Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation

Devulapalli, Rishi K.; Jones, Natalie; Farrell, Kayla; Musaus, Madeline; Kugler, Hannah; McFadden, Taylor; Orsi, Sabrina A.; Martin, Kiley; Nelsen, Jacob L.; Navabpour, Shaghayegh; O'Donnell, Madison; McCoig, Emmarose; Jarome, Timothy J.

doi:10.1016/j.nlm.2021.107404

Cited by 28 publications

(85 citation statements)

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“…An important outcome of our study was data showing that males and females differed in the protein targets of, but not requirement for, linear polyubiquitination in the amygdala during fear memory formation. These data are similar to our recently reported result where we found that males and females differed in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation (Devulapalli et al, 2021). While much still remains unknown about the role of sex in ubiquitin-proteasome signaling in the brain, our data strongly indicate that males and females may differ in the functional need for degradationdependent and degradation-independent ubiquitin signaling in the amygdala during fear memory formation.…”

Section: Discussionsupporting

confidence: 92%

“…Collectively, these results expand our understanding of the role of protein polyubiquitination in memory formation and challenge conventional models that focus largely on protein degradation-specific roles of the UPS in learning-dependent synaptic plasticity. Furthermore, these results expand on the recently reported sex differences in the role of ubiquitinproteasome signaling in fear memory formation in the amygdala (Devulapalli et al, 2021).…”

Section: Discussionsupporting

confidence: 85%

“…As our previous work only used male rats, we repeated the experiment using female rats. Surprisingly, we found that nuclear (t 18 = 0.3738, P = 0.7129; Figure 1C) and cytoplasmic (t 18 = 0.6873, P = 0.5006; Figure 1D) linear polyubiquitination levels did not change in the BLA of female rats following fear conditioning, which is likely due to the high resting levels of ubiquitination typically seen in the amygdala of female rats (Devulapalli et al, 2021). In order to further examine the relationship between linear polyubiquitination levels and behavioral performance, we next performed correlational analyses.…”

Section: Linear Polyubiquitination Is Globally Increased In the Amygdala Of Males But Not Females After Contextual Fear Conditioningmentioning

confidence: 80%

“…After a 1 min post-shock period, the animals were returned to their homecages. Importantly, we recently reported that male and female Sprague-Dawley rats perform similar on this task and do not differ in shock reactivity (Devulapalli et al, 2021), eliminating concerns of any biochemical effects seen between sexes being due to differences in behavioral performance or sensory processing. For testing, which occurred 24 h after training, animals were placed back into the training context for 5 min in the absence of shock, unless otherwise noted below.…”

Section: Behavioral Proceduresmentioning

confidence: 91%

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Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Musaus

Farrell

Navabpour

et al. 2021

Front. Behav. Neurosci.

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Strong evidence supports that protein ubiquitination is a critical regulator of fear memory formation. However, as this work has focused on protein degradation, it is currently unknown whether polyubiquitin modifications that are independent of the proteasome are involved in learning-dependent synaptic plasticity. Here, we present the first evidence that atypical linear (M1) polyubiquitination, the only ubiquitin chain that does not occur at a lysine site and is largely independent of the proteasome, is critically involved in contextual fear memory formation in the amygdala in a sex-specific manner. Using immunoblot and unbiased proteomic analyses, we found that male (49) and female (14) rats both had increased levels of linear polyubiquitinated substrates following fear conditioning, though none of these protein targets overlapped between sexes. In males, target protein functions involved cell junction and axonal guidance signaling, while in females the primary target was Adiponectin A, a critical regulator of neuroinflammation, synaptic plasticity, and memory, suggesting sex-dependent functional roles for linear polyubiquitination during fear memory formation. Consistent with these increases, in vivo siRNA-mediated knockdown of Rnf31, an essential component of the linear polyubiquitin E3 complex LUBAC, in the amygdala impaired contextual fear memory in both sexes without affecting memory retrieval. Collectively, these results provide the first evidence that proteasome-independent linear polyubiquitination is a critical regulator of fear memory formation, expanding the potential roles of ubiquitin-signaling in learning-dependent synaptic plasticity. Importantly, our data identify a novel sex difference in the functional role of, but not a requirement for, linear polyubiquitination in fear memory formation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 85%

Section: Linear Polyubiquitination Is Globally Increased In the Amygdala Of Males But Not Females After Contextual Fear Conditioningmentioning

confidence: 80%

Section: Behavioral Proceduresmentioning

confidence: 91%

See 2 more Smart Citations

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Musaus

Farrell

Navabpour

et al. 2021

Front. Behav. Neurosci.

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“…There may be additional effects of age and sex following TFC memory retrieval in cytoplasmic and nuclear fractions (e.g., Orsi et al, 2019). One recent study found that young male, but not female, rats had increased protein degradation in the nuclei of amygdala cells after fear conditioning, while females had elevated baseline levels of overall UPS activity in amygdala nuclei (Devulapalli et al, 2021). Additionally, we only took brain tissue at 90 min following retrieval.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Dulka

Trask

Helmstetter

2021

Front. Aging Neurosci.

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Aging is marked by an accumulation of damaged and modified brain proteins, and the ubiquitin-proteasome system (UPS) is important for cellular protein degradation. Recent work has established a critical role for the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. We trained young, middle-aged, and aged male and female rats using trace fear conditioning (TFC) to investigate the effects of age and sex on memory. We then measured markers of UPS-related protein degradation (phosphorylation of the Rpt6 proteasome regulatory subunit and K48-linked polyubiquitination) using western blots. We found that aged males, but not aged females, showed behavioral deficits at memory retrieval. Aged males also displayed reduced phosphorylation of the Rpt6 proteasome subunit and accumulation of K48 in the basolateral amygdala, while aged females displayed a similar pattern in the medial prefrontal cortex. These findings suggest that markers of UPS function are differentially affected by age and sex in a brain region-dependent manner. Together these results provide an important step toward understanding the UPS and circuit-level differences in aging males and females.

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Fear response of rat pups to a non‐aversive social stimulus: Evidence for the involvement of memory processes

Zuluaga,

Agrati,

Athaíde

et al. 2023

Developmental Psychobiology

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Learning processes in rats during early development are importantly mediated by the mother, which represents the primary source of environmental information. This study aimed to determine whether aversive early experiences can induce the expression of pups' fear responses toward a non‐aversive stimulus as a consequence of a memory process. First, we determined pups’ fear responses toward an anesthetized female after being exposed to this stimulus or an empty cage together with their mothers from Postnatal Day (PNDs) 1 to 4. Second, we evaluated if the administration of the protein synthesis inhibitor cycloheximide (CHX; 0.2 mg/kg, subcutaneously (sc).) disrupted the reconsolidation processes and abolished the fear response on PND 9. Only female pups previously exposed to the female intruder expressed fear responses toward an anesthetized female on PND 8. CHX administration to female pups immediately after exposure to an anesthetized female on PND 8 suppressed fear responses on PND 9, indicating that the fear expression was the result of a memory process, probably mediated by the mother. These findings demonstrated that early experiences can shape responses to social stimuli in a sex‐dependent manner and emphasize the critical role of the mother in influencing fear learning in a social context.

show abstract

Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation

Cited by 28 publications

References 60 publications

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Age-Related Memory Impairment and Sex-Specific Alterations in Phosphorylation of the Rpt6 Proteasome Subunit and Polyubiquitination in the Basolateral Amygdala and Medial Prefrontal Cortex

Fear response of rat pups to a non‐aversive social stimulus: Evidence for the involvement of memory processes

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