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Dissociated cortical neurons in vitro display spontaneously synchronized, low-frequency firing patterns, which can resemble the slow wave oscillations characterizing sleep in vivo. Experiments in humans, rodents, and cortical slices have shown that awakening or the administration of activating neuromodulators decrease slow waves, while increasing the spatio-temporal complexity of responses to perturbations. In this study, we attempted to replicate those findings using in vitro cortical cultures coupled with micro-electrode arrays and chemically treated with carbachol (CCh), to modulate sleep-like activity and suppress slow oscillations. We adapted metrics such as neural complexity (NC) and the perturbational complexity index (PCI), typically employed in animal and human brain studies, to quantify complexity in simplified, unstructured networks, both during resting state and in response to electrical stimulation. After CCh administration, we found a decrease in the amplitude of the initial response and a marked enhancement of the complexity during spontaneous activity. Crucially, unlike in cortical slices and intact brains, PCI in cortical cultures displayed only a moderate increase. This dissociation suggests that PCI, a measure of the complexity of causal interactions, requires more than activating neuromodulation and that additional factors, such as an appropriate circuit architecture, may be necessary. Exploring more structured in vitro networks, characterized by the presence of strong lateral connections, recurrent excitation, and feedback loops, may thus help to identify the features that are more relevant to support causal complexity.

Background: In recent years, biomedical devices have proven to be able to target also different neurological disorders. Given the rapid ageing of the population and the increase of invalidating diseases affecting the central nervous system, there is a growing demand for biomedical devices of immediate clinical use. However, to reach useful therapeutic results, these tools need a multidisciplinary approach and a continuous dialogue between neuroscience and engineering, a field that is named neuroengineering. This is because it is fundamental to understand how to read and perturb the neural code in order to produce a significant clinical outcome. Results: In this review, we first highlight the importance of developing novel neurotechnological devices for brain repair and the major challenges expected in the next years. We describe the different types of brain repair strategies being developed in basic and clinical research and provide a brief overview of recent advances in artificial intelligence that have the potential to improve the devices themselves. We conclude by providing our perspective on their implementation to humans and the ethical issues that can arise. Conclusions: Neuroengineering approaches promise to be at the core of future developments for clinical applications in brain repair, where the boundary between biology and artificial intelligence will become increasingly less pronounced.

Background DNA methylation has emerged as an important epigenetic regulator of brain processes, including circadian rhythms. However, how DNA methylation intervenes between environmental signals, such as light entrainment, and the transcriptional and translational molecular mechanisms of the cellular clock is currently unknown. Here, we studied the after-hours mice, which have a point mutation in the Fbxl3 gene and a lengthened circadian period. Methods In this study, we used a combination of in vivo, ex vivo and in vitro approaches. We measured retinal responses in Afh animals and we have run reduced representation bisulphite sequencing (RRBS), pyrosequencing and gene expression analysis in a variety of brain tissues ex vivo. In vitro, we used primary neuronal cultures combined to micro electrode array (MEA) technology and gene expression. Results We observed functional impairments in mutant neuronal networks, and a reduction in the retinal responses to light-dependent stimuli. We detected abnormalities in the expression of photoreceptive melanopsin (OPN4). Furthermore, we identified alterations in the DNA methylation pathways throughout the retinohypothalamic tract terminals and links between the transcription factor Rev-Erbα and Fbxl3. Conclusions The results of this study, primarily represent a contribution towards an understanding of electrophysiological and molecular phenotypic responses to external stimuli in the Afh model. Moreover, as DNA methylation has recently emerged as a new regulator of neuronal networks with important consequences for circadian behaviour, we discuss the impact of the Afh mutation on the epigenetic landscape of circadian biology.

In this paper, we show that neuronal assemblies plated on Micro Electrode Arrays present synchronized, low frequency firing patterns similar to in vivo slow wave oscillations, which are a key parameter of sleep-like state. Although neuronal cultures lack the characteristic high-frequency waves of wakefulness, it is possible to modulate their spontaneous firing pattern through the administration of specific neurotransmitters such as acetylcholine. We thus stimulated the cortical cultures with an agonist of acetylcholine receptor, Carbachol, which caused a desynchronization of the spontaneous firing of the cultures. We recorded and monitored the cultures for a period of over 31 h. We analyzed the electrophysiological signals by exploiting novel methodological approaches, taking into account the different temporal scales of the recorded signals, and considering both spikes and local field potentials. Supporting the electrophysiological analysis results, gene expressions of targeted genes showed the activation of specific markers involved in sleep-wake rhythms. Our results demonstrate that the Carbachol treatment induces desynchronization of neuronal activity, altering sleep-like properties in an in vitro model.

Neurosci. 10:315. doi: 10.3389/fnins.2016.00315 Reason for Corrigendum: The primer pairs for the gene Homer1 reported in the original manuscript referred to the longer isoforms Homer1b/c and not Homer1a. [...]we added some missing references. [...]at Page 2, Third paragraph, 11th line: the reference (Tateno et al., 2005; Corner, 2013) is corrected with (Tateno et al., 2005; Kaufman et al., 2012; Corner, 2013). [...]PER2 is a marker of the circadian control of sleep (Kopp et al., 2002; Shiromani et al., 2004) while Homer1a is an important marker of the homeostatic process of sleep” is corrected with the phrase “can we use in vitro experimental model to dissect molecular markers of synaptic homeostasis and circadian control of sleep?

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that is characterized by rapid eye movement (REM) sleep abnormalities. The disease is caused by genomic imprinting defects that are inherited through the paternal line. Among the genes located in the PWS region on chromosome 15 (15q11-q13), small nucleolar RNA 116 (Snord116) has been previously associated with intrusions of REM sleep into wakefulness in both humans and mice. Here, we further explore the processes of sleep regulation by studying the PWScrm+/p- mouse line, which carries a paternal deletion of Snord116. We focused on microstructural electrophysiological components of sleep, such as REM sleep features and sleep spindles within NREM sleep. While the former are thought to contribute to neuronal network formation early in brain development, the latter are markers of thalamocortical processes. Both signals are often compromised in neurodevelopmental disorders and influence functional properties of cortical neurons. Thus, we isolated and characterized the intrinsic activity of cortical neurons using in vitro microelectrode array (MEA) studies. Our results indicate that the Snord116 gene in mice selectively influences REM sleep properties, such as theta rhythms and the organization of REM episodes throughout sleep-wake cycles. Moreover, sleep spindles present specific abnormalities in PWS model systems, indicating that these features of sleep may translate as potential biomarkers in human PWS. We observed abnormalities in the synchronization of cortical neuronal activity that are accounted for by high levels of norepinephrine. In conclusion, our results provide support for an important role of Snord116 in regulating brain activity during sleep and, in particular, cortical neuronal properties, thereby opening new avenues for developing interventions in PWS.

The correct identification of burst events is crucial in many scenarios, ranging from basic neuroscience to biomedical applications. However, none of the burst detection methods that can be found in the literature have been widely adopted for this task. As an alternative to conventional techniques, a novel neuromorphic approach for real-time burst detection is proposed and tested on acquisitions from in vitro cultures. The system consists of a Neuromorphic Auditory Sensor, which converts the input signal obtained from electrophysiological recordings into spikes and decomposes them into different frequency bands. The output of the sensor is sent to a trained spiking neural network implemented on a SpiNNaker board that discerns between bursting and non-bursting activity. This data-driven approach was compared with 8 different conventional spike-based methods, addressing some of their drawbacks, such as being able to detect both high and low frequency events and working in an online manner. Similar results in terms of number of detected events, mean burst duration and correlation as current state-of-the-art approaches were obtained with the proposed system, also benefiting from its lower power consumption and computational latency. Therefore, our neuromorphic-based burst detection paves the road to future implementations for neuroprosthetic applications. Competing Interest Statement The authors have declared no competing interest.

Recent advances in neurotechnology allow neurological impairments to be treated or reduced by brain machine interfaces and neuroprostheses. To develop energy-efficient and real-time capable devices, neuromorphic computing systems are envisaged as the core of next-generation neurobiohybrid systems for brain repair. We demonstrate here the first exploitation of a neuromorphic prosthesis to restore bidirectional interactions between two neuronal populations, even when one is damaged or completely missing. We used in vitro modular cell cultures to mimic the mutual interaction between neuronal assemblies and created a focal lesion to functionally disconnect the two populations. Then, we employed our neuromorphic prosthesis for two specific applications with future clinical implications: bidirectional bridging to artificially reconnect two disconnected neuronal modules and hybrid bidirectional bridging to replace the activity of one module with a neuromorphic spiking neural network. Our neuroprosthetic system opens up new avenues for the development of novel bioelectrical therapeutics for human applications.