A major challenge in neuroscience is to decipher the structural layout of the brain. The term "connectome" has recently been proposed to refer to the highly organized connection matrix of the human ...brain. However, defining how information flows through such a complex system represents so difficult a task that it seems unlikely it could be achieved in the near future or, for the most pessimistic, perhaps ever. Circuit diagrams of the nervous system can be considered at different levels, although they are surely impossible to complete at the synaptic level. Nevertheless, advances in our capacity to marry macro- and microscopic data may help establish a realistic statistical model that could describe connectivity at the ultrastructural level, the "synaptome," giving us cause for optimism.
In other words, the reliability of the data varies. ...we need to have a deep understanding of the techniques and experimental design used to obtain the data. Since in general the research focus, ...expertise and methodological approaches differ greatly between laboratories, the efficacy of this collaboration will depend not only on the understanding of how data is collected and on how robust it is, but also on substantial communication between all the research teams. In this way, ambitious objectives addressing a well-defined scientific question can be achieved. ...it is imperative to promote interdisciplinary collaboration and data sharing, at both national and international levels, to make better use of the expertise and resources of individual laboratories.
...at the electron microscopy level, our mission is to quantitatively analyze key ultrastructural characteristics of axonal and dendritic processes (e.g., density and type of synaptic vesicles, ...density of mitochondria); synaptic connectivity (e.g., types of synapses, identification of synaptic targets); the relationship between glial processes and synapses, etc. ...we will have a solid foundation for answering with more certainty the fundamental question in neuroscience of how neuronal circuits contribute to the functional organization of the brain, giving rise to cognition and behavior. Conflict of interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The tremendous expansion and the differentiation of the neocortex constitute two major events in the evolution of the mammalian brain. The increase in size and complexity of our brains opened the way ...to a spectacular development of cognitive and mental skills. This expansion during evolution facilitated the addition of microcircuits with a similar basic structure, which increased the complexity of the human brain and contributed to its uniqueness. However, fundamental differences even exist between distinct mammalian species. Here, we shall discuss the issue of our humanity from a neurobiological and historical perspective.
•The E/I balance is a fundamental mechanism for maintaining effective neuronal communication and support cognitive performance.•AD research has been approached by different levels of analysis with no ...integration between them. Results need harmonization in a common framework.•E/I imbalance is the endpoint of all AD-related micro-level synaptic pathology, and the starting point of the network disruption and cognitive impairment.•Computational neurophysiological models can integrate data from different levels, creating a framework to test hypotheses and propose new strategies of intervention.
Our incomplete understanding of the link between Alzheimer’s Disease pathology and symptomatology is a crucial obstacle for therapeutic success. Recently, translational studies have begun to connect the dots between protein alterations and deposition, brain network dysfunction and cognitive deficits. Disturbance of neuronal activity, and in particular an imbalance in underlying excitation/inhibition (E/I), appears early in AD, and can be regarded as forming a central link between structural brain pathology and cognitive dysfunction. While there are emerging (non-)pharmacological options to influence this imbalance, the complexity of human brain dynamics has hindered identification of an optimal approach. We suggest that focusing on the integration of neurophysiological aspects of AD at the micro-, meso- and macroscale, with the support of computational network modeling, can unite fundamental and clinical knowledge, provide a general framework, and suggest rational therapeutic targets.
The axon initial segment (AIS) is a region of the neuron that is critical for action potential generation as well as for the regulation of neural activity. This specialized structure-characterized by ...the expression of different types of ion channels as well as adhesion, scaffolding and cytoskeleton proteins-is subjected to morpho-functional plastic changes in length and position upon variations in neural activity or in pathological conditions. In the present study, using immunocytochemistry with the AT8 antibody (phospho-tau S202/T205) and 3D confocal microscopy reconstruction techniques in brain tissue from Alzheimer's disease patients, we found that around half of the cortical pyramidal neurons with hyperphosphorylated tau showed changes in AIS length and position in comparison with AT8-negative neurons from the same cortical layers. We observed a wide variety of AIS alterations in neurons with hyperphosphorylated tau, although the most common changes were a proximal shift or a lengthening of the AISs. Similar results were found in neocortical tissue from non-demented cases with neurons containing hyperphosphorylated tau. These findings support the notion that the accumulation of phospho-tau is associated with structural alterations of the AIS that are likely to have an impact on normal neuronal activity, which might contribute to neuronal dysfunction in AD.
Knowledge about empathy is part of the study of artistic expressions, among which stand out works of personalities such as the Renaissance polymath Leonardo da Vinci, who was concerned with the ...connection between science and art during his creative research full of imagination and sensitivity to nature and human anatomy. The word empathy emerged among critics of German art as the term
, which was used within the aesthetic bias by philosophers and art historians. It emphasized the idea that a viewer perceiving an object could establish a link between it and themselves, projecting the object 'into themselves'. That is, the artwork could be experienced by the observer as if the viewer belonged predominantly to the object, in such a way that its characteristics could be actually felt through the expression of emotions, feelings and thoughts. This analysis of art appreciation required a great deal of knowledge and contemplation of nature, as understood by the German Romanticists, who had enormous admiration for da Vinci and his universal and systematic mind-a mind which reacted against formalisms, building his intellectual and sensory systems based on both his observation of nature and his own criteria. In particular, the art of painting for Leonardo was a way to demonstrate a mental discourse, just as the most important aspect of human portraits is to represent-in gestures and facial expressions-the states of mind and emotions. These are facts that German Romanticists tried to explain as the relationship between empathy and a work of art. The present manuscript aims to describe empathy from an artistic view, considering the roots of this word in German Romanticism; to comment about Leonardo da Vinci and the expression of art in the Renaissance; and, finally, to discuss the expression of his art in relation to empathy.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks ...of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization.
The hippocampal CA1 field integrates a wide variety of subcortical and cortical inputs, but its synaptic organization in humans is still unknown due to the difficulties involved studying the human ...brain via electron microscope techniques. However, we have shown that the 3D reconstruction method using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) can be applied to study in detail the synaptic organization of the human brain obtained from autopsies, yielding excellent results. Using this technology, 24,752 synapses were fully reconstructed in CA1, revealing that most of them were excitatory, targeting dendritic spines and displaying a macular shape, regardless of the layer examined. However, remarkable differences were observed between layers. These data constitute the first extensive description of the synaptic organization of the neuropil of the human CA1 region.
Determining the number of synapses that are present in different brain regions is crucial to understand brain connectivity as a whole. Membrane-associated guanylate kinases (MAGUKs) are a family of ...scaffolding proteins that are expressed in excitatory glutamatergic synapses. We used genetic labeling of two of these proteins (PSD95 and SAP102), and Spinning Disc confocal Microscopy (SDM), to estimate the number of fluorescent puncta in the CA1 area of the hippocampus. We also used FIB-SEM, a three-dimensional electron microscopy technique, to calculate the actual numbers of synapses in the same area. We then estimated the ratio between the three-dimensional densities obtained with FIB-SEM (synapses/µm
) and the bi-dimensional densities obtained with SDM (puncta/100 µm
). Given that it is impractical to use FIB-SEM brain-wide, we used previously available SDM data from other brain regions and we applied this ratio as a conversion factor to estimate the minimum density of synapses in those regions. We found the highest densities of synapses in the isocortex, olfactory areas, hippocampal formation and cortical subplate. Low densities were found in the pallidum, hypothalamus, brainstem and cerebellum. Finally, the striatum and thalamus showed a wide range of synapse densities.
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