In collaboration with the laboratory of Dr Réjean Dubuc at the Université de Montréal and Dr Heidi Hamm at Vanderbilt University, we have  investigated modulation of descending command systems in the brainstem and spinal spinal cord. 

This work has demonstrated how descending command systems are modulated by cholinergic and dopaminergic systems in the brainstem of vertebrates as well as how serotenergic presynaptic neuromodulation alters activity in the spinal cord. 

Descending dopaminergic systems:

Dopamine neurons are known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson’s disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminer- gic inputs that potentiate locomotor output. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor net- works were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neu- rons projecting to the striatum also innervated the pedunculopon- tine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. The Dubuc Laboratory has also found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine’s role in locomotion.

Ryczko D, Grätsch  F, Auclair F, Dubé C, Bergeron S,  Alpert M, Cone J, Roitman M, Alford S, Dubuc R. (2013) Forebrain dopamine neurons project down to a brainstem region controlling locomotion. Proc Natl Acad Sci U S A. 110(34): E3235-3242.

Ryczko D, Cone JJ, Alpert MH, Goetz L, Auclair F, Dubé C, Parent M, Roitman MF, Alford S, and Dubuc R. A descending dopamine pathway conserved from basal vertebrates to mammals (2016) Proceedings of the National Academy of Sciences 113 (17), E2440-E2449

 D Ryczko, S Grätsch, MH Alpert, JJ Cone, J Kasemir, A Ruthe, P-A Beauséjour, F Auclair, MF Roitman, S Alford, R Dubuc (2020) Descending dopaminergic inputs to reticulospinal neurons promote locomotor movements Journal of Neuroscience 40 (44), 8478-8490.

Cholinergic (muscarinic) modulation:

The brainstem locomotor system is believed to be organized serially from the mesencephalic locomotor region (MLR) to reticulospinal neurons, which in turn project to locomotor neurons in the spinal cord. We have identified brainstem muscarinoceptive neurons in lampreys (Petromyzon marinus) that received parallel inputs from the MLR and projected back to reticulospinal cells to amplify and extend the duration of locomotor output. These cells responded to muscarine with extended periods of excitation, received direct muscarinic excitation from the MLR and projected glutamatergic excitation to reticulospinal neurons. Targeted blockade of muscarine receptors over these neurons profoundly reduces MLR-induced excitation of reticulospinal neurons and markedly slowed MLR-evoked locomotion. The presence of these neurons forces us to rethink the organization of supraspinal locomotor control, to include a sustained feedforward loop that boosts locomotor output.

Smetana RW, Alford S & Dubuc R. (2007) Muscarinic receptor activation elicits sustained, recurring depolarizations in reticulospinal neurons, Journal of Neurophysiology. 97:3181-3192

Smetana R, Juvin L, Dubuc R, Alford S. (2010) A parallel cholinergic brainstem pathway for enhancing locomotor drive. Nature Neuroscience. 2010 13:731-738. 

Spinal Modulation by presynaptic serotenergic signalling:

Blackmer, T., Larsen, E., Takahashi, M., Martin, T. F. J., Alford, S. & Hamm, H. E. (2001) Heterotrimeric G protein Gbgsubunits mediate presynaptic inhibition by regulating exocytotic fusion downstream of Ca2+ entry. Science, 292:293-297

Schwartz, E., Gerachshenko, T. and Alford S. (2005) 5-HT Prolongs Ventral Root Bursting via Presynaptic Inhibition of Synaptic Activity During Fictive Locomotion in Lamprey. Journal of Neurophysiology 93: 980-988.

Gerachshenko T, Blackmer T, Yoon EJ, Bartleson C, Hamm HE, Alford S. (2005)  Gbg acts at the C terminus of SNAP-25 to mediate presynaptic inhibition. Nature Neuroscience 8: 597-605. 

Gerachshenko T, Schwartz E, Bleckert A, Photowala H, Seymour A and Alford S (2009) Presynaptic G protein-coupled receptors dynamically modify vesicle fusion, synaptic cleft glutamate concentrations and motor behavior. Journal of Neuroscience 29:10221-10233

Z Zurawski, YY Yim, S Alford, HE Hamm (2019) The expanding roles and mechanisms of G protein–mediated presynaptic inhibition. Journal of Biological Chemistry 294 (5), 1661-1670