A Century Searching for the Neurons Necessary for Wakefulness

Abstract

Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. In contrast to the influential concept of a diffuse "reticular activating system," the past century of neuroscience research has identified a focal region of the upper brainstem that, when damaged, causes coma. This region contains diverse neuronal populations with different axonal projections, neurotransmitters, and genetic identities. Activating some of these populations promotes wakefulness, but it remains unclear which specific neurons are necessary for sustaining consciousness. In parallel, pharmacological evidence has indicated a role for special neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine. However, genetically targeted experiments have indicated that none of these neurotransmitters or the neurons producing them are individually necessary for maintaining wakefulness. In this review, we emphasize the need to determine the specific subset of brainstem neurons necessary for maintaining arousal. Accomplishing this will enable more precise mapping of wakefulness circuitry, which will be useful in developing therapies for patients with coma and other disorders of arousal.

Keywords: arousal; ascending reticular activating system; brainstem; coma; wakefulness.

FIGURE 1

Comparison of coma-causing and non-coma-causing lesions in the brainstem. (A) Bremer’s cerveau isolé midbrain transections caused coma but encéphale isolé transections between the brainstem and spinal cord did not. (B) Later, rostral pontine transections caused coma, but more caudal transections did not. (C) An iterative search for the coma-causing region identified a small region of the rostral pons. (D) Transections at a different angle identified the importance of the pontine tegmentum. (E) Micro-injection of the anesthetic pentobarbital produced anesthesia at the lowest doses in the pons-midbrain tegmentum. (F) Orexin-saporin lesions of the parabrachial region caused coma. (G) Overlap analysis of patients with coma-causing lesions identified a similar area of the human brainstem. (H) Subsequent comparison of coma-causing versus control lesions identified a more focal region of the human pontine tegmentum. This figure adopted from Devor and Zalkind (2001).

FIGURE 2

Brain regions and neuromodulators discussed in this review. PPT, pedunculopontine tegmental nucleus; LDT, laterodorsal tegmental nucleus.