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Caccamo, A.

Publications and source records attributed to Caccamo, A..

2 recordsLinked to original sources

Dynamics-Informed Priors (DIP) for Neural Mass Modelling

Neural Mass Models (NMMs) are important mathematical tools for inferring hidden neural mechanisms that generate healthy and pathological brain activities. A critical step in the inference process is parameter estimation, which calibrates NMMs based on measured neuroimaging data. While parameter estimation can be conducted via various approaches, one of the most influential methods is Dynamic Causal Modelling (DCM). DCM adopts a Bayesian inference approach that relies on, and is sensitive to, the specification of prior parameter distributions reflecting a priori hypotheses about the causes of data. However, most parameters of NMMs encode neuronal properties that are not directly measurable. For this reason, in the absence of sufficient empirical data and well-founded prior beliefs, inference becomes increasingly susceptible to bias. Therefore, it was imperative to establish a comprehensive strategy for mapping model parameters to data. This study proposes a computational extension of DCM, named DCM with dynamics-informed priors (DIP-DCM), which adopts a genetic algorithm (GA) to map parameter values to model dynamics. Optimal sub-regions of the parameter space were subsequently selected and translated into groups of parameter priors for DCM. DIP-DCM was compared to the standard DCM inference and to the standalone GA, using two independent neuroimaging datasets. Results indicated that DIP-DCM models were the best predictors of data and captured key mechanistic signatures of psychiatric disease and pharmacological interventions. Overall, DIP-DCM addressed degeneracy, handled local minima, and explored diverse parameter regimes following trajectories informed directly by model dynamics and data. This study suggests that DIP-DCM is an advantageous route to parameter estimation when information is limited, enabling a data-driven derivation of parameter priors - or hypotheses - in exploratory studies, across different biological contexts and datasets.

systems biology↗

ERK1/2-dependent TSPO overactivation associates with the loss of mitophagy and mitochondrial respiration in ALS

Mitochondrial dysfunction and the loss of mitophagy, aimed at recycling irreversibly damaged organelles, contribute to the onset of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting spinal cord motor neurons. In this work, we showed that the reduction of mitochondrial respiration, exactly oxygen flows linked to ATP production and maximal capacity, correlates with the appearance of the most common ALS motor symptoms in a transgenic mice model expressing SOD1 G93A mutant. This is the result of the equal inhibition in the respiration linked to complex I and II of the electron transport chain, but not their protein levels. Since the overall mitochondrial mass was unvaried, we investigated the expression of the Translocator Protein (TSPO), a small mitochondrial protein whose overexpression was recently linked to the loss of mitophagy in a model of Parkinsons disease. Here we clearly showed that levels of TSPO are significantly increased in ALS mice. Mechanistically, this increase is linked to the overactivation of ERK1/2 pathway and correlates with a decrease in the expression of the mitophagy-related marker, Atg12, indicating the occurrence of impairments in the activation of mitophagy. Overall, our work sets out TSPO as a key regulator of mitochondrial homeostasis in ALS.

neuroscience↗