Cortical nNOS neurons co-express the NK1 receptor and are depolarized by Substance P in multiple mammalian species

We have previously demonstrated that Type I neuronal nitric oxide synthase (nNOS)-expressing neurons are sleep-active in the cortex of mice, rats, and hamsters. These neurons are known to be GABAergic, to express Neuropeptide Y (NPY) and, in rats, to co-express the Substance P (SP) receptor NK1, suggesting a possible role for SP in sleep/wake regulation. To evaluate the degree of co-expression of nNOS and NK1 in the cortex among mammals, we used double immunofluorescence for nNOS and NK1 and determined the anatomical distribution in mouse, rat, and squirrel monkey cortex. Type I nNOS neurons co-expressed NK1 in all three species although the anatomical distribution within the cortex was species-specific. We then performed in vitro patch clamp recordings in cortical neurons in mouse and rat slices using the SP conjugate tetramethylrhodamine-SP (TMR-SP) to identify NK1-expressing cells and evaluated the effects of SP on these neurons. Bath application of SP (0.03–1 μM) resulted in a sustained increase in firing rate of these neurons; depolarization persisted in the presence of tetrodotoxin. These results suggest a conserved role for SP in the regulation of cortical sleep-active neurons in mammals

The Down Syndrome Critical Region Regulates Retinogeniculate Refinement

Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the “Down syndrome critical region” (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH- or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL