Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment. We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex/parieto-occipital sulcus and anterior hippocampus did not change systematically as a function learning in older compared to younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects ...

Secondary damage after spinal cord injury (SCI) occurs because of a sequence of events after the initial injury, including exacerbated inflammation that contributes to increased lesion size and poor locomotor recovery. Thus, mitigating secondary damage is critical to preserve neural tissue and improve neurologic outcome. In this work, we examined the therapeutic potential of a novel antisense oligonucleotide (ASO) with special chemical modifications [2′-deoxy-2-fluoro-D-arabinonucleic acid (FANA) ASO] for specifically inhibiting an inflammatory molecule in the injured spinal cord. The chemokine CCL3 plays a complex role in the activation and attraction of immune cells and is upregulated in the injured tissue after SCI. We used specific FANA ASO to inhibit CCL3 in a contusive mouse model of murine SCI. Our results show that self-delivering FANA ASO molecules targeting the chemokine CCL3 penetrate the spinal cord lesion site and suppress the expression of CCL3 transcripts. Furthermore, they reduce other proi...

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.

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...

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...

The striatum plays a key role in both reward-related and affective behaviors and disruptions to this circuit contributes to depression and drug addiction. However, our understanding of the molecular factors that facilitate and modify these processes are incomplete. Striatal function is modulated by G-protein-coupled receptors (GPCRs) that process vast neuromodulatory inputs. GPCR signaling is negatively regulated by regulator of G-protein signaling (Rgs) proteins. In this study, we examine the role of striatal Rgs proteins in depressive-like and reward-related behaviors in male mice. Using a genetic mouse model with specific elimination of Rgs7 in striatal neurons we found that these mice exhibit an anxiolytic-like and antidepressant-like phenotype. In contrast, knock-out of Rgs9, an abundant Rgs protein in the same neuronal population did not affect the behavioral outcome in the depressive-like tests. Mice lacking striatal Rgs7 did not show significant differences in cocaine-induced psychomotor activation...

Developmental epileptic encephalopathies (DEEs) are severe seizure disorders that occur in infants and young children, characterized by developmental delay, cognitive decline, and early mortality. Recent efforts have identified a wide variety of genetic variants that cause DEEs. Among these, variants in the DNM1 gene have emerged as definitive causes of DEEs, including infantile spasms and Lennox–Gastaut syndrome. A mouse model of Dnm1 -associated DEE, known as “Fitful” ( Dnm1Ftfl ), recapitulates key features of the disease, including spontaneous seizures, early lethality, and neuronal degeneration. Previous work showed that DNM1 is a key regulator of synaptic vesicle (SV) endocytosis and synaptic transmission and suggested that inhibitory neurotransmission may be more reliant on DNM1 function than excitatory transmission. The Dnm1Ftfl variant is thought to encode a dominant negative DNM1 protein; however, the effects of the Dnm1Ftfl variant on synaptic transmission are largely unknown. To understand thes...

Neurite orientation dispersion and density imaging (NODDI) is an emerging magnetic resonance (MR) diffusion-weighted imaging (DWI) technique that permits non-invasive quantitative assessment of neurite density and morphology. NODDI has improved our ability to image neuronal microstructure over conventional techniques such as diffusion tensor imaging (DTI) and is particularly suited for studies of the developing brain as it can measure and characterize the dynamic changes occurring in dendrite cytoarchitecture that are critical to early brain development. Neurodevelopmental alterations to the diffusion tensor have been reported in psychiatric illness, but it remains unknown whether advanced DWI techniques such as NODDI are able to sensitively and specifically detect neurodevelopmental changes in brain microstructure beyond those provided by DTI. We show, in an extension of our previous work with a Disc1 svΔ2 rat genetic model of psychiatric illness, the enhanced sensitivity and specificity of NODDI to ident...

Voluntary movements are usually preceded by a slow, negative-going brain signal over motor areas, the so-called readiness potential (RP). To date, the exact nature and causal role of the RP in movement preparation have remained heavily debated. Although the RP is influenced by several motorical and cognitive factors, it has remained unclear whether people can learn to exert mental control over their RP, for example, by deliberately suppressing it. If people were able to initiate spontaneous movements without eliciting an RP, this would challenge the idea that the RP is a necessary stage of the causal chain leading up to a voluntary movement. We tested the ability of participants to control the magnitude of their RP in a neurofeedback experiment. Participants performed self-initiated movements, and after every movement, they were provided with immediate feedback about the magnitude of their RP. They were asked to find a strategy to perform voluntary movements such that the RPs were as small as possible. We ...