Biology subjects

Perini, I.

Publications and source records attributed to Perini, I..

4 recordsLinked to original sources

bioRxiv2025

White matter reorganization of motor and affective-motivational networks in pain-indifferent carriers of the R221W mutation

Congenital insensitivity to pain (CIP) due to the R221W mutation on the nerve growth factor gene results in reduced peripheral C-nociceptor density and behavioural indifference to painful stimuli. While functional neuroimaging has revealed altered cortical and sub-cortical pain processing in R221W carriers, structural white matter changes remain unexplored and may suggest an anatomical basis of symptoms. Heterozygous R221W carriers (n = 11) and age-, sex-, education-matched controls (n = 11) diffusion tensor imaging data were compared using fixel-based analysis, and complimentary edge and node analyses using graph theory, and network-based statistics. Whole-brain and region of interest (ROI) fixel-based analyses revealed significantly reduced fibre density and fibre-bundle cross-section in brainstem motor tracts of R221W carriers, encompassing the corticospinal pathways, corona radiata, external capsule, cerebellar peduncles, and pontine crossing (p < 0.05). Graph theory analysis of pain-processing ROIs demonstrated reduced local efficiency in right anterior cingulate cortex (ACC) and altered betweenness centrality in bilateral insula and left ACC of R221W carriers. Despite R221W carriers showing higher node degrees in the somatosensory cortex and ACC, these connections had reduced efficiency and integration with cortical network regions. Network-based statistics identified a possible compensatory subnetwork with stronger connectivity from right thalamus to left ACC and left insula in R221W carriers (p < 0.019). These findings suggest that congenitally reduced peripheral nociception could lead to abnormalities in the thalamocortical and motor efferent pathway, but not sensory afferent pathways. The combination of reduced brainstem motor tract integrity and altered cortical network efficiency, alongside potentially compensatory thalamo-cortical connectivity, could support a model of R221W CIP as motor under-reactivity rather than sensory insensitivity.

neuroscience↗

bioRxiv2025

PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1α-dependent mechanism

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease where the majority of ACM patients carry a (likely) pathogenic variant in desmosomal genes, predominantly in plakophilin-2 (PKP2). While the genetic cause of the disease is well studied, the molecular disease-driving mechanisms and how exercise can drive disease progression remain poorly understood. In this study, we identified the oxidative phosphorylation (OXPHOS) pathway to be downregulated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and human explanted hearts carrying pathogenic PKP2 variants. The reduced expression of OXPHOS related genes was a result of lower PPARGC1A expression which led to decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. Induction of PPARGC1A expression partially restored the expression of OXPHOS components and improved contractility in PKP2 mutant cells. These results suggest that improving oxidative capacity through modulation of PPARGC1A in cardiomyocytes could be considered as a new therapeutic target for ACM patients in the future.

molecular biology↗

bioRxiv2024

PREFRONTAL CORRELATES OF FEAR GENERALIZATION DURING ENDOCANNABINOID DEPLETION

Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging from a childhood maltreatment exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and suggest 2-AG deficiency could represent a trauma-related disorder susceptibility endophenotype.

neuroscience↗

bioRxiv2018

A congenital pain insensitivity mutation in the nerve growth factor gene uncouples nociception from affective pain in heterozygous humans and mice

Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, such as fear. Despite recent advances, the question of how the pain experience influences learning of the fear response is still debated1,2. Genetic disorders rendering patients congenitally unable to feel pain have been described, and are usually explained by defects in peripheral nociceptors3-5. It is not known how growing up without pain affects central emotional and motivational responses to aversive stimuli. The rare autosomal recessive Hereditary Sensory and Autonomic Neuropathy type V (HSAN V) is caused by a mutation in the nerve growth factor (NGF) gene (R100W). HSAN V homozygous patients display a congenital indifference to painful events, with deficits in peripheral nociceptors but without overt cognitive impairment6. In contrast, heterozygous carriers do not present with pain-related deficits and have been identified only through pedigree and genetic screening7,8. We exploited this clinically silent population to dissociate nociceptive from affective features of pain. To address this we investigated both heterozygous knock-in mice bearing the R100W mutation (NGFR100W/m mice) and a cohort of HSAN V heterozygous human carriers. Surprisingly, we found that NGFR100W/m mice, despite normal responses to a noxious conditioning stimulus, show a deficit in learned fear while their social and innate fear responses are normal. The lack of pain-related fear response was linked to a reduced activation of anterior cingulate and motor cortices and of striatum, but not in primary somatosensory cortex. Likewise, human heterozygous R100W carriers, despite perceiving noxious stimuli and reporting subjective pain thresholds, show increased reaction latencies in response to painful stimulation, alongside a decreased subjective urgency to react. Functional magnetic resonance imaging (fMRI) revealed, comparably to the mouse data, an altered processing of painful stimuli in rostral anterior cingulate, medial premotor cortical regions and striatum. These findings from both human and mouse HSAN V carriers uncover behavioural and motivational consequences of a mild genetic pain insensitivity on the establishment of pain-dependent affective responses and memories.

neuroscience↗