Paul F. McCulloch, PhD

Professor of Physiology


Midwestern University
Chicago College of Osteopathic Medicine
Professor of Physiology
Science Hall #422K
555 31st St.
Downers Grove, IL 60515

Office: (630) 515-6386
e-mail: pmccul@midwestern.edu 

 

EDUCATION

BSc Zoology University of British Columbia 1986
MSc Zoology University of British Columbia 1989
PhD Physiology University of Saskatchewan 1995

RESEARCH SUMMARY

The long-term goal of my research is to establish the mechanisms and circuitry by which signals from cardiorespiratory afferents integrate within the brainstem to produce reflex autonomic responses. Specifically, I am interested in how trigeminal neurons reflexly modulate cardiorespiratory control mechanisms within the mammalian brainstem. Upon submersion under water, or after stimulation of the nasal passages with noxious vapors, mammals exhibit a powerful functional reorganization of the cardiorespiratory system to protect against asphyxic apnea, the so-called "diving response". This complex autonomic response includes apnea in the expiratory position, an intense bradycardia, and an alteration of peripheral vascular tone resulting in a redistribution of cardiac output. Initiation of this response results primarily from stimulation of receptors of the trigeminal nerves that innervate the face and nasal passages.

Although the afferent and efferent aspects of this response have been well characterized, the brainstem circuitry that links the afferent stimuli to efferent response is still unknown. Therefore, the objective of my current research is to investigate the central neural connections and functional relationships between stimulation of the trigeminal system and neuronal activity in autonomic nuclei in the medulla. I use multiple experimental approaches to investigate this objective. The first approach is to train rats to swim and dive underwater through a 5m long Plexiglas maze, and then identify and characterize brainstem neurons that were activated by voluntary diving. The second approach is to identify neuronal connections between brainstem nuclei using anterograde and retrograde tracers. The third approach is to record physiological variables in anesthetized rats while stimulating the nasal passages or the individual nerves that innervate the nasal passages.

This research has implications for understanding the mechanisms of neurogenic hypertension because it hypothesizes that a defensive reflex (upper respiratory tract stimulation) can inhibit a homeostatic reflex (arterial baroreflex). Also, this proposal could provide a neurological basis for the etiology of Sudden Infant Death Syndrome (SIDS).

Research projects

Project I:

Identification of brainstem neurons activated during voluntary diving in rats

The general aim of this research is to identify and characterize brainstem neurons that are activated during voluntary diving. Rats are trained to voluntarily dive underwater through a maze to elicit the diving response. The brainstems from these animals are then immunohistologically processed to identify or characterize the brainstem neurons that were activated by voluntary diving. In some cases brainstem tissue is immunohistologically processed for double or triple labeling. The hypothesis of these experiments is that specific neurons within the brainstem of rats are activated during voluntary diving. A second set of rats trained to voluntarily dive underwater are fitted with implantable heart rate and blood pressure transmitters to allow correlation of physiological responses to diving with brainstem neuronal activation.

Project II:

Determination of neuronal connections using anterograde or retrograde tracers

The general aim of this research is to identify neuronal connections between brainstem nuclei using anterograde and retrograde tracers. Commercially available anterograde or retrograde tracers are stereotaxically injected into specific brainstem nuclei. In a second set of animals, nerves that innervate the nasal passages, such as the anterior ethmoidal and infrorbital nerves are injected with a transganglionic tracer to determine their central projections. In a third set of animals, the nasal passages are injected with a transganglionic tracer to determine the central projections of nerves that innervate this region. After allowing neuronal transport of the tracer substance, brainstem tissue is immunologically processed to identify the projection sites of the neuronal tissue. The hypothesis of these experiments is that neurons activated during diving have specific brainstem projections.

Project III:

Determination of brainstem neuronal involvement in the diving response

The general aim of this research is to record physiological variables (i.e. heart rate, arterial blood pressure, and respiration) in anesthetized rats while stimulating the nasal passages, or nerves that innervate the nasal passages such as the anterior ethmoidal nerve (AEN) or infraorbital nerve (ION). To initiate cardiovascular and respiratory changes, either water or ammonia vapors is drawn through the nasal passages. Alternatively, the AEN is electrically stimulated to initiate the cardiovascular and respiratory responses. In some cases after nasal or AEN or ION stimulation, brainstem tissue is immunohistologically processed to determine which nuclei are activated during the cardiorespiratory responses. The hypothesis of these experiments is that specific neurons within the brainstem of rats are activated during stimulation of the nasal passages.

Selected Publications

Reviews:

  1. McCulloch P.F. 2012 Animal models for investigating the central control of the Mammalian diving response. Front. Aquat. Physiol. 3:1-16. Epub 2012 May 29. PMID: 22661956

Papers:

  1. McCulloch P.F. and D.R. Jones. 1990 Cortical influences on diving bradycardia in muskrats (Ondatra zibethicus). Physiol. Zool. 63:1098-1117. PMID:NA
  2. McCulloch P.F. and N.H. West. 1992 Cardiovascular responses to nasal water flow in rats are unaffected by chemoreceptor drive. Am. J. Physiol. 263 (Reg. Int. and Comp. Physiol. 32): R1049-R1056. PMID:1443222
  3. McCulloch P.F., I.A. Paterson, and N.H. West. 1995 An intact glutamatergic trigeminal pathway is essential for the cardiac response to simulated diving. Am. J. Physiol. 269 (Reg. Int. and Comp. Physiol. 38): R669-R677. PMID: 7573570
  4. Yavari P., P.F. McCulloch, and W.M. Panneton. 1996 Trigeminally-mediated alteration of cardiorespiratory rhythms during nasal application of carbon dioxide in the rat. J. Auton. Nerv. Syst. 61:195-200. PMID:8946342
  5. Panneton W.M., P.F. McCulloch, Y. Tan, Y.Tan and P. Yavari. 1996 Brainstem origin of preganglionic cardiac motoneurons in the muskrat. Brain Res. 738:342-346. PMID: 8955533
  6. McCulloch P.F. and W.M. Panneton. 1997 Fos immunohistochemical determination of brainstem neuronal activation in the muskrat after nasal stimulation. Neurosci. 78:913-925. PMID: 9153669
  7. McCulloch P.F., G.P. Ollenberger, L.K. Bekar, and N.H. West. 1997 Trigeminal and chemoreceptor contributions to bradycardia during voluntary dives in rats. Am. J. Physiol. 273 (Reg. Int. and Comp. Physiol. 42): R814-R822. PMID: 9277573
  8. McCulloch P.F., W.M. Panneton and P.G. Guyenet. 1999 The rostral ventrolateral medulla mediates the sympathoactivation produced by chemical stimulation of the rat nasal mucosa. J. Physiol. (Lond). 516: 471-484. PMID: 10087346
  9. McCulloch P.F., K.M. Faber and W.M. Panneton. 1999 Electrical stimulation of the anterior ethmoidal nerve produces the diving response. Brain Res. 830:24-31. PMID: 10350556
  10. Kim E.-S., H. Li, P.F. McCulloch, L.A. Morrision, K.-W. Yoon, and X.M. Xu. 2000 Spatial and temporal patterns of transneuronal labeling in CNS neurons after injection of pseudorabies virus into the sciatic nerve of adult rats. Brain Res. 857:41-55. PMID:10700551
  11. Panneton W.M., P.F. McCulloch and W. Sun. 2000 Trigemino-autonomic connections in the muskrat: the neural substrate for the diving response. Brain Res. 874:48-65. 10936223
  12. West N.H., P.F. McCulloch and P.M. Browne. 2001 Facial immersion bradycardia in teenagers and adults accustomed to swimming. Autonom. Neurosci.: Basic and Clinical 94:109-116. PMID: 11775699
  13. McCulloch, P.F. 2003 Globosa neurons: a distinct subgroup of noradrenergic neurons in the caudal pons of rats. Brain Res. 964:164-167. PMID: 12573526
  14. McCulloch, P.F. and W.M. Panneton. 2003 Activation of brainstem catecholaminergic neurons during voluntary diving in rats. Brain Res. 984:42-53. PMID: 12932838
  15. McCulloch, P.F. 2004 A simple model illustrating the balancing forces of lung and chest wall recoil. Advan. Physiol. Ed. 28:125-127. PMID: 15319196
  16. McCulloch, P.F. 2005 Activation of the trigeminal medullary dorsal horn during voluntary diving in rats. Brain Res. 1051:194-198. PMID: 15978555
  17. Rybka, E.J. and P.F. McCulloch 2006 The anterior ethmoidal nerve is necessary for the initiation of the nasopharyngeal response in the rat. Brain Res. 1075:122-132. PMID: 16466647
  18. Hollandsworth, M.P., K.M. DiNovo and P.F. McCulloch. 2009 Unmyelinated fibers of the anterior ethmoidal nerve in the rat co-localize with neurons in the medullary dorsal horn and ventrolateral medulla activated by nasal stimulation. Brain Res. 1298:131-144. PMID: 19732757
  19. McCulloch P.F., K.M. DiNovo, and T.M. Connolly. 2010 The cardiovascular and endocrine responses to voluntary and forced diving in trained and untrained rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298: R224-R234. Epub 2009 Nov 18. PMID: 19923359
  20. Chotiyanonta, J.S. K.M. DiNovo, and P.F. McCulloch 2013 Bilateral sectioning of the anterior ethmoidal nerves does not eliminate the diving response in voluntarily diving rats. Physiological Reports 1 (6) e00141, DOI - 10.1002/phy2.141 PMID: 24400143
  21. McCulloch P.F., K.M. DiNovo, D.J. Westerhaus, T.A. Vizinas, J.F. Peevey, M. A. Lach and P. Czarnocki 2013 Trigeminal Medullary Dorsal Horn Neurons Activated by Nasal Stimulation Coexpress AMPA, NMDA, and NK1 Receptors. ISRN Neuroscience, vol. 2013, Article ID 152567, 10 pages, 2013. doi: 10.1155/2013/152567 PMID: 24967301
  22. McCulloch P.F. 2014 Training rats to voluntarily dive underwater: investigations of the mammalian diving response. Journal of Visualized Experiments e52093, doi:10.3791/52093 (2014). PMID: 25407626
  23. McCulloch P.F., E.A. Warren and K.M. DiNovo. 2016 Repetitive Diving in Trained Rats Still Increases Fos Production in Brainstem Neurons after Bilateral Sectioning of the Anterior Ethmoidal Nerve. Frontiers in Physiology. 7:148. Doi: 10.3389/fphys.2016.00148 PMID: 27148082