Biology subjects

Rojas, G. R.

Publications and source records attributed to Rojas, G. R..

3 recordsLinked to original sources

bioRxiv2023

Differential processing of delay versus uncertainty in male but not female 16p11.2 hemideletion mice

Neurodevelopmental disorders are associated with differences in learning and motivation that can influence executive function, including behavioral flexibility and decision making. 16p11.2 hemideletion is a chromosomal copy number variant that is linked to neurodevelopmental disorders. 16p11.2 hemideletion in mice has been previously found to produce male-biased changes in reward learning, but the link between this and altered flexible decision making is poorly understood. We challenged 16p11.2 hemideletion mice with two reward-guided decision making tasks assessing flexible decision making under cost, delay and probability discounting. Both tasks elicited long-term changes in flexible decision making that separated 16p11.2 hemideletion males from wildtype males. In delay discounting,16p11.2 hemideletion males had a stronger, less flexible preference for the large reward at long delays, and this effect was reduced as wildtype males adjusted their preference to match that of the hemideletion males. In probability discounting, 16p11.2 hemideletion males initially had a similar preference for seeking improbable large rewards as did wildtype males, but over time began to prefer certainty to a greater extent than did wildtype males. Female mice discounted similarly for delayed or risky rewards regardless of the presence of the copy number variant. We have previously seen that male 16p11.2 hemideletion mice commit fewer nonreinforced responses than male wildtype mice in an operant setting, which we replicate here in delay discounting, while the introduction of risky rewards eliminates genotype differences in nonreinforced responses. Overall these data suggest that 16p11.2 hemideletion in males leads to differential processing of costs of delay versus inconsistency, with greater aversion to uncertainty than delays, and greater behavioral control by cues that consistently predict an outcome.

animal behavior and cognition↗

bioRxiv2022

Endosomal removal and disposal of dysfunctional, immunostimulatory mitochondrial DNA

Maternally inherited mitochondrial DNA (mtDNA) encodes essential subunits of the mitochondrial oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation1. This function of mtDNA contributes to antiviral resistance, but unfortunately also causes pathogenic inflammation in many disease contexts2. Cells experiencing mtDNA stress due to depletion of the mtDNA-packaging protein, Transcription Factor A, Mitochondrial (TFAM), or HSV-1 infection exhibit elongated mitochondria, mtDNA depletion, enlargement of nucleoids (mtDNA-protein complexes), and activation of cGAS/STING innate immune signaling via mtDNA released into the cytoplasm3. However, the relationships between altered mitochondrial dynamics and mtDNA-mediated activation of the cGAS-STING pathway remain unclear. Here, we show that entire enlarged nucleoids are released from mitochondria that remain bound to TFAM and colocalize with cGAS. These nucleoids arise at sites of mtDNA replication due to a block in mitochondrial fission at a stage when endoplasmic reticulum (ER) actin polymerization would normally commence, which we propose is a fission checkpoint to ensure that mtDNA has completed replication and is competent for segregation into daughter mitochondria. Released nucleoids also colocalize with the early endosomal marker RAB5 as well as the late endosomal marker RAB7 in TFAM-deficient cells and in response to mtDNA stress caused by the HSV-1 UL12.5 protein. Loss of RAB7 increases interferon stimulated gene (ISG) expression. Thus, we propose that defects in mtDNA replication and/or segregation enact a late mitochondrial fission checkpoint that, if persistent, leads to selective removal of dysfunctional nucleoids by a mitochondrial-endosomal pathway. Early steps in this pathway are prone to mtDNA release and cGAS-STING activation, but the immunostimulatory mtDNA is ultimately disposed of through a mechanism involving RAB7-containing late endosomes to prevent excessive innate immune signaling. This mtDNA quality control pathway might represent a therapeutic target to prevent mtDNA-mediated inflammation and associated pathology.

cell biology↗

bioRxiv2021

Sequential delay and probability discounting tasks in mice reveal anchoring effects partially attributable to decision noise

Delay discounting and probability discounting decision making tasks in rodent models have high translational potential. However, it is unclear whether the discounted value of the large reward option is the main contributor to variability in animals choices in either task, which may limit translatability to human discounting data. Male and female mice underwent sessions of delay and probability discounting in sequence to assess how choice behavior adapts over experience with each task. To control for "anchoring" (persistent choices based on the initial delay or probability), mice experienced "Worsening" schedules where the large reward was offered under initially favorable delay or probability conditions that became less favorable during testing, followed by "Improving" schedules where the large reward was offered under initially unfavorable conditions that improved over a session. During delay discounting, both male and female mice showed elimination of anchoring effects over training. In probability discounting, both sexes of mice continued to show some anchoring even after months of training. One possibility is that noisy action selection could contribute to these anchoring effects, rather than persistent fluctuations in value discounting. We fit choice behavior in individual animals using models that included both a value-based discounting parameter and a decision noise parameter that captured variability in choices deviating from value maximization. Changes in anchoring behavior over time were tracked by changes in our decision noise parameter, not the value parameter. Thus, changes in discounting behavior in mice can result from changes in exploration of the environment rather than changes in reward valuation.

animal behavior and cognition↗