Human Brain Stem Functions

The Brain Stem

• The brain stem is superior to, but continuous with, the spinal cord
• It is made up of:
  • The midbrain
  • Pons
  • Medulla oblongata

The Medulla Oblongata

• The medulla begins at the inferior border of the pons and extends to the foramen magnum (~3 cm)
• It contains all ascending and descending tracts extending between the spinal cord and cerebrum
• The medulla contains nuclei which are regulators for various vital body functions
• Vital functional centers regulated by the medulla include:
  • The cardiovascular center - controls the rate and force of heartbeat, and the diameter of blood vessels
  • The respiratory rhythmicity center - controls the rate and rhythm of breathing
  • The vomiting, coughing, and sneezing centers

The Pons

• The pons lies directly above the medulla and anterior to the cerebellum
• It acts as a bridge connecting the spinal cord with the brain and parts of the brain with each other
• Together with the medulla, areas in the pons help control breathing
• The pontine respiratory group is normally inactive during quiet breathing
• This group of neurons acts like an "off-switch" to terminate medullary inspiratory activity

The Midbrain

• The midbrain extends from the pons to the diencephalon
• The cerebral aqueduct passes through the midbrain connecting the 3rd ventricle above with the 4th ventricle below
• The midbrain contains several other nuclei, including:
  • Substantia nigra (dopamine expressing neurons)
  • Raphe nuclei (serotonin expressing neurons)
  • Locus coeruleus (noradrenaline expressing neurons)
  • Pedunculopontine nucleus (acetylcholine expressing neurons)

The Reticular Formation

• The Reticular Activating System (RAS) functions to maintain consciousness, a state of wakefulness in which an individual is fully alert, aware, and oriented
• Inactivation of the RAS produces sleep, a state of partial consciousness from which an individual can be aroused
• The RAS also prevents sensory overload by filtering out insignificant information

The Cerebellum

• The cerebellum or "little brain" is the second largest part of the brain and lies inferior to the cerebrum and posterior to the brain stem
• The type of neuron within the cerebellum is the Purkinje neuron
• Important for:
  • Unconscious motor coordination
  • Emerging functions such as cognition and emotion
• Diseases associated with cerebellum dysfunction include:
  • Autism
  • Ataxia
• The cerebellum is an important target for alcohol

Serotonin (5HT)

• 13 known 5HT receptors in humans
• Divided into 7 classes (5HT1-7)
• Also divided into sub-classes e.g. 5HT1A
• All are G-protein coupled receptors (GPCRs) apart from 5HT3 (which is an ionotropic receptor)
• Activation of some of the 5HT GPCRs results in neuronal inhibition (5HT1-2) and some result in neuronal excitation (5HT4-7)
• The effect of 5HT on a neuron depends on what 5HT receptor is expressed on that neuron

Clinical Pharmacology of 5HT receptors/systems

• Buspirone; gepirone: partial agonist at 5HT1A receptors
  • Used to treat generalized anxiety disorder (GAD)
• Sumatriptan (and other Triptans): agonists at 5HT1B receptors
  • Used to treat migraine headaches
• Clozapine; Risperidone; olanzapine: antagonists at 5HT2A receptors (also antagonist at Dopamine 2 Receptors)
  • Used in the therapy of psychosis (e.g. Schizophrenia)
• Odansetron; Granisetron: antagonists at 5HT3 receptors
  • Used as antiemetics
• Fenfluramine: stimulates reversible transport of 5HT into the synapse => more SHT in synapse => more 5HT available to act on receptors
  • Used as an anti-obesity agent
• Selective serotonin reuptake inhibitors (SSRIs) e.g. Fluoxetine: block the 5HT transporter => more SHT stays in the synapse
  • Used to treat depression

Dopamine (DA)

• Major DA Nuclei:
  1. Substantia nigra (SN) - voluntary movement
  2. Ventral tegmental area - motivation; cognition; reward
  3. Hypothalamus - control of breast milk production
• The effect of DA will vary depending on brain regions
• Major brain disorders associated with impaired DA regulation:
  1. Parkinson's disease (SN DA neurons die)
  2. Psychosis (schizophrenia)
  3. Addiction
  4. Hormonal disorders

DA Receptors

• Five receptors in total named: D1, 2, 3, 4, 5
• All are G-protein coupled receptors (GPCRs)
• Functionally, they are divided into: the D1 family (D1 & D5) & D2 family (D2-3-4)
• DA receptor activation can result in neuronal excitation or inhibition depending upon the G-proteins they are coupled to

DA pharmacology

• L-dopa: precursor to Dopamine. When it enters the CNS, it is converted to DA. The result is increased DA levels in the brain.
  • Used in the treatment of Parkinson's disease
• Bromocriptine: D2 agonist
  • Sometimes used in the treatment of Parkinson's disease
  • Used in the treatment of hyperprolactinaemia
• Haloperidol: D2 antagonist
  • Used in the treatment of schizophrenia
• Clozapine: antagonist at D4 receptors
  • Used in the treatment of schizophrenia
• Cocaine: inhibits the dopamine transporter (also noradrenaline)
  • Used in the treatment of schizophrenia

Noradrenaline (NA) in the CNS

• NA pharmacology in the CNS:
  • Alpha (1-2) & Beta (1-3) adrenergic receptors
  • Alphas further divided into sub-classes (Alpha1A, Alpha1B, Alpha1C, Alpha2A, Alpha2B, Alpha2C)
  • All are metabotropic coupled to different G-proteins
• Noradrenergic transmission in the CNS important in:
  • the 'arousal' system, controlling wakefulness and alertness
  • blood pressure regulation
  • control of mood (functional deficiency contributing to depression)
• Selective noradrenergic reuptake inhibitors (NRIs) inhibit the NA transporter => more NA left in the synapse used as antidepressants e.g. bupropion, reboxetine, atomoxetine
• Mixed noradrenaline-serotonin reuptake inhibitors (SNRIs) e.g. Venlafaxine => more serotonin and NA left in the synapse
  • antidepressants
• Psychotropic drugs that act partly or mainly on noradrenergic transmission in the CNS include:
  • Cocaine
  • Amphetamine
• Reserpine: VMAT inhibitor => depletes the amount NA in synaptic vesicles => decreased NA released into the synapse. => its use can induce depression

Acetylcholine

• Major Ach nuclei in the CNS:
  1. Nucleus basal (Basal Nucleus)
  2. The medial septal nucleus and Diagonal band
     • #1 & #2 send axons to the cortex => important for arousal; emotion; cognition
  3. Pedunculopontine nucleus (in the brainstem) => sends axons to dopamine neurons of the VTA => important for reward systems
• Diseases associated with Ach dysfunction:
  • Impaired cognition and memory (Cholinergic neurons die in Alzheimer's disease)
  • Mood disorders e.g. Depression
  • Motor coordination