Biology subjects

Murgia, N.

Publications and source records attributed to Murgia, N..

3 recordsLinked to original sources

bioRxiv2026

Reduced Prefrontal PRDM2 Increases Stress-Induced Reinstatement Across Sexes via a dmPFC-Nucleus Accumbens Pathway

Stress is a major driver of relapse in alcohol use disorder (AUD), partly through stress-induced dysregulation of prefrontal cortex (PFC) circuits that govern executive control, craving regulation, and adaptive behavioral responses. Such dysfunction may be partly driven by epigenetic regulation of transcriptional programs that shape PFC responses to stress. Here, we investigated the role of the histone methyltransferase PRDM2 in stress-induced relapse to alcohol seeking. Analysis of postmortem human tissue showed that PRDM2 expression in the PFC was reduced in both men and women with AUD compared with control individuals. To examine the functional significance of this reduction in alcohol-related behaviors, we used viral-mediated knockdown of Prdm2 in the dorsomedial prefrontal cortex (dmPFC) of male and female rats. Prdm2 knockdown increased vulnerability to stress-induced reinstatement of alcohol seeking in both sexes, without altering pain sensitivity or being influenced by estrous cycle stage. To determine whether this effect was mediated through specific prefrontal output pathways, we selectively reduced Prdm2 expression in dmPFC neurons projecting to the nucleus accumbens (NAc). Projection-specific knockdown also increased stress-induced reinstatement of alcohol seeking in male and female rats in a shock intensity-dependent manner. Together, these findings suggest that reduced PRDM2 expression in the PFC contribute to stress-induced relapse-like behavior and identify the dmPFC-NAc projection as a circuit through which PRDM2 influences alcohol seeking.

neuroscience↗

bioRxiv2026

Network reorganization distinguishes vulnerability and resilience to observational fear

Individuals vary widely in their responses to stress and threat, with some developing persistent fear after adverse experiences while others remain resilient. Such variability also extends to social contexts, where individuals can acquire information about danger by observing others in distress through observational fear learning. The neural mechanisms underlying individual differences in responses to socially conveyed threat remain poorly understood. Here, we examined how variability in OFL relates to large-scale brain network organization. Rats observed conspecifics receiving tone-shock pairings and were later tested for fear responses to the conditioned stimulus. Behavioral analysis revealed two phenotypes: observational-susceptible rats displaying robust freezing and observational-resilient rats showing freezing levels comparable to controls. Despite these differences, both groups exhibited elevated corticosterone responses, indicating that socially conveyed threat was detected across animals. Brain-wide c-Fos mapping across 84 regions combined with graph-theoretical analysis revealed distinct network architectures associated with each phenotype. These findings suggest that susceptibility and resilience to socially acquired fear emerge from differences in distributed brain network organization.

neuroscience↗

bioRxiv2025

Selective abundance of the stemness-promoting cluster miR-290-295 within the adult substantia nigra dopamine neurons is neuroprotective via preservation of protein synthesis

Locomotor, reward and other critical functions of the body are regulated by the ventral midbrain, with the central role played by dopamine (DA) neurons. The function of these cells from the early development to maturity is critically dependent on the orchestrated expression of coding and non-coding genes. For example, in the stem cells the miR-290-295 cluster constitutes the majority of expressed microRNAs and is critical for stemness in rodents. During development towards various terminally differentiated lineages, such as neurons, the cells typically switch off transcription of these stem cell-specific microRNAs. Here we report that within the adult Substantia Nigra pars compacta (SNpc), the miR-290-295 cluster is exclusively expressed in DA neurons (SNDA), preventing the locomotor deficits and maintaining an adequate expression of proteins involved in DA biogenesis, such as tyrosine hydroxylase (TH), dopa decarboxylase (DDC) and DA transporter (DAT). Importantly, a global knock-out of the miR-290-295 cluster leads to decreased numbers of SNDA neurons in adult mice. Using in vitro and in vivo DA cell-specific loss-of-function models, we demonstrated that miR-292a-3p, the most abundant microRNA in this cluster, directly targets PTEN, a phosphatase antagonizing the neuroprotective phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT-mechanistic target of rapamycin kinase (mTOR) pathways regulating translation initiation. Accordingly, when labelled with the click chemistry-compatible methionine analogue L-azidohomoalanine, miR-290-295 cluster-deficient SNDA neurons revealed a drastic impairment of protein synthesis, which is critical for DA biogenesis. Our surprising findings demonstrate for the first time a selective expression of stem cell-specific and stemness-promoting microRNAs in a distinct population of mature neurons to maintain their physiological functions in the adulthood, suggesting that similar epigenetic disinhibition mechanisms may be also critical for other terminally differentiated cells across species.

neuroscience↗