A team led by Afsaneh Gaillard (Inserm Unit 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers), in collaboration with the Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM) in Brussels, has just taken an important step in the area of cell therapy: repairing the cerebral cortex of the adult mouse using a graft of cortical neurons derived from embryonic stem cells. These results have just been published in Neuron.

The cerebral cortex is one of the most complex structures in our brain. It is composed of about a hundred types of neurons organised into 6 layers and numerous distinct neuroanatomical and functional areas.

Brain injuries, whether caused by trauma or neurodegeneration, lead to cell death accompanied by considerable functional impairment. In order to overcome the limited ability of the neurons of the adult nervous system to regenerate spontaneously, cell replacement strategies employing embryonic tissue transplantation show attractive potential.

A major challenge in repairing the brain is obtaining cortical neurons from the appropriate layer and area in order to restore the damaged cortical pathways in a specific manner.

The results obtained by Afsaneh Gaillard’s team and that Pierre Vanderhaeghen at the Institute of Interdisciplinary Research in Human and Molecular Biology show, for the first time, using mice, that pluripotent stem cells differentiated into cortical neurons make it possible to reestablish damaged adult cortical circuits, both neuroanatomically and functionally.

These results also suggest that damaged circuits can be restored only by using neurons of the same type as the damaged area.

This study constitutes an important step in the development of cell therapy as applied to the cerebral cortex.

This approach is still at the experimental stage (laboratory mice only). Much research will be needed before there is any clinical application in humans. Nonetheless, for the researchers, “The success of our cell engineering experiments, which make it possible to produce nerve cells in a controlled and unlimited manner, and to transplant them, is a world first. These studies open up new approaches for repairing the damaged brain, particularly following stroke or brain trauma,” they explain.

© A. Gaillard/Inserm. An illustration showing the integration of neurons transplanted into the brain following injury, two months after transplantation. Specific projections of the adult brain (red) into the transplanted neurons (green)

Why are we not aware of external noises while we sleep? A study carried out at NeuroSpin (French Atomic Energy Commission [CEA]/Inserm), in collaboration with the Sleep and Alertness Centre at Hôtel-Dieu Hospital, Paris (AP-HP), the Brain and Spinal Cord Institute (ICM), Collège de France, and Paris-Sud and Paris Descartes Universities, has shown that even though sounds continue to penetrate the auditory cortex, sleep disrupts the brain’s ability to anticipate them. The researchers have demonstrated that the brain is no longer capable of making predictions during sleep, because the predictive signals coming from the higher cortical areas seem to be eliminated. These results are published in the American journal PNAS, on 2 March 2015.

While listening to a melody during wakefulness, the brain uses the regularities in the sound sequence to predict the future sounds. This predictive ability is based on the functioning of a hierarchy of areas in the brain. If a sound breaks the regularity of the sequence, the brain then generates a series of “prediction error” signals responsible for, among other things, reactions to novelty or reactions of surprise. Previous studies using electroencephalography (EEG) have made it possible to describe at least two consecutive error signals, mismatch negativity (MMN) and P300. MMN has already been observed in subjects in an unconscious state (including a comatose state), whereas P300 may be specific for conscious processing, since it reflects the integration of information over a vast brain network, beyond the auditory regions.

During sleep, ambient sounds are not consciously perceived. However, we do not know the extent to which the integration of these sounds by the brain is disrupted, or whether the brain remains capable of perceiving their regularities and anticipating them. This particular aspect of brain function was tested by the NeuroSpin team (Inserm/CEA), in collaboration with the Sleep and Alertness Centre at Hôtel-Dieu Hospital, Paris (AP-HP), the Brain and Spinal Cord Institute (ICM), Collège de France, and Paris-Sud and Paris Descartes Universities. The researchers used electro- and magnetoencephalography (E/MEG) to study the prediction error signals (MMN and P300) in subjects during sleep and wakefulness.

The researchers invited volunteers to go to sleep inside NeuroSpin’s magnetoencephalography machine, in the presence of repetitive sounds. Results confirmed that P300 is a specific marker for conscious processing of sounds, since it disappeared as soon as the volunteers fell asleep, from which time the subjects no longer reacted to sounds. In contrast, MMN was observed at all stages of sleep (slow-wave sleep and rapid eye movement [REM] sleep). However, this signal is only partially retained, since some areas of the brain, which are normally activated during wakefulness, no longer respond to the sound stimulus. Indeed, the peak of activity resulting from a predictive error in an awake individual disappears during sleep. The only remaining phenomena are those of passive sensory adaptation, and confined to the primary auditory areas.

The researchers have thus shown that, due to a defect in communication between its different areas, the brain can no longer make predictions during sleep.

However, it remains capable of representing sounds within the auditory areas, and can get used to them if they are frequent, explaining why we are awakened by an alarm but not by the ticking of a clock.

©S. Dehaene. Reconstruction of the sources of error signals in the brain based on magnetoencephalographic recordings. The signals that indicate predictive error; the intermediate component of MMN and P300, disappear during sleep. Only passive mechanisms for sensory adaptation (the early and late components of MMN), confined to the auditory areas, remain. (Times are expressed in milliseconds, and measure the time taken to respond to the sound).