Biology subjects

Botta, P.

Publications and source records attributed to Botta, P..

4 recordsLinked to original sources

bioRxiv2026

Human CNS-3D organoids predict clinical seizure liability from calcium network activity

Drug-induced seizures remain a major safety concern in drug development, yet human seizure liability is difficult to predict using conventional preclinical models. Here, we evaluated whether spontaneous calcium network activity in human induced pluripotent stem cell-derived CNS-3D Brain Organoids could predict clinically observed seizure risk across a pharmacokinetically anchored drug set. CNS-3D organoids contained neuronal and astrocytic populations, expressed neuroactive receptor and ion-channel gene programs that aligned with human cortical tissue, and exhibited reproducible spontaneous calcium oscillations across production batches. A retrospective drug panel of 66 small-molecule drugs was assembled from human clinical evidence, including 30 seizure-associated drugs and 36 comparator drugs without documented clinical seizure liability. Drugs were tested across concentration ranges anchored to reported clinical Cmax, and calcium time-series responses were integrated with chemical structure features using a machine-learning workflow. The final model predicted clinical seizure liability with an AUROC of 0.872, achieving 83.3% sensitivity and 88.9% specificity in drug-level cross-validation. Model scores also stratified seizure-associated drugs by clinical context and prevalence, suggesting that CNS-3D activity profiles capture clinically meaningful differences in seizure risk. Compared with published in vitro and preclinical seizure-liability models, CNS-3D organoid-based predictions showed improved balanced sensitivity and specificity. These findings support high-throughput calcium profiling in human CNS-3D organoids as a scalable, exposure-aware platform for predicting human seizure liability and contributing functional human data to neuro-safety assessment.

pharmacology and toxicology↗

bioRxiv2022

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimers Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Spectral power analysis revealed a reduction of basal theta oscillations in rTg4510 mice. Enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol was further indicated by an increase in theta power and higher number of absence-like seizures in rTg4510 compared to control mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as a biomarker candidate in early stages of neurodegenerative tauopathies.

neuroscience↗

bioRxiv2022

Visual evoked potentials as an early-stage biomarker in the rTg4510 tauopathy mouse model

Tauopathies such as Alzheimers Disease (AD) and frontotemporal dementia (FTD) are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Early pathophysiological and functional changes related to neurofibrillary tangles formation are considered to occur prior to extensive neurodegeneration. Hyperphosphorylated tau has been detected in postmortem retinas of AD and FTD patients, and the visual pathway is an easily accessible system in a clinical setting. Hence, assessment of the visual function may offer the potential to detect consequences of early tau pathology in patients. In this study we explored the association between the visual system and functional consequences of tau pathology progression using a tauopathy rTg4510 mouse model. To this end, we recorded full-field electroretinography and visual evoked potentials in anesthetized and awake states at different ages. While retinal function remained mostly intact within all the age groups investigated, we detected significant changes in amplitudes of visual evoked potential responses in young rTg4510 mice exhibiting early tau pathology prior to neurodegeneration. These functional alterations in the visual cortex were positively correlated with pathological tau levels. Our findings suggest that visual processing could be useful as a novel electrophysiological biomarker for early stages of tauopathy.

neuroscience↗

bioRxiv2019

An amygdala circuit mediates experience-dependent momentary exploratory arrests

Exploration of novel environments ensures survival and evolutionary fitness. This behavior is expressed through exploratory bouts and arrests, which change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase of momentary arrests in visited locations where animals previously arrested. Quantitative analyses of neuronal calcium activity in freely-exploring mice revealed that a large neuronal ensemble in basolateral amygdala is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests. Additionally, we found that neurons in the basolateral amygdala projecting to central amygdala mediate these momentary arrests. These findings uncover an amygdala circuit that mediates momentary exploratory arrests in familiar places, without changing place preference or anxiety/fear-like behaviors.

neuroscience↗