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Author of Lecture: Dampney, Roger (Prof.)

Title of Lecture: Lower brainstem functions(Problem 6.03, Lecture 3, 2014)

medulla

pons

midbrain

Lowerbrainstem Brainstem

Main functions of lower brain stem

• Contains ascending tracts conveying sensory information from spinal cord to higher brain regions, and descending tracts conveying signals from higher regions to motor outputs (e.g. corticospinal tract)

• Essential role in regulation of breathing, blood pressure, and other functions such as swallowing and vomiting

• Like medulla, contains ascending and descending tracts connecting higher brain regions and spinal cord

• Relays signals from the cerebellum to the forebrain• Also plays an important role in regulation of breathing

Medulla oblongata

Pons

Essential facts and questions about breathing• It is automatic, not dependent on conscious control. What central

mechanisms generate respiratory rhythm?• The blood CO2 level is the major factor that drives breathing (Haldane

& Priestley, J. Physiol. 32: 225-266, 1905). Where is the CO2 level sensed and how does it drive breathing?

• Arterial hypoxia (a fall in the blood O2 level) can also stimulate breathing. Where is the blood O2 level sensed and how does it drive breathing?

• Breathing increases during exercise, fear or arousal. What mechanisms cause that? (It is not blood O2 or CO2 levels)

• The pattern of breathing (i.e. duration of inspiration) is reflexly affected by afferent inputs from lungs. What are the receptors and reflex pathways?

Respiratory rhythm - inspiratory motor nerve activity

• The basic respiratory rhythm is generated by neurons (nerve cells) within the lower brain stem. This group of cells is collectively called the respiratory centre

• Inspiration is initiated by an increase in the firing rate of neurons in the respiratory centre. These neurons make connections with other neurons in the cervical and upper thoracic spinal cord, which in turn innervate the inspiratory muscles, causing inspiration.

• The rate and depth of respiration are regulated by (1) inputs to the respiratory centre signalling the PCO2, pH and PO2 of the arterial blood (2) afferent (sensory) inputs from receptors in the lungs (3) inputs arising from higher centres of the brain, such as the motor cortex

Diaphragm andIntercostal muscles

motor cortex

respiratory centreneurons

Lung stretch receptors,arterial chemoreceptors

forebrain

brainstem

spinal cordmedullary chemoreceptors

INSPIRATION

afferent fibres inIX & X

Phrenic &Intercostal n.

Modified fromFig. 13-32 in Sherwood L Human Physiology6th ed., Brooks-Cole, 2007

Pons

Pneumotaxic centreApneustic centre

Pre-Bötzingercomplex

Dorsal respiratorygroup

Ventral respiratorygroup Medulla

Dorsolateralpons(respiratorycentres)

Medullaryrespiratorycentre

Respiratorycontrolcenters inbrain stem

Respiratory centres in brainstem

• Dorsal respiratory group (DRG) neurons consist mainly of inspiratory neurons (i.e. those which fire during inspiration)

• Neurons in the ventral respiratory group (VRG) neurons consist of both inspiratory neurons and expiratory neurons (i.e. those which fire during expiration)

• Neurons in the pontine “pneumotaxic centre” inhibit inspiratory neurons, thus limiting inspiration.

• Neurons in the pontine “apneustic centre” excite inspiratory neurons, thus promoting inspiration.

• Many inspiratory neurons have axons which descend to the spinal cord and control motoneurons supplying inspiratory muscle. These neurons drive inspiration.

• In contrast, expiration is usually a passive process, but during active expiration some expiratory neurons, with axons which also descend to the spinal cord, drive expiration

• There are two basic theories to explain respiratory rhythmogenesis: (1) the “pacemaker” theory, (2) the “network” theory”

Respiratory centres in brainstem

brainstempathways

"PACEMAKER" THEORYpacemaker

neuron

Spinal cordmotoneuron

Inspiratorymuscle

tonic input

inhibitory interneuron(fires only when input

exceeds threshold)

"NETWORK THEORY"

excitatory synapseinhibitory synapse

Spinal cordmotoneuron

Inspiratorymuscle

May be inpre-Bötzinger

group

Medullary chemoreceptors and the drive to breathe

increased CO2 is a very powerful stimulus to breathing: “air hunger”

Arterial blood [CO2]

[CO2] in medulla

[H+] in medulla

Medullary chemoreceptorsstimulated

Increased breathingrate and depth

Current hypothesis: the central chemoreceptors are located in the retrotrapezoid nucleus (RTN) in caudal pons/rostral medulla

Fig. 13-32 in Sherwood L Human Physiology 6th ed., Brooks-Cole, 2007

RTN

Dorsolateral ponsrespiratory centres

Pre-Bötzingercomplex

Dorsal respiratorygroup

Ventral respiratorygroup

Evidence that RTN neurons drive CO2 respiratory response

• Patients with congenital central hypoventilation syndrome (CCHS) show an almost complete loss of respiratory response to increased CO2, but a normal respiratory response to exercise and arousal

• In CCHS there is a mutation of the gene for Phox2b (a transcription factor) that controls differentiation & survival of a subset of pontomedullary neurons.

• Phox2b is not expressed in neurons above the pons or in the cerebellum

• Neurons containing Phox2b that are also highly sensitive to increased CO2 are located within the RTN

• Inhibition of the RTN greatly reduces the respiratory response to increased CO2

• CO2-activated neurons in RTN project to respiratory neurons in the VRG, pre-Bötzinger group and dorsolateral pons

• The RTN also receives inputs from peripheral chemoreceptors

Humans

Rats

CPG: central pattern generatorRTN: retrotrapezoid nucleus

Respiratory activity

Ventilation

Blood[CO2]

Medullary[H+]

Peripheralchemoreceptors(carotid body)

Fear, arousal,exercise

Forebraincentres

RTN

CPG

Other reflexes

Modified from Fig. 2 In Guyenet PG (2008)J Appl Physiol 105: 404-416.

• Located in the walls of the bronchi and bronchioles throughout the lungs are receptors (pulmonary stretch receptors) that are excited as the lungs inflate

• Nerve impulses travel to the respiratory centre in the brainstem from these receptors via sensory nerve fibres in the vagus, and cause an inhibition of inspiration (via pneumotaxic centre in pons)

• The effect of this reflex, therefore, is to limit inspiration and thus reduce the depth of breathing and increases its rate

• It acts as a protective mechanism against over-inflation of the lungs

• It may also play a role in minimizing the work of breathing• Inputs from receptors in the chest wall also influence respiratory

rate and depth, and also are thought to be important in minimizing respiratory work

Hering-Breuer reflex

Lower brainstem (rat)

Nucleus tractus solitarius (NTS)Nucleus ambiguus (NA)Ventral respiratory group (VRG)Rostral ventrolateral medulla (RVLM)Retrotrapezoid nucleus (RTN)

From Paxinos & Watson (1982) The Rat Brain inStereotaxic Co-ordinates, Academic Press

Nucleus tractus solitarius (NTS)Nucleus ambiguus (NA)

Ventral respiratory group (VRG)Rostral ventrolateral medulla (RVLM)

Medulla oblongata (rat)

IX and X afferent fibresfrom visceral receptors inCV system, lungs, gut etc (e.g. from baroreceptors,chemoreceptors and lung inflation receptors)

VRG neurons(controlling respiratory activity)

RVLM neurons(regulating sympatheticoutflow to heart, bloodvessels, adrenal medulla)

Vagal preganglionic neurons, regulating heart rate

Area postrema (AP, lacks blood-brainbarrier)

Circulating substances(e.g. angiotensin II, act directly on AP neurons)

rostral level

caudal level

From SW Ranson & SL Clark (1959) The Anatomyof the Nervous System, WB Saunders, Philadelphia

• project directly to sympathetic preganglionic neurons in spinal cord• are tonically active, and this tonic activity maintains resting sympathetic activity and hence resting blood pressure• receive inputs (excitatory and inhibitory) from a wide range of peripheral receptors and from cardiovascular nuclei in the pons, midbrain, and forebrain• are a critical component of baroreceptor and other cardiovascular reflex pathways, as well as pathways mediating cardiovascular responses from higher centres.

RVLM sympathetic premotor neurons

Modified from Dampney RAL (1994) Physiol Rev 74:323-364

RVLM neurons:

CVLM: caudal ventrolateral medullaIML: intermediolateral cell columnKF: Kölliker-Fuse nucleus (pons)NTS: nucleus tractus solitariusPAG: periaqueductal grey (midbrain)PVN: paraventricular nucleus

(hypothalamus)RVLM: rostral ventrolateral medulla

BP(mmHg)

100

250

2

0

5

0 0

4

0

10

BP(mmHg)

Skin SNA(imp/sec)

Muscle SNA(imp/sec)

Glu Glu1 minModified from Dampney RALand McAllen RM (1988) J Physiol 395:41-56

Point A Point B

Sympathetic outflow todifferent vascular beds:

Modified from McAllen RM et al (1997) Clin Exp Hypert119: 607-618.

Premotor sympathetic neurons in RVLM consist ofsubgroups that regulate specific vascular beds

Cardiovascular challenges evoke reflex changes in sympathetic nerve activity which tends to restore homeostasis

Anaphylactic shock

vasodilation

fall in blood pressure

reflex increase in sympathetic activity

recovery inblood pressure

EXAMPLE:

Brainstem pathway subserving baroreceptor reflex

Modified from Dampney RAL (1994) Physiol Rev 74:323-364

From SW Ranson & SL Clark (1959) The Anatomyof the Nervous System, WB Saunders, Philadelphia