The cortex consists of two major cell types: neurons and glia. Most research in cortical function has focused primarily on the role of neurons in signal processing. Glial cells, including astrocytes, have been considered as secondary actors in brain function, providing physical and metabolic support to neurons. In primary visual cortex (V1), precise neuronal responses and representations are considered to anchor visual processing. However, astrocytes contact synapses as well as blood vessels, and recent evidence suggests that astrocytes receive synaptic inputs and influence neuronal as well as vascular responses. The accumulated results of the past decade have led to the ?tripartite synapse? concept, in which excitatory synapses in cortex are composed of a presynaptic, a postsynaptic, and an astrocytic element. An over-arching and novel theme of this proposal is that astrocytes partner with neurons in synaptic transmission and plasticity. Any complete framework for understanding and modeling the network basis of cortical responses must account for both astrocytic and neuronal contributions. The goal of this proposal is to combine experimental and computational modeling approaches to understand the role astrocytes play in the generation, development and plasticity of neuronal responses in visual cortex.
Many aspects of astrocyte biology and physiology have been described in vitro, but little is known about the role of astrocytes in the context of intact functional circuits. This project will utilize novel experimental approaches, including specific cellular markers, optical probes of cellular function, and genetically engineered mice with optical reporters, that provide new ways to examine the cooperative roles of neurons and astrocytes in visual cortex responses and representations. The US laboratory of Mriganka Sur has pioneered the use of these approaches, in combination with in vivo two-photon calcium imaging of cells, optical imaging of intrinsic signals, and electrophysiological recording, to study the influence of astrocytes on visual processing. The modeling portion of this project will develop the first network models of visual cortex to include astrocyte influences on synaptic transmission, in addition to neuronal excitation and inhibition. The German laboratory of Klaus Obermayer has made seminal contributions to a computational understanding of how visual cortex networks generate, develop and alter emergent responses. Previous joint efforts of the Sur and Obermayer groups have been influential in revealing operating regimes of visual cortex networks, the influence of map structure on cortical network function, and the dynamics of feature-selective responses. In each instance, computational models influenced experiments, and vice versa.
This project is jointly funded by Collaborative Research in Computational Neuroscience and the Office of International Science and Engineering. A companion project is being funded by the German Ministry of Education and Research (BMBF).
The cortex consists of two major cell types: neurons and glia. Until recently, most research in cortical function focused on processing performed by neurons. In primary visual cortex (V1) for example, precise neuronal responses and representations are considered to anchor visual processing. Glial cells (of which astrocytes are a majority, constituting half of all cortical cells) had been thought to play only a secondary role in brain function, providing physical and metabolic support to neurons, and had until efforts undertaken in this project and others in recent years, been excluded from consideration in functional models of cortical connectivity, processing, and development. The goal of this project was to combine experimental and computational modeling approaches to understand the role of astrocytes in the generation, development and plasticity of neuronal responses in visual cortex. In the first phase of the project, the Sur Laboratory used ferrets and transgenic mice to explore the role of astrocytic glutamate transporters in modulating excitatory transmission within circuits in primary visual cortex. The Obermayer group used data collected in these experiments to build models of visual cortical circuits. Collaborative efforts in this phase included visits to Berlin by members of the Sur group and to Cambridge by members of the Obermayer group. With data from the mouse experiments, the Obermayer group developed a recurrent network model of rodent primary visual cortex to examine the roles of excitatory and inhibitory neuron types and astrocytes in synaptic and network aspects of orientation selectivity. Exploring another role of astrocytes, the Sur Lab looked at a signaling pathway originating in the nucleus basalis, whereby cholinergic inputs from nucleus basalis induce plasticity at visual cortex synapses through an astrocyte-mediated mechanism. These observations, together with imaging data of calcium signaling in visual cortex astrocytes of awake mice, and findings implicating astrocytes in synaptic potentiation, contributed to a further refinement of the Obermayer Lab’s computational model. Experiments under this project have revealed several novel properties of and roles for astrocytes. Their incorporation into models of cortical function and development has helped us refine our hypotheses about what this class of cell might be doing in cortex to affect plastic changes at the synaptic and network level. This quiet cell type, which does not spike as neurons do, and which exhibits transient changes in calcium signals at various time scales, nonetheless occupies several key niches in the establishment and maintenance of cortical network processing. In this project, we have developed methods for examining and modeling the actions of astrocytes in the context of the individual synapse, the excitatory-inhibitory cortical circuit, and the visual cortical network. Our findings suggest that astrocytes are active components in the development of functional maps in visual cortex; that they integrate and communicate inputs from deep brain into primary sensory cortex; and that their function depends on subtle and complex interactions between their neurotransmitter receptors and transporters, ion channels, and internal buffering mechanisms to produce long-lasting modulatory influence over synaptic domains. The models developed in this project test and constrain our hypotheses about astrocytic contributions to cortical signaling, while providing rich demonstrations of some astrocyte-enabled functional dynamics. The ratio of astrocytes to neurons increases with brain size and with phylogenetic order. The robustness of this relationship indicates a strong role for astrocytes in making possible the complex perceptions, sensory integration, and capacity to learn exhibited at the very heights of this progression. Astrocytes contribute to sensory and other areas of cortex in ways we are just beginning to understand. With this project we have begun to incorporate observation of their function into a central role in cortical circuits and processing.
