Contact Information:
Michael M. Francis, Ph.D.
University of Massachusetts Medical School
Department of Neurobiology, 715 Lazare Research Building
364 Plantation Street
Worcester, MA 01605 USA
phone: 508-856-1496 (office)
phone: 508-856-1609 (lab)
Biography
Michael Francis pursued undergradate studies in psychology (psychobiology) at the University of Virginia. He earned his Ph.D. from the Department of Neuroscience at the University of Florida College of Medicine. He pursued postdoctoral training in the Department of Molecular Medicine at Cornell University and the Biology Department at the University of Utah in the lab of Villu Maricq. His predoctoral and postdoctoral studies were supported by NIH NRSA awards. Mike joined the Neurobiology Department at the University of Massachusetts Chan Medical School as a faculty member in 2007.
Francis Lab Link
Research Interests
Our laboratory investigates genetic pathways that sculpt the connectivity of circuits, alter their performance, and shape behavior. In particular, we seek to identify regulatory mechanisms that control synaptic activity and understand their contribution to nervous system development, as well as neural circuit output and behavior. To address these questions, we use tools for manipulating or recording neuronal activity in a genetically tractable model system, the nematode Caenorhabditis elegans. In addition to an abundance of available genetic tools, C. elegans offers a number of features that make it ideally suited for our work. The pattern of neural connectivity has been established by electron microscopy, allowing for detailed knowledge of synaptic partners in a circuit. The organism is optically transparent, enabling (1) easy imaging of the cellular and subcellular distribution of fluorescent reporters, (2) Ca2+ imaging studies, and (3) optogenetic approaches for cell-specific optical stimulation or inhibition of neurons, all in the intact animal. Finally, we have extensive expertise in patch clamp electrophysiology in order to measure synaptic currents from defined neurons or muscles in vivo.
Neural circuit development & function
We are interested in understanding how the complex molecular structure of synapses is achieved and are working to identify molecular pathways that regulate synaptic connectivity. Our studies addressing these questions utilize the experimentally tractable motor circuit of the nematode Caenorhabditis elegans (Fig. 1). In this circuit, a balance of excitatory and inhibitory signaling onto muscles is required to drive sinusoidal movement, and we have found that this is regulated by ionotropic nicotinic acetylcholine receptors (iAChR) bearing strong similarity to mammalian brain iAChRs (Fig. 2). In particular, we have identified an iAChR that is localized at synapses onto GABA neurons and mediates their synaptic excitation. Based on the anatomical connectivity of this circuit (Fig. 1), models of C. elegans locomotion have long assumed that GABA motor neurons respond to cholinergic signals from upstream motor neurons. Our work provides direct molecular support for this AChàGABA neurotransmission model and provides a unique opportunity to investigate conserved mechanisms underlying the formation and functional regulation of neuronal cholinergic synapses. To address these questions, we have developed a system in which we can monitor iAChR localization and trafficking in a single inhibitory neuron dendrite in vivo (Fig. 3)
Neuromodulation & context-dependent behavior
We are seeking to understand how neural circuit activity and behavior is shaped through the actions of neuropeptide modulators. To address these questions, we developed a genetic strategy for elevating synaptic excitation of muscles by enhancing the activity of muscle iAChRs, and identified an important role for the cholecystokinin (CCK) homolog nlp-12. We found that deletion of nlp-12/CCK reduced the duration of cholinergic synaptic currents at the NMJ and disrupted local food searching, a behavioral program triggered by reduced food availability (Fig. 4). While CCK function is associated with satiety signaling in mammals, the neural circuit basis for this remains unclear. We found that behavioral responses to reduced food availability are shaped through context-dependent NLP-12/CCK modulation of motor circuit responsiveness to sensory information about food (Fig. 4), a striking example of how the approaches we are pursuing enable us to gain novel insights into signaling pathways directly relevant to mammalian neurobiology. In related studies, we are investigating context-dependent neuropeptide modulation in other behavioral paradigms, such as egg-laying.
Ion channel-mediated neurodegeneration
Roles for ionotropic receptor mediated signaling in the nervous system extend far beyond a well-characterized participation in cell-cell communication at synapses. Ionotropic receptor activation is one of several key factors that influences cell survival in developing and mature nervous systems. We have found that that hyperactivation of iAChRs located on excitatory motor neurons leads to motor neuron degeneration. Interestingly, under conditions in which death of the cell bodies was attenuated, we noted iAChR hyperactivation led to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our work to date suggests that ion channel hyperactivation has distinct consequences for the cell soma compared with neurites. We are now working to uncover the molecular pathways that underlie ion channel mediated toxicity in neuronal cell bodies as well as processes.
Fig. 1. Adult C. elegans motor circuit. For clarity, only ventral ACh to dorsal GABA is shown. ACh motor neurons (MNs, gray) make synaptic connections with ventral muscle cells (brown) and dorsally projecting GABA MNs (purple).
Fig 2. Two iAChR classes control motor neuron excitation. ACh motor neurons (gray) form dyadic synapses onto muscles (tan) and GABA motor neurons (purple).Distinct iAChR populations (ACR-2/12ACh and ACR-12GABA) regulate motor neuron activity. ACR-2/12ACh receptors are diffusely localized along dendrites of ACh motor neurons and play a primarily modulatory role. ACR-12GABA receptors form a punctate pattern along the dendrites of GABA motor neurons and mediate synaptic activation of GABA motor neurons.
Fig 3. ACR-12 iAChR localization in the GABA motor neuron, DD1.
Fig 4. Context-dependent dopamine regulation of NLP-12 release from the interneuron DVA modulates food seeking behavior.