The ability of an animal to rapidly respond to important environmental changes is fundamentally dependent upon swift changes in neuronal connectivity and excitability. In order to execute appropriate responses, these connectional changes must involve rapid reorganization of network activity, increasing and suppressing activity in different regions, and a host of other physiological changes that are necessary to respond successfully. Though these changes alter the way in which inputs are perceived and handled, their effects must occur across very large regions of the brain in order to facilitate a flexible, adaptive response. Beyond this, behavioral adaptation requires a bridge from immediate events to long term responses. Due to its broad activity and effects on most cell-types of the brain, this review will argue that norepinephrine (NE) plays a major role in optimizing and facilitating these responses.
To begin to understand how this function can arise from a single transmitter system, it is important to consider the anatomy of NE signaling. The exclusive source of NE in the cortex, the locus coeruleus (LC), is a small, pontine nucleus made up of approximately 1,500 noradrenergic neurons in the rat [1
] with broad projections that pervade the cortex. These projections have been shown to primarily consist of non-junctional varicosities that may release NE into the extracellular space, with molecules diffusing to nearby receptors [1
]. This process of volume transmission, conceived by Agnati et al. [3
], permits the activation of receptors over a broad field, promoting coordinated responses from many cells within a given diffusion zone. With more than 1.2 million varicosities per LC neuron [4
], LC activation drives NE release over a broad area of cortex [5
]. As a result, LC signaling can be seen as a global regulator of the brain, although, functionally, there is likely some selectivity in release to permit more specific sculpting of responses in the brain.
This broad release is coupled with two primary modes of NE release; tonic and burst firing of the LC. These modes have been associated with tonic control of wakefulness [6
], as well as novelty and behaviorally driven phasic firing [6
]. While phasic firing can be considered a mechanism of rapid reorientation and control during behaviorally-relevant moments, NE is also able to optimize responses to benign and pathological stimuli by controlling the state of the brain. Through tonic firing, NE exerts effects on sleep, attention, stress, inflammation and many other processes. This activity helps to integrate internal physiological demands with how external environmental inputs are gated. As such, NE has the potential to alter cortical responses both to slow changes in physiological function and critical moments of behaviorally-relevant stimuli.
To accomplish this feat, the noradrenergic system relies upon differential expression of several receptor types in both neurons and glial cells throughout CNS. This complexity extends even within fairly similar cell types, with expression depending on brain layer, neuron firing pattern, and other seemingly minor cellular differences. It is through this complexity that NE is able to simultaneously, and differentially, induce major changes in network connectivity, behavioral outcomes, inflammatory responses, and other system-wide changes.
The effects of NE in the brain are driven largely by changes in the responses of local circuits to inputs, with very little specific targeting of individual cells. As NE varicosities are preferentially associated with perivascular astrocytic endfeet [10
] and microglia express receptors for and respond to NE [13
], NE’s effects are realized through glia as well as neurons. Through this targeting, NE is able to change a myriad of processes, including metabolic activity, glutamate and potassium buffering, inflammatory activity and a host of other functions that alter gating across large populations of cells.
With these functions in mind, and given the astounding breadth of research on the effects of NE in all cell-types in the brain, this review can only begin to approach the question of how NE exerts its effects on the brain. To do so, we will first address some of the known effects of NE on individual cell types, including astrocytes, microglia and neurons. With a basic understanding of how NE can exert its adaptive influences on these cell-types this review will then address the broader question of how NE promotes rapid responses to behaviorally-relevant stimuli on both a cellular and network scale. Finally, we will look at how NE facilitates some of the long-term changes necessary to transform transient events into long-term plastic and homeostatic changes. Throughout this discussion emphasis will be placed on understanding how these processes interact to permit neuroglial networks to optimally respond and adapt.