Biology subjects

Porcu, A.

Publications and source records attributed to Porcu, A..

4 recordsLinked to original sources

bioRxiv2025

Evening blue light exposure during adolescence induces avoidance behaviors and rewires medial amygdala circuit.

Adolescents are being increasingly exposed to artificial blue light from electronic devices, raising concerns about its effects on brain development and mental health. The medial amygdala (MeA), a brain region critical for emotional regulation, is light-sensitive, yet how evening blue light during puberty influences its circuitry and behavior remains unknown. Using a light cycle disruption paradigm, we found that adolescent mice exposed to evening blue light displayed increased avoidance behaviors compared to those exposed to darkness or reduced blue light conditions. Single-nuclei RNA sequencing revealed altered cell-type composition and disrupted synaptic communication pathways in the MeA. In vivo calcium imaging showed increased activity in MeA somatostatin neurons during avoidance behaviors, while chemogenetic inhibition of these neurons reduced these behaviors. Our findings identify the MeA as a key integrator of emotional responses to environmental blue light, suggesting evening blue light exposure during puberty as a potential risk factor for affective disorders. TeaserEvening blue light exposure during adolescence alters medial amygdala functions, leading to anxiety-like behaviors.

neuroscience↗

bioRxiv2022

Nuclear Receptor 5A2 Regulation of Agrp underlies Olanzapine-induced Hyperphagia

Summary/AbstractAntipsychotic (AP) drugs are highly efficacious treatments for psychiatric disorders, but a serious side effect of their use is excessive weight gain and subsequent development of metabolic disease. Increased food intake is the underlying driver of AP-induced weight gain, although the underlying mechanisms remain unknown. In previous studies, we identified hypothalamic genes whose expression level was altered following APs-induced hyperphagia. Among these genes, the orexigenic peptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) were two of the most significantly upregulated genes by APs. NR5a2 is broadly expressed throughout the body, but little is known about its role in the brain. In this study, we investigated the role of hypothalamic NR5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, OLZ treatment resulted in a dose-dependent increase in gene expression of NR5a2 and Agrp. In mice, administration of a specific Nr5a2 inhibitor decreased olanzapine-induced hyperphagia and weight gain, while knockdown of Nr5a2 in the arcuate nucleus (ARC) partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation-PCR studies showed for the first time that NR5a2 directly binds to the Agrp promoter region. In addition, in situ hybridization studies confirm that NR5a2 and Agrp are co-localized in a subset of cells in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake and these findings can be used to inform future clinical development of APs that do not activate hyperphagia and weight gain.

physiology↗

bioRxiv2021

GABAB receptor/HCN channel complexes in VTA dopamine neurons limit synaptic inhibition and prevent anxiety-like behavior

Aversive stimuli inhibiting dopamine neurons in the ventral tegmental area (DAVTA neurons) induce anxiety-like behaviors. The inhibition of DAVTA neurons is prolonged by GABAB receptor (GBR)-activated K+-currents, which exhibit a rapid desensitization of unknown physiological relevance. We now report that GBRs associate via auxiliary KCTD16 subunits with HCN channels, which facilitates activation of hyperpolarization- activated currents (Ih) by GBR-activated K+ currents. Activation of Ih underlies rapid K+ current desensitization in DAVTA neurons and limits GBR-mediated inhibition. Disruption of the GBR/HCN complex in KCTD16-/- mice or blockade of Ih prolongs optogenetically driven inhibition of DAVTA neuron firing. KCTD16-/- mice exhibit an increased anxiety-like behavior in response to stressful stimuli, which is reproduced by in vivo CRISPR/Cas9-mediated KCTD16 ablation in DAVTA neurons or intra-VTA infusion of HCN antagonist to wild-type mice. Our data reveal that GBR-induced Ih protect DAVTA neurons from prolonged GBR- mediated inhibition in response to stressors, which moderates anxiety-like behaviors.

neuroscience↗

bioRxiv2020

Photoperiod-Induced Neurotransmitter Switching in the Circadian Pacemaker Regulates Hypothalamic Dopamine Expression

Light, circadian clocks, and rhythmic behaviors interact closely to produce a temporal order that is essential for the survival of most living organisms. In mammals, the principal circadian pacemaker in the brain is the suprachiasmatic nucleus (SCN), which receives direct retinal input and synchronizes itself and other brain regions to the external light-dark cycle. Altered day length (photoperiod) and disrupted circadian rhythms are associated with impaired memory and mood in both humans and animal models. Prior work demonstrated that altering photoperiod can change neurotransmitter (NT) expression in the periventricular nucleus (PeVN) of the hypothalamus in adult rat brain. Here we show that neuromedin S-(NMS-) and vasoactive intestinal polypeptide-(VIP-) expressing neurons in the SCN also display photoperiod-induced neurotransmitter switching. Such photoperiod-dependent NT plasticity is retained in Bmal1-KO mice, indicating that NT plasticity in the SCN does not require a functional circadian clock. Utilizing a conditional viral DO-DIO vector as an historical marker of NT expression in the SCN, we further reveal that short-day photoperiod induces a cluster of non-NMS-expressing neurons to undergo NT switching and acquire the NMS phenotype. Selective chemogenetic activation of NMS neurons, but not VIP neurons, during the dark phase induces a significant delay in the timing of locomotor activity onset and is sufficient to increase the number of dopaminergic neurons in the PeVN. Our findings provide novel insights into molecular adaptations of the SCN neuronal network in response to altered photoperiod that affect neuronal circuit function in the hypothalamus and lead to changes in circadian behavior.

neuroscience↗