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Summary Previous observations suggest the existence of ‘Active sleep' in cephalopods. To investigate in detail the behavioral structure of cephalopod sleep, we video-recorded four adult specimens of Octopus insularis and quantified their distinct states and transitions. Changes in skin color and texture and movements of eyes and mantle were assessed using automated image processing tools, and arousal threshold was measured using sensory stimulation. Two distinct states unresponsive to stimulation occurred in tandem. The first was a ‘Quiet sleep' state with uniformly pale skin, closed pupils, and long episode durations (median 415.2 s). The second was an ‘Active sleep' state with dynamic skin patterns of color and texture, rapid eye movements, and short episode durations (median 40.8 s). ‘Active sleep' was periodic (60% of recurrences between 26 and 39 min) and occurred mostly after ‘Quiet sleep' (82% of transitions). These results suggest that cephalopods have an ultradian sleep cycle analogous to that of amniotes.

Background Intrauterine infection with the Zika virus (ZIKV) has been connected to severe brain malformations, microcephaly, and abnormal electrophysiological activity. Methods We describe the interictal electroencephalographic (EEG) recordings of 47 children born with ZIKV-derived microcephaly. EEGs were recorded in the first year of life and correlated with brain morphology. In 31 subjects, we tested the association between computed tomography (CT) findings and interictal epileptiform discharges (IED). In eighteen, CTs were used for correlating volumetric measurements of the brainstem, cerebellum, and prosencephalon with the rate of IED. Findings Twenty-nine out of 47 (62%) subjects were diagnosed as having epilepsy. Those subjects presented epileptiform discharges, including unilateral interictal spikes (26/29, 90%), bilateral synchronous and asynchronous interictal spikes (21/29, 72%), and hypsarrhythmia (12/29, 41%). Interestingly, 58% of subjects with clinical epilepsy were born with rhombencephalon malformations, while none of the subjects without epilepsy showed macroscopic abnormalities in this region. The presence of rhombencephalon malformation was associated with epilepsy (odds ratio of 34; 95% CI: 2 - 654). Also, the presence of IED was associated with smaller brain volumes. Age-corrected total brain volume was inversely correlated with the rate of IED during sleep. Finally, 11 of 44 (25%) subjects presented sleep spindles. We observed an odds ratio of 0·25 (95% CI: 0·06 - 1·04) for having sleep spindles given the IED presence. Interpretation The findings suggest that certain CT imaging features are associated with an increased likelihood of developing epilepsy, including higher rates of IED and impaired development of sleep spindles, in the first year of life of CZVS subjects. Funding This work was supported by the Brazilian Federal Government through a postdoctoral fellowship for EBS (Talented Youth, Science without Borders), an undergraduate scholarship for AJR (Institutional Program of Science Initiation Scholarships, Federal University of Rio Grande do Norte, Brazil), by International Centre for Genetic Engineering and Biotechnology (CRP/BRA18–05_EC) and by CAPES (Grant number 440893/2016-0), and CNPq (Grant number 88881.130729/2016-01).

Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that duringXenopus laevisneural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation.SIGNIFICANCE STATEMENTNeural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy.

The combination of body quiescence and skin pattern changes displayed periodically by Sepia officinalis, as well as the high threshold for arousal upon stimulation and increased brain activity in quiescent Octopus vulgaris, suggest the existence of a state akin to rapid-eye-movement sleep (REM) in cephalopods. Would be possible that cephalopods, as amniotes, sleep through the alternation of distinct quiescent states, analogous to slow-wave sleep (SWS) and REM? To investigate this possibility, we video-recorded 4 adult specimens of Octopus insularis and quantified in detail their behavioral states and transitions. We also performed sensory stimulation to measure reaction times across all behavioral states. Two distinct quiescent states occurred in tandem, both quite unresponsive to stimulation (median reaction time: 50 s). The first state was SWS-like, characterized by uniformly pale skin, closed pupils, and long episode durations (median 415.2 s). The second state was REM-like, characterized by dynamic skin patterns, rapid eye movements and short episode durations (median 40.8 s). The REM-like state was periodic (60% of all recurrences between 26.85-39.15 min) and occurred mostly after the SWS-like state (82% of all transitions). These observations support the existence in cephalopods of an ultradian sleep cycle analogous to the SWS/REM alternation.

Psychedelic agonists of serotonin receptors induce neural plasticity and synaptogenesis, but their potential to enhance learning remains uncharted. Here we show that a single dose of d-LSD, a potent serotonergic agonist, increased novel object preference in young and adult rats several days after treatment. d-LSD alone did not increase preference in old animals, but could rescue it to young levels when followed by a 6-day exposure to enriched environment (EE). Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions, with alterations of long-range synapses. Better pattern separation within EE explained its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.

Nervous system development relies on the generation of neurons, their differentiation and establishment of synaptic connections. These events exhibit remarkable plasticity and are regulated by many developmental cues. Here, we review the mechanisms of three classes of these cues: morphogenetic proteins, electrical activity, and the environment. We focus on second messenger dynamics and their role as integrators of the action of diverse cues, enabling plasticity in the process of neural development. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 349–359, 2015

The generation and specification of pyramidal neuron subpopulations during development relies on a complex network of transcription factors. The CB(1) cannabinoid receptor is the major molecular target of endocannabinoids and marijuana active compounds. This receptor has been shown to influence neural progenitor proliferation and axonal growth, but its involvement in neuronal differentiation and the functional impact in the adulthood caused by altering its signaling during brain development are not known. Here we show that the CB(1) receptor, by preventing Satb2 (special AT-rich binding protein 2)-mediated repression, increased Ctip2 (COUP-TF interacting protein 2) promoter activity, and Ctip2-positive neuron generation. Unbalanced neurogenic fate determination found in complete CB(1)(-/-) mice and in glutamatergic neuron-specific Nex-CB(1)(-/-) mice induced overt alterations in corticospinal motor neuron generation and subcerebral connectivity, thereby resulting in an impairment of skilled motor function in adult mice. Likewise, genetic deletion of CB(1) receptors in Thy1-YFP-H mice elicited alterations in corticospinal tract development. Altogether, these data demonstrate that the CB(1) receptor contributes to the generation of deep-layer cortical neurons by coupling endocannabinoid signals from the neurogenic niche to the intrinsic proneurogenic Ctip2/Satb2 axis, thus influencing appropriate subcerebral projection neuron specification and corticospinal motor function in the adulthood.

During embryonic development, the telencephalon is specified along its axis through morphogenetic gradients, leading to the positional-dependent generation of multiple neuronal types. After embryogenesis, however, the fate of neuronal progenitors becomes more restricted, and they generate only a subset of neurons. Here, we review studies of postnatal and adult neurogenesis, challenging the notion that fixed genetic programs restrict neuronal fate. We hypothesize that the adult brain maintains plastic neural stem cells that are capable of responding to changes in environmental cues and generating diverse neuronal types. Thus, the limited diversity of neurons generated under normal conditions must be actively maintained by the adult milieu.

The mammalian subventricular zone (SVZ) contains progenitorsderived from cerebral cortex radial glia cells, which give riseto glutamatergic pyramidal neurons during embryogenesis.However, during postnatal life, SVZ generates neurons thatmigrate and differentiate into olfactory bulbg-aminobutyric acid(GABA)ergic interneurons. In this work, we tested if SVZ cells areable to produce glutamatergic neurons if confronted with theembryonic cortical ventricular zone environment. Different fromtypical SVZ chain migration, cells from P9--P11 SVZ explantsmigrate into embryonic cortical slices individually, many of whichradially oriented. An average of 82.5% of green fluorescentprotein--positive cells were immunolabeled for neuronal markerclass III b-tubulin. Invading cells differentiate into multiplemorphologies, including a pyramidal-like morphotype. A subsetof these cells are GABAergic; however, about 28% of SVZ-derivedcells are immunoreactive for glutamate. Adult SVZ explants alsogive rise to glutamatergic neurons in these conditions. Takentogether, our results indicate that SVZ can be a source ofglutamatergic cortical neurons when submitted to properenvironmental cues.Keywords: cerebral cortex, GABAergic, neurogenesis, olfactory bulb,plasticityIntroductionThe subventricular zone (SVZ) is a continuous source of newneurons in postnatal and adult mammals (for review, see Gage2000). The newly generated neurons migrate to the ipsilateralolfactory bulb (OB; Altman 1969; Luskin 1993) where theydifferentiate into granular and periglomerular neurons (Luskin1993). A known feature of these cells is that they differentiateinto c-aminobutyric acid (GABA)ergic neurons (Betarbet et al.1996). It was recently described that a subpopulation ofperiglomerular neurons could be devoid of GABA (Gutie`rrez-Mecinas et al. 2005). However, recent evidence shows that all OBperiglomerular neurons activate the promoter of the gene for 1 ofthe 2 forms of glutamic acid decarboxilase, 67KD form of glutamicacid decarboxilase (GAD67), as detected by green fluorescentprotein (GFP) expression in transgenic mice (Panzanelli et al.2007). In addition, a subpopulation of periglomerular neurons(Kosaka et al. 1985; Betarbet et al. 1996; Hack et al. 2005) andsuperficial granular neurons (Kohwi et al. 2005) are doublelabeled for GABA and tyrosine hydroxylase.It is suggested that the telencephalic embryonic germinallayer, the ventricular zone (VZ), gives rise to differentneurochemical phenotypes in a spatial-dependent fashion(Marin and Rubenstein 2001). In the telencephalon, glutama-tergic neurons are generated by the dorsal VZ (Schuurmanset al. 2004) and GABAergic neurons from its ventral domain(Anderson et al. 1997). At the end of embryonic neurogenesis,radialglia(RG),themainprogenitorsoftheVZ(Noctoretal.2001),start to transform into other cell types, including SVZ astrocytes(Alves et al. 2002; Tramontin et al. 2003) and ependymal cells(Spassky et al. 2005). Postnatal progenitors, derived from RG, arealso known to give rise to inhibitory interneurons of the OB,irrespective of dorsoventral position (Merkle et al. 2007). Theseobservations lead to the question of whether dorsal progen-itors, which initially make glutamatergic neurons, respecifytheir program for neurotransmitter choice after embryonicneurogenesis ends. An alternative possibility is that dorsaltelencephalic progenitors are still capable of giving rise toglutamatergic neurons, and the external signals present in thepostnatal brain do not allow or stimulate this phenotype. SVZneuroblasts already express GABA in route to the OB (Bolteusand Bordey 2004), suggesting an early commitment by thesecells with a GABAergic destiny.Recent data suggest that most GABA-immunoreactive neuro-blasts of the SVZ are not endowed with the GABA syntheticmachinery typical of differentiated neurons (De Marchis et al.2004; Sequerra et al. 2007). Instead, an alternative syntheticpathway has been identified, which converts putrescine intoGABA (Sequerra et al. 2007). Therefore, neuroblasts in the SVZmay not be irreversibly committed to a GABAergic destiny. Thequestion herein addressed is whether the dorsal embryonic VZenvironment could drive postnatal and adult SVZ progenitorsto a glutamatergic phenotype.Materials and Methods