bioRxiv Science⌕ Search

Biology subjects

Hedges, A.

Publications and source records attributed to Hedges, A..

2 recordsLinked to original sources

Stress induces distinct social behavior states encoded by the ventral hippocampus

A single, acute traumatic experience can result in a host of negative impacts on behavior, such as increased violence, reduced sociability, and exaggerated fear responses. Despite the large body of research on the neurobiology of stress, we have a poor understanding of how trauma rewires social circuits in the brain. To identify how social circuits are re-organized by stress, we interrogated the role of the ventral hippocampus (VH), a key node for both the orchestration of emotionally-relevant behavior and the integration of sensory information. Using a footshock-based model of traumatic stress, we established that a single exposure to a series of unpredictable, inescapable footshocks was sufficient to negatively alter social behavior, resulting in increased violence and social hesitancy. Critically, we found that stress-induced changes to social behavior engaged neural ensembles in the VH, a critical node in the regulation of emotion states. Using a virally-mediated, activity-dependent cellular tagging approach to label two neural ensembles activated by temporally distinct experiences, we were surprised to find that stress-induced violence and stress-induced social hesitancy recruited largely non-overlapping populations of cells in the VH, in contrast to higher degrees of ensemble overlap in unstressed control mice, suggesting that stress biases the brain towards stronger differentiation of distinct social states. Additionally, we found that activity of VH neurons was required for stress-induced aggression. Finally, we found that stress-induced changes to social behaviors and VH activity profiles could be reversed by the introduction of social buffering post-stress. Collectively, our findings suggest that stress drives the VH to dissociably encode specific behavioral states, rather than a single state of negative valence, consistent with a role for multiple structures and distributed ensembles in the modulation of traumatic stress.

neuroscience↗

DAF-16/Foxo suppresses the transgenerational sterility of prg-1 piRNA mutants via a systemic small RNA pathway

Mutation of the daf-2 insulin/IGF-1 receptor activates the DAF-16/Foxo transcription factor to suppress the transgenerational sterility phenotype of prg-1/piRNA mutants that are deficient for piRNA-mediated genome silencing. As with PRG-1/piRNAs, mutations in the nuclear RNA interference gene nrde-1 compromised germ cell immortality, but deficiency for daf-2 did not suppress the transgenerational sterility of nrde-1 or nrde-4 single mutants or of prg-1; nrde-4 or prg-1; hrde-1 double mutants. NRDE-1 and NRDE-4 promote transcriptional silencing in somatic cells via the nuclear Argonaute protein NRDE-3, which was dispensable for germ cell immortality. However, daf-2 deficiency failed to promote germ cell immortality in prg-1; nrde-3 mutants. Consistently, we found that DAF-16 activity in somatic cells suppressed the transgenerational sterility of prg-1 mutants via the SID-1 dsRNA transmembrane channel that promotes systemic RNAi as well as Dicer, the dsRNA binding protein RDE-4 and the RDRP RRF-3. We conclude that DAF-16 activates a cell-non-autonomous systemic RNAi pathway that promotes small RNA-mediated genome silencing in germ cells to suppress loss of the genomic immune surveillance factor Piwi/PRG-1. Author SummarySmall RNAs can promote genome silencing. The Argonaute protein Piwi interacts with thousands of small RNAs termed piRNAs in germ cells to suppress expression of transposons and foreign genetic elements. However, the Piwi silencing system may be commonly targeted by viral or transposon genomic parasites that seek to suppress the endogenous defences against their expression and replication. Activation of the DAF-16 stress response pathway promotes adult longevity and can also abolish the transgenerational sterility of C. elegans Piwi mutants. We found that DAF-16 accomplishes this by activating a somatic small RNA pathway where small RNAs are initially produced in the soma and are then transported into the germline to suppress expression of a toxic genetic locus in Piwi mutants. Thus, the DAF-16 stress response pathway activates a systemic small RNA cascade to suppress defects in the Piwi/piRNA genome silencing system.

genetics↗