Adjunct: Department of Medical Pharmacology and Physiology
Investigator, Dalton Cardiovascular Research Center
Member, Interdisciplinary Neuroscience Program
Member, Translational Biosciences Graduate Program
- PhD: Wright State University
- Postdoctoral Training: University of Wisconsin-Madison (Prof. Gordon S. Mitchell)
Multi-Disciplinary Approaches to Biomedical Sciences, Neural Control of the Circulation, Veterinary Microanatomy, Veterinary Endocrinology and Reproductive Physiology
Office: Veterinary Medicine Building W145
Lab: Veterinary Medicine Building W146-W151
Phone: 573-882-2534 (office); 573-882-3715 (lab)
Preservation and/or improvement of respiratory and swallowing function and coordination following motor neuron loss
Our laboratory focuses on the central nervous system, and one research direction includes the control of breathing in models of motor neuron death. Breathing is essential to life and cannot cease for more than the briefest periods, or life will not continue. At the same time, breathing must be continuously adjusted throughout life to maintain homeostasis in response to physiological (for example exercise, pregnancy or high altitude) or pathological (for example disease or disorder) situations. One way the neural system controlling breathing maintains homeostasis is to express plasticity, which is defined as a persistent change in the neural control system based on a prior experience. A well-known model of respiratory plasticity is phrenic long-term facilitation (pLTF), a long-lasting increase in phrenic motor output elicited by acute exposure to intermittent hypoxia. Although, we know a great deal about the mechanism that underlies pLTF under normal circumstances, the mechanism that underlies pLTF and how it is affected by contributing factors (e.g., inflammation) in models of motor neuron death is not well understood. Determining the mechanism that underlies pLTF and how it can be enhanced in models of motor neuron death to preserve and/or improve breathing is one focus of the laboratory.
Another focus of the Nichols laboratory is to investigate the function and coordination of swallowing and breathing in models of motor neuron death in collaboration with the laboratory of Dr. Teresa Lever. Swallowing and breathing rely on shared upper airway structures that are damaged in many motor neuron diseases. These co-dependent functions are life-sustaining and require reciprocal roles of the tongue during swallowing. The impaired control and coordination of these opposing behaviors ultimately results in respiratory failure and death. In order to combat this impaired control, we are exploring the effects that tongue exercise and induction of plasticity have on upper airway function and coordination.
We utilize a multidisciplinary approach in the Nichols lab. These include: 1) novel pharmacological injections to induce models of motor neuron death; 2) whole animal plethysmography to measure respiration in unanesthetized animals; 3) videofluoroscopy swallow studies in conjunction with the Lever lab; 4) in vivo neurophysiology to measure spontaneous nerve output and nerve output in response to targeted drug delivery; 5) EMG to measure output in muscles responsible for breathing and swallowing function; 6) immunohistochemical localization of neurotransmitter receptors and proteins of interest on individual neurons, astrocytes and microglia; 7) PCR to measure gene expression; 8) TEM to study morphological changes in neurons, nerves, and muscles; and 9) MRI to quantify degenerative changes in the CNS. Using these techniques, we have developed novel models of motor neuron death that mimics aspects of neurodegenerative diseases related to ventilatory and swallowing functions. Further, using these models, we can study the mechanism that underlies plasticity in surviving motor neurons responsible for breathing and swallowing, and how plasticity can be enhanced following motor neuron death.
- Nguyen, N.P., Lopez, S., Smith, C.L., Lever, T.E., Nichols, N.L., and Bunyak, F. Axon and Myelin Sheath Segmentation In Electron Microscopy Images Using Meta Learning. IEEE Appl. Imag. Pattern Recogni. Workshop. pp. 1-6, 2022. PMCID: PMC10197949.
- Murphy, E.R., Thompson, R., Osman, K.L., Haxton, C., Brothers, M., Lee, L., Warncke, K., Smith, C.L., Keilholz, A.N., Hamad, A., Golzy, M., Bunyak, F., Ma, L., Nichols, N.L.,* and Lever T.E.* A strength endurance exercise paradigm mitigates deficits in hypoglossal-tongue axis function, strength, and structure in a rodent model of hypoglossal motor neuron degeneration. Frontiers in Neuroscience doi: 10.3389/fnins.2022.869592, 2022. PMCID: PMC9279620.
- Mueller, M., Thompson, R., Osman, K.L., Andel, E., DeJonge, C.A., Kington, S., Stephenson, Z., Hamad, A., Bunyak, F., Nichols, N.L., and Lever, T.E.* Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS. Dysphagia 37(6): 1777-1795, 2022. PMCID: PMC9568622.
- Borkowski, L.F., Keilholz, A.N., Smith, C.L., Canda, K.A., and Nichols, N.L.* Nonsteroidal anti-inflammatory drug (ketoprofen) delivery differentially impacts phrenic long-term facilitation in rats with motor neuron death induced by intrapleural CTB-SAP injections. Exper. Neurol. 347:113892, 2022. PMID: 34634309.
- Smith, C.E., Lorson, M.A., Hernandez-Ricardez, S.M., Al Rawi, Z., Mao, J., Marquez, J., Villalón, E., Keiholz, A.N., Smith, C.L., Garro-Kacher, M.O., Morcos, T., Davis, D.J, Bryda, E.C, Nichols, N.L., Lorson, C.L.* The Ighmbp2D564N mouse model is the first SMARD1 model to demonstrate respiratory defects. Hum. Mol. Genet. 31(8): 1293-1307, 2022. PMCID: PMC9029233.
- Borkowski, L.F., Smith, C.L., Keilholz, A.N., and Nichols, N.L.*. Divergent receptor utilization is necessary for phrenic long-term facilitation over the course of motor neuron loss following CTB-SAP intrapleural injections. J. Neurophysiol. 126(3): 709-722, 2021. PMCID: PMC8461823
- Allen, L.L., Nichols, N.L., Asa, Z.A., Emery, A.T., Ciesla, M.C., Santiago, J.V., Holland, A.E., Mitchell, G.S., and Gonzalez-Rothi, E.J. Phrenic motor neuron survival below cervical spinal cord hemisection. Exper. Neurol. 346:113832, 2021. PMCID: PMC9065093.
- Nichols, N.L.*. and Mitchell, G.S. Mechanisms of severe acute intermittent hypoxia induced phrenic long-term facilitation. J. Neurophysiol. 125(4): 1146-1156, 2021. PMCID: PMC8282229.
- Lind, L.A., Lever, T.E., and Nichols, N.L.* Tongue and hypoglossal morphology after intralingual CTB-saporin injection. Muscle & Nerve 63(3): 413-420, 2021. PMCID: PMC8117177.
- Borkowski, L.F. and Nichols, N.L.* Differential mechanisms are required for phrenic long-term facilitation over the course of motor neuron loss following CTB-SAP intrapleural injections. Exper. Neurol. 334:113460, 2020. PMID: 32916172.
- Borkowski, L,F., Craig, T.A., Stricklin, O.E., Johnson, K.A., and Nichols, N.L.* (2020). 5-HT2A/B receptor expression in the phrenic motor nucleus in a rat model of ALS (SOD1G93A). Respir. Physiol. Neurobiol. 279: 103471.
- Lind, L.A., Andel, E.M., McCall, A.L., Dhindsa, J.S., Johnson, K.A., Stricklin, O.E., Mueller, C., ElMallah, M.K., Lever, T.E., and Nichols, N.L.* (2020). Intralingual administration of AAVrh10-miRSOD1 improves respiratory but not swallowing function in a SOD1 mouse model of ALS. Human Gene Therapy 31(15-16): 828-838.
- Kloepper, A., Arnold, J., Ruffolo, A., Kinealy, B., Haxton, C., Nichols, N., Takahashi, K., and Lever, T.E. (2020). An experimental swallow evoked potential protocol to investigate the neural substrates of swallowing. OTO-Open 4(1): 1-5.
- Litvin, D.G., Denstaedt, S.J., Borkowski, L.F, Nichols, N.L., Dick, T.E., Smith, C.B., and Jacono, F.J. (2020). Peripheral-to-central immune communication at the area postrema glial-barrier following bleomycin-induced sterile lung injury in adult rats. Brain, Behavior and Immunity 87: 610-633.
- Haney, M., Hamad, A., Woldu, H., Ciucci, M., Nichols, N., Bunyak, F., and Lever, T. (2020). Recurrent Laryngeal Nerve Transection in Mice Results in Translational Upper Airway Dysfunction. J. Comp. Neurol. 528(4): 574-596.
- Osman, K.L., Kohlberg, S., Mok, A., Brooks, R., Lind, L.A., McCormack, K., Ferreira, A., Kadosh, M., Fagan, M.K., Bearce, E., Nichols, N.L., Coates, J.R., and Lever, T.E. (2020). Optimizing the translational value of mouse models of ALS for dysphagia therapeutic discovery. Dysphagia 35(2): 343-359.
- Lind, L.A., Murphy, E.R., Lever, T.E., and Nichols, N.L.* (2018). Hypoglossal motor neuron death via intralingual CTB-saporin (CTB-SAP) injections mimic aspects of amyotrophic lateral sclerosis (ALS) related to dysphagia. Neuroscience 390: 303-316.
- Agosto-Marlin, I.M., Nichols, N.L. and Mitchell, G.S. (2018). Systemic inflammation inhibits serotonin receptor 2-induced phrenic motor facilitation upstream from BDNF/TrkB signaling. J. Neurophysiol. 119(6): 2176-2185.
- Seven, Y.B., Nichols, N.L., Kelly, M.N., Hobson, O.R., Satriotomo, I. and Mitchell, G.S. (2018). Compensatory plasticity in diaphragm and intercostal muscle utilization in a rat model of ALS. Exper. Neurol. 299(Pt A): 148-156.
- Nichols, N.L.,* Craig, T.A., and Tanner M.A. (2018). Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death. Respir. Physiol. Neurobiol. 256: 43-49.
- Nichols, N.L.,* Satriotomo, I., Allen, L.L., Grebe, A.M. and Mitchell, G.S. (2017). Mechanisms of enhanced phrenic long-term facilitation in SOD1G93A J. Neurosci. 37(24): 5834-5845.
- Nichols, N.L., Ilatovskaya, D.V. and Matyas, M.L. (2017). Monitoring undergraduate student needs and activities at Experimental Biology: APS pilot survey. Adv. Physiol. Educ. 41(2): 186-193.
- Agosto-Marlin, I.M., Nichols, N.L. and Mitchell, G.S. (2017). Adenosine-dependent phrenic motor facilitation is inflammation resistant. J. Neurophysiol. 117(2): 836-845.
- Devinney, M.J., Nichols, N.L. and Mitchell, G.S. (2016). Sustained hypoxia elicits competing spinal mechanisms of phrenic motor facilitation. J. Neurosci. 36(30): 7877-7885.
- Nichols, N.L.* and Mitchell, G.S. (2016). Quantitative assessment of integrated phrenic nerve activity. Respir. Physiol. Neurobiol. 226: 81-86.
- Satriotomo, I., Nichols, N.L., Dale, E.A., Emery, A.T., Dahlberg, J. and Mitchell, G.S. (2016). Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons. Neuroscience 322: 479-488.
- Nichols, N.L.,* Satriotomo, I., Harrigan, D.J. and Mitchell, G.S. (2015). Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS. Exper. Neurol. 273: 138-150
- Nichols, N.L.,Vinit, S., Bauernschmidt, L. and Mitchell, G.S. (2015). Respiratory function after selective respiratory motor neuron death from intrapleural CTB-saporin injections. Exper. Neurol. 267: 18-29.
- Nichols, N.L., Johnson, R.A., Satriotomo, I. and Mitchell, G.S. (2014). Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats. Respir. Physiol. Neurobiol.197: 19-28.
- Huxtable, A.G., MacFarlane, P.M., Vinit, S., Nichols, N.L., Dale, E.A. and Mitchell, G.S. (2014). Adrenergic a1 receptor activation is sufficient, but not necessary for phrenic long-term facilitation. J. Appl. Physiol.116(11): 1345-1352.
- Nichols, N.L. and Sasser, J.M. (2014). The other side of the submit button: how to become a reviewer for scientific journals. Physiologist. 57(2): 88-91.
- Nichols, N.L., Powell, F.L., Dean, J.B. and R.W. Putnam. (2014). Substance P differentially modulates firing rate of solitary complex (SC) neurons from control and chronic hypoxia-adapted adult rats. PLoS ONE. 9(2): e88161.
- Nichols, N.L.,Van Dyke, J., Suzuki, M. and Mitchell, G.S. (2013). Ventilatory control in ALS. Respir. Physiol. Neurobiol. 183(2): 429-437.
- Devinney, M.J., Huxtable, A.G., Nichols, N.L.and Mitchell, G.S. (2013). Hypoxia-induced phrenic long-term facilitation: emergent properties. Ann. N Y Acad. Sci. 1279(1): 143-153.
- Nichols, N.L., Gowing, G., Satriotomo, I., Nashold, L.J., Dale, E.A., Suzuki, M., Avalo, P., Mulcrone, P.L., McHugh, J., Svendsen, C.N. and Mitchell, G.S. (2013). Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of ALS. Am. J. Resp. Crit. Care Med. 187(5): 535-542.
- Nichols, N.L., Punzo, A.M., Duncan, I.D., Mitchell, G.S. and Johnson, R.A. (2013). Cervical spinal demyelination with ethidium bromide impairs respiratory (phrenic) activity and forelimb motor behavior in rats. Neuroscience 229: 77-87.
- Strey, K.A., Nichols, N.L., Baertsch, N., Broytman, O. and Baker-Herman, T.L. (2012). Spinal atypical protein kinase C activity is necessary to stabilize inactivity-induced phrenic motor facilitation. J. Neurosci. 32(46): 16510-16520.
- Hoffman, M.S., Nichols, N.L., Macfarlane, P.M. and Mitchell, G.S. (2012). Phrenic long term facilitation following acute intermittent hypoxia requires spinal ERK activation but not TrkB synthesis. J. Appl. Physiol. 113(8): 1184-1193.
- Nichols, N.L., Dale, E.A. and Mitchell, G.S. (2012). Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism. J. Appl. Physiol. 112(10): 1678-1688.
- Nichols, N.L., Wilkinson, K.A., Powell, F.L. and Putnam R.W. (2009). Chronic hypoxia suppresses the CO2response of solitary complex (SC) neurons from rats. Respir. Physiol. Neurobiol. 168(3): 272-280.
- Nichols, N.L., Mulkey, D.K., Wilkinson, K.A., Powell, F.L., Dean J.B. and Putnam R.W. (2009). Characterization of the chemosensitive response of individual solitary complex (SC) neurons from adult rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296(3): 763-773.
- Conrad, S.C., Nichols, L., Ritucci, N.A., Dean, J.B. and Putnam R.W. (2009). Development of chemosensitivity in neurons from the nucleus tractus solitarii (NTS) of neonatal rats. Respir. Physiol. Neurobiol. 166(1): 4-12.
- Nichols, N.L., Hartzler, L.K., Conrad, S.C., Dean, J.B. and R.W. Putnam. (2008). Intrinsic chemosensitivity of individual nucleus tractus solitarius (NTS) and locus coeruleus (LC) neurons from neonatal rats. Adv. Exp. Med. Biol. 605: 348-352.