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Understanding the brain functioning is essential for governing brain processes with the aim of managing pathological network dysfunctions. Due to the morphological and biochemical complexity of the central nervous system, the development of general models with predictive power must start from in vitro brain network engineering. In the present work, we realized a micro-electrode array (MEA)-based in vitro brain network and studied its emerging dynamical properties. We obtained four-neuron-clusters (4N) assemblies by plating rat embryo cortical neurons on 60-electrode MEA with cross-shaped polymeric masks and compared the emerging dynamics with those of sister single networks (1N). Both 1N and 4N assemblies exhibited spontaneous electrical activity characterized by spiking and bursting signals up to global activation by means of network bursts. Data revealed distinct patterns of network activity with differences between 1 and 4N. Rhythmic network bursts and dominant initiator clusters suggested pacemaker activities in both assembly types, but the propagation of activation sequences was statistically influenced by the assembly topology. We proved that this rhythmic activity was ivabradine sensitive, suggesting the involvement of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and propagated across the real clusters of 4N, or corresponding virtual clusters of 1N, with dominant initiator clusters, and nonrandom cluster activation sequences. The occurrence of nonrandom series of identical activation sequences in 4N revealed processes possibly ascribable to neuroplasticity. Hence, our multi-network dissociated cortical assemblies suggest the relevance of pacemaker neurons as essential elements for generating brain network electrophysiological patterns; indeed, such evidence should be considered in the development of computational models for envisaging network behavior both in physiological and pathological conditions., (© 2023. Springer Nature Limited.)

Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

Recent studies reported that the uptake of [18F]-fluorodeoxyglucose (FDG) is increased in the spinal cord (SC) and decreased in the motor cortex (MC) of patients with ALS, suggesting that the disease might differently affect the two nervous districts with different time sequence or with different mechanisms. Here we show that MC and SC astrocytes harvested from newborn B6SJL-Tg (SOD1 G93A ) 1Gur mice could play different roles in the pathogenesis of the disease. Spectrophotometric and cytofluorimetric analyses showed an increase in redox stress, a decrease in antioxidant capacity and a relative mitochondria respiratory uncoupling in MC SOD1 G93A astrocytes. By contrast, SC mutated cells showed a higher endurance against oxidative damage, through the increase in antioxidant defense, and a preserved respiratory function. FDG uptake reproduced the metabolic response observed in ALS patients: SOD1 G93A mutation caused a selective enhancement in tracer retention only in mutated SC astrocytes, matching the activity of the reticular pentose phosphate pathway and, thus, of hexose-6P dehydrogenase. Finally, both MC and SC mutated astrocytes were characterized by an impressive ultrastructural enlargement of the endoplasmic reticulum (ER) and impairment in ER-mitochondria networking, more evident in mutated MC than in SC cells. Thus, SOD1 G93A mutation differently impaired MC and SC astrocyte biology in a very early stage of life.