SUMMARY Systems of coupled oscillators abound in nature. How they establish stable phase relationships under diverse conditions is fundamentally important. The mammalian suprachiasmatic nucleus (SCN) is a self-sustained, synchronized network of circadian oscillators that coordinates daily rhythms in physiology and behavior. To elucidate the underlying topology and signaling mechanisms that modulate circadian synchrony, we discriminated the firing of hundreds of SCN neurons continuously over days. Using a novel analysis method to identify functional interactions between neurons based on changes in their firing, we characterized a GABAergic network comprised of fast, excitatory and inhibitory connections that is both stable over days and changes in strength with time of day. By monitoring PERIOD2 protein expression, we provide the first evidence that these millisecond-level interactions actively oppose circadian synchrony and inject jitter into daily rhythms. These results provide a new mechanism by which circadian oscillators can tune their phase relationships under different environmental conditions.

Cannabinoids (CBs) exert untoward effects on reproduction by reducing LH secretion and suppressing gonadal function. Recent evidence suggests these effects are due primarily to hypothalamic dysfunction; however, the mechanism is obscure. Using immortalized hypothalamic GnRH neurons, we find these cells produce and secrete at least two different endocannabinoids. After release, 2-arachidonyl monoacylglycerol and anandamide are rapidly transported into GnRH neurons and are degraded to other lipids by fatty-acid amide hydrolase. The immortalized GnRH neurons also possess CB1 and CB2 receptors that are coupled to Gi/Go proteins whose activation leads to inhibition of GnRH secretion. In perifusion experiments, CBs block pulsatile release of GnRH. When a CB receptor agonist is delivered into the third ventricle of adult female mice, estrous cycles are prolonged by at least 2 d. Although in situ hybridization experiments suggest either that GnRH neurons in vivo do not possess CB1 receptors or that they are very low, transcripts are localized in close proximity to these neurons. Inasmuch as GnRH neurons in vivo possess G protein receptors that are coupled to phospholipase C and increased intracellular Ca2+, these same neurons should also be able to synthesize endocannabinoids. These lipids, in turn, could bind to CB receptors on neighboring cells, and perhaps GnRH neurons, to exert feedback control over GnRH function. This network could serve as a novel mechanism for regulating GnRH secretion where reproductive functions as diverse as the onset of puberty, timing of ovulation, duration of lactational infertility, and initiation/persistence of menopause may be affected.

NSAIDs given prophylactically or within 30 days of flare onset may shorten neuropsychiatric symptom duration in patients with new-onset and relapsing/remitting PANS and PANDAS. A randomized placebo-control clinical trial of NSAIDs in PANS is warranted to formally assess treatment efficacy.