Biology subjects

Feig, L.

Publications and source records attributed to Feig, L..

4 recordsLinked to original sources

bioRxiv2024

Astrocyte-Derived Exosomes Regulate Sperm miR-34c Levels to Mediate the Transgenerational Effects of Paternal Chronic Social Instability Stress

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not understood. Here we describe evidence for astrocyte-derived exosomes (A-Exos) containing miR-34c mediating how chronic social instability (CSI) stress suppesses levels of miR-34c in sperm, which we showed previously contributes to how this stress protocol leads to both elevated anxiety and defective sociability in their female offspring and reduced sperm miR-34c in their male offspring. In particular, we found that CSI stress decreases content of miR-34c in A-Exos isolated from the prefrontal cortex and amygdala, as well as in blood of CSI-stressed males. Strikingly, miR-34c content is also reduced in A-Exos isolated from these tissues of their F1 male offspring, who also display reduced sperm miR-34c levels despite never being directly exposed to stress and transmit these stress related traits to their offspring. In addition, restoring A-Exos miR-34c content in the blood of CSI-stressed males by IV injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal a surprising role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.

genetics↗

bioRxiv2023

Preimplantation Embryos Amplify Sperm-Derived miRNA Levels to Mediate Transgenerational Epigenetic Inheritance

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here we describe evidence that astrocyte-derived exosomes (A-Exos) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.

genetics↗

bioRxiv2020

Ras-GRF1 in CRF Cells Controls the Early Adolescent Female Response to Repeated Stress

Ras-GRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates Ras and Rac GTPases. In hippocampal neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed that GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after exposure to 7-days of restraint-stress (7DRS) (30 min/day) elevation of serum CORT levels are suppressed in early adolescent (EA) female, but not EA male or adult female GRF1 knockdown mice. Here, we show that this phenotype is due, at least in part, to the loss of GRF1 expression in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockdown specifically in these cells also reduces serum CORT response to 7DRS in EA females, but not EA males or adult females. Moreover, it reduces females CORT levels to those to found in comparably stressed control male mice. GRF1 knockdown in CRF cells also blocks the anxiolytic phenotype normally found in EA females 24 hrs after 7DRS. Interestingly, loss of GRF1 in these cells has no effect after only 3 exposures to restraint stress, revealing a role for GRF1 in repeated stress-induced CRF cell plasticity that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response early-adolescent female display to repeated stress.

neuroscience↗

bioRxiv2020

Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model

Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.

neuroscience↗