Assoc. Prof. MUDr. Markéta Bébarová, Ph.D.
Department of Physiology, Faculty of Medicine, Masaryk University
Modulatory Systems of the Brain
This presentation includes only the most 
important terms and facts. Its content by 
itself is not a sufficient source of
information required to pass the
Neuroscience exam. 
Sources :
‐ Principles of Neural Science (5th ed.), Kandel et al. (2013)
‐ Ganong's Review of Medical Physiology, (24th ed.), Barret (2010)
‐ Textbook of Medical Physiology (11th ed.), Guyton and Hall (2006)
‐ Color Atlas of Physiology (6th ed.), Silbernagl and Despopoulos (2009)
Brain stem
• contains ascending (sensory) tracts and 
descending (motor) tracts
• nuclei of the cranial nerves
• contains centers that control respiration
and heartbeat
• contains centers crutial for consciousness and sleep
• six neurochemical modulatory systems
The brain stem is a modulatory center that
orchestrates the activity of the rest of the CNS, 
ensuring that its activity is optimized. 
Brain stem – Modulatory Function
• mediated by small groups of neurons which project
widely
• neurotransmitters: 
• enable and modulate many of the higher‐order
behaviours – processes localized in the forebrain
(memory, language, compassion) 
‐ acetylcholine
‐ monoamines (catecholamines ‐ norepinephrine, 
epinephrine, dopamine; serotonin; histamine) 
• involved in pathophysiology, drug targets
Brain stem – Modulatory Function
Monoamines (catecholamines ‐ norepinephrine, 
epinephrine, dopamine; serotonin; histamine) 
• Neurons using these neurotransmitters fire action
potentials in a highly regular pattern. 
• continuous delivery of monoamines (e.g. basal ganglia)
(action potentials followed by a slow membrane depolarization
that results in the next spike ‐ intrinsic pacemaker currents) 
Brain stem – Modulatory Function
Monoamines (catecholamines ‐ norepinephrine, 
epinephrine, dopamine; serotonin; histamine) 
• some axon terminals release neurotransmitter diffusely
to many targets at once
Brain stem – Modulatory Function
Monoamines (catecholamines ‐ norepinephrine, 
epinephrine, dopamine; serotonin; histamine) 
• responses both fast and slower
Cholinergic neurons – share some of the properties (e.g.
acting also through G protein‐coupled muscarinic
receptors).
Brain stem – Modulatory Function
• Some neurons in the brain stem that project to the
forebrain control wakefulness and sleep by changing
arousal.
• located namely in the rostral pons and caudal midbrain
• reticular formation, reticular activating system
• ascending arousal system (AAS)
‐ together with sleep‐promoting regions in other parts of the
brain regulates sleep and waking
‐ damage of its projections in the thalamus and 
hypothalamus leads to coma
‐ remarkable connectivity (widespread projections
almost to every part of the CNS)
Brain stem – Modulatory Function
Arousal – Ascending Arousal System
Major parts:
Brain stem – Modulatory Function
Arousal – Ascending Arousal System
Regulate sleep and waking together with other neurons:
Brain stem – Modulatory Function
Arousal – Ascending Arousal System
• directly
AAS activates the cortical neurons:
• indirectly – by modulating activity of neurons:
‐ in the hypothalamus
‐ in the basal forebrain
‐ in the thalamus
Activation of the thalamic and 
cortical neurons is caused by 
different mode of firing of the
neurons.
Brain stem – Modulatory Function
Arousal – Ascending Arousal System
• during sleep – firing in bursts
• during wakefullness – firing in 
single spikes
Following application of
acetylcholine, norepinephrine, 
serotonin, and histamine.
Brain stem – Modulatory Function
Regulation of Brain Functions
Other than Arousal
1. Optimization of Cognitive Performance
2. Involvement in Autonomic Regulations and 
Breathing
3. Modulation of Pain and Anti‐nociceptive
Pathways
4. Facilitation of Motor Activity
Brain stem – Modulatory Function
1. Optimization of Cognitive Performance
‐ monoaminergic inputs to dorsolateral prefrontal
cortex improve the working memory
‐ dopamine is also linked to reward‐based learning
increased activity of dopaminergic neurons when a reward is
unexpectedly given
The same pathways are involved in addiction to drugs
of abuse.
‐ locus ceruleus (NE) ‐ important role in attention
depressor reflexes by inhibition of the preganglionic
sympathetic neurons ‐ e.g. due to deep pain
Brain stem – Modulatory Function
2. Involvement in Autonomic Regulations and 
Breathing
‐ maintenance of resting vascular tone
‐ changes of vascular tone at specific situations:
e.g. orthostasis disinhibits the neurons – baroreflex
Brain stem – Modulatory Function
2. Involvement in Autonomic Regulations and 
Breathing
Serotonin
‐ regulates many autonomic functions
‐ stimulation of serotoninergic neurons (raphe nuclei in medulla)
  respiratory motor
  heart rate and blood pressure
Brain stem – Modulatory Function
2. Involvement in Autonomic Regulations and 
Breathing
Serotonin
  ventilation
‐ serotoninergic neurons as central chemoreceptors
(in the medulla, increased firing at higher pCO2)
(increased firing at higher pCO2)
 arousal, anxiety, changes in the
cerebral blood flow
(important for survival at airways obstruction, 
SIDS)
Brain stem – Modulatory Function
3. Modulation of Pain and Anti‐nociceptive
Pathways
‐ acute pain – beneficial to avoid/reduce injury
‐ chronic pain – may be maladaptive
Descending monoamine projections to the dorsal
horn of the spinal cord modulate pain perception.
Treatment of:
‐ migraine headaches ‐ agonists of 5‐HT1B and 5‐HT1D
receptors (triptans) 
‐ migraine headaches and chronic pain – blockers of
monoamine reuptake (antidepressant drugs including SSRIs)
Brain stem – Modulatory Function
4. Facilitation of Motor Activity
Dopaminergic system – critical for normal motor 
performance, release inhibition on motor responses
(Parkinson disease).
Serotoninergic neurons – important for generation of
motor programs (serotonin syndrome). 
Noradrenergic neurons – facilitates excitatory inputs to 
motor neurons, namely in stereotypic and repetitive
behaviours (through β and 1 receptors; stress – exaggerated
motor responses, tremor; β‐blockers ‐ to reduce certain type of
tremor, musicians)
Brain stem – Modulatory Function
Ascendent projections
‐ to the forebrain
‐ control of various aspects of mood and cognition
(AAS ‐ arousal and sleep, attention, memory, reward‐
based learning)  
Summary
Descendent projections
‐ to the spinal cord
‐ regulation of autonomic, somatosensory (modulation
of pain perception), and motor functions
Plays an important role in 
normal brain function!