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Neuroanatomy of Wakefulness

There are several key areas involved in promoting wakefulness:

• Ascending Reticular Activating System

• Brainstem reticular formation

– Located in the medulla, pons & midbrain

• Thalamus

• Subthalamus, hypothalamus

• Basal forebrain

• Locus Coeruleus

• Raphe nuclei

• Ventral Tegmental Area (VTA)

• Mesopontine cholinergic nuclei

– Lateral Dorsal Tegmental Tract (LDT)

– Pedunculopontine Tegmental Tract ( PPT)

Brainstem Reticular formation

• Medulla, pons, midbrain

• Uses glutamate (major excitatory neurotransmitter)

• The brainstem reticular formation has 2 major outputs:

– Dorsal projection to thalamus

• Thalamocortical projections

– Ventral projection to subthalamus, hypothalamus, basal forebrain

• Project to cortex

Thalamus

• Important for processing sensory input

• Receives excitatory input from:

– Brainstem reticular formation

– Locus coeruleus

– LDT/PPT

• Thalamocortical projection neurons are a diffuse network of neurons which activate the cortex and use glutamate

Subthalamus, Hypothalamus, and Basal forebrain

• Receives excitatory input from brainstem reticular formation

• Projects to cortex to activate the cortex

• Anterior hypothalamus uses acetylcholine and projects to the cortex and hippocampus

Posterior hypothalamus

• Histamine

• Hypocretin / Orexin

• Project diffusely throughout the brain and directly to the cortex

Locus Coeruleus

• Located in the Dorsal pons

• Norepinephrine

• Projects diffusely to the cortex and subcortical way stations to promote cortical activation

VTA

• Located in the Ventral midbrain

• Dopamine

• Projects to the basal ganglia (including the caudate) and frontal cortex

• Related to behavioral arousal

LDT/PPT

• Lateral Dorsal Tegmental Tract

• Pedunculopontine Tegmental Tract

• Very small area of the brain near the junction of the pons and midbrain

• Uses acetylcholine as neurotransmitter

– Dense projections to the thalamus (medial and intralaminar thalamic nuclei) to facilitate glutamatergic projection neurons

– Also projects to the lateral hypothalamus and basal forebrain

• Also very important in REM sleep

Raphe nuclei

• Serotonin

• Complex interactions in sleep and wakefulness

References:

Kryger, Principles and Practice of Sleep Medicine, Elsevier 2005

Sleep Neurobiology for the Clinician. Espana and Scammell. Sleep 2004;27:811. (excellent review)

Hypocretins (orexins) and sleep-wake disorders. Lancet Neuro 2005; 4:673.