Silvia Natale

All Publications

• A fast and responsive voltage indicator with enhanced sensitivity for unitary synaptic events. Neuron Hao, Y. A., Lee, S., Roth, R. H., Natale, S., Gomez, L., Taxidis, J., O'Neill, P. S., Villette, V., Bradley, J., Wang, Z., Jiang, D., Zhang, G., Sheng, M., Lu, D., Boyden, E., Delvendahl, I., Golshani, P., Wernig, M., Feldman, D. E., Ji, N., Ding, J., Südhof, T. C., Clandinin, T. R., Lin, M. Z. 2024

  Abstract

  A remaining challenge for genetically encoded voltage indicators (GEVIs) is the reliable detection of excitatory postsynaptic potentials (EPSPs). Here, we developed ASAP5 as a GEVI with enhanced activation kinetics and responsivity near resting membrane potentials for improved detection of both spiking and subthreshold activity. ASAP5 reported action potentials (APs) in vivo with higher signal-to-noise ratios than previous GEVIs and successfully detected graded and subthreshold responses to sensory stimuli in single two-photon trials. In cultured rat or human neurons, somatic ASAP5 reported synaptic events propagating centripetally and could detect ∼1-mV EPSPs. By imaging spontaneous EPSPs throughout dendrites, we found that EPSP amplitudes decay exponentially during propagation and that amplitude at the initiation site generally increases with distance from the soma. These results extend the applications of voltage imaging to the quantal response domain, including in human neurons, opening up the possibility of high-throughput, high-content characterization of neuronal dysfunction in disease.

  View details for DOI 10.1016/j.neuron.2024.08.019

  View details for PubMedID 39305894

• A role for cerebral cortex in the suppression of innate defensive behavior. The European journal of neuroscience Natale, S., Masferrer, M. E., Deivasigamani, S., Gross, C. T. 2021

  Abstract

  The cerebral cortex is widely accepted to be involved in the control of cognition and the processing of learned information. However, data suggest that it may also have a role in the regulation of innate responses since rodents, cats or primates with surgical removal of cortical regions show excessive aggression and rage elicited by threatening stimuli. Nevertheless, the imprecision and chronic nature of these lesions leaves open the possibility that compensatory processes may underlie some of these phenotypes. In the present study we applied a precise, rapid and reversible inhibition approach to examine the contribution of the cerebral cortex to defensive behaviors elicited by a variety of innately aversive stimuli in laboratory mice. Pharmacological treatment of mice carrying the pharmacogenetic inhibitory receptor hM4D selectively in neocortex, archicortex and related dorsal telencephalon-derived structures resulted in the rapid inhibition of cerebral cortex neural activity. Cortical inhibition was associated with a selective increase in defensive behaviors elicited by an aggressive conspecific, a novel prey, and a physically stressful stimulus. These findings are consistent with a role for cortex in the acute inhibition of innate defensive behaviors.

  View details for DOI 10.1111/ejn.15426

  View details for PubMedID 34405470

• A neural circuit for competing approach and defense underlying prey capture PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rossier, D., La Franca, V., Salemi, T., Natale, S., Gross, C. T. 2021; 118 (15)

  Abstract

  Predators must frequently balance competing approach and defensive behaviors elicited by a moving and potentially dangerous prey. Several brain circuits supporting predation have recently been localized. However, the mechanisms by which these circuits balance the conflict between approach and defense responses remain unknown. Laboratory mice initially show alternating approach and defense responses toward cockroaches, a natural prey, but with repeated exposure become avid hunters. Here, we used in vivo neural activity recording and cell-type specific manipulations in hunting male mice to identify neurons in the lateral hypothalamus and periaqueductal gray that encode and control predatory approach and defense behaviors. We found a subset of GABAergic neurons in lateral hypothalamus that specifically encoded hunting behaviors and whose stimulation triggered predation but not feeding. This population projects to the periaqueductal gray, and stimulation of these projections promoted predation. Neurons in periaqueductal gray encoded both approach and defensive behaviors but only initially when the mouse showed high levels of fear of the prey. Our findings allow us to propose that GABAergic neurons in lateral hypothalamus facilitate predation in part by suppressing defensive responses to prey encoded in the periaqueductal gray. Our results reveal a neural circuit mechanism for controlling the balance between conflicting approach and defensive behaviors elicited by the same stimulus.

  View details for DOI 10.1073/pnas.2013411118

  View details for Web of Science ID 000641176100003

  View details for PubMedID 33876745

  View details for PubMedCentralID PMC8053977

• Genetically modified mice to unravel physiological and pathophysiological roles played by NCX isoforms CELL CALCIUM Molinaro, P., Natale, S., Serani, A., Calabrese, L., Secondo, A., Tedeschi, V., Valsecchi, V., Pannaccione, A., Scorziello, A., Annunziato, L. 2020; 87: 102189

  Abstract

  Since the discovery of the three isoforms of the Na+/Ca2+ exchanger, NCX1, NCX2 and NCX3 in 1990s, many studies have been devoted to identifying their specific roles in different tissues under several physiological or pathophysiological conditions. In particular, several seminal experimental works laid the foundation for better understanding gene and protein structures, tissue distribution, and regulatory functions of each antiporter isoform. On the other hand, despite the efforts in the development of specific compounds selectively targeting NCX1, NCX2 or NCX3 to test their physiological or pathophysiological roles, several drawbacks hampered the achievement of these goals. In fact, at present no isoform-specific compounds have been yet identified. Moreover, these compounds, despite their potency, possess some nonspecific actions against other ion antiporters, ion channels, and channel receptors. As a result, it is difficult to discriminate direct effects of inhibition/activation of NCX isoforms from the inhibitory or stimulatory effects exerted on other antiporters, channels, receptors, or enzymes. To overcome these difficulties, some research groups used transgenic, knock-out and knock-in mice for NCX isoforms as the most straightforward and fruitful strategy to characterize the biological role exerted by each antiporter isoform. The present review will survey the techniques used to study the roles of NCXs and the current knowledge obtained from these genetic modified mice focusing on the advantages obtained with these strategies in understanding the contribution exerted by each isoform.

  View details for DOI 10.1016/j.ceca.2020.102189

  View details for Web of Science ID 000533609700007

  View details for PubMedID 32199207

• Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory MOLECULAR NEUROBIOLOGY Natale, S., Anzilotti, S., Petrozziello, T., Ciccone, R., Serani, A., Calabrese, L., Severino, B., Frecentese, F., Secondo, A., Pannaccione, A., Fiorino, F., Cuomo, O., Vinciguerra, A., D'Esposito, L., Sadile, A., Cabib, S., Di Renzo, G., Annunziato, L., Molinaro, P. 2020; 57 (5): 2358-2376

  Abstract

  The Na+/Ca2+ exchanger 1 (NCX1) participates in the maintenance of neuronal Na+ and Ca2+ homeostasis, and it is highly expressed at synapse level of some brain areas involved in learning and memory processes, including the hippocampus, cortex, and amygdala. Furthermore, NCX1 increases Akt1 phosphorylation and enhances glutamate-mediated Ca2+ influx during depolarization in hippocampal and cortical neurons, two processes involved in learning and memory mechanisms. We investigated whether the modulation of NCX1 expression/activity might influence learning and memory processes. To this aim, we used a knock-in mouse overexpressing NCX1 in hippocampal, cortical, and amygdala neurons (ncx1.4over) and a newly synthesized selective NCX1 stimulating compound, named CN-PYB2. Both ncx1.4over and CN-PYB2-treated mice showed an amelioration in spatial learning performance in Barnes maze task, and in context-dependent memory consolidation after trace fear conditioning. On the other hand, these mice showed no improvement in novel object recognition task which is mainly dependent on non-spatial memory and displayed an increase in the active phosphorylated CaMKIIα levels in the hippocampus. Interestingly, both of these mice showed an increased level of context-dependent anxiety.Altogether, these results demonstrate that neuronal NCX1 participates in spatial-dependent hippocampal learning and memory processes.

  View details for DOI 10.1007/s12035-020-01888-4

  View details for Web of Science ID 000516211700001

  View details for PubMedID 32048166