Tommaso Fellin graduated in Physics at the University of Padova in 1998 studying enzyme kinetics with time-resolved spectroscopy. From 1998 to 2003, as a PhD student in the Dept. of Biomedical Sciences at University of Padova, he investigated the biophysical properties of voltage-gated calcium channels and the functional consequences of mutations in calcium channels linked to human neurological disorders (supervisor, D. Pietrobon). During his first postdoctoral training period (2003-2004), he integrated electrophysiological and imaging techniques to study neuron-glia communication in brain slices (supervisors, G. Carmignoto and T. Pozzan). In 2005 he moved to the Dept. of Neuroscience at University of Pennsylvania School of Medicine as a senior post doctoral researcher and continued his research on neuron-glia interaction (supervisor, P. Haydon). In 2008, he joined the department of Neuroscience and Brain Technologies at the Italian Institute of Technology (IIT) as a junior team leader. He is currently senior team leader at the IIT, head of the Optical Approaches to Brain Function Laboratory, and co-head (together with Dr. S. Panzeri) of the Neural Coding Laboratory. He is also recipient of the European Research Council (ERC) consolidator grant NEURO-PATTERNS and co-founder of the start-up SmartMicroOptics. Since 2019, he serves as Coordinator of the Neuroscience Area at the IIT.
The research activity of the 'Optical Approaches to Brain Function Laboratory' focuses on the study of the brain microcircuits involved in the processing of sensory information and on the development of innovative optical methods to probe their function.
When we see an object, hear a sound or smell an odor, precise spatial and temporal patterns of electrical activity are generated within neuronal networks located in specialized brain areas. This electrical representation of the external stimulus is believed to mediate perception of the sensory experience. However, how information about the external stimulus is encoded in the spatial and temporal dimension of sensory-evoked activities and which specific feature of evoked network dynamics are used to drive behavior is largely unknown. Moreover, even in the same apparent state of vigilance, sensory-evoked activities are highly variable, and repetition of the very same sensory experience results in distinct network dynamics. What does this variability mean for sensory experience? Do distinct network dynamics carry different information about the stimulus? Or rather, does the brain code the same information coming from the outside world in multiple and equivalent ways?
My laboratory has taken a multidisciplinary approach to causally address these questions and decipher the computational principles of brain networks by combining new cell type-specific manipulations with innovative optical technologies for brain circuit investigation. Using mainly the mouse somatosensory cortex as a model system, we focus our research on four critical aspects of this challenging task: i) how specific network dynamics are regulated by the activity of distinct cellular subpopulations, including principal neurons, interneurons and glial cells, ii) how these dynamics are transferred between presynaptic and postsynaptic networks, iii) how distinct electrical representations of the stimulus may generate different perception of sensory experience, and iv) how a derangement of the cellular interactions underlying these circuit activities may contribute to the genesis and progression of specific brain diseases.
To achieve these goals, we use state-of-the-art approaches including cell type-specific optogenetic manipulations, patch-clamp recordings and two-photon microscopy in vivo and in brain slice preparation. Given that what we know about brain networks is limited by current methodologies, we are also developing new and more accurate tools for the investigation of cortical microcircuits. We are using patterned illumination by means of liquid crystals spatial light modulators and digital micromirror technology to illuminate cellular networks with high spatial and temporal resolutions. We aim to combine these novel approaches with genetically-encoded molecules and microendoscopes to probe and manipulate neuronal circuits with high spatial and temporal precision.
To understand how specific network dynamics are regulated by the activity of distinct cellular subpopulations, we have focused our attention on a main circuit activity that characterizes cortical networks in the absence of external stimuli. This spontaneous activity, named slow oscillations, served as an initial model to test the role of different cellular subpopulations in the control of cortical circuit dynamics. We have applied advanced optical approaches to dissect out the cellular circuits underlying slow network oscillations in the mouse cortex. We used optogenetics, which allows the remote control of cellular excitability with light, to investigate the role of excitatory cells (Beltramo et al. Nat. Neurosci. 2013), inhibitory neurons (Zucca et al. eLife 2017), and glial cells (Fellin et al. PNAS 2009) in the control and propagation of cortical slow oscillations. For example, by combining selective expression of excitatory and inhibitory opsins in layer V and layer II/III pyramidal neurons with electrophysiological recordings in vivo, we showed that activation/inactivation of a subset of pyramidal neurons located in layer V, but not layer II/III, was sufficient and necessary to generate and attenuate slow oscillations, respectively (Beltramo et al. Nat. Neurosci. 2013). Based on patch-clamp recordings, we proposed that the differential role of layer V and II/III in the regulation of slow network activity is linked to the differential ability of these neurons to propagate prolonged depolarization within and across cortical layers. These results demonstrate that the cortex is endowed with layer-specific excitatory circuits that have distinct roles in the coordination of ongoing cortical activity. Moreover, these data underscore the importance of understanding the specific functional microcircuitry of cortical layers, rather than considering the entire cortical column as a uniform processing element. We have also combined optogenetic manipulations with electrophysiological recordings in vitro and in vivo to investigate the cellular mechanisms underlying the genesis of epileptic syndromes (Sessolo et al. J. Neurosci. 2015, De Stasi et al. Cer. Cortex. 2016).
From a more technical point of view, we have been developing optical tools for monitoring and manipulating brain networks with improved spatial and temporal resolution. More specifically, we have been focusing on a particular technique, patterned illumination using ‘wave-front engineering’ and we have been pioneering its application in living rodents. We first designed and built a 'patterned illumination module', a compact, simple optical path that can be easily implemented with commercial two-photon scanheads to allow spatial shaping of laser light (Dal Maschio et al. Optics Express 2010). The patterned illumination module is based on phase modulation of the wave-front of laser light by a liquid crystal spatial light modulator (SLM). The combination of this module with the scanhead constitutes a patterned two-photon illumination microscope capable of simultaneous imaging and stimulating using two independent laser sources at different wavelengths. We reported the first application of this optical set-up for in vivo experimental conditions in living rodents, using wave-front modulation to provide inertia-free focus control, i.e., dynamically focusing in depth while keeping the objective in a fixed position (Dal Maschio et al. Optics Letters 2011). As a necessary step towards the development of an optical system that allows the generation of artificial patterns of network activation in vivo, we applied our patterned two-photon illumination microscope to map the activity of cortical cells with millisecond temporal resolution and subcellular spatial resolution (Bovetti et al. Sci. Reports 2017). We also validated this approach in GRIN lens-based endoscopes for fast imaging in deep brain regions (Moretti et al. Biom. Optics Express 2016). Moreover, we combined holographic scanless imaging of GCaMP6 signals in population of neurons with wide-field single-photon optogenetic stimulation of the inhibitory opsin Archaerhodopsin (Bovetti et al. Sci. Reports 2017). This new experimental approach can be used to effectively map the response of neuronal circuits in the intact mammalian brain with unprecedented spatiotemporal resolution and no stimulation artifacts during inhibitory optogenetic manipulations. More recently we combined two-photon holography to stimulate neurons expressing blue light-sensitive opsins (ChR2 and GtACR2) with two-photon imaging of the red-shifted indicator jRCaMP1a in the mouse neocortex in vivo. We demonstrated efficient control of neural excitability across cells types and layers with holographic stimulation and improved spatial resolution by opsin somatic targeting. Moreover, we performed simultaneous two-photon imaging of jRCaMP1a and bidirectional two-photon manipulation of cellular activity with negligible effect of the imaging beam on opsin excitation (Forli et al. Cell Reports 2018).
Patterned two-photon illumination is being proposed as a powerful tool to investigate the role of precise spatiotemporal patterns of neuronal activity in driving behavior (Bovetti et al. J. Neurosci. Methods 2015). However, there is no clear theoretical framework for the application of patterned illumination to this aim. We are contributing to develop such a conceptual framework in the context of perceptual behavior (Panzeri et al. Neuron 2017).
1) Vecchia D., Beltramo R., Vallone F., Chéreau R., Forli A., Molano-Mazón M., Bawa T., Binini N., Moretti C., Holtmaat A., Panzeri S., and Fellin T. “Temporal sharpening of sensory responses by layer V in the mouse primary somatosensory cortex” Current Biology (2020), 30:1589-1599.
2) Brondi M., Moroni M., Vecchia D., Molano-Mazón M., Panzeri S., Fellin T. “High accuracy detection of neuronal ensemble activity in two-photon functional microscopy using smart line scanning “ Cell Reports (2020), 25:2567-2580.
3) Zucca S., Pasquale V., Lagomarsino P., Panzeri S., Fellin T. "Thalamic drive of parvalbumin-positive interneurons during cortical down-states in anesthetized mice" Current Biology (2019), 29:1481-1490.
4) Zerlaut Y., Zucca S., Panzeri S., Fellin T. “The spectrum of asynchronous dynamics in spiking networks: a theory for the diversity of non-rhythmic waking states in neocortex“ Cell Reports (2019), 27:1119-1132.
5) Forli A., Vecchia D., Binini N., Succol F., Bovetti S., Moretti C., Nespoli F., Mahn M., Baker C.A., Bolton M.M., Yizhar O., Fellin T. “Two-photon bidirectional control and imaging of neuronal excitability with high spatial resolution in vivo“ Cell Reports (2018), 22: 3087-3098.
6) Mariotti L., Losi G., Lia A., Melone M., Chiavegato A., Gomez-Gonzalo M., Sessolo M., Bovetti S., Forli A., Zonta M., Requie L.M., Marcon I., Pugliese A., Viollet C., Bettler B., Fellin T., Conti F., Carmignoto G. "Interneuron-specific signalling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes" Nature Communications (2018) 9: 82.
7) Gobbo F., Marchetti L., Jacob A., Pinto B., Binini N., Pecoraro Bisogni F., Alia C., Luin S., Caleo M., Fellin T., Cancedda L., Cattaneo A. “Activity-dependent expression of Channelrhodopsin at neural synapses” Nature Communications (2017) 8: 1629.
8) Zucca S., D'Urso G., Pasquale V., Vecchia D., Pica G., Bovetti S., Moretti C., Varani S., Molano-Mazon M., Chiappalone M., Panzeri S., Fellin T. "An inhibitory gate for state transition in cortex" eLife (2017) 6: e26177.
9) Panzeri S., Harvey C.D., Piasini E., Latham P.E., Fellin T. "Cracking the neural code for sensory perception by combining statistics, intervention and behavior" Neuron (2017) 93: 491-507.
10) Bovetti S., Moretti C., Zucca S., Dal Maschio M., Bonifazi P., Fellin T. "Simultaneous high-speed imaging and optogenetic inhibition in the intact mouse brain" Scientific Reports (2017) 7: 40041.
11) Moretti C., Antonini A., Bovetti S., Liberale C., Fellin T. "Scanless functional imaging of hippocampal networks using patterned two-photon illumination through GRIN lenses" Biomedical Optics Express (2016) 7: 3958-3967.
12) De Stasi A.M., Farisello P., Marcon I., Cavallari S., Forli A., Vecchia D., Losi G., Mantegazza M., Panzeri S., Carmignoto G., Bacci A., Fellin T. "Unaltered network activity and interneuronal firing during spontaneous cortical dynamics in vivo in a mouse model of Severe Myoclonic Epilepsy of Infancy" Cerebral Cortex (2016) 26:1778-94.
13) Sessolo M., Marcon I., Bovetti S., Losi G., Cammarota M., Ratto G.M., Fellin T.*, Carmignoto G.* "Parvalbumin-positive inhibitory interneurons oppose propagation but favor generation of focal epileptiform activity" Journal of Neuroscience (2015) 35:9544-9557.
14) Bovetti S., Fellin T. ”Optical dissection of brain circuits with patterned illumination through the phase modulation of light” Journal of Neuroscience Methods (2015) 241: 66-77.
15) Antonini A., Liberale C., Fellin T. ”Fluorescent layers for characterization of sectioning microscopy with coverslip-uncorrected and water immersion objectives” Optics Express (2014) 22: 14293–14304.
16) Bovetti S., Moretti C., Fellin T. “Mapping brain circuit function in vivo using two-photon fluorescence microscopy” Microscopy Research and Techniques (2014) 77: 492-501.
17) Beltramo R., D’Urso G., Dal Maschio M., Farisello P., Bovetti S., Clovis Y., Lassi G., Tucci V., De Pietri Tonelli D., Fellin T. ”Layer-specific excitatory circuits differentially control recurrent network dynamics in the neocortex” Nature Neuroscience (2013) 16(2):227-34.
18) FellinT., Ellenbogen J.M., De Pittà M., Ben-Jacob E., Halassa M.M. “Astrocyte regulation of sleep circuits: experimental and modeling perspectives” Front. Compt. Neurosci. (2012) 6: 65. doi: 10.3389/fncom.2012.00065.
19) Dal Maschio M., Difato F., De Stasi A.M., Beltramo R., Blau A., Fellin T. ”Optical investigation of brain networks using structured illumination” in Cellular Imaging Techniques for Neuroscience and Beyond (2012), Elsevier.
20) Dal Maschio M., Beltramo R., A. De Stasi., Fellin T. ”Two-photon calcium imaging in the intact brain” Adv. Exp. Med. Biol. (2012) 740:83-102.
21) Difato F., Dal Maschio M., Beltramo R., Blau A., Benfenati F., Fellin T. ”Spatial light modulators for complex spatio-temporal illumination of neuronal networks” in Neuronal Network Analysis: concepts and experimental approaches (2012), Neuromethods book series, Springer.
22) Dal Maschio M., De Stasi A.M., Benfenati F., Fellin T. ”Three dimensional in vivo scanning microscopy with inertia-free focus control” Optics Letters (2011) 36:3503-05.
23) Difato F., Dal Maschio M., Marconi E., Ronzitti G., Maccione A., Fellin T., Berdondini L., Chieregatti E., Benfenati F., Blau A. "Combined optical tweezers and laser dissector for controlled ablation of functional connections in neural networks" J. Biom. Optics (2011) 16: 051306.
24) Deng Q, Terunuma M, Fellin T, Moss SJ, Haydon PG ”Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway” Glia (2011) 59:1084-93.
25) Dal Maschio M., Difato F., Beltramo R., Blau A., Benfenati F., Fellin T. ”Simultaneous two-photon imaging and photo-stimulation with structured light illumination” Optics Express (2010) 18:18720-18731.
26) Halassa M.M., Dal Maschio M., Beltramo R., Haydon P.G., Benfenati F., Fellin T. ”Integrated Brain Circuits: neuron-astrocyte interaction in sleep-related rhythmogenesis” ScientificWorldJournal (2010) 10:1634-1645.
27) Fellin T., Halassa M., Terunuma M., Succol F., Takano H., Frank M.G., Moss S.J., Haydon P.G. “Endogenous non neuronal modulators of synaptic transmission control cortical slow oscillations in vivo” PNAS (2009) 106:15037-42.
28) Halassa M., Fellin T., Haydon P.G. “Tripartite synapse: roles of astrocytic purines in the control of synaptic physiology and behavior” Neuropharmacology (2009), 57:343-6.
29) D’Ascenzo M., Podda M.V., Fellin T., Azzena G.B., Haydon P.G., Grassi C. “Activation of mGluR5 induces spike afterdepolarization and enhanced excitability in medium spiny neurons of the nucleus accumbens by modulating persistent Na+ currents” Journal of Physiology (2009), 587:3233-3250.
30) Dityatev A., Fellin T. “Extracellular matrix in plasticity and epileptogenesis” Neuron Glia Biology (2009), June 5:1-13.
31) Fellin T. “Communication between neurons and astrocytes: relevance to the modulation of synaptic and network activity” Journal of Neurochemistry (2009) 108:533-544.
- Fellin T., Halassa M.M. (2012) “Neuronal network analysis: concepts and experimental approaches”, Neuromethods Book Series, Springer.
32) Halassa M., Florian C., Fellin T., Munoz J.R., Lee S.Y., Abel T., Haydon P.G., Frank M. “Astrocytic adenosine controls sleep homeostasis and cognitive consequences of sleep loss” Neuron (2009) 61:213-219.
33) FellinT., D’AscenzoM., HaydonP.G. “Astrocytes control neuronal excitability in the nucleus accumbens” ScientificWorldJournal (2007) 7:89-97.
34) Ding S.*, Fellin T.*, Zhu Y.*, Lee S.Y., Auberson Y.P., Meany D., Coulter D.A., Carmignoto G., Haydon P.G. ” Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus” Journal of Neuroscience (2007) 27(40):10674-84.
35) Halassa M.*, Fellin T.*, Takano H., Dong J.H., Haydon P.G. “Synaptic islands defined by the territory of a single astrocyte” Journal of Neuroscience (2007) 27(24):6473-6477.
36) Halassa M., Fellin T., Haydon P.G. “The Tripartite Synapse: Roles for Gliotransmission in Health and Disease” Trends in Molecular Medicine (2007) 13(2):54-63.
37) D’Ascenzo M.*, Fellin T.*, Terunuma M., Revilla-Sanchez R., Meany D., Auberson Y.P., Moss S.J., Haydon P.G. “mGluR5 stimulates gliotransmission in the nucleus accumbens” Proc. Natl. Acad. Sci. (2007) 104(6):1995-2000.
38) Fellin T., Gomez-Gonzalo M., Gobbo S., Carmignoto G., Haydon P.G. “Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices” Journal of Neuroscience (2006) 26:9312-9322.
39) Fellin T., Sul JY, D’Ascenzo M, Takano H, Pascual O, Haydon PG. “Bidirectional astrocyte-to-neuron communication: the many roles of glutamate and ATP.” Novartis Found Symp (2006) 276:208-217.
40) Fellin T., Pascual O, Haydon PG. “Astrocytes coordinate synaptic networks: balanced excitation and inhibition” Physiology (2006) 21:208-215.
41) Carmignoto G., Fellin T. “Glutamate release from astrocytes as a non-synaptic mechanism for neuronal synchronization in the hippocampus.” J. Physiol. Paris (2006) 99(2-3):98-102.
42) Fellin T., Pozzan T., Carmignoto G. “Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes.” J Biol Chem. (2006) 281(7):4274-84.
43) Fellin T., Haydon PG. “Do astrocytes provide excitation underlying seizures?” Trends in Molecular Medicine (2005) 11(12):530-3.
44) A. Tottene, F. Pivotto, T.Fellin, T. Cesetti, A.M. van den Maagdenberg, D. Pietrobon. “Specific Kinetic Alterations of Human CaV2.1 Calcium Channels Produced by Mutation S218L Causing Familial Hemiplegic Migraine and Delayed Cerebral Edema and Coma after Minor Head Trauma.” J. Biol. Chem. (2005) 280(18):17678-86.
45) Fellin T., Luvisetto S., Spagnolo M., Pietrobon D. “Modal Gating of Human CaV2.1 (P/Q-type) Calcium Channels: II. The b Mode and Reversible Uncoupling of Inactivation”.J. Gen. Physiol. (2004), 124: 463-474.
46) Luvisetto S., Fellin T., Spagnolo M., Hivert B., Brust P.F., Harpold M.M, Stauderman K.A., Williams M.E., Pietrobon D. “Modal Gating of Human CaV2.1 (P/Q-type) Calcium Channels: I. The Slow and the Fast Gating Modes and their Modulation by Beta Subunits“. J. Gen. Physiol. (2004), 124: 445-461.
47) Fellin T., Pascual O., Gobbo S., Pozzan T., Haydon P.G., Carmignoto G. “Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors”. Neuron (2004), 43: 729-743.
48) Fellin T, Carmignoto G. “Neuron-to-astrocyte signaling in the brain represents a distinct multifunctional unit”. J Physiol. (2004), 559: 3-15.
49) Zonta M, Sebelin A, Gobbo S, Fellin T, Pozzan T, Carmignoto G. “Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes”. J Physiol. (2003), 553.2: 407-414.
50) A. Tottene*, T.Fellin*, S. Pagnutti, S. Luvisetto, J. Striessnig, C. Fletcher, D. Pietrobon; “Familial Hemiplegic Migraine Mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal current density in neurons”. Proc. Natl. Acad. Sci. (2002), 99(20):13284-13289.
51) S. Guida, F. Trettel, S. Pagnutti, E. Mantuano, A. Tottene, L. Veneziano, T. Fellin, M. Spadaro, K.A. Stauderman, M.E. Williams, S. Volsen, R. Ophoff, R.R. Frants, C. Jodice, M. Frontali, D. Pietrobon; ”Complete Loss of P/Q Calcium Channel Activity Caused by a CACNA1A Missense Mutation Carried by Episodic Ataxia Type 2 Patients”. American Journal of Human Genetics (2001), 68: 759-764.