Biology subjects

Braccagni, G.

Publications and source records attributed to Braccagni, G..

4 recordsLinked to original sources

bioRxiv2026

Sleep deprivation impairs information processing via dysregulation of chloride homeostasis in the prefrontal cortex

Sleep deprivation (SD) impairs information processing through alterations of prefrontal cortex (PFC) function, yet the molecular underpinnings of this process remain poorly understood. We previously showed that SD disrupts sensorimotor gating by elevating prefrontal levels of the neurosteroid allopregnanolone (AP), a positive allosteric modulator of GABA-A receptors. Here we identify a complementary, mechanistically independent process whereby SD alters GABA-A currents in the PFC of mice and rats. SD reduced membrane expression of the chloride exporter KCC2, leading to intracellular chloride accumulation and a depolarizing shift in GABA-A receptor reversal potential that weakened GABAergic inhibition. Pharmacological normalization of chloride homeostasis with bumetanide fully rescued SD-induced deficits in sensorimotor gating and information encoding. SD also upregulated BDNF, and intra-PFC antagonism of its receptor TrkB restored KCC2 expression and normalized information processing, identifying BDNF-TrkB signaling as an upstream driver of chloride dysregulation. Notably, blocking AP synthesis rescued behavioral deficits without correcting chloride imbalance, confirming mechanistic independence. Finally, combined administration of AP and a KCC2 blocker produced information-processing deficits akin to those induced by SD. These findings identify TrkB-dependent disruption of prefrontal chloride homeostasis as a druggable mechanism underlying sleep loss-induced cognitive dysfunction.

animal behavior and cognition↗

bioRxiv2025

Prefrontal 5-HT2A receptors directly contribute to tic ontogeny: translational evidence

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics and frequently accompanied by comorbidities such as obsessive-compulsive disorder (OCD) and pathological aggression. Although approved pharmacotherapies often reduce tic severity, they frequently cause adverse effects and are insufficient for managing comorbid symptoms, underscoring the need for improved treatments. Recent evidence indicates that the serotonin 5-HT2A receptor (5-HT2AR) antagonist pimavanserin reduces tic severity and improves quality of life, yet its mechanism of action in TS remains unclear. Here, we combine postmortem human and preclinical approaches to gain insight into the role of 5-HT2ARs in TS. Western-blot analyses of postmortem prefrontal cortex (PFC) samples obtained from individuals with TS revealed a pronounced, male-specific elevation of 5-HT2AR protein levels in Brodmann Area (BA) 10. We then tested pimavanserin and the selective 5-HT2AR antagonist volinanserin in two mouse models of TS: D1CT-7 transgenic mice and mice with early-life depletion of striatal cholinergic interneurons. Systemic administration of pimavanserin (1-2 mg{middle dot}kg-{superscript 1}, IP) or volinanserin (0.1-0.3 mg{middle dot}kg-{superscript 1}, IP) robustly reduced tic-like movements and stereotypies in both models. Local infusion of pimavanserin into the medial PFC, but not the dorsal striatum, recapitulated these effects, indicating a cortical locus of action. Pimavanserin also reduced resident-intruder aggression, but not locomotion or anxiety-like behavior. Together, these findings identify elevated prefrontal 5-HT2ARs as a key mechanistic contributor to TS and a promising therapeutic target for individuals with TS and pathological aggression.

neuroscience↗

bioRxiv2024

Prefrontal 5α-reductase 2 mediates male-specific acute stress response

A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). While the rate-limiting step of this reaction is catalyzed by 5-reductase (5R), the role of its two primary isoenzymes, 5R1 and 5R2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5R2, but not 5R1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Downregulation of 5R2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5R2 knockout rats. Notably, 5R1 regulated baseline AP synthesis, while 5R2 enabled AP production under stress. Acute AP administration restored stress response in 5R2 knockdown rats. Single-nucleus transcriptomics showed that 5R2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5R2 in mediating sex-specific differences in acute stress reactivity.

neuroscience↗

bioRxiv2023

CELSR3 deficiency leads to tic-related behaviors and dopaminergic alterations in the striatum

The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.

neuroscience↗