Dopamine-dependent prefrontal reactivations explain long-term benefit of fear extinction.
Ontology highlight
ABSTRACT:
SUBMITTER: Gerlicher AMV
PROVIDER: S-EPMC6191435 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-12-21 | GSE76109 | GEO
Project description:Extinction of conditioned fear necessitates the dynamic involvement of hippocampus, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA), but key molecular players that regulate these circuits to achieve fear extinction remain largely unknown. Here, we report that acid-sensing ion channel 1a (ASIC1a) is a crucial molecular regulator of fear extinction, and that this function requires ASIC1a in ventral hippocampus (vHPC), but not dorsal hippocampus, mPFC, or BLA. While genetic disruption or pharmacological inhibition of ASIC1a in vHPC attenuated the extinction of conditioned fear, overexpression of the channel in this area promoted fear extinction. Channelrhodopsin-2-assisted circuit mapping revealed that fear extinction involved an ASIC1a-dependent modification of the long-range hippocampal-prefrontal correlates in a projection-specific manner. Gene expression profiling analysis and validating experiments identified several neuronal activity-regulated and memory-related genes, including Fos, Npas4, and Bdnf, as the potential mediators of ASIC1a regulation of fear extinction. Mechanistically, genetic overexpression of brain-derived neurotrophic factor (BDNF) in vHPC or supplement of BDNF protein in mPFC both rescued the deficiency in fear extinction and the deficits on extinction-driven adaptations of hippocampal-prefrontal correlates caused by the Asic1a gene inactivation in vHPC. Together, these results establish ASIC1a as a critical constituent in fear extinction circuits and thus a promising target for managing adaptive behaviors.
| S-EPMC6223961 | biostudies-literature
Project description:The ventromedial prefrontal cortex (vmPFC; rodent infralimbic cortex (IL)), is posited to be an important locus of fear extinction-facilitating effects of the dopamine (DA) bio-precursor, L-DOPA, but this hypothesis remains to be formally tested. Here, in a model of impaired fear extinction (the 129S1/SvImJ inbred mouse strain; S1), we monitored extracellular DA dynamics via in vivo microdialysis in IL during fear extinction and following L-DOPA administration. Systemic L-DOPA caused sustained elevation of extracellular DA levels in IL and increased neuronal activation in a subpopulation of IL neurons. Systemic L-DOPA enabled extinction learning and promoted extinction retention at one but not ten days after training. Conversely, direct microinfusion of DA into IL produced long-term fear extinction (an effect that was insensitive to ɑ-/ß-adrenoreceptor antagonism). However, intra-IL delivery of a D1-like or D2 receptor agonist did not facilitate extinction. Using ex vivo multi-electrode array IL neuronal recordings, along with ex vivo quantification of immediate early genes and DA receptor signalling markers in mPFC, we found evidence of reduced DA-evoked mPFC network responses in S1 as compared with extinction-competent C57BL/6J mice that were partially driven by D1 receptor activation. Together, our data demonstrate that locally increasing DA in IL is sufficient to produce lasting rescue of impaired extinction. The finding that systemic L-DOPA increased IL DA levels, but had only transient effects on extinction, suggests L-DOPA failed to reach a threshold level of IL DA or produced opposing behavioural effects in other brain regions. Collectively, our findings provide further insight into the neural basis of the extinction-promoting effects of DA and L-DOPA in a clinically relevant animal model, with possible implications for therapeutically targeting the DA system in anxiety and trauma-related disorders.
| S-EPMC10774374 | biostudies-literature
Project description:Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.
| S-EPMC4313856 | biostudies-other
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.
2016-12-21 | GSE76108 | GEO
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.
2016-12-21 | GSE76103 | GEO
Project description:The prefrontal cortex is an important regulator of fear expression in humans and rodents. Specifically, the rodent prelimbic (PL) prefrontal cortex drives fear expression during both encoding and retrieval of fear memory. Neuronal ensembles have been proposed to function as memory encoding units, and their re-activation is thought to be necessary for memory retrieval and expression of conditioned behavior. However, it remains unclear whether PL cortex neuronal ensembles that encode fear memory contribute to long-term fear expression during memory retrieval. To address this, we employed a viral-mediated TRAP (Targeted Recombination in Active Population) technology to target PL cortex ensembles active during fear conditioning and expressed the inhibitory Gi-DREADD in fear-encoding ensembles. Male and female rats were trained to lever press for food and subjected to Pavlovian delay fear conditioning, then 28 days later, they underwent a fear memory retrieval test. Chemogenetic inhibition of TRAPed PL cortex ensembles reduced conditioned suppression of food seeking in females, but not males. Neither context nor tone freezing behavior was altered by this manipulation during the same retrieval test. Thus, fear-encoding ensembles in PL cortex drive long-term fear expression in a sex and fear modality dependent manner.
| S-EPMC6656710 | biostudies-literature
Project description:HDAC inhibition, dopamine and long-term fear inhibition
| PRJNA306245 | ENA
Project description:BACKGROUND:Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging-navigated transcranial magnetic stimulation (TMS). METHODS:Subjects (N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear. RESULTS:During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear. CONCLUSIONS:The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large-scale networks for targeting in future studies.
| S-EPMC5936658 | biostudies-literature
Project description:N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKII? positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.
| S-EPMC7952093 | biostudies-literature