Recent developments in the quantitative analysis of complex networks, based largely on graph theory, have been rapidly translated to studies of brain network organization. The brain's structural and functional systems have features of complex networks--such as small-world topology, highly connected hubs and modularity--both at the whole-brain scale of human neuroimaging and at a cellular scale in non-human animals. In this article, we review studies investigating complex brain networks in diverse experimental modalities (including structural and functional MRI, diffusion tensor imaging, magnetoencephalography and electroencephalography in humans) and provide an accessible introduction to the basic principles of graph theory. We also highlight some of the technical challenges and key questions to be addressed by future developments in this rapidly moving field.

Complex brain networks: graph theoretical analysis of structural and functional systems

The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.

http://science.sciencemag.org/content/sci/308/5726/1314.full.pdf

Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

/pdf/neuroinflammation-in-alzheimer-s-disease-36czdowiut.pdf

Neuroinflammation in Alzheimer's disease

With few exceptions biological tissues strongly scatter light, making high-resolution deep imaging impossible for traditional⎯including confocal⎯fluorescence microscopy. Nonlinear optical microscopy, in particular two photon–excited fluorescence microscopy, has overcome this limitation, providing large depth penetration mainly because even multiply scattered signal photons can be assigned to their origin as the result of localized nonlinear signal generation. Two-photon microscopy thus allows cellular imaging several hundred microns deep in various organs of living animals. Here we review fundamental concepts of nonlinear microscopy and discuss conditions relevant for achieving large imaging depths in intact tissue.

/pdf/deep-tissue-two-photon-microscopy-2aqu6d6n65.pdf

Deep tissue two-photon microscopy

Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.

/pdf/atp-mediates-rapid-microglial-response-to-local-brain-injury-4capw6j3mj.pdf

ATP mediates rapid microglial response to local brain injury in vivo

Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor

Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.

http://www2.neuroscience.umn.edu/eanwebsite/pdf gjclub/nat neurosci 9 1512 2006.pdf

The P2Y12 receptor regulates microglial activation by extracellular nucleotides

The structural dynamics of synapses probably has a crucial role in the development and plasticity of the nervous system. In the mammalian brain, the vast majority of excitatory axo-dendritic synapses occur on dendritic specializations called 'spines'. However, little is known about their long-term changes in the intact developing or adult animal. To address this question we developed a transcranial two-photon imaging technique to follow identified spines of layer-5 pyramidal neurons in the primary visual cortex of living transgenic mice expressing yellow fluorescent protein. Here we show that filopodia-like dendritic protrusions, extending and retracting over hours, are abundant in young animals but virtually absent from the adult. In young mice, within the 'critical period' for visual cortex development, approximately 73% of spines remain stable over a one-month interval; most changes are associated with spine elimination. In contrast, in adult mice, the overwhelming majority of spines (approximately 96%) remain stable over the same interval with a half-life greater than 13 months. These results indicate that spines, initially plastic during development, become remarkably stable in the adult, providing a potential structural basis for long-term information storage.

Long-term dendritic spine stability in the adult cortex

Connections between neurons are thought to be remodelled when we learn new tasks or acquire new information. However, this plasticity must also occur against a backdrop of stable memory maintenance. In mice, a paradigm of either enhanced sensory experience or specific motor learning produced new putative neuronal connections that remained stable alongside developmentally preserved connections much later in life. This suggests that learning can produce changes in the neuronal connectivity that can be stable for the lifetime of the network. Connections between neurons are thought to be remodelled when we learn new tasks or acquire new information; however, it is unclear how neural circuits undergo continuous synaptic changes during learning while maintaining lifelong memories. Here, by following post-synaptic dendritic spines in the mouse cortex, it is shown that a small fraction of new spines induced by novel experience are preserved and provide a structural basis for lifelong memory retention. Changes in synaptic connections are considered essential for learning and memory formation1,2,3,4,5,6. However, it is unknown how neural circuits undergo continuous synaptic changes during learning while maintaining lifelong memories. Here we show, by following postsynaptic dendritic spines over time in the mouse cortex7,8, that learning and novel sensory experience lead to spine formation and elimination by a protracted process. The extent of spine remodelling correlates with behavioural improvement after learning, suggesting a crucial role of synaptic structural plasticity in memory formation. Importantly, a small fraction of new spines induced by novel experience, together with most spines formed early during development and surviving experience-dependent elimination, are preserved and provide a structural basis for memory retention throughout the entire life of an animal. These studies indicate that learning and daily sensory experience leave minute but permanent marks on cortical connections and suggest that lifelong memories are stored in largely stably connected synaptic networks.

/pdf/stably-maintained-dendritic-spines-are-associated-with-pi4ox5o3hw.pdf

Wen-Biao Gan

Papers

ATP mediates rapid microglial response to local brain injury in vivo

Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor

The P2Y12 receptor regulates microglial activation by extracellular nucleotides

Long-term dendritic spine stability in the adult cortex

Stably maintained dendritic spines are associated with lifelong memories