Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicates that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression, may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aβ and tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aβ production suffer from seizures and epilepsy before the development of plaques. Similarly, pathologic accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aβ on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments.

Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory (STM) were not affected in the rats although focal ischemia was induced 5 h before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and STM were impaired when ischemia was induced 24 h before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in one region because of is...

The recent trend toward an industrialization of brain exploration and the technological prowess of artificial intelligence algorithms and high-performance computing has caught the imagination of the public. These impressive advances are fueling an uncontrolled societal hype, the more amplified, the more “Blue Sky” the claim is. Will we ever be able to simulate a brain in silico ? Will “it” (the digital avatar) be conscious? The Blue Brain Project (BBP) and the European flagship the Human Brain Project (HBP) have surfed on this wave for the past 10 years. Their already significant lifetimes now offer new case studies for neuroscience sociology and epistemology, as the projects mature. Their distinctive “Blue Sky” flavor has been a key feature in securing unprecedented funding (more than one billion Euros) mostly through supranational institutions. The longitudinal analysis of these ventures provides clues to how the neuromyth they propagate sells science, in a scientific world based on an economy of promises.

About one year ago, I learnt of the existence of In Silico . It did not come as a surprise, as I had expected that toward the end of the Human Brain Project (HBP)’s 10-year funding period, there will be a rush of articles and generally increased media interest in covering the project’s progress, achievements, and failures, although In Silico is special, given its 10-year time frame. I joined the HBP in 2014 and lead today one of three science work packages. For this documentary, I expected to hear requests for interviews, but there was literally nothing of that sort. After I have finally watched In Silico , I understand why. The documentary is in fact not about HBP, despite claims to the contrary by a previous review (Abbott, 2020). In Silico director, Noah Hutton, rather focuses on his fascination with Henry Markram’s 10-year vision of building a brain from the bottom up, the Blue Brain Project (BBP). As will be described towards the end, the HBP follows a stringent and much broader concept of integrating...

Feeding and breathing are two functions vital to the survival of all vertebrate species. Throughout the evolution, vertebrates living in different environments have evolved drastically different modes of feeding and breathing through using diversified orofacial and pharyngeal (oropharyngeal) muscles. The oropharyngeal structures are controlled by hindbrain neural circuits. The developing hindbrain shares strikingly conserved organizations and gene expression patterns across vertebrates, thus begs the question of how a highly conserved hindbrain generates circuits subserving diverse feeding/breathing patterns. In this review, we summarize major modes of feeding and breathing and principles underlying their coordination in many vertebrate species. We provide a hypothesis for the existence of a common hindbrain circuit at the phylotypic embryonic stage controlling oropharyngeal movements that is shared across vertebrate species; and reconfiguration and repurposing of this conserved circuit give rise to more c...

The processing of emotional facial expressions is underpinned by the integration of information from a distributed network of brain regions. Despite investigations into how different emotional expressions alter the functional relationships within this network, there remains limited research examining which regions drive these interactions. This study investigated effective connectivity during the processing of sad and fearful facial expressions to better understand how these stimuli differentially modulate emotional face processing circuitry. Ninety-eight healthy human adolescents and young adults, aged between 15 and 25 years, underwent an implicit emotional face processing fMRI task. Using dynamic causal modeling (DCM), we examined five brain regions implicated in face processing. These were restricted to the right hemisphere and included the occipital and fusiform face areas, amygdala, and dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC). Processing sad and fearful facia...

Psychosis disorder is a debilitating disorder characterized by multiple admissions to psychiatric care facilities, higher unemployment rates, and decreased life expectancy. All of which create a high burden on the patient, their family, and the healthcare system. Understanding the basic mechanisms of psychotic disorder is essential for early discovery and facilitating better care for those suffering from it (Correll et al., 2018). The dopamine hypothesis of schizophrenia (Howes et al., 2009) suggests that dysregulation in dopamine signaling is the main cause of psychosis. Consistent with this theory, the ventral-tegmental area (VTA) is a pivoting region in psychosis in both animals and humans (Modinos et al., 2015). Individuals suffering from psychosis have elevated dopaminergic activity in the VTA. Such dysregulations were also found in prodromal syndromes (before full-blown development of psychosis; Howes et al., 2009), suggesting a causal effect of …

Charismatic leaders play fascinating roles in society, for good and for ill. In the United States, we are aware of the power of Martin Luther King and John Lewis in the fight for equal rights, and every country will have its heroes in its struggles for freedom. And, we are equally aware of the impact of despots who have led to terrible miscarriages of justice. We are less accustomed to think of the roles of charismatic leaders in our scientific communities, as we prefer to believe that we all “follow the science” rather than the scientist! Nonetheless, my eyes were opened to the impact of personal charisma in science at the Society for Neuroscience Meeting in 1980. I was chatting with a very fine membrane biophysicist when Eric Kandel walked by and my colleague said, “Kandel is my hero.” I was surprised, as the work my friend did was detailed characterization of membrane currents, far from the grand sweep of Kandel’s work. And when I asked my friend why he revered Kandel, he said that he didn’t dare to dre...

How can we evaluate the positive impact that visionary people can have on science? Should we support funneling large amounts of money to big projects? Both questions arose when I watched Noah Hutton’s film, In Silico .* I invited several prominent scientists to comment on the film’s main topic, modeling the human brain, in a special collection for eNeuro . The film tells the 10-year journey beginning with Henry Markram’s 2009 TED talk (https://www.ted.com/talks/henry\_markram\_a\_brain\_in\_a\_supercomputer), where he announced that the brain could be modeled within 10 years in a supercomputer. The scientific initiative began in 2005 at École Polytechnique Fédérale de Lausanne when Markram founded and directed the first scientific initiative toward his goal: the Blue Brain Project (https://www.epfl.ch/research/domains/bluebrain/). Then, in 2012, the European Union selected the Human Brain Project (https://www.humanbrainproject.eu/en/), also then led by Markram, as one of two flagship programs to be awarde...

Elaboration of neuronal processes is an early step in neuronal development. Guidance cues must work closely with intracellular trafficking pathways to direct expanding axons and dendrites to their target neurons during the formation of neuronal networks. However, how such coordination is achieved remains incompletely understood. Here, we characterize an interaction between fasciculation and elongation protein zeta 1 (FEZ1), an adapter involved in synaptic protein transport, and collapsin response mediator protein (CRMP)1, a protein that functions in growth cone guidance, at neuronal growth cones. We show that similar to CRMP1 loss-of-function mutants, FEZ1 deficiency in rat hippocampal neurons causes growth cone collapse and impairs axonal development. Strikingly, FEZ1-deficient neurons also exhibited a reduction in dendritic complexity stronger than that observed in CRMP1-deficient neurons, suggesting that the former could partake in additional developmental signaling pathways. Supporting this, FEZ1 coloc...