Final Report Summary - COGNITIONNET (Multilevel brain network analyses leading to improved therapeutics for cognitive impairments)
MSCA IDP CognitionNet project summary
Cognitive abilities change with development and age. Cognitive development during childhood and adolescence depends on an intellectually challenging environment, but is robustly affected in various forms of mental retardation. Adult cognitive abilities are strongly correlated with a person’s success in life. Finally, cognitive decline is an important problem during aging and is accelerated in neurodegenerative disorders like Alzheimer’s disease. Lifetime cognitive wellbeing is of the utmost importance in a society where life expectancy and individual demand for socio-economic participation are increasing, and where the financial burden on health care needs to be contained. CognitionNet investigated brain mechanisms of cognition at the molecular, cellular, neural network and behavioural level, both from a basic and a clinical perspective and aimed to integrate the results to develop novel treatment options for various forms of cognitive impairment.
With this aim in mind four scientific work packages (WPs) had been constructed, in which 14 official and 1 affiliated early stage researchers (ESRs) have been employed. At the end of the project in September 2017, several contracts have been elongated in order to allow for scientific excellence. Thus far, 15 scientific publications have emerged, and several (approximately 28) are either already under review or in preparation.
Four Early Stage Researchers (ESRs) in Work package 1 (WP1) studied plasticity of cognition during adulthood from the molecular to the behavioural level. One of the two papers that have been published focussed on the architecture of pyramidal neurons in the human cortex. From the papers in preparation, one discovered many synaptic proteins related to associative learning, and this will be followed up in the coming year(s) with intervention studies to show their causal role. Four ESRs in WP2 studied the role of genes with human mutations related to these diseases in the context of synaptic plasticity and cognitive control in adulthood. There was a focus on Rett syndrome, for which mouse models and human induced pluripotent stem cells were used. Data from human post-mortem brain tissue showed specific protein changes that are now being studied in Rett-derived iPSC neurons as well. These neurons seem to have a slower development, likely contributing to the observed disease symptoms of cognitive decline. In addition, critical for heathy development of neurons in the prefrontal cortex is that the main inhibitory receptor evolves from being excitatory to inhibitory. Three ESRs in WP3 worked on novel therapeutic entry points for treatment of age-related cognitive decline. A paper authored by one ESR showed that resting state EEG measurements could be used as possible biomarkers, in this case for insomnia. This could bring diagnostic and prognostic use of these tools one step closer to the clinic in which personalized treatment strategies can be designed. Furthermore, in a paper on a mouse model of Alzheimer’s disease, the authors showed the specific role of the disease-related increase in extracellular matrix in the hippocampus contributing to memory loss. After using enzymes to degrade this matrix, memory impairments were alleviated in these mice. Three ESRs in WP4 reported affected states of the network that lead to maladaptive behavioural output. These ESRs studied emotional memory, drug addiction, attention and depression, for which they formed the molecular and cellular basis of subsequent functional network analysis. Using optogenetic intervention of subregions of the prefrontal cortex, the authors showed involvement of these regions in attention. Furthermore, specifically the ventral part of the medial prefrontal cortex is important for the exact timing of attention in the second-range.
Taken together, three years of basic and clinical research in the healthy and diseased brain has provided new insight into basal (developmental) mechanisms of cognitive processing, and these insights will contribute to the development of novel treatment options for various forms of cognitive impairment in future.
A major component of the CognitionNet MSCA International Training Netwerk was the time invested on training, both in scientific and transferable skills. Trainees were introduced in several basic theories of the different scientific disciplines to understand each other and be able to communicate and cooperate across disciplines. For example, one of our trainees was educated as computer programmer, and now learned how to do electrical recordings from nerve cells, and subsequently used this information to construct computer models of neuronal communication. To train ESRs to actively participate in discussions on several levels, they have publicly presented their research plans at an early stage to each other, to the general public using lay language as well as to a scientific peer public. For their personal development and effectiveness, several transferable skill courses have been followed as amongst others designing, developing and marketing products and services to be able to apply for a job in industry after defending their PhD; planning and executing projects including finance; working as teams with a variety of assignments from designing and printing a prototype 3D project related product, to writing, directing and producing YouTube films for the general public on neuroscientific topics. To be able to fully integrate in the Dutch Society we offered several Dutch language courses.
ESRs also had secondments, one with an industrial partner, and one within academia. In this way, trainees have gained experience in both ‘worlds’, preparing them for a future career in either of them. In addition, specific focus has been on broadening the career prospects of the trainees by providing inter-ITN training and dissemination together with the FP7 MSCA ITN INSENS network.
In the final year, all have prepared a thesis set-up, in which finally 3–4 experimental chapters are bundled together with a scholarly introduction on the topic and aims of the thesis, as well as a general discussion putting their work into the context of the field. In the final CognitionNet meeting, this was presented to the entire network.
Dissemination (scientific & general): Trainees have presented their results (in poster-format or by oral presentation) in both host organized CNCR-based meetings, as well as scientific national (Dutch Neuroscience meeting, mid-term meeting with FP7 MSCA ITN INSENS ESRs, Graduate school Neuroscience meeting), and international meetings (Society for Neuroscience meeting (USA), FENS meeting (Europe), and smaller topically more focused meetings abroad). In addition, trainees have participated in several outreach and dissemination events, e.g. for prospective academic students in high school (last grade students) in Barneveld and at the VU, as well as for the general public in a Dutch museum (Dolhuys, Haarlem), where they also generated a video clip about their scientific motivation and goals (https://www.youtube.com/watch?v=ZAQbjPVg7qk) and spending a day socializing with terminal cancer patients. Some ESRs participated in the national science weekend ‘Weekend van de Wetenschap’.
www.cognitionnet.eu
Cognitive abilities change with development and age. Cognitive development during childhood and adolescence depends on an intellectually challenging environment, but is robustly affected in various forms of mental retardation. Adult cognitive abilities are strongly correlated with a person’s success in life. Finally, cognitive decline is an important problem during aging and is accelerated in neurodegenerative disorders like Alzheimer’s disease. Lifetime cognitive wellbeing is of the utmost importance in a society where life expectancy and individual demand for socio-economic participation are increasing, and where the financial burden on health care needs to be contained. CognitionNet investigated brain mechanisms of cognition at the molecular, cellular, neural network and behavioural level, both from a basic and a clinical perspective and aimed to integrate the results to develop novel treatment options for various forms of cognitive impairment.
With this aim in mind four scientific work packages (WPs) had been constructed, in which 14 official and 1 affiliated early stage researchers (ESRs) have been employed. At the end of the project in September 2017, several contracts have been elongated in order to allow for scientific excellence. Thus far, 15 scientific publications have emerged, and several (approximately 28) are either already under review or in preparation.
Four Early Stage Researchers (ESRs) in Work package 1 (WP1) studied plasticity of cognition during adulthood from the molecular to the behavioural level. One of the two papers that have been published focussed on the architecture of pyramidal neurons in the human cortex. From the papers in preparation, one discovered many synaptic proteins related to associative learning, and this will be followed up in the coming year(s) with intervention studies to show their causal role. Four ESRs in WP2 studied the role of genes with human mutations related to these diseases in the context of synaptic plasticity and cognitive control in adulthood. There was a focus on Rett syndrome, for which mouse models and human induced pluripotent stem cells were used. Data from human post-mortem brain tissue showed specific protein changes that are now being studied in Rett-derived iPSC neurons as well. These neurons seem to have a slower development, likely contributing to the observed disease symptoms of cognitive decline. In addition, critical for heathy development of neurons in the prefrontal cortex is that the main inhibitory receptor evolves from being excitatory to inhibitory. Three ESRs in WP3 worked on novel therapeutic entry points for treatment of age-related cognitive decline. A paper authored by one ESR showed that resting state EEG measurements could be used as possible biomarkers, in this case for insomnia. This could bring diagnostic and prognostic use of these tools one step closer to the clinic in which personalized treatment strategies can be designed. Furthermore, in a paper on a mouse model of Alzheimer’s disease, the authors showed the specific role of the disease-related increase in extracellular matrix in the hippocampus contributing to memory loss. After using enzymes to degrade this matrix, memory impairments were alleviated in these mice. Three ESRs in WP4 reported affected states of the network that lead to maladaptive behavioural output. These ESRs studied emotional memory, drug addiction, attention and depression, for which they formed the molecular and cellular basis of subsequent functional network analysis. Using optogenetic intervention of subregions of the prefrontal cortex, the authors showed involvement of these regions in attention. Furthermore, specifically the ventral part of the medial prefrontal cortex is important for the exact timing of attention in the second-range.
Taken together, three years of basic and clinical research in the healthy and diseased brain has provided new insight into basal (developmental) mechanisms of cognitive processing, and these insights will contribute to the development of novel treatment options for various forms of cognitive impairment in future.
A major component of the CognitionNet MSCA International Training Netwerk was the time invested on training, both in scientific and transferable skills. Trainees were introduced in several basic theories of the different scientific disciplines to understand each other and be able to communicate and cooperate across disciplines. For example, one of our trainees was educated as computer programmer, and now learned how to do electrical recordings from nerve cells, and subsequently used this information to construct computer models of neuronal communication. To train ESRs to actively participate in discussions on several levels, they have publicly presented their research plans at an early stage to each other, to the general public using lay language as well as to a scientific peer public. For their personal development and effectiveness, several transferable skill courses have been followed as amongst others designing, developing and marketing products and services to be able to apply for a job in industry after defending their PhD; planning and executing projects including finance; working as teams with a variety of assignments from designing and printing a prototype 3D project related product, to writing, directing and producing YouTube films for the general public on neuroscientific topics. To be able to fully integrate in the Dutch Society we offered several Dutch language courses.
ESRs also had secondments, one with an industrial partner, and one within academia. In this way, trainees have gained experience in both ‘worlds’, preparing them for a future career in either of them. In addition, specific focus has been on broadening the career prospects of the trainees by providing inter-ITN training and dissemination together with the FP7 MSCA ITN INSENS network.
In the final year, all have prepared a thesis set-up, in which finally 3–4 experimental chapters are bundled together with a scholarly introduction on the topic and aims of the thesis, as well as a general discussion putting their work into the context of the field. In the final CognitionNet meeting, this was presented to the entire network.
Dissemination (scientific & general): Trainees have presented their results (in poster-format or by oral presentation) in both host organized CNCR-based meetings, as well as scientific national (Dutch Neuroscience meeting, mid-term meeting with FP7 MSCA ITN INSENS ESRs, Graduate school Neuroscience meeting), and international meetings (Society for Neuroscience meeting (USA), FENS meeting (Europe), and smaller topically more focused meetings abroad). In addition, trainees have participated in several outreach and dissemination events, e.g. for prospective academic students in high school (last grade students) in Barneveld and at the VU, as well as for the general public in a Dutch museum (Dolhuys, Haarlem), where they also generated a video clip about their scientific motivation and goals (https://www.youtube.com/watch?v=ZAQbjPVg7qk) and spending a day socializing with terminal cancer patients. Some ESRs participated in the national science weekend ‘Weekend van de Wetenschap’.
www.cognitionnet.eu