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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.

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.

[...]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.

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. There are billions of nerve cells or neurons in the human brain, and each one can form thousands of connections, also called synapses, with other neurons. That means there are trillions of synapses in the brain that keep information flowing. Studying the arrangement of individual neurons in the human brain, and the connections between them, is incredibly difficult because of its complexity. Scientists have tools that can image the whole brain and can measure the activity in different regions, but these tools only visualize brain structures that are large enough to be seen with human eyes. Synapses are much smaller (in the range of nanometers), and can only be seen using thin slices of preserved brain tissue through a technique called electron microscopy. The hippocampus is a part of the human brain that is critical for memory, learning and spatial orientation, and is affected in epilepsy and Alzheimer’s disease. Although numerous studies of the hippocampus have been performed in laboratory animals, such as mice, the question remains as to how much of the information gained from these studies applies to humans. Thus, studying the human brain directly is a major goal in neuroscience. However, the scarcity of human brain tissue suitable for the study of synapses is one of the most important issues to overcome. Fortunately, healthy human brain tissue that can be studied using electron microscopy is sometimes donated after death. Using these donations could improve the understanding of the synapses in normal brains and possible changes associated with disease. Now, Montero-Crespo et al. have mapped synapses in the normal human hippocampus in three dimensions – providing the first detailed description of synaptic structure in this part of the brain. Using high-powered electron microscopes and donated brain tissue samples collected after death, Montero-Crespo et al. imaged almost 25,000 connections between neurons. The analysis showed that synapses were more densely packed in some layers of the hippocampus than in others. Most synapses were found to be connected to tiny dendritic ‘spines’ that sprout from dendritic branches of the neuron, and they activated (not suppressed) the next neuron. Beyond its implications for better understanding of brain health and disease, this work could also advance computer modelling attempts to mimic the structure of the brain and its activity.

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.

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 3 ) and the bi-dimensional densities obtained with SDM (puncta/100 µm 2 ). 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.