In order to understand how the CNS encodes, modifies, stores and retrieves information it is necessary to explore the diverse cell populations that comprise the CNS. There is an emerging consensus that the CNS cannot be satisfactorily understood solely as a collection of circuits1. One significant missing aspect in our collective strategy to comprehensively understand the CNS is the largely unmet need to understand additional cell types such as astrocytes1. Astrocytes represent around 40% of all CNS cells and are found throughout the brain. Their close proximity to neurons has been known for over a century. It is now well established that astrocytes serve vital support roles including buffering of K+ around neurons, clearing neurotransmitters from synapses as well as providing nutrients. Astrocytes may also regulate blood flow to meet demands set by neuronal activity. In addition to these varied supportive roles, increasing evidence suggests that astrocytes regulate neuronal function via synapse formation, synapse removal, and regulation of synaptic function through uptake and release of neuromodulators and neurotransmitters. In addition, astrocytes are proposed to engage in bidirectional communication with neurons in a Ca2+-dependent manner, which in some circumstances involves bidirectional ATP signaling. However, despite progress, experimental studies of astrocytes have lagged behind those of neurons by decades, largely because twentieth century neuroscience was dominated by the emergent field of electrophysiology that provided a precise and valuable way to study electrical activity in neurons and its relationship to neural circuit function and behavior. In contrast, astrocytes do not fire action potentials or display any other type of propagated electrical signals, and thus electrophysiology was ill suited to study these cells. As a result, our understanding of astrocytes, their identity, diversity and dynamics is still in its infancy. We seek to capitalize on recent breakthroughs in our laboratories to advance tools that will allow neuroscientists to study in detail the molecular make-up of astrocytes in different brain areas at multiple levels from gene expression, to proteins (Aim 1), to physiology within neural circuit functions in vivo (Aim 2). We will also provide tools to target astrocytes in a selective and non-invasive manner by gene delivery across the blood-brain-barrier (Aim 3). Our overarching hypothesis is that the availability and open dissemination of new, selective tools to study astrocytes at molecular, cellular and circuit levels of investigation may reveal insights about the CNS as striking and as influential as those revealed by early measurements of electrical signals in neurons. Furthermore, the free dissemination of such tools will catalyze additional advances in the context of physiology and brain disease.
statement We will generate and share new tools to study the molecular, cellular and circuit-level properties and functions of astrocytes in the adult brain. The availability of new tools will transform our ability to study astrocytes in the healthy CNS and in multiple types of CNS diseases.