Delivery and utilisation of energy in the brain

Question 1

Brain at rest consumuption:

Answer 1

• 60% of glucose utilisation of human at rest
• 20% of oxygen utilisation
• 120 g of glucose a day
• 1760 kJ / day = 20 Watts = dim light bulb

Question 2

Astrocytes

Answer 2

Type of Glial cell

wrap around the blood vessels

Question 3

NT Release 1

Answer 3

• Action potential arrives
  
  • Presynaptic cell depolarises
  • ‘physiological’ depolarisation
• Release by vesicle fusion
• Vesicles each contain
  
  • 250-5000 molecules of Glutamate

Question 4

NT release 2

Answer 4

• Diffusion across the synapse
• Activation of next cell
  
  • Na+ enters cell
  • K+ released
  • Post synaptic cell depolarises

Question 5

What 2 key tasks remain after NT release?`

Answer 5

• REPOLARISATION of cells
• REMOVAL OF NT

Question 6

Features of Repolarisation

Answer 6

• Requires ATP for energy
• Net REMOVAL of cations from cell - ELECTROGENIC

Question 7

GLUTAMATE

Answer 7

• Highly active at receptors
• Depolarises post-synaptic cells
  
  • they can not pass on new messages
  • Can swell and die
  • Gives rise to major energy use (75% in primates)

EFFECTIVE REMOVAL OF GLUTAMATE IS VITAL

Question 8

What takes up Glutamate?

what is the uptake powered by?

Answer 8

Astrocytes

uptake powered by ionic gradients running down

hence Na/K ATPase - needs ATP

Question 9

What happens to the Glutamate inside the Astrocyte?

Answer 9

• Glutamate is converted in to Glutamine 
  
  • Requires another ATP
• Glutamine exported and taken-up pre-synaptically
• Converted and packed into vesicles - requires ATP

Question 10

What is Neurovascular coupling?

What does activity in the neuron lead to?

Answer 10

Neurovascular coupling

• name of process in which local neuron activity is monitored and then subsequent changes in cerebral blood flow occur

Activity leads to:

• increased blood flow to deliver OXYGEN and GLUCOSE

astrocytes uptaking the NT are made aware of the energy requirements and are responsible for sending numerous messages to the blood vessels to change blood supply

Question 11

GLUCOSE

Answer 11

• only source of energy for the brain
• transported into the glial cells mainly
• conversion into glc-6-phosphate needs energy
  
  • from here either
    
    • metabolised
    • or stored as glycogen
• N.B glycogen stores limited, rapid turnover, imp local energy source “brain’s battery”

Question 12

Brain when can it work/can’t work?

Answer 12

Brain is able to work in the ABSENCE OF OXYGEN:

• e.g. in hypoxia or stroke etc
• lactate/NAD+ production, allows glycolysis to continue

Brain CAN’T work in the ABSENCE OF GLUCOSE

Question 13

Where does glucose metabolism take place?

Answer 13

Cytosol

Question 14

What are the 2 fail safe anatomical features of the Brain’s circulation?

Answer 14

1. Circle of Willis
2. surface network : Leptomeningeal collateral circulation

Question 15

Leptomeningeal Collateral Circulation

Answer 15

• like a fishing net draped over the brain
• supplied by 3 major inputs:
  
  • MCA, ACA, PCA
• From the meshwork that sits over the hemispheres
  
  • penetrating arteries descend into cerebral cortex and white matter
  • perforating arteries from proximal vessels supply the deep grey matter

Question 16

What depends on normal B.P?

Answer 16

The Leptomeningeal collateral circulation

does its best if the Middle Cerebral Artery is occluded

If B.P. is lowered then the leptomenigeal collateral circulation can’t do as good a job and the middle territory will suffer

Question 17

What is the Penumbra?

Answer 17

The area around the core

here the blood flow is low but not too low like in the core

Question 18

How long does it take before the Penumbra deteriorates and then what happens?

Answer 18

• 12-48 hours
• then it is recruited into the expanding core
  
  • more brain tissue dies

Question 19

Core Ischaemia

Answer 19

• Perfusion BELOW the survival threshold
  
  • ~10ml/100g/min
  • below this
    
    • all cells will die (neurones and astrocytes)
    • serious capillary damage

Question 20

Penumbra

Answer 20

• The “ grey ” area around the core, nearer the collaterals
• Perfusion partly reduced, below the FUNCTION threshold only (function impaired but cells don’t die)
• Neuronal and synaptic function suppressed
• Responds to EARLY reperfusion - tissue will recover and not go into infarction
• Depends on glucose + glycolysis, which increases to generate the required ATP

Question 21

WHy does the core expand

(without a drop in bp to reduce the collaterals)?

Answer 21

Due to SPREADING DEPOLARIZATIONS

these are PATHOLOGICAL

Question 22

SPREADING DEPOLARIZATION

Answer 22

• K+ out
• Na+ in
• INput:
  
  • flooding of the extracellular space with K+ and glutamate by neurons and astrocytes upstream in the wave - ripple effect
• Output:
  
  • massive release of K+, allowing wave to propagate
• PATHOLOGICAL: suspends function
• Lasts 1-2 mins; needs ~10mins to recover
• All neighbouring cells depolarise, massive ATP use
  
  • REQUIRES MASSIVE INFLOW OF BLOOD TO FIX THIS (huge energy requirement)

Question 23

What is the normal brain respone to functional activity or a spreading depolarisation?

Answer 23

Hyperaemia

Increase in blood flow

Question 24

what happens to bld glc levels after 1 depol?

how long will it take to recover

Answer 24

bld glc levels will fall

needs to repolarise

wont recover levels for 30 mins

Question 25

What happens in the Penumbra when a depol occurs?

Answer 25

VASOCONSTRICTION in the microcirculation causing the blood flow to drop Opposite to normal where it causes an increase in blood flow Therefore it is vital to reperfuse quickly to try and restore function

Question 26

How do neurones die?

Answer 26

* Due to lack of oxygen, no ATP production from Krebs cycle * hence the Na/H antiporter stops working same with Ca antiporter * in depol: * Ca2+ and Na+ enter cell, H+ levels also increase as lactic acid builds up, small amount of K+ leaves * Net osmotic effect, water goes in to cell with cations * results in CYTOXIC OEDEMA; cell swells as water moves in

Question 27

Main mechanism of spread of depol?

Answer 27

K+ leaking out and depolarising the surroundin cells

Question 28

Why do brain's swell with reperfusion?

Answer 28

***_Reactive hyperaemia_*** * Whole territory , dilates, so.. * More capillaries open, so Increase in brain volume..7 * Capillaries weak, and leak… * Haemorrhagic conversion

Question 29

Summary 1

Answer 29

The brain uses large amounts of energy, principally to: * **Repolarise neuronal membranes** * **Maintain a cation imbalance** (3Na+ outward / 2K+ inward) that keeps some water out of cells that keeps some water out of cells * **Re-uptake neurotransmitters** from the synaptic space

Question 30

Summary Without Oxygen

Answer 30

* glucose breakdown to lactate yields only a fraction of the potential ATP yield * That means much more glucose utilisation - 18x more * Since the brain’s glucose store is very small (glycogen), it is **heavily dependent on adequate glucose delivery from perfusion**

Question 31

***_Ischaemia_***

Answer 31

**_Defintion:_** * Is a state in which perfusion no longer meets the metabolic needs of the tisssue There are **two collateral circulation systems that reduce the risk of ischaemia:** * Circle of Willis * leptomeningeal collaterals

Question 32

How was it that some of the weakness got better?

Answer 32

**_In the penumbra function_** may recover function may recover with reperfusion with reperfusion (without this, the core will gradually expand into the penumbra by starting “tsunamis” around itself, so that the pneumbra area also infarcts)

Question 33

Why did the brain swell soon after reperfusion?

Answer 33

**Tissue in the ischaemic Core** * Will die unless reperfused “in time” * May swell and bleed if reperfused too late