Claudia Lodovichi

Circuit formation and function in the olfactory system

Field of Interest

The specificity of connections in the nervous system is essential to translate the electrical activity into meaningful neuronal codes.
The olfactory system is an attractive model for the study of neuronal wiring and information processing in the mammalian brain for several reasons. 1. Its high degree of plasticity allows an ongoing view on circuit formation and function. 2. The principles and the neural circuits underlying the sense of smell have been highly conserved during evolution. 3. The olfactory bulb is a well-layered structure where inputs and outputs, can be easily identified.

The olfactory system is an extremely sophisticated system able to recognize and discriminate thousands of different odors. In humans, odors are associated with strong emotional reactions, such as pleasure or disgust, and are able to evoke vivid memories. But in most animals, the olfactory system is critical to accomplish vital functions such as finding food, detecting predators and locating mates. The logic underpinning such complex functions remains largely to be understood.

We are committed to understand the logic underpinning circuit formation and function in the olfactory system. To accomplish these goals, we combine several different and innovative experimental approaches including anatomy, behavior, imaging and electrophysiological recordings.

Sensory map in the olfactory bulb

Figure 1. Example of an olfactory sensory neuron genetically labeled with GFP. Arrow: cilia; arrowhead: soma.

In most sensory systems, peripheral neurons are spatially organized and project their axons to precise locations in the brain to create an internal representation of the external world. The spatial segregation of afferent inputs provides topographic maps that define the location of the sensory stimulus in the environment as well as the quality of the stimulus itself. The topographic organization of the olfactory system presents several unique features. Each olfactory sensory neuron (Figure 1) expresses only one odorant receptor gene out of a repertoire of ~1000. In the olfactory epithelium is present only a coarse topographic organization. Spatial order, however, is achieved in the olfactory bulb (the first re-transmission station of the olfactory system) where olfactory sensory neurons expressing the same odorant receptor converge with exquisite precision to form glomeruli in specific loci on the medial and lateral side of each bulb. Unlike other neurons, olfactory sensory neurons continuously regenerate but the specificity of the sensory neuron axonal convergence is maintained throughout the entire life. How do neurons expressing a given receptor identify their target with such precision? A unique aspect in the topographic organization of the olfactory bulb is the “dual” role of the odorant receptor. Indeed, the odorant receptor is involved in the transduction of chemical signals (odors) but it is thought to play also an instructive role in the glomerular convergence of the sensory neuron axons. This hypothesis is supported by several genetic experiments and by the demonstration that the odorant receptor is expressed not only at the cilia but also at the axon terminal-growth cone. The odorant receptor is a G protein coupled receptor, that upon binding odors at the cilia, leads to cAMP and Ca2+ rise. The signaling pathway coupled to the odorant receptor at the axon terminal remained unknown. By studying the spatio-temporal dynamics of cyclic nucleotides and calcium in real time imaging in olfactory sensory neurons, we demonstrated, for the first time, that the odorant receptor at the axon terminal is coupled to local increases of cAMP, cGMP and Ca2+ (Maritan et al., 2009, Pietrobon et al., 2011; Lodovichi and Belluscio, 2012).

 

Topographic organization and neural circuitry in the olfactory bulb

Figure 3. Example of a focal tracer injection centered in a GFP labeled glomerulus. The injection labels ETC (arrowhead) innervating the glomerulus. GL, glomerular layer, EPL, external plexiform layer, MC, mitral cell layer.

A glomerulus defines a functional unit consisting of the mitral, tufted and periglomerular cells receiving inputs from a specific group of olfactory sensory neurons, along with the granule cells connected to those cells (Figure 2). Axons of olfactory sensory neurons expressing the same odorant receptor converge to form glomeruli in specific locations on the medial and the lateral side of each olfactory bulb. A unique feature of this initial sensory projection is that each bulb presents two mirror symmetric maps of homologous glomeruli. We found that the two maps are reciprocally connected through an inhibitory link related to external tufted cells (Belluscio L. et al., 2002; Lodovichi C. et al., 2003). This connection adds another level of topographic organization to the sensory map of the olfactory bulb.

 

The formation of a topographic map is regulated by the complex interaction between molecules expressed in a specific spatio-temporal pattern and by electrical activity.  We are interested in understanding the mechanism underlying the topographic organization of the olfactory bulb, in particular the role of afferent spontaneous activity. Spontaneous  electrical activity plays a prominent role in the topographic organization of other sensory modalities, such as vision. The role of spontaneous activity in neuronal wiring and information processing in the olfactory bulb, remained poorly understood. We thorough dissected the role of spontaneous afferent activity in circuit formation and function, combining electrophysiology, anatomy, functional imaging in vivo and behavior. We found that dramatically reduced afferent spontaneous activity leads to unrefined connectivity of the sensory map and of the intrabulbar link between homologous glomeruli. The unrefined connectivity was reflected, with remarkable precision, in altered functional representation of odors in the olfactory bulb and deeply affected the odor discrimination behavior (Lorenzon et al2015) (Figure 3). In this work (Lorenzon et al, 2015) we described how altered neuronal connections affects the function of the corresponding circuitry and, ultimately, how altered neuronal wiring and information processing affects the behaviour.

From physiology to diseases

The olfactory system is an attractive model for the study of neuronal wiring and information processing not only in physiological but also in pathological conditions. The olfactory system is affected in several neurodegenerative and psychiatric disorders.

Noteworthy, 90% of patients with Parkinson’s disease presents olfactory dysfunction years before the motor symptoms. The mechanism underlying olfactory deficits are still unknown. We are committed to understand the mechanism underlying olfactory dysfunctions in Parkinson and in other neurodegenerative and psychiatric disorders.

Combining anatomical approaches, behaviour, functional imaging and electrophysiological recordings, in vitro an in vivo, we are working on several mouse models of diseases to understand the pathogenesis of these disorders.

Claudia Lodovichi synoptic CV

testo alternativo2012 present VIMM Junior Principal Investigator
2009 present Assistant Professor, Institute of Neurosciences, CNR, Padua
2006 present Principal Investigator Armenise-Harvard Career Development Award, VIMM
2003-2005 Fellow, Columbia University, Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behaviour, New York, NY, USA.
1999-2003 Fellow ( HHMI Research Assistant) Department of Neurobiology,  Duke University, Durham USA
1999 Ph.D. in Neuroscience, Scuola di Studi Superiore Universitari e Perfezionamento, S. Anna, Pisa
1995 MD, University of Pisa Medical School, Pisa

 

Group members

Post Doc

Luisa Galla
Nelly Redolfi

PhD students
Simona Francia
Andrea Maset

Undergrad
Filippo Michelon
Ilaria Prete
Alessandra Scapolon

Selected publications

  • Belluscio L, Lodovichi C, Feinstein P, Mombaerts P, Katz LC (2002) Odorant receptors instruct functional circuitry in the mouse olfactory bulb. Nature 419:296-300.
  • Lodovichi C, Belluscio L, Katz LC (2003) Functional topography of connections linking mirror symmetric maps in the mouse olfactory bulb. Neuron 38:265-27.
  • Maritan M, Monaco G, Zamparo I, Zaccolo M, Pozzan T, Lodovichi C (2009) Odorant receptor at the growth cone are coupled to localized cAMP and Ca2+ increases. Proc Natl Acad Sci USA 106:3537-3542.
  • Pietrobon M, Zamparo I, Maritan M, Franchi SA, Pozzan T, Lodovichi C (2011) Interplay among cGMP, cAMP and Ca2+ in living olfactory sensory neurons in vitro and in vivo. J Neurosci 31:8395-8405.
  • Lodovichi C and Belluscio L (2012) Odorant receptors in the formation of the olfactory bulb circuitry. Physiology 27:200-212.
  • Lorenzon P,  Redolfi N, Podolsky MJ, Zamparo I, Franchi SA, Pietra, G.Boccaccio A,  Menini, A, Murthy VN, Lodovichi C (2015) Circuit formation and function in the olfactory bulb of mice with reduced spontaneous activity. J Neurosci 35(1): 146).