W6L1 - Neurobiology of Sleep

Question 1

Wakefulness System

• NT involved
• Location

Answer 1

Wakefulness System

• Acetycholinergic Neurons
• In LDT, PPT and BF

Question 2

Sleep System

• NT involved
• Location

Answer 2

Sleep System

• NA in LC
• 5HT in Dorsal & Medial Raphe Nuclei
• Histaminergic Neuron in TMN
• Dopaminergic Neuron in PAG

Question 3

Noradrenergic Pathway. Expain how it links to sleep.

Answer 3

• NA cells in LC project to all areas (esp. thalamus and hypothalamus)
  
  • NA/LC cells more active in wake
    
    • Agents promote NA (e.g., amphetamine) + wake
    • Agents inhibit NA (e.g. AMPT) - wake

Question 4

What is Orexin/Hypocretin. Where is the located?

Answer 4

Orexin/Hypocretin

• Cells located in lateral hypothalamus
• Active during wake
• Master control that have excitatory projections to
  
  • TMN (Histamine), Raphe (5HT), LC (NA)
  • PPT, LDT, BF (Ache)
  • and Cortex

Question 5

Summarise Wakefulness

Answer 5

• Wakefulness is maintained by numerous cell groups projecting to halamus, hypothalamus, basal forebrain and ultimately cortex.
• Orexin/hypocretin cells in the lateral hypothalamus have a general excitatory influence over this system and act as the master controller of wakefulness

Question 6

What is the Sleep System. Key neuron. How do they work?

Answer 6

Sleep System (VLPO and BF)

• VLPO
  
  • In anterior hypothalamuse
  • Inhibits all nuclei in wake (including orexinergic neuron)
  • Uses GABA and Galanin (Inhibitory NTs)
• TMN, LC, Raphe also inhibit VLPO (bidirectional)

Question 7

When are VLPO neurons activated/not activated

Answer 7

Elevated during sleep but not during sleep deprivation

• VLPO activity does not make one sleepy, but it shuts wakeflness centres during sleep

Question 8

What are the regions of VLPO and what happens if it is lesioned?

Answer 8

2 Regions

• VLPO Core
  
  • NREM Loss of Sleep (50%)
• VLPO Extended
  
  • REM Loss of Sleep (50%)

Question 9

In cats, what happened when BF is stimulated and lesioned

Answer 9

Stimulation Study

• Induced sleep

Lesion Study

• Reduction of REM sleep and extended wake
• But over 6 weeks, recovery of sleep suggest compensatory role of VLPO

Question 10

Flip-Flop Switch: What are Sleep-on Neurons in REM

Answer 10

REM Sleep-On Neurons

• LDT/PPT:
  
  • Very active during REM
  • Moderately active during wakefulness
  • Inactive during Non-REM sleep
• Cholinergic cells located in the LDT/PPT act like the finger on the switch for GABA neurons
  
  • GABA neurons in SLD active in REM
  • Inhibiting REM-off neurons
• LDT/PPT also stimulate other pontine structures responsible for the generation of REM phenomena.

Question 11

Flip-Flop Switch: What are Sleep-off Neurons in REM

Answer 11

REM Sleep-Off Neurons

• vlPAG/LPT GABA neurons inhibit REM.
  
  • Inactive during REM
  • Active during Non-REM and waking.
  • Inhibit SLD and REM sleep phenomena when active.
• Activated by LC and raphe (“finger” on switch) and inhibited by the extended VLPO neurons.

Question 12

What is the role of orexin in REM

Answer 12

Orexin in REM

• Stimulates arousal, inhibits VLPO, inhibits REM
• Stimulation of LC and Raphe inhibits REM
  
  • Low level of activity in Orexin during sleep allows REM sleep occuring
  • Low level of activity in Orexin during wake would
    
    • Make it difficult to maintain wake
    • Allow intrusion of REM

Question 13

Run through the flip-flop switch.

Answer 13