Biology subjects

Cristiano, C.

Publications and source records attributed to Cristiano, C..

3 recordsLinked to original sources

bioRxiv2026

Maternal separation remodels Purkinje cell circuits and impairs cerebellar synaptic plasticity

Introduction: Early-life adversity has been associated with cerebellar abnormalities, but the cellular and circuit-level changes involved and their persistence across development remain poorly understood. We examined whether maternal separation (MS) disrupts cerebellar circuit maturation and whether these changes are accompanied by alterations in synaptic function and behavior. Methods: CD1 mice underwent daily maternal separation from postnatal day 2 to 18, whereas control litters remained undisturbed. Cerebellar alterations were assessed using transcriptomic and DNA methylation profiling, RT-qPCR, immunoblotting, Purkinje-cell morphometric analysis, and VGLUT1/VGLUT2 immunofluorescence. Patch-clamp electrophysiology was used to examine synaptic transmission and plasticity. Motor coordination, spontaneous locomotion, social approach, and stress-coping behavior were also evaluated. Results: RNA sequencing of whole cerebellar tissue revealed early transcriptional remodeling, involving synaptic transmission, neuronal architecture, and plasticity-related pathways. Consistent with this profile, we found that MS altered Purkinje cell dendritic arborization and excitatory input remodeling, together with deficits in cerebellar long-term synaptic plasticity and reduced BDNF-related signaling. In parallel, methylation analysis revealed hypermethylation of the glucocorticoid receptor promoter and reduced cerebellar receptor expression, indicating that early-life stress also engages stress-related epigenetic mechanisms in this region. Importantly, these neurobiological changes were associated with motor coordination deficits, altered stress-coping behavior, and impaired social interaction. Discussion: These findings identify the developing cerebellum as a target of early-life adversity and suggest that disrupted cerebellar maturation may contribute to lasting functional consequences. This study extends our understanding of the effects of maternal separation beyond the brain regions traditionally associated with stress responses.

neuroscience↗

bioRxiv2025

Brain serotonin circuit reverses decline in physical activity with age

Physical inactivity increases with age and is the fourth leading risk factor for mortality. Establishing the mechanisms underpinning declining physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HTDR tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT2C receptors (5-HT2CRs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT2CRs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.

neuroscience↗

bioRxiv2022

Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in mice

Overweight and obesity are rapidly becoming the "new normal" in developed countries, which promotes a widespread negative impact on human health. Amongst recently developed obesity medications are the serotonin 2C receptor (5-HT2CR) agonist lorcaserin and glucagon-like peptide-1 receptor (GLP-1R) agonists, but the brain circuits employed by these medications to produce their therapeutic effects remain to be fully defined. 5-HT2CRs and GLP-1Rs are widely distributed in the brain, including in the key homeostatic region the nucleus of the solitary tract (NTS) where GLP-1 is produced by preproglucagon (PPGNTS) neurons. PPGNTS cells were profiled using histochemistry and single nucleus RNA sequencing (Nuc-Seq) of mouse brainstem. Transcriptomic analyses revealed 5-HT2CR expression was widespread in PPGNTS clusters. Demonstrating the functional significance of this co-expression, lorcaserin required PPGNTS to reduce food intake. Analysis of second order neurons revealed that local GLP1-R neurons within the NTS are necessary for 5-HT2CRNTS food intake suppression. In contrast, GLP-1RNTS were not required for GLP-1R agonist liraglutide and exendin-4s short term feeding reduction, suggesting scope for lorcaserin and GLP1-R agonist combination therapy. In support of this, lorcaserin+liraglutide and lorcaserin+exendin-4 produced greater reductions in food intake when administered in combination as compared to monotherapies. These data provide insight into the therapeutic mechanisms of lorcaserin and identify a combination strategy to improve the therapeutic profile of lorcaserin and GLP1-R agonists.

neuroscience↗