How is specificity of neuronal connections and information processing achieved?
How are these features affected by experience and aging?
Specificity of connections among neurons is essential for normal brain function. We are interested in understanding 1. how an ensemble of neurons wires together to form specific neuronal circuits and 2. how these circuits process neuronal information. These events are highly dynamic and susceptible to modifications in the face of a continuously changing flow of sensory information, in physiological and pathological situations. We study circuit formation and function, mostly in the olfactory system and connected areas, using several experimental approaches, including imaging, electrophysiology, quantitative anatomy and behaviour.
The olfactory system is a unique interesting system to study circuit formation and function, due to its high degree of plasticity, with different types of cells that constantly regenerate and re-form specific synaptic contacts. It offers the possibility to study not only sensory but also cognitive functions, due to its connections with brain areas involved in processing memory and emotional responses. Olfaction is involved in several genetic and neurodegenerative diseases. It is worth noticing that olfactory dysfunctions are among the earliest features in Parkinson and Alzheimer disease.
The Lodovichi lab provided a new vision of the mechanism underpinning specificity of synaptic contacts and neuronal wiring in the olfactory system. We study neuronal circuits to understand how their structure affects information processing and behavior. We are also interested in understanding how these processes are affected in pathological conditions
Role of the odorant receptor in circuit formation
We know for more than 20 years that the odorant receptor (OR) not only detects odors but it also plays a key role in the convergence of sensory neuron axons to form the sensory map in the olfactory bulb. The OR is indeed expressed at the cilia, that protrude in the nostril, but also at the axon terminal, that projects to the olfactory bulb.
By combining real time imaging of cAMP and Ca2+ in sensory neurons, we demonstrated that the OR at the axon terminal is functional and coupled to local increases of cAMP, cGMP and Ca2+ (Maritan et al, 2009, Pietrobon et al, 2011, Lodovichi Belluscio, 2012). We then investigated the mechanism underlying activation of the OR expressed at the axon terminal.
Role of afferent spontaneous activity in neuronal wiring and topography of the olfactory bulb
The formation of a sensory map is regulated by molecules expressed in a specific spatio-temporal pattern and by electrical activity. Several studies suggested that, unlike in other sensory systems, in olfaction odor-evoked activity does not impact the topographic organization of the olfactory bulb. We reasoned therefore that spontaneous afferent activity could play a role. We addressed this issue by analysing the topographic organization of the olfactory bulb in transgenic mice engineered to have very little afferent spontaneous activity due to the overexpression of the inwardly rectifying potassium channel Kir2.1 in the olfactory sensory neurons (Kir2.1 mice). Combining several different experimental approaches, including electrophysiology, functional imaging, quantitative anatomy and behaviour, we found that, in absence of spontaneous afferent activity, connectivity in the olfactory bulb was unrefined. Coarser connectivity was reflected in coarser functional response to odour and impaired ability in odour discrimination. In addition, we demonstrated that spontaneous afferent activity is required not only for the refinement but also for the maintenance of specificity of connectivity in the olfactory bulb. We aim now to investigate the impact of afferent spontaneous activity on network activity and oscillations in the olfactory bulb and in higher brain areas.
Adult neurogenesis of forebrain interneurons
Interneurons continue to be generated postnatally in the subventricular zone of the lateral ventricles. From here neuronal precursors migrate to the olfactory bulb, but also to several cortical and subcortical areas, to become mature inhibitory interneurons, that exert a prominent role in the excitatory – inhibitory balance of neuronal networks.
Combining quantitative anatomy, birthdating experiments and real time imaging we analysed the impact of gene associated to intellectual disability, such as oligophrenin1 (OPHN1), on formation and function of postnatal inhibitory interneurons. We found that the complement of inhibitory interneurons that reach the olfactory bulb is dramatically reduced, indicating a deeply perturbed migratory process, in mouse model carrying a null mutation in OPHN1 (Redolfi et al, 2016). We found that the reduced number of inhibitory interneurons deeply affect network activity and oscillations in the olfactory bulb (Redolfi N, Rubega M). We are now investigating the mechanism underlying migration of neuronal precursors of inhibitory interneurons, both in physiological and pathological conditions.
Neurogenesis is also perturbed in aging and neurodegenerative disorders. We are currently investigating how gene mutations associated to neurodegenerative diseases affect adult neurogenesis.
- 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).
- Redolfi N, Galla L, Maset, A, Murru L, Savoia, E, Zamparo I, Gritti A, Billuart P, Passafaro M, Lodovichi C (2016) Oligophrenin-1 regulates number, morphology and synaptic properties of adult-born inhibitory interneurons in the olfactory bulb (Hum Mol Genet. 2016 Oct 13. pii: ddw340. doi: 10.1093/hmg/ddw340. [Epub ahead of print] PMID: 27742778 Genetics).
- MD: University of Pisa Medical School and S. Anna School of Advanced Study, Pisa, Italy (1995).
- PhD: Neuroscience, S. Anna School of Advanced Study, Pisa, Italy (1999).
- Post doc: HHMI Research Assistant, Department of Neurobiology, Duke University, Durham, USA (1999-2003)
- Post doc: Columbia University, Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behaviour, New York, NY, USA (2003-2005)
- Group Leader-: Venetian Institute of Molecular Medicine (VIMM), Armenise-Harvard Career Development Awardee (since 2006)
- Tenured scientist: Neuroscience Institute CNR, Padua (since 2009)
- 2006 – Armenise-Harvard Career Developmental Award