The Neuromodulator Adenosine Regulates Oligodendrocyte Migration at Motor Exit Point Transition Zones.

During development, oligodendrocyte progenitor cells (OPCs) migrate extensively throughout the spinal cord. However, their migration is restricted at transition zones (TZs). At these specialized locations, unique glial cells in both zebrafish and mice play a role in preventing peripheral OPC migration, but the mechanisms of this regulation are not understood. To elucidate the mechanisms that mediate OPC segregation at motor exit point (MEP) TZs, we performed an unbiased small-molecule screen. Using chemical screening and in vivo imaging, we discovered that inhibition of A2a adenosine receptors (ARs) causes ectopic OPC migration out of the spinal cord. We provide in vivo evidence that neuromodulation, partially mediated by adenosine, influences OPC migration specifically at the MEP TZ. This work opens exciting possibilities for understanding how OPCs reach their final destinations during development and identifies mechanisms that could promote their migration in disease.

Melatonin is required for the circadian regulation of sleep.

Sleep is an evolutionarily conserved behavioral state whose regulation is poorly understood. A classical model posits that sleep is regulated by homeostatic and circadian mechanisms. Several factors have been implicated in mediating the homeostatic regulation of sleep, but molecules underlying the circadian mechanism are unknown. Here we use animals lacking melatonin due to mutation of arylalkylamine N-acetyltransferase 2 (aanat2) to show that melatonin is required for circadian regulation of sleep in zebrafish. Sleep is dramatically reduced at night in aanat2 mutants maintained in light/dark conditions, and the circadian regulation of sleep is abolished in free-running conditions. We find that melatonin promotes sleep downstream of the circadian clock as it is not required to initiate or maintain circadian rhythms. Additionally, we provide evidence that melatonin may induce sleep in part by promoting adenosine signaling, thus potentially linking circadian and homeostatic control of sleep.

Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9.

Loss of neurons that express the neuropeptide hypocretin (Hcrt) has been implicated in narcolepsy, a debilitating disorder characterized by excessive daytime sleepiness and cataplexy. Cell replacement therapy, using Hcrt-expressing neurons generated in vitro, is a potentially useful therapeutic approach, but factors sufficient to specify Hcrt neurons are unknown. Using zebrafish as a high-throughput system to screen for factors that can specify Hcrt neurons in vivo, we identified the LIM homeobox transcription factor Lhx9 as necessary and sufficient to specify Hcrt neurons. We found that Lhx9 can directly induce hcrt expression and we identified two potential Lhx9 binding sites in the zebrafish hcrt promoter. Akin to its function in zebrafish, we found that Lhx9 is sufficient to specify Hcrt-expressing neurons in the developing mouse hypothalamus. Our results elucidate an evolutionarily conserved role for Lhx9 in Hcrt neuron specification that improves our understanding of Hcrt neuron development.

Plasticity of local GABAergic interneurons drives olfactory habituation.

Despite its ubiquity and significance, behavioral habituation is poorly understood in terms of the underlying neural circuit mechanisms. Here, we present evidence that habituation arises from potentiation of inhibitory transmission within a circuit motif commonly repeated in the nervous system. In Drosophila, prior odorant exposure results in a selective reduction of response to this odorant. Both short-term (STH) and long-term (LTH) forms of olfactory habituation require function of the rutabaga-encoded adenylate cyclase in multiglomerular local interneurons (LNs) that mediate GABAergic inhibition in the antennal lobe; LTH additionally requires function of the cAMP response element-binding protein (CREB2) transcription factor in LNs. The odorant selectivity of STH and LTH is mirrored by requirement for NMDA receptors and GABA(A) receptors in odorant-selective, glomerulus-specific projection neurons(PNs). The need for the vesicular glutamate transporter in LNs indicates that a subset of these GABAergic neurons also releases glutamate. LTH is associated with a reduction of odorant-evoked calcium fluxes in PNs as well as growth of the respective odorant-responsive glomeruli. These cellular changes use similar mechanisms to those required for behavioral habituation. Taken together with the observation that enhancement of GABAergic transmission is sufficient to attenuate olfactory behavior, these data indicate that habituation arises from glomerulus-selective potentiation of inhibitory synapses in the antennal lobe. We suggest that similar circuit mechanisms may operate in other species and sensory systems.

Normative data for the Words-in-Noise Test for 6- to 12-year-old children.

PURPOSE: To establish normative data for children on the Words-in-Noise Test (WIN; R. H. Wilson, 2003; R. H. Wilson & R. McArdle, 2007). METHOD: Forty-two children in each of 7 age groups, ranging in age from 6 to 12 years (n=294), and 24 young adults (age range: 18-27 years) with normal hearing for pure tones participated. All listeners were screened at 15 dB HL (American National Standards Institute, 2004) with the octave interval between 500 and 4000 Hz. Randomizations of WIN Lists 1, 2, and 1 or WIN Lists 2, 1, and 2 were presented with the noise fixed at 70 dB SPL, followed by presentation at 90 dB SPL of the 70 Northwestern University Auditory Test No. 6 (T. W. Tillman & R. Carhart, 1966) words used in the WIN. Finally, the Peabody Picture Vocabulary Test-Revised (L. M. Dunn & L. M. Dunn, 1981) was administered. Testing was conducted in a quiet room. RESULTS: There were 3 main findings: (a) The biggest change in recognition performance occurred between the ages of 6 and 7 years; (b) from 9 to 12 years, recognition performance was stable; and (c) performance by young adults (18-27 years) was slightly better (1-2 dB) than performance by the older children. CONCLUSION: The WIN can be used with children as young as 6 years of age; however, age-specific ranges of normal recognition performance must be used.