Biology subjects

Bontempi, B.

Publications and source records attributed to Bontempi, B..

3 recordsLinked to original sources

bioRxiv2024

Cerebral Small Vessel Disease genetic determinant TRIM47 controls brain homeostasis via the NRF2 antioxidant system

Cerebral small vessel disease (cSVD) is a leading cause of stroke, cognitive decline and dementia, for which no specific mechanism-based treatments are available to date. Genome-wide and whole-exome association studies previously identified robust associations of common variants at chr17q25 with cSVD features on magnetic resonance imaging, with converging bioinformatic and experimental data for a causal involvement of TRIM47. Preliminary functional evaluation of TRIM47, an ubiquitin ligase enriched in brain endothelial cells (ECs), suggested its potential role in blood brain barrier (BBB) integrity. Here, we show that TRIM47 regulates brain EC resilience and adaptive responses to oxidative stress by binding to KEAP1, stabilizing NRF2 protein levels and promoting the NRF2 antioxidant signaling pathway. In vivo, Trim47-deficient mice exhibit downregulation of NRF2 target genes, BBB dysfunction, astrogliosis and cognitive impairments. Endothelial-specific deletion of Trim47 recapitulates these phenotypes. Treatment with the NRF2 activator tert- butylhydroquinone normalized BBB integrity and cognitive function in Trim47-deficient mice, highlighting the role of endothelial TRIM47 in driving brain homeostasis through NRF2 pathway activation. This work indicates that loss of the protective TRIM47/NRF2 axis may increase the susceptibility to developing human cSVD and that targeting the TRIM47/NRF2 axis could be a promising therapeutic approach for vascular cognitive impairment and dementia.

neuroscience↗

bioRxiv2024

Early intrinsic plasticity of ACC engram neurons defines memory formation and precision

Neocortical memory engrams are thought to stabilize and mature via enhanced interconnectivity during the so-called systems-consolidation process 1,2. While synaptic plasticity of these engram connections is considered an important mechanism for storing memories 3,4, it cannot fully account for the dynamic vividness of remote, cortically-based memories. Indeed, cell-intrinsic plasticity has been touted as the crucial early priming mechanism that renders nascent engram neurons susceptible to ongoing plastic processes while providing flexibility for later encoding events 5-7. Here, we reveal that learning-related neuron-wide intrinsic excitability (IE) plasticity of nascent cortical engram neurons is a permissive mechanism for the formation and specificity of remote associative memories. Using a c-fos-dependent genetic and viral system for the targeted labeling of engram neurons in the anterior cingulate cortex (ACC) combined with ex vivo electrophysiology, we found that contextual fear learning triggered a time-dependent increase in their IE signature expressed over days during the early, but not late, phase of memory formation. Remarkably, chemogenetically hyperpolarizing engram neurons during this early plastic phase enhanced their maturation, increasing the strength and context-precision of consolidated memories and preventing memory disturbance caused by an interference event. Altogether, our findings identify cell-intrinsic plasticity within nascent ACC engram neurons as an essential tagging mechanism whose features determine the fate and dynamic content of remote memories.

neuroscience↗

bioRxiv2024

Effects of head-only exposure to 900 MHz GSM electromagnetic fields in rats : changes in neuronal activity as revealed by c-Fos imaging without concomitant cognitive impairments

Over the last decade, animal models have been used to evaluate the physiological and cognitive effects of mobile phone exposures. Here, we used a head-only exposure system in rats to determine whether exposure to 900MHz GSM electromagnetic fields (EMF) induces regional changes in neuronal activation as revealed by c-Fos imaging. In a first study, rats were exposed for 2h to brain average specific absorption rates (BASARs) ranging from 0.5 to 6W/kg. Changes in neuronal activation were found to be dose-dependent with significant increases in c-Fos expression occurring at BASAR of 1W/kg in prelimbic, infralimbic, frontal and cingulate cortices. In a second study, animals were submitted to either a spatial working memory (WM) task in a radial maze or a spatial reference memory (RM) task in an open field arena. Exposures (45min) were conducted before each training session (BASARs of 1 and 3.5W/kg). Control groups included sham-exposed and control cage animals. In both tasks, behavioral performance evolved similarly in the four groups over testing days. However, c-Fos staining was significantly reduced in cortical areas (prelimbic, infralimbic, frontal, cingulate and visual cortices) and in hippocampus of animals engaged in the WM task (BASARs of 1 and 3.5W/kg). In the RM task, EMF exposure-induced decreases were limited to temporal and visual cortices (BASAR of 1W/kg). These results demonstrate that both acute and subchronic exposures to 900MHz EMFs can produce biological effects, but these effects were not sufficient to induce detectable cognitive deficits in the tasks used here.

neuroscience↗