Dataset Information

Proteomic Insights into Extinction Memory Deficits in Stress-Susceptible Female Rats

ABSTRACT: Stress exposure can disrupt fear extinction, which is a hallmark of some stress-related disorders. The underlying molecular mechanisms of impaired extinction, especially in females, remain poorly understood. In this study, we investigated proteomics changes in the infralimbic cortex, a region critical for fear suppression, in female rats exposed to single prolonged stress (SPS). One week after SPS exposure, adult female rats underwent auditory fear conditioning and extinction training and were classified as susceptible or resilient based on their extinction performance. Quantitative proteomics analysis using tandem mass tag labeling and bioinformatics revealed distinct proteins and pathways between groups. Susceptible rats exhibited distinct proteomic profiles in the infralimbic cortex. Several of the 53 differentially expressed proteins are associated with synaptic plasticity and memory, including neurogranin and microtubule-associated protein tau (MAPT). Pathway enrichment analysis identified alterations in synaptogenesis, clathrin-mediated endocytosis, calcium signaling, and chaperone-mediated autophagy. Functional validation using AAV-shRNA knockdown of neurogranin or MAPT in glutamatergic neurons of the infralimbic cortex improved extinction memory in SPS-exposed animals. Our findings suggest that dysregulated protein expression in the infralimbic cortex contributes to impaired extinction memory and traumatic stress susceptibility in female rats, offering insight into the neurobiological mechanisms underlying vulnerability to stress-related disorders.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain, Diploid Cell

DISEASE(S): Post-traumatic Stress Disorder

SUBMITTER: Loyda Melendez

LAB HEAD: Loyda M. Meléndez, phd

PROVIDER: PXD069169 | Pride | 2026-02-09

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	TMTAnalysis_NashalyIrizarry_29nov2023_rev.msf	Msf
	TMTAnalysis_NashalyIrizarry_29nov2023_rev.mzML	Mzml
	TMTAnalysis_NashalyIrizarry_29nov2023_rev.mzTab	Mztab
	TMTPool_Fraction1_Nashaly_QE_14nov2023.raw	Raw
	TMTPool_Fraction2_Nashaly_QE_14nov2023.raw	Raw

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Proteomic insights into extinction memory deficits in stress-susceptible female rats.

Irizarry-Méndez Nashaly N Acosta-Pierantoni Yelitza Y Diaz-Vazquez Alondra A Hernández Anixa A Colón Maria M Tosado-Rodríguez Eduardo L EL Cantres-Rosario Yadira M YM Roche-Lima Abiel A Rodríguez-De Jesús Ana E AE Meléndez Loyda M LM Porter James T JT

Frontiers in behavioral neuroscience 20260113

Stress exposure can disrupt fear extinction, which is a hallmark of some stress-related disorders. The underlying molecular mechanisms of impaired extinction, especially in females, remain poorly understood. In this study, we investigated proteomics changes in the infralimbic cortex, a region critical for fear suppression, in female rats exposed to single prolonged stress (SPS). One week after SPS exposure, adult female rats underwent auditory fear conditioning and extinction training and were c ...[more]

PMID: 41608082

Similar Datasets

Project description:Background: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena. Methods: Spontaneous recovery and fear renewal tests, assessed persistence and context-independence of treatments rescuing deficient fear extinction in 129S1/SvImJ mice. To reveal neurobiological mechanisms supporting long-lasting extinction rescue, whole-genome expression profiling, qRT-PCR, immunohistochemistry and chromatin immunoprecipitation were used. Results: Persistent and context-independent rescue of deficient fear extinction induced by dietary zinc-restriction was associated with enhanced expression of dopamine-related genes, such as genes encoding the dopamine- D1 (Drd1a) and -D2 (Drd2) receptor in the medial prefrontal cortex (mPFC) and amygdala. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a possibly involved gene regulatory mechanism. While enhancing histone acetylation, via administering the HDAC inhibitor MS275, does not induce successful fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated. This was associated with enhanced neuronal histone acetylation in the mPFC and amygdala. Finally, as a proof of principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. Conclusion: Current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear inhibitory memory.

Project description:Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example the expression of an aversive behavior upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinctionare only beginning to emerge. Here we show that fear extinction initiates up-regulation of hippocampal insulin-growth factor 2 (Igf2) and down-regulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2-signaling during fear extinction. To this end we show that fear extinction-induced IGF2/IGFBP7-signaling promotes the survival of 17-19 day-old newborn hippocampal neurons. In conclusion, our data suggests that therapeutic strategies that enhance IGF2-signaling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory. We employed mice to investigate fear extinction in the hippocampus-dependent contextual fear conditioning paradigm. To this end, male C57BL/6J mice were exposed to the fear conditioning box (context) followed by an electric foot-shock which elicits the acquisition of conditioned contextual fear. For extinction training animals were repeatedly reexposed to the conditioned context on consecutive days (24h interval) without receiving the footshockagain (extinction trial, E). This procedure eventually results in the decline of the aversive freezing behavior. Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups. To gain a better understanding of the molecular processes underlying fear extinction we performed a genome-wide analysis of the hippocampal transcriptome during fear extinction. In the employed paradigm fear extinction is a gradual process. To capture the longitudinal course of fear extinction we decided to perform hippocampal microarray analysis at two time points: (1) After the first extinction trial (E1) when animals display high levels of aversive freezing behavior and (2) at the extinction trial on which the freezing behavior was significantly reduced when compared to E1. This extinction trial, in the case of this experiment E5, we termed “extinction trial low freezing” (ELF). Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups (3). For all three groups we hybridized 5 samples (biological replicates).