Biology subjects

Ferri, S. L.

Publications and source records attributed to Ferri, S. L..

3 recordsLinked to original sources

bioRxiv2024

A chromosome region linked to neurodevelopmental disorders acts in distinct neuronal circuits in males and females to control locomotor behavior

Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs). These disorders often demonstrate male-specific vulnerabilities; however, the identification of underlying mechanisms remains a significant challenge in the field. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and mice modeling 16p11.2 del/+ exhibit sex-specific striatum-related phenotypes relevant to NDDs. Striatal circuits, crucial for locomotor control, consist of two distinct pathways: the direct and indirect pathways originating from D1 dopamine receptor (D1R) and D2 dopamine receptor (D2R) expressing spiny projection neurons (SPNs), respectively. In this study, we define the impact of 16p11.2 del/+ on striatal circuits in male and female mice. Using snRNA-seq, we identify sex- and cell type-specific transcriptomic changes in the D1- and D2-SPNs of 16p11.2 del/+ mice, indicating distinct transcriptomic signatures in D1-SPNs and D2-SPNs in males and females, with a [~]5-fold greater impact in males. Further pathway analysis reveals differential gene expression changes in 16p11.2 del/+ male mice linked to synaptic plasticity in D1- and D2-SPNs and GABA signaling pathway changes in D1-SPNs. Consistent with our snRNA-seq study revealing changes in GABA signaling pathways, we observe distinct changes in miniature inhibitory postsynaptic currents (mIPSCs) in D1- and D2-SPNs from 16p11.2 del/+ male mice. Behaviorally, we utilize conditional genetic approaches to introduce the hemideletion selectively in either D1- or D2-SPNs and find that conditional hemideletion of genes in the 16p11.2 region in D2-SPNs causes hyperactivity in male mice, but hemideletion in D1-SPNs does not. Within the striatum, hemideletion of genes in D2-SPNs in the dorsal lateral striatum leads to hyperactivity in males, demonstrating the importance of this striatal region. Interestingly, conditional 16p11.2 del/+ within the cortex drives hyperactivity in both sexes. Our work reveals that a locus linked to NDDs acts in different striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner, providing new insight into male vulnerability for NDDs. Highlights- 16p11.2 hemideletion (16p11.2 del/+) induces sex- and cell type-specific transcriptomic signatures in spiny projection neurons (SPNs). - Transcriptomic changes in GABA signaling in D1-SPNs align with changes in inhibitory synapse function. - 16p11.2 del/+ in D2-SPNs causes hyperactivity in males but not females. - 16p11.2 del/+ in D2-SPNs in the dorsal lateral striatum drives hyperactivity in males. - 16p11.2 del/+ in cortex drives hyperactivity in both sexes. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/594746v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@19542baorg.highwire.dtl.DTLVardef@4ff570org.highwire.dtl.DTLVardef@17aa1c3org.highwire.dtl.DTLVardef@123e48_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Excess neonatal testosterone causes male-specific social and fear memory deficits in wild-type mice

Neurodevelopmental disorders disproportionately affect males compared to females. The biological mechanisms of this male susceptibility or female protection have not been identified. There is evidence that fetal/neonatal gonadal hormones, which play a pivotal role in many aspects of development, may contribute. Here, we investigate the effects of excess testosterone during a critical period of sex-specific brain organization on social approach and fear learning behaviors in C57BL/6J wild-type mice. Male, but not female, mice treated with testosterone on the day of birth (PN0) exhibited decreased social approach as juveniles and decreased contextual fear memory as adults, compared to vehicle-treated controls. These deficits were not driven by anxiety-like behavior or changes in locomotion or body weight. Mice treated with the same dose of testosterone on postnatal day 18 (PN18), which is outside of the critical period of brain masculinization, did not demonstrate impairments compared to the vehicle group. These findings indicate that excess testosterone during a critical period of early development, but not shortly after, induces long-term deficits relevant to the male sex bias in neurodevelopmental disorders. Significance statementExcess testosterone during a critical period of sex-specific brain organization, results in male-specific social and cognitive deficits in mice while testosterone treatment outside of this developmental window did not alter behavior. This time-sensitive, brief hormonal dysregulation induces long-term changes, and may be involved in the male sex bias in neurodevelopmental disorders.

animal behavior and cognition↗

bioRxiv2020

Age- and Sex-Specific Fear Conditioning Deficits in Mice Lacking Pcdh10, an Autism Associated Gene

PCDH10 is a gene associated with Autism Spectrum Disorder. It is involved in the growth of thalamocortical projections and dendritic spine elimination. Previously, we characterized mice Pcdh10 haploinsufficient mice (Pcdh10+/- mice) and found male-specific social deficits that are rescued by N-methyl-D-aspartate receptor (NMDAR) partial agonist d-cycloserine, increased ultrasonic vocalizations in pups, and dark phase hypoactivity. In addition, we determined that the basolateral amygdala (BLA) of these mice exhibited increased dendritic spine density of immature morphology, decreased NMDAR expression, and decreased gamma synchronization. Here, we further characterize Pcdh10+/- mice by testing for fear memory, which relies upon BLA function. We used both male and female Pcdh10+/- mice and their wild-type littermates at two ages, juvenile and adult, and in two learning paradigms, cued and contextual fear conditioning. We found that males at both ages and in both assays exhibited fear conditioning deficits, but females were only impaired as adults in the cued condition. These data are further evidence for male-specific alterations in BLA-related behaviors in Pcdh10+/- mice, and suggest that these mice may be a useful model for dissecting male specific brain and behavioral phenotypes relevant to social and emotional behaviors.

neuroscience↗