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Tag: Netherlands Institute for Neuroscience

  • How do we know if our brain is capable of repairing itself?

    How do we know if our brain is capable of repairing itself?

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    Newswise — Is our brain able to regenerate? And can we harness this regenerative potential during aging or in neurodegenerative conditions? These questions sparked intense controversy within the field of neuroscience for many years. A new study from the Netherlands Institute for Neuroscience shows why there are conflicting results and proposes a roadmap on how to solve these issues.

    The notion of exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing or restoring brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders like Alzheimer’s disease. The question of whether the human brain does possess the ability to regenerate or not has been at the center of a fierce scientific debate for many years and recent studies yielded conflicting results. A new study from Giorgia Tosoni and Dilara Ayyildiz, under the supervision of Evgenia Salta in the laboratory of Neurogenesis and Neurodegeneration, critically discusses and re-analyzes previously published datasets. How is it possible that we haven’t yet found a clear answer to this mystery?

    Previous studies in which dividing cells were labeled in postmortem human brain, showed that new cells can indeed arise throughout adulthood in the hippocampus of our brain, a structure that plays an important role in learning and memory, and is also severely affected in Alzheimer’s disease. However, other studies contradict these results and cannot detect the generation of new brain cells in this area. Both conceptual and methodological confounders have likely contributed to these seemingly opposing observations. Hence, elucidating the extent of regeneration in the human brain remains a challenge.

    New state-of-the-art technologies

    Recent advances in single-cell transcriptomics technologies have provided valuable insights into the different cell types found in human brains from deceased donors with different brain diseases. To date, single-cell transcriptomic technologies have been used to characterize rare cell populations in the human brain. In addition to identifying specific cell types, single-nucleus RNA sequencing can also explore specific gene expression profiles to unravel full the complexity of the cells in the hippocampus.

    The advent of single-cell transcriptomics technologies was initially viewed as a panacea to resolving the controversy in the field. However, recent single-cell RNA sequencing studies in human hippocampus yielded conflicting results. Two studies indeed identified neural stem cells, while a third study failed to detect any neurogenic populations. Are these novel approaches – once again – failing to finally settle the controversy regarding the existence of hippocampal regeneration in humans? Will we eventually be able to overcome the conceptual and technical challenges and reconcile these -seemingly- opposing views and findings?

    Technical issues

    In this study, the researchers critically discussed and re-analyzed previously published single-cell transcriptomics datasets. They caution that the design, analysis and interpretation of these studies in the adult human hippocampus can be confounded by specific issues, which ask for conceptual, methodological and computational adjustments. By re-analyzing previously published datasets, a series of specific challenges were probed that require particular attention and would greatly profit from an open discussion in the field.

    Giorgia Tosoni: ‘We analyzed previously published single-cell transcriptomic studies and performed a meta-analysis to assess whether adult neurogenic populations can reliably be identified across different species, especially when comparing mice and humans. The neurogenic process in adult mice is very well characterized and the profiles of the different cellular populations involved are known. These are actually the same molecular and cellular signatures that have been widely used in the field to also identify neurogenic cells in the human brain. However, due to several evolutionary adaptations, we would expect the neurogenesis between mice and humans to be different. We checked the markers for every neurogenic cell type and looked at the amount of marker overlap between the two species.’

    ‘We found very little, if no, overlap between the two, which suggests that the mouse-inferred markers we have been long using may not be suitable for the human brain. We also discovered that such studies require enough statistical power: if regeneration of neuronal cells does happen in the adult human brain, we expect it to be quite rare. Therefore, enough cells would need to be sequenced in order to identify those scarce, presumably neurogenic populations. Other parameters are also important, for example the quality of the samples. The interval between the death of the donor and the downstream processing is critical, since the quality of the tissue and of the resulting data drops over time.’

    Reproducibility is key

    Dilara Ayyildiz: ‘These novel technologies, when appropriately applied, offer a unique opportunity to map hippocampal regeneration in the human brain and explore which cell types and states may be possibly most amenable to therapeutic interventions in aging, neurodegenerative and neuropsychiatric diseases. However, reproducibility and consistency are key. While doing the analysis we realized that some seemingly small, but otherwise very critical details and parameters in the experimental and computational pipeline, can have a big impact on the results, and hence affect the interpretation of the data.’

    ‘Accurate reporting is essential for making these single-cell transcriptomics experiments and their analysis reproducible. Once we re-analyzed these previous studies applying common computational pipelines and criteria, we realized that the apparent controversy in the field may in reality be misleading: with our work we propose that there may actually be more that we agree on than previously believed.’

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  • What happens to our dopamine system when we experience aversive events?

    What happens to our dopamine system when we experience aversive events?

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    Newswise — A new study at the Netherlands Institute for Neuroscience has examined how the dopamine system processes aversive unpleasant events.

    It is well known that the dopamine system plays a crucial role in motivation, learning and movement. One of the main functions of dopamine is to predict the occurrence of rewarding experiences and the availability of rewards in our environment. In this context, the dopamine system informs our brains about so-called ‘reward prediction errors’ – the difference between received and predicted rewards. Dopamine neurons become more active when a reward occurs unexpectedly or if it is bigger than expected, and they show depressed activity when we receive less reward than predicted. These error signals help us to learn from our mistakes and teach us how to achieve rewarding experiences.

    Rewarding versus aversive stimuli

    While a large number of studies has focused on the relationship between dopamine release and rewarding stimuli, few have looked at the effect of unpleasant and aversive stimuli on dopamine. Although the results of these few experiments have been inconsistent, it has become clear that aversive stimuli have an impact on the dopamine system. But there is an active debate among neuroscientists on what precise role dopamine neurons play in processing aversive stimuli: Does their activity change in response to aversive events? Do they predict aversive events? Do they encode an aversive prediction error?

    New findings on the role of dopamine in aversive events

    A new study at the Netherlands Institute for Neuroscience has examined how the dopamine system processes aversive events. The team around PhD student Jessica Goedhoop and group leader Ingo Willuhn exposed rats to white noise in combination with stimuli that predicted the white noise, while they measured the release of dopamine in the brain. White noise is a well-known example of an unpleasant auditory stimulus for rats.

    The researchers found that the release of dopamine gradually decreased during the exposure to white noise. Furthermore, after consistent presentation, stimuli that occurred a few seconds before white-noise exposure began to have the same depressing effect on dopamine neurons. However, in contrast to how it processes rewards, dopamine did not encode a prediction error for this aversive stimulus. Overall, this new study demonstrates that the dopamine system helps the brain to anticipate the occurrence and duration of unpleasant events, but without taking prediction errors into account.

    Group leader Ingo Willuhn: ‘This is a very thorough and systematic study that takes a lot of variables into account. The results give us a better understanding of the role of dopamine release in processing aversive events. There is a growing interest into the role of dopamine in aversion. We used a novel aversive stimulus that enabled to conduct a more thorough analysis of dopamine than previously possible.’

    Addictive drugs hijack and amplify dopamine signals and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. This study brings us closer to understanding the underlying mechanism behind this pathological phenomenon.

    Source: eLife

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  • What is the effect of hierarchy on moral behavior?

    What is the effect of hierarchy on moral behavior?

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    Newswise — Researchers from the Netherlands Institute for Neuroscience show that powerful hierarchical situations make it easier to commit harmful actions, as agency and empathy are split across multiple individuals.

    There are numerous historical examples where horrific acts and mass destruction have occurred as a result of a hierarchical structure. A superior communicates a plan and a subordinate carries it out. The superior then bears responsibility for the decision but is distanced from the results, while the subordinate experiences authorship over the action but may experience reduced responsibility for its outcomes.  And in our daily lives too, hierarchy is acquired throughout our society. In many organizations, orders are embedded in an even longer chain of commands in which a given commander often merely relays on the orders received from a superior. But what effect does this have on our actions?

    A new study from the social brain lab looked at how your position within a hierarchical structure (commander or intermediary) influences the sense of agency and empathy for pain. The aim was to understand how these two different neurocognitive processes differ in commanders and intermediaries. And guess what? Commanders and intermediaries show reduced activation in empathic brain regions when pain is inflicted on the victim compared to people who can decide and act for themselves. The results were published in the journal eNeuro.

    The team used functional MRI (fMRI) and electroencephalogram (EEG) techniques in order to perform their experiments. fMRI measures brain activity by tracking changes in blood flow over time. The changes visible on the scan are related to change in oxygen levels: when areas of the brain are active, they will need more oxygen, causing them to ‘light up’. Using EEG, brain activity is measured electrically. During this test, small sensors are attached to the scalp to pick up the electrical signals produced by the brain.

    Reduced empathy

    The fMRI study shows that activity in empathy-related brain regions was low in both the commander and the intermediary, compared to someone who delivered the shock directly of their own free will. During the both studies, pain was administered by a human or robot. The EEG results show that the sense of agency did not differ between commanders and intermediaries, regardless of whether the execution was performed by a robot or a human. However, it turned out that the neural response to the pain of the victim were higher when participants commanded a robot compared to a human. This suggests that when there is a second human involved, the responsibility tends to be diffused and commanders’ pain processing of the victim’s pain is reduced. Diffusing such responsibility onto a robot is perhaps more difficult.

    Emilie Caspar (first co-author of the paper): “The law generally punished those who gave out orders more severely than those who carried out the orders. But what do people feel exactly in a hierarchical chain? Recently, Khieu Samphan, one of the main Khmer Rouge leaders, was sentenced to life imprisonment for crimes against humanity and genocide. Yet, he claimed that he did not know what was happening during the Khmer Rouge Era, where millions of Cambodians died of execution, starvation, and diseases. It seems that people commanding may not always experience the responsibility they should, an aspect which would nonetheless be crucial to avoid mass atrocities. This is why it is important to understand better their subjective experience and how their brain processes the consequences of their orders, to perhaps in the future offer interventions that would prevent a diminution of responsibility in hierarchical chain”

    Kalliopi Ioumpa (first co-author of the paper): ‘These results complement previous research showing that hierarchy has a measurable effect on people’s behaviour and brain activation, making them less engaged in the harm they cause. This study can raise questions on how we can ensure that people feel responsibility despite being in a hierarchical chain. Is it easier for executors to take responsibility over their actions since they are the ones acting – or for commanders because they bear the responsibility of the order? We show how powerful hierarchical situations can facilitate committing actions that harm others, as agency and empathy are distributed across multiple individuals.’

    Prof Dr Christian Keysers (One of the senior author of the study heading the lab in which it was performed): ‘Times are changing. The solder at the forefront, whose empathy sometimes prevented the worst atrocities, is increasingly replaced by drones that feel no empathy. Has this removed any empathy from the chain of command? Indeed, we find that merely commanding someone to deliver pain reduces how much your brain processes the pain you command compared to directly triggering the pain. What was really exciting to see, however, is that knowing that you command a machine, that you cannot defer the responsibility to, restores some of the reactions to the pain in commanders. Perhaps there is hope, after all, that the empathy we reduce at the forefront might be replaced – at least in part – by an increase is the sense of responsibility at higher levels in the hierarchy…”

     

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