Melanin concentrating hormone (MCH) is a cyclic neuropeptide present in the hypothalamus of all vertebrates. MCH is implicated in a number of behaviors but direct evidence is lacking. To selectively stimulate the MCH neurons the gene for the light-sensitive cation channel, channelrhodopsin-2, was inserted into the MCH neurons of wild-type mice. Three weeks later MCH neurons were stimulated for 1 min every 5 min for 24 h. A 10 Hz stimulation at the start of the night hastened sleep onset, reduced length of wake bouts by 50%, increased total time in non-REM and REM sleep at night, and increased sleep intensity during the day cycle. Sleep induction at a circadian time when all of the arousal neurons are active indicates that MCH stimulation can powerfully counteract the combined wake-promoting signal of the arousal neurons. This could be potentially useful in treatment of insomnia.

Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter β-catenin pathways. However, evidence linking malfunction of β-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of β-catenin, leads to excessive β-catenin levels and multiple salient features of human IS. Compared with wild-type littermates, neonatal APC cKO mice exhibit flexion-extension motor spasms and abnormal high-amplitude electroencephalographic discharges. Additionally, the frequency of excitatory postsynaptic currents is increased in layer V pyramidal cells, the major output neurons of the cerebral cortex. At adult ages, APC cKOs display spontaneous electroclinical seizures. These data provide the first evidence that malfunctions of APC/β-catenin pathways cause pathophysiological changes consistent with IS. Our findings demonstrate that the APC cKO is a new genetic model of IS, provide novel insights into molecular and functional alterations that can lead to IS, and suggest novel targets for therapeutic intervention.

Serial EEG recordings from immature rat pups are extremely difficult to obtain but important for analyzing animal models of neonatal seizures and other pediatric neurological conditions as well as normal physiology. In this report, we describe the features and applications of a novel miniature telemetry system designed to record EEG in rat pups as young as postnatal day 6 (P6). First, we have recorded electrographic seizure activity in two animal models of neonatal seizures, hypoxia- and kainate-induced seizures at P7. Second, we describe a viable approach for long-term continuous EEG monitoring of naturally reared rat pups implanted with EEG at P6. Third, we have used serial EEG recordings to record age-dependent changes in the background EEG signal as the animals matured from P7 to P11. The important advantages of using miniature wireless EEG technology are: 1) minimally invasive surgical implantation; 2) a device form-factor that is compatible with housing of rat pups with the dam and littermates; 3) serial recordings of EEG activity; and 4) low power consumption of the unit, theoretically allowing continuous monitoring for up to 2 yr without surgical reimplantation. The miniature EEG telemetry system provides a technical advance that allows researchers to record continuous and serial EEG recordings in neonatal rodent models of human neurological disorders, study the progression of the disease, and then assess possible therapies using quantitative EEG as an outcome measure. This new technical approach should improve animal models of human conditions that rely on EEG monitoring for diagnosis and therapy.

Zayachkivsky A, Lehmkuhle MJ, Ekstrand JJ, Dudek FE. Ischemic injury suppresses hypoxia-induced electrographic seizures and the background EEG in a rat model of perinatal hypoxic-ischemic encephalopathy. J Neurophysiol 114: 2753-2763, 2015. First published September 9, 2015 doi:10.1152/jn.00796.2014.-The relationship among neonatal seizures, abnormalities of the electroencephalogram (EEG), brain injury, and long-term neurological outcome (e.g., epilepsy) remains controversial. The effects of hypoxia alone (Ha) and hypoxia-ischemia (HI) were studied in neonatal rats at postnatal day 7; both models generate EEG seizures during the 2-h hypoxia treatment, but only HI causes an infarct with severe neuronal degeneration. Single-channel, differential recordings of acute EEG seizures and background suppression were recorded with a novel miniature telemetry device during the hypoxia treatment and analyzed quantitatively. The waveforms of electrographic seizures (and their behavioral correlates) appeared virtually identical in both models and were identified as discrete events with high power in the traditional delta (0.1-4 Hz) and/or alpha (8 -12 Hz) bands. Although the EEG patterns during seizures were similar in Ha-and HI-treated animals at the beginning of the hypoxic insult, Ha caused a more severe electrographic seizure profile than HI near the end. Analyses of power spectral density and seizure frequency profiles indicated that the electrographic seizures progressively increased during the 2-h Ha treatment, while HI led to a progressive decrease in the seizures with significant suppression of the EEG background. These data show that 1) the hypoxia component of these two models drives the seizures; 2) the seizures during Ha are substantially more robust than those during HI, possibly because ongoing neuronal damage blunts the electrographic activity; and 3) a progressive decrease in background EEG, rather than the presence of electrographic seizures, indicates neuronal degeneration during perinatal HI.EEG; hypoxia-ischemia; neonatal; stroke; seizure SEIZURES ARE RELATIVELY COMMON in neonates and are a potential harbinger of intractable epilepsy, cerebral palsy, cognitive deficits, and other negative neurological outcomes. Prolonged periods of hypoxia alone (Ha; e.g., birth asphyxia or apnea) or hypoxia-ischemia (HI; e.g., perinatal stroke) are thought to be a major cause of neonatal seizures, but metabolic disturbances, encephalitis, and genetic abnormalities can also lead to seizures in neonates (Sarnat and Sarnat 1976;Finer et al. 1981; Watanabe et al. 1982a,b;Corey et al. 1988;Mercuri et al. 1999;Marin-Padilla 2000;Nelson and Lynch 2004;Malm 2009;Sorge and Sorge 2010). Although considerable EEG data are available on neonatal seizures, their predictive value is poor because outcomes range from benign to devastating. A definitive causal link between the characteristics of the neonatal EEG and the subsequent neurological outcome is difficult to establish in humans. Thus it is unclear whether acute neonatal seizures ...

EphA-ephrin signaling has recently been implicated in the establishment of motor innervation patterns, in particular in determining whether motor axons project into dorsal versus ventral nerve trunks in the limb. We investigated whether sensory axons, which grow out together with and can be guided by motor axons, are also influenced by Eph-ephrin signaling. We show that multiple EphA receptors are expressed in DRGs when limb innervation is being established, and EphA receptors are present on growth cones of both NGF-dependent (predominantly cutaneous) and NT3-dependent (predominantly proprioceptive) afferents. Both soluble and membrane-attached ephrin-A5 inhibited growth of approximately half of each population of sensory axons in vitro. On average, growth cones that collapsed in response to soluble ephrin-A5 extended more slowly than those that did not, and ephrin-A5 significantly slowed the extension of NGF-dependent growth cones that did not collapse. Finally, we show that ectopic expression of ephrin-A5 in ovo reduced arborization of cutaneous axons in skin on the limb. Together these results suggest that sensory neurons respond directly to A-class ephrins in the limb. Thus, ephrins appear to pattern sensory axon growth in two ways-both directly, and indirectly via their inhibitory effects on neighboring motor axons.