Intellectual disabilities (ID) represent a large and heterogeneous group of cognitive disorders. Robust genome interrogation methods applied to ID patients are revealing numerous genes that are crucial for cognitive functioning. However, knowledge about the normal and pathophysiological processes involving ID genes is still in its infancy. An emerging concept is that ID genes are hubs in a selected number of key signalling pathways whose dysregulation underlies synaptic and cortical network dysfunction. Moreover, evidence is accumulating that chromatin modifications are important in cognitive processes and in the etiology of an increasing number of ID disorders. Here we propose a strategy to study the genes identified in a clinical well-defined ID syndrome as an excellent stepping-stone to understand how the corresponding proteins contribute to synaptic function and ultimately to learning and memory. We will study a chromatin-modification module that underlies a recognizable form of ID. This module consists of EHMT1, MBD5, MLL3, SMARCB1, and NR1I3, all of which encode epigenetic regulators of transcription. Here we will test the hypothesis that a genetic hit in each of these genes will lead to a similar cellular outcome at the level of synaptic and network (dys)function. To this end we will use the potential of human-derived induced pluripotent stem cells (hIPSC) and differentiate them into neurons (iNeurons). Subsequently, we will measure neural network formation and maturation capabilities by functionally characterizing these iNeurons at the level of synaptic activity and network properties during development. Together our experiments will provide insight into the ?multiple gene-one outcome hypothesis?.

Het begrijpen van het menselijk brein is cruciaal voor hersenfunctie, neuro-ontwikkelingsstoornissen, neurale techniek en kunstmatige intelligentie. Huidige benaderingen missen echter de precisie en resolutie om te bestuderen hoe menselijke neuronen signalen verwerken en reacties produceren. Het ELEANOR-project onderzoekt de signaalverwerking van menselijke neuronen met een hoog-precieze alles-optische aanpak, waarbij een veelzijdige fotonische microchip en optische dynamische klemmen worden gebruikt voor precieze en selectieve stimulatie van individuele dendritische vertakkingen. Deze innovatieve benadering belooft huidige beperkingen in het begrijpen van de hersenfunctie van de mens aan te pakken, en de neurowetenschappen en gerelateerde vakgebieden significant vooruit te helpen.

Many natural sounds are composed of a large number of stochastic events, e.g. the sound of wind, rain or insect swarms, called acoustic textures. Humans can easily recognize these sounds, despite substantial variability between different examples from the same type. An acoustic texture is characterized by its statistical composition, which has been shown to be sufficient for recognition. However, the neural representation of these statistics remains unaddressed. We recently investigated human performance of detecting changes in acoustic textures, and estimated cortical locations that represent the sound and the decision process. Here, we will address the low-level, neuronal representation in these locations directly by recording from populations of optogenetically identified neurons simultaneously in the mouse. The animals listen to naturalistic acoustic textures which change at a random time, and indicate their percept by licking to receive a reward. Simultaneously, we will monitor the neuronal responses in primary and secondary auditory cortex and parietal areas. The recordings will provide insight into (1) the representation of statistical stimuli in neuronal responses, (2) the dynamic estimation process of textures and (3) the transformations in stimulus representation up to the point of decision making. Passive experiments will be performed as well to demonstrate the contribution of active processing. In summary, the proposed project will substantially improve our understanding of auditory processing in complex, natural acoustic environments, and more generally the representation of probabilistic quantities in the brain. Applications include the design of speech recognition systems and hearing aids which work robustly in everyday environments.

Dutch National Research Agenda, support routes application

In the complex visual environment of everyday life, we have to select relevant over irrelevant information to achieve our current goals. From an evolutionary viewpoint, survival is our main goal in life. Therefore, our visual system has to prioritize emotional stimuli over neutral stimuli. Previous research, however, has not yet led to a converging theory on emotional modulation of early cognitive processes. Possibly because previous research emphasized the dissociation between unconscious and conscious emotional processing. Accordingly, two theories have emerged from this research; one claiming that emotional stimuli are processed via a subcortical route, the other claiming that emotional stimuli are processed via cortical networks. Unlike previous research, I will not dissociate between unconscious and conscious processing but I will investigate emotional modulation of visual selection as a function of time. The main questions I want to answer are 1) how prioritization of emotional stimuli occurs, 2) when in time prioritization occurs, 3) how the prioritization process evolves as a function of time and 4) what neural mechanisms may be involved. In this proposal I outline four projects in which I will use measures of eye movement behavior to index the time-course of emotional modulation and I will use transcranial magnetic stimulation (TMS) to investigate the cortical contributions to emotional modulation of visual selection. The combination of methods makes this research proposal unique and challenging and it is expected that these studies will lead to publications in a high impact journals. In addition, this research will contribute to the field of clinical research and clinical practice. Solving the questions outlined above are crucial in understanding excessive responses to potentially threatening events, as in anxiety disorders, as well as in (sub)optimal conditions in everyday life in which we appropriately have to respond to threatening stimuli.