Contextual guidance: An integrated theory for astrocytes function in brain circuits and behavior

The participation of astrocytes in brain computation was formally hypothesized in 1992, coinciding with the discovery that these glial cells display a complex form of Ca2+ excitability. This fostered conceptual advances centered on the notion of reciprocal interactions between neurons and astrocytes, which permitted a critical leap forward in uncovering many roles of astrocytes in brain circuits, and signaled the rise of a major new force in neuroscience: that of glial biology. In the past decade, a multitude of unconventional and disparate functions of astrocytes have been documented that are not predicted by these canonical models and that are challenging to piece together into a holistic and parsimonious picture. This highlights a disconnect between the rapidly evolving field of astrocyte biology and the conceptual frameworks guiding it, and emphasizes the need for a careful reconsideration of how we theorize the functional position of astrocytes in brain circuitry. Here, we propose a unifying, highly transferable, data-driven, and computationally-relevant conceptual framework for astrocyte biology, which we coin contextual guidance. It describes astrocytes as contextual gates that decode multiple environmental factors to shape neural circuitry in an adaptive, state-dependent fashion. This paradigm is organically inclusive of all fundamental features of astrocytes, many of which have remained unaccounted for in previous theories. We find that this new concept provides an intuitive and powerful theoretical space to improve our understanding of brain function and computational models thereof across scales because it depicts astrocytes as a hub for circumstantial inputs into relevant specialized circuits that permits adaptive behaviors at the network and organism level.