D. BIOPHYSICS OF BRAIN PATHOLOGY.
1) Computation in the diseased brain.
Contact person:
Gian Michele Ratto
In this activity we study the largely mysterious relationship between alterations of brain cells excitability due to genetic or acute insult and the onset of cognitive deficits. Our leading theory is that in pathological conditions it occurs an impairment of gain control in the brain circuitry and this deficit leads both to acute manifestations, such as epilepsy or epileptiform activity, and to cognitive deficits due to defective brain computation. The impaired brain computation can ultimately lead to the social and behavioral deficits proper of the diseases of the autistic spectra. These studies are performed in vivo on pharmacological models of acute impairment or in genetic models of human pathologies, by means of state of the art imaging and electrophysiological tools.
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A) Schematic representation of the interaction between inhibitory and excitatory neurons. Gain adaptation is one of the fundamental computations performed by cortical micro-circuitry. Weak synaptic inputs, such as those evoked by a low-contrast visual stimulus, must be amplified substantially in order to produce a detectable response. As the synaptic input increases, amplification must be reduced to avoid response saturation. Several mechanisms participate in this non-linear computation, with an especially important role played by the reciprocal equilibrium between inhibitory interneurons and pyramidal neurons. As synaptic input increases, interneurons are recruited at an increasing rate and their feedback on pyramidal cells shift the response function to the right (continuous green lines). B) Loose-patch recording from a L2/3 neuron during interictal activity (upper trace) and the simultaneous LFP recording from a nearby extracellular electrode. The inset shows the neuronal firing during a single IS event. C) Mean VEP waveforms recorded in the same mouse at three different contrasts for different relative timing between the stimulus presentation and the interictal spike.
S. S. Sato, P. Artoni, S. Landi, O. Cozzolino, R. Parra, E. Pracucci, F. Trovato, J. Szczurkowska, S. Luin, D. Arosio, F. Beltram, L. Cancedda, K. Kaila, and G. M. Ratto, Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo, PNAS, 144, E8770-E8779 (2017)
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2) Computation in the diseased brain.
Contact person:
Gian Michele Ratto
Molecular basis of the aggregation processes of neurotoxic amyloidogenic peptides responsible for Alzheimer Disease and other neurological pathologies.
3) Biophysics of the neuronal negative feedback.
Contact person:
Gian Michele Ratto
Proper brain computation requires a fine equilibrium between a positive neuronal feed-back, necessary to recruit large neuronal ensembles responsible for computation and behavioral responses to the ever changing environment, and a negative feedback that maintains activity within the rather limited dynamic range available to neurons. The inhibitory feedback is provided by the activity of a specific set of inhibitory synapses permeable to chloride. The direction of chloride flux determines the extent of neuronal inhibition and these currents depend critically on the intracellular concentration of chloride.The regulation of the intracellular concentration exerts wide-ranging effects on synaptic signaling and plasticity and on development and disorders of the brain.
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Novel technique for the measurement of the intracellular concentration of chloride by means of two photon imaging and spectroscopy. A specific hardware for the control of the spectroscopic measurementsand for the delivery of the genetic sensorhave been developed.
P. Artoni, S. Landi, S. S. Sato, S. Luin, and G. M. Ratto, Arduino Due based tool to facilitate in vivo two-photon excitation microscopy, Biomed. Opt. Express, 7, 1604-1613 (2016)
J. Szczurkowska, A. W. Cwetsch, M. dal Maschio, D. Ghezzi, G. M. Ratto, and L. Cancedda, Targeted in vivo genetic manipulation of the mouse or rat brain by in utero electroporation with a triple-electrode probe, Nat.Protoc., 11, 399-412 (2016)
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