Knowledge of the neurons with which the brain detects and responds to changes in CO2/pH (central chemosensitivity) is critical to understanding both homeostatic regulation and the nature of diseases resulting from failures in chemosensitivity, such as sleep apnea, Congenital Central Hypoventilation Syndrome and the Sudden Infant Death Syndrome. Medullary raphe neurons synthesizing the neurotransmitter serotonin (5HT) or ?-aminobutyric acid (GABA) are proposed as 1st order chemosensory neurons. Unknown, however, are the critical potential reciprocal interactions between 1st order neurons, and the role of 2nd order chemosensory neurons that may integrate, amplify and coordinate activities of 1st order neurons, to modulate homeostatic reflex responses to chemosensory stimuli. We postulate that 1st order raph 5HT and GABA chemosensory neurons interact between themselves and drive a specific population of 2nd order neurons. Together, these form a local raph chemosensory amplifier (RCA) network. Our overarching hypothesis is that 1st order sensory neurons of the medullary raph are integrated by reciprocal interactions and 2nd order neurons to form a local coordinated network. We have two aims.
Specific Aim 1 : Intrinsic sensitivity of raph 5HT and GABA neurons is shaped by the RCA network.
Specific Aim 2 : RCAI integrate and amplify inputs from 1st order 5HT and/or GABA neurons. Proposed studies will confirm and localize, or refute the existence of critical network interactions within the raph influencing chemo responsiveness of neurons when within an intact nervous system. Results will test the validity of the RCA model, and will suggest an organization of the raph chemosensory system and advance the understanding of central chemoreception by contributing definitive information about the network characteristics involved in this vital process.
Brainstem raph dysfunctions have been linked to severe pathologies, including Sleep Apnea, Central Congenital Hypoventilation Syndromes (CCHS) and the Sudden Infant Death Syndrome (SIDS). Failure of central chemosensitivity is proposed as a causative factor in these disorders. This proposal is designed to identify the raph cellular network involving 1st order chemosensory neurons and previously unknown 2nd order neurons, and network properties through which 1st order neurons interact between themselves and are integrated and amplified by 2nd order neurons. Studies will contribute to an understanding of central chemosensitivity, by characterizing the connections and network properties critical to producing the coordinated signal that modulates homeostatic reflex responses to ventilatory demand. Understanding this network will provide insight into the basis central chemosensitivity and consequences of brainstem dysfunction associated with severe pathologies.
|Hueffer, Karsten; Khatri, Shailesh; Rideout, Shane et al. (2017) Rabies virus modifies host behaviour through a snake-toxin like region of its glycoprotein that inhibits neurotransmitter receptors in the CNS. Sci Rep 7:12818|
|Hoffman, M; Taylor, B E; Harris, M B (2016) Evolution of lung breathing from a lungless primitive vertebrate. Respir Physiol Neurobiol 224:11-6|
|Johansen, S L; Iceman, K E; Iceman, C R et al. (2015) Isoflurane causes concentration-dependent inhibition of medullary raphé 5-HT neurons in situ. Auton Neurosci 193:51-6|