Central Pattern Generators and the Control of Motor Behavior
Repetitive movements, such as locomotion, feeding, and breathing are controlled by neural circuits known as central pattern generators (CPGs). We investigate the structure and function of CPG circuits in simpler model systems, where individual neurons and their synaptic interactions can be directly examined. Our studies focus on specific neurotransmitters and modulators, such as dopamine and GABA, that control repetitive motor activity in all nervous systems, including our own. These studies will therefore disclose principles that are broadly applicable to adaptive motor activity and to the dysfunctional conditions associated with presently incurable movement disorders, such as Parkinson’s Disease and Huntington’s Disease.
Current Research Projects:
Nervous System Structure and Function in an Intermediate Host for Schistosomiasis
The parasitic disease schistosomiasis (also referred to as ‘snail fever’) is estimated to impact the lives of up to ten percent of the people on Earth. Due to the chronic and debilitating nature of its symptoms, schistosomiasis ranks second only to malaria in terms of the costs inflicted on the economic productivity of developing countries. One obligatory factor that is shared by all schistosome blood flukes is the presence of specific snail species that serve as intermediate hosts, supporting critical stages of their multiplication and transformation into forms that are capable of infecting humans. The class of schistosomiasis that occurs in the Western Hemisphere is caused by Schistosoma mansoni, which requires the planorbid pond snail Biomphalaria glabrata to serve as its primary intermediate host. As human infections would cease if parasite infections in snails were prevented, our investigation explores the Biomphalaria nervous system for potential interventions in this host-parasite system.
Delgado N, Vallejo D, Miller MW. (2012). Localization of serotonin in the nervous system of Biomphalaria glabrata, an intermediate host for schistosomiasis. J Comp Neurol. 520: 3236-3255. doi: 10.1002/cne.23095.
Vallejo D, Habib MR, Delgado N, Vaasjo LO, Croll RP, Miller MW.(2014) Localization of tyrosine hydroxylase-like immunoreactivity in the nervous systems of Biomphalaria glabrata and Biomphalaria alexandrina, intermediate hosts for schistosomiasis. J Comp Neurol. 522: 2532-2552. PMID: 24477836
Habib MR, Mohamed AH, Osman GY, Sharaf El-Din AT, Mossalem HS, Delgado N, Torres G, Rolón-Martínez S, Miller MW, Croll RP. (2015) Histamine Immunoreactive Elements in the Central and Peripheral Nervous Systems of the Snail, Biomphalaria spp., Intermediate Host for Schistosoma mansoni. PLoS One. 2015 Jun 18;10(6):e0129800. doi: 10.1371/journal.pone.0129800. eCollection 2015. PMID: 26086611
Mansour TA, Habib MR, Rodríguez LCV, Vázquez AH, Alers JM, Ghezzi A, Croll RP, Brown CT, Miller MW. Central nervous system transcriptome of Biomphalaria alexandrina, an intermediate host for schistosomiasis. BMC Res Notes. 2017 Dec 11;10(1):729. doi: 10.1186/s13104-017-3018-6. PMID: 29228974
Vaasjo LO, Quintana AM, Habib MR, Mendez de Jesus PA, Croll RP, Miller MW. GABA-like Immunoreactivity in Biomphalaria: Colocalization with Tyrosine Hydroxylase-like Immunoreactivity in the Feeding Motor Systems of Panpulmonate Snails. J Comp Neurol. 2018 Apr 6. doi: 10.1002/cne.24448. [Epub ahead of print] PMID: 29633264
Principles of "Brain"-"Body" Coupling and Motor Control
Adaptive behavior is produced not by the nervous system (“brain”) alone, but by the nervous system coupled to the effector systems (“body) that execute actions. In the coupled system, the motor output of the nervous system is matched to the biomechanical properties of the peripheral effectors that it actuates. The periphery, in turn, typically transmits information back to the nervous system to modify the motor output, ensuring that the entire brain-body system functions in an integrated fashion. In collaboration with Dr. Vladimir Brezina (Mount Sinai School of Medicine) and Dr. Charles Peskin (NYU) we are examining CPG-effector interactions in the crustacean cardiac system. The neurogenic heartbeat of decapod crustaceans, such as lobsters and crabs, is controlled by a simple (9 neuron) CPG, the cardiac ganglion (CG). A number of neuromodulators (e.g. dopamine, serotonin, and FMRFamide-related peptides), acting both as blood borne neurohormones and through direct modulatory innervation of the CG, operate in distinct ways at multiple sites to achieve coherent regulation of the heartbeat. In contrast to many other systems, the functional output of a heart is relatively self-evident, easily measurable, and of obvious physiological importance. The crustacean cardiac system is thus a complete, self-contained, functionally interpretable brain-body system that is exceptionally simple, yet has a sufficient number of interacting components and modes of operation to yield principles of general relevance to much more complex systems.
Garcia-Crescioni K, Miller. (2011) Revisiting the reticulum: feedforward and feedback contributions to motor program parameters in the crab cardiac ganglion microcircuit. J Neurophysiology 106: 2065-2077.
García-Crescioni, K Stern E, Fort, T.J., Brezina, V., and Miller M.W. (2010) Feedback from peripheral musculature to central pattern generator in the neurogenic heart of the crab Callinectes sapidus: Role of mechanosensitive dendrites. J Neurophysiology 103: 83-96.
Stern E, García-Crescioni, K., Miller, M.S., Peskin, C.S., and Brezina, V. (2009) A method for decoding the neurophysiological spike-response transform. Journal of Neuroscience Methods 184: 337-356.
Fort, T.J., Brezina, V., and Miller, M.W. (2007) Regulation of the crab heartbeat by FMRFamide-like peptides: Multiple interacting effects on center and periphery. J. Neurophysiology 98: 2887-2902.
Fort, T.J., García Crescioni, K., Agricola, H.-.J., Brezina, V. and Miller, M.W. (2007) Regulation of the crab heartbeat by crustacean cardioactive peptide (CCAP): Central and peripheral actions. J. Neurophysiology. 97: 3407-3420.
Stern, E., Fort, T., Miller, M., Peskin, C., and Brezina, V. (2007) Decoding modulation of the neuromuscular transform. Neurocomputing 70: 1753-1758.
Fort, T.J., Brezina V., Miller M.W. (2004) Modulation of an integrated central pattern generator – effector system: Dopaminergic regulation of cardiac activity in the blue crab Callinectes sapidus. J Neurophysiology 92: 3455-3470.
Cotransmitters and the Regulation of Motor Activity
Once considered a curiosity, the notion that individual neurons can contain more than one classical neurotransmitter has gained increasing credibility in recent years. The large identified neurons that comprise certain invertebrate model systems make it possible to directly examine the function of colocalized classical neurotransmitters in well-characterized neural circuits. Our studies examine five specific interneurons in the feeding circuit of the marine mollusc Aplysia californica that colocalize GABA and dopamine (DA). These GABA-DA neurons are key determinants in the selection of specific behaviors from the multifunctional feeding CPG. We are testing the hypothesis that GABA-DA cotransmission enables these interneurons to specify both qualitative and quantitative aspects of motor program selection.
Martínez-Rubio, C., Serrano, G.E., and Miller, M.W. (2009) Localization of biogenic amines in the foregut of Aplysia: Catecholaminergic and serotonergic innervation. J Comparative Neurology 514: 329–342.
Miller, M.W. (2009) Colocalization and cotransmission of classical neurotransmitters: an invertebrate perspective. In: Co-existence and Co-release of Classical Neurotransmitters (R. Gutiérrez, Ed.) Springer. New York. 243-262.
Díaz-Ríos, M., and Miller M.W. (2006) Target-specific regulation of synaptic efficacy in the feeding central pattern generator of Aplysia: Potential substrates for behavioral plasticity? Biol Bulletin 210: 215-229.
Díaz-Ríos M., and Miller M.W. (2005) Rapid dopaminergic signaling by interneurons that contain markers for catecholamines and GABA in the feeding circuitry of Aplysia. J Neurophysiology 93: 2142-2156.
Wu J.S., Jing J., Díaz-Ríos M., Miller M.W., Kupfermann I., Weiss K.R. (2003) Identification of a GABA-containing cerebral-buccal interneuron-11 in Aplysia californica. Neurosci Letters 341:5-8
Díaz-Ríos, M., Oyola, E., and Miller, M.W. (2002) Colocalization of GABA-like immunoreactivity and catecholamines in the feeding network of Aplysia californica. J Comparative Neurology, 445:29-46.
Conditional Rhythmicity and Synchrony of Motor Activity
In many biological systems, the propensity of pulse-coupled oscillators to become synchronized reflects two factors, their relative frequencies and the amplitude of their mutual coupling. We are studying how neuromodulator substances (e.g. dopamine, octopamine, and serotonin) can regulate the burst activity of a bilateral pair of motor neurons (B67) in the feeding system of Aplysia. Under control conditions the two B67 motor neurons exhibit spontaneous burst activity that is infrequent (< 0.1 per sec), irregular, and asynchronous. Although both dopamine and octopamine cause rapid rhythmic bursting in the B67 pair, only dopamine causes them to burst synchronously. These studies indicate that one adaptive benefit conferred upon motor systems by the convergent and divergent actions of neuromodulators could be to regulate the extent to which the rhythmicity and synchrony of specific actions are coupled.
Common and distinct modulatory actions of octopamine and dopamine on B67 bursting. (A) Sequential application of octopamine and dopamine illustrate their common and distinct actions on B67 burst activity. While octopamine and dopamine both produce increases in the duration, frequency, and rhythmicity of B67 bursting, only dopamine also imposes synchronous bilateral B67 bursting. Right panels: Circular plots illustrate phase relations between the two B67 neurons under control conditions (top), in octopamine (middle), and in dopamine (bottom). (B) Schematic interpretation of proposed modulator actions on B67. It is hypothesized that synchrony of bursting between the two B67’s requires that their rhythmicity and mutual coupling both exceed a critical level (horizontal dashed line). Although dopamine and octopamine both exert comparable increases in the rhythmicity of B67 bursting (vertical arrows), only DA enhances their coupling sufficiently to achieve burst synchrony.
Serrano, G.E., and Miller, M.W. (2006) Conditional rhythmicity and synchrony in a bilateral pair of bursting motor neurons in Aplysia. Journal of Neurophysiology 96:2057-2071. PMID: 16738215.
Martínez-Rubio, C., Serrano, G.E., and Miller, M.W. (2010) Octopamine promotes rhythmicity but not synchrony in a bilateral pair of bursting neurons in the feeding circuit of Aplysia. Journal of Experimental Biology 213: 1182-1194. PMID: 20228355.