN) contains thousands of neurons that are coupled through a complex network of interactions. In addition to the established role of the SCN in generating rhythms of ~24 hours in many physiological functions, the SCN was recently shown to be necessary for normal self-similar/fractal organization of motor activity and heart rate over a wide range of time scales--from minutes to 24 hours. To test whether the neural network within the SCN is sufficient to generate such fractal patterns, we studied multi-unit neural activity of in vivo and in vitro SCNs in rodents.

Dynamic neuronal network organization of the circadian clock and possible deterioration in disease.

In mammals, the suprachiasmatic nuclei (SCNs) function as a circadian pacemaker that drives 24-h rhythms in physiology and behavior. The SCN is a multicellular clock in which the constituent oscillators show dynamics in their functional organization and phase coherence. Evidence has emerged that plasticity in phase synchrony among SCN neurons determines (i) the amplitude of the rhythm, (ii) the response to continuous light, (iii) the capacity to respond to seasonal changes, and (iv) the phase-resetting capacity.

Ultraviolet light provides a major input to non-image-forming light detection in mice.

The change in irradiance at dawn and dusk provides the primary cue for the entrainment of the mammalian circadian pacemaker. Irradiance detection has been ascribed largely to melanopsin-based phototransduction [1-5]. Here we examine the role of ultraviolet-sensitive (UVS) cones in the modulation of circadian behavior, sleep, and suprachiasmatic nucleus (SCN) electrical activity.

Amplitude of the SCN clock enhanced by the behavioral activity rhythm.

Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a small structure at the base of the hypothalamus. While light effects on the SCN are well established, little is known of behavioral effects. This study elucidates direct modulating action of behavioral activity on the SCN by use of in vivo electrophysiology recordings, assessments of general locomotor behavior, and video-tracking of mice.

Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock.

Aging is associated with a deterioration of daily (circadian) rhythms in physiology and behavior. Deficits in the function of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) have been implicated, but the responsible mechanisms have not been clearly delineated. In this report, we characterize the progression of rhythm deterioration in mice to 900 d of age.

Role of vasoactive intestinal peptide in seasonal encoding by the suprachiasmatic nucleus clock.

The neuropeptide vasoactive intestinal peptide (VIP) is critical for the proper functioning of the neural circuit that generates circadian rhythms. Mice lacking VIP show profound deficits in the ability to generate many behavioral and physiological rhythms. To explore how the loss of VIP impacts on the intact circadian system, we carried out in vivo multiunit neural activity (MUA) recordings from the suprachiasmatic nucleus of freely moving VIP knockout (KO) mice.

Correlation with behavioral activity and rest implies circadian regulation by SCN neuronal activity levels.

The SCN of the hypothalamus contains a major pacemaker, which exhibits 24-h rhythms in electrical impulse frequency. Although it is known that SCN electrical activity is high during the day and low during the night, the precise relationship between electrical activity and behavioral rhythms is almost entirely unknown. The authors performed long-term recordings of SCN multiple unit activity with the aid of implanted microelectrodes in parallel with the drinking activity in freely moving mice.

Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice.

Objective: Mammalian circadian rhythms are driven by the circadian pacemaker of the suprachiasmatic nucleus (SCN) and are synchronized to the external 24-hour light/dark cycle. After advance time zone transitions (eastbound jet lag), overt circadian rhythms require several days to adjust. The retarded adaptation may protect against acute imbalance of different brain systems.

Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood.

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10].

Seasonal encoding by the circadian pacemaker of the SCN.

The circadian pacemaker of the suprachiasmatic nucleus (SCN) functions as a seasonal clock through its ability to encode day length [1-6]. To investigate the mechanism by which SCN neurons code for day length, we housed mice under long (LD 16:8) and short (LD 8:16) photoperiods. Electrophysiological recordings of multiunit activity (MUA) in the SCN of freely moving mice revealed broad activity profiles in long days and compressed activity profiles in short days.