+ INTRODUCTION (I) The most important thing our brain does is to keep us alive. One of the essential tasks for maintaining life is breathing, not only for oxygen, but also to maintains carbon dioxide levels within a narrow range. A variations of pH in blood as little as 0.1μM is fatal. Central chemoreceptors in the brainstem ( VLMS) monitor carbon dioxide levels (PCO2) and control lung ventilation. Central Respiratory Control Diaphragm Chemoreceptors Network (e.g. Hypercapnic Acidosis) (Tonic drive in respiratory centre) (Contraction of muscles)
+ SEROTONINERGIC NEURONS (II) Serotonergic neurons in the medullary raphé project to all of the main respiratory nuclei, including the nucleus tractus solitarius, nucleus ambiguus, preBötzinger complex, Bötzinger complex, hypoglossal motor nucleus (XII) and phrenic motor nucleus. There is a high concentration of serotonin (5-HT)-immunoreactive nerve terminals within the main respiratory nuclei, and these nuclei also contain nerve terminals that are immunoreactive for substance P and thyrotropin- releasing hormone (TRH). The nerve terminals arise from serotonergic neurons in the medullary raphé and ventrolateral medulla.
+ SEROTONINERGIC NEURONS (III) Serotonergic neurons seem primarily to have an EXCITATORY effect on breathing, and they are thought to provide tonic drive to maintain respiratory output during wakefulness. (see fig.) However, there is evidence that 5-HT can have an INHIBITORY effect on some elements of the network that controls Respiratory airflow in a rat in vivo respiratory output, and a Fentanyl induces respiratory depression, and subset of 5-HT neurons is reversed 5-HT4a agonist BIMU8. might inhibit respiratory output.
+ CARBON DIOXIDE SENSORS (IV) MEDULLARY 5-HT NEURONS ARE CO2/PH CHEMORECEPTORS A subset is highly sensitive to changes in CO2 (see figure) A different subset of neurons (15%) is equally sensitive to changes in CO2 but with an opposite response All CO2 stimulated neurons from the medullary raphé, but none of the CO2 inhibited neurons, are serotonergic. SEROTONERGIC NEURONS MIGHT MODULATE SOME NON-RESPIRATORY BRAINSTEM AND SPINAL CORD FUNCTIONS IN RESPONSE TO CHANGES IN CARBON DIOXIDE.
+ CARBON DIOXIDE SENSORS (V) Changes in arterial carbon dioxide probably influence breathing indirectly through changes in brain pH. Medullary serotonergic neurons are highly sensitive to intracellular pH, and their relationship with blood vessels is consistent with a specialized role as arterial carbon dioxide sensors. Lesions of these neurons lead to blunting of the ventilatory response to increased carbon dioxide. Confocal imaging after immunohistochemistry for tryptophan hydroxylase shows SEROTONINERGIC NEURONS closely associated with the BASILARY ARTERY (B) and its main MIDLINE BRANCHES
+ RESPIRATORY NETWORK STIMULI(VII) 5-HT, TRH and substance P enhance excitability of the respiratory network through numerous mechanisms and at multiple sites within the respiratory network, including rhythm-generating neurons, respiratory premotor neurons and respiratory motor neurons. SEROTONERGIC RAPHE HAS A ROBUST ABILITY TO CONTROL VENTILATION
+ MIDBRAIN 5-HT NEURONS (IX) Serotonergic neurons in the midbrain also sense carbon dioxide. Confocal images of arteries and 5ht neurons in the midbrain. SEROTONINERGIC NEURONS closely associated with ARTERIES
+ MIDBRAIN 5-HT NEURONS (X) 5HT-neurons in the midbrain might have a role in inducing various non-respiratory effects, such as AROUSAL from sleep, ANXIETY and changes in cerebrovascular TONE (migraine) (A single breath of 35% of CO2 induces anxiety in normal people) Exercise has profound effect on acid/base balance, serotoninergic system could couple motor control with Ph control (Co2 level drop during exercise in many species) CONTROL OF PH HOMEOSTASIS, MOTOR CONTROL AND NEURAL TISSUE HOMEOSTASIS ARE NOT ACTUALLY RELATED, BUT ARE DISTINCT AND INDEPENDENT ROLES THAT ARE SHARED BY THE 5HT SYSTEM
+ CONCLUSION (XI) A role for serotonergic neurons in pH control might help to explain how three seemingly unrelated human disorders — sudden infant death syndrome (SIDS), panic disorder and migraine — could all be linked to this single, relatively homogeneous, small group of neurons.
+ MIDBRAIN 5-HT NEURONS (X)FUTURE STUDIES SHOULD CONSIDER THE RELEVANCE OF THE LARGE RESPONSE OF THE RAPHE NEURONS TO ACIDOSIS, AND THE DIRECT INVOLVEMENT OF A SUBSET OF THESE NEURONS IN CENTRAL RESPIRATORY CHEMORECEPTION. “Focusing too closely on individual parts blurs a bigger picture” Parable of the Blind Man (drawing from K. Hokusai)