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Location of [ 3 H]muscimol at various intervals after intrahippocampal infusions (experiment 3). Phosphoimages of [ 3 H]muscimol were made and overlaid on postfixed cresyl-violet-stained sections. Rats were killed immediately (0 min), 20, 60, or 360 min after intrahippocampal [ 3 H]muscimol infusions. Sections shown are from representative rats from each infusionkilling interval and range from 0.6 mm rostral (leftmost section) to 0.6 mm caudal (rightmost section) to the infusion site.
Source publication
In recent studies, inactivation of the dorsal hippocampus before the retrieval of extinguished fear memories disrupted the context-dependent expression of these memories. In the present experiments, we examined the role of the dorsal hippocampus in the acquisition of extinction. After pairing an auditory conditional stimulus (CS) with an aversive f...
Contexts in source publication
Context 1
... [ 3 H]muscimol images overlaid on cresyl- violet-stained sections from representative rats from each infu- sion-kill interval are shown in Figure 6. Although 20 sections were taken through each rat's hippocampus, only seven from each rat are shown in Figure 6. ...
Context 2
... [ 3 H]muscimol images overlaid on cresyl- violet-stained sections from representative rats from each infu- sion-kill interval are shown in Figure 6. Although 20 sections were taken through each rat's hippocampus, only seven from each rat are shown in Figure 6. Visual inspection of the sections revealed that rats killed at 0, 20, and 60 min after infusion re- tained strong radioactive signal across many sections, whereas there was very little signal remaining 360 min after infusion. ...
Context 3
... [ 3 H]muscimol images overlaid on cresylviolet-stained sections from representative rats from each infusion-kill interval are shown in Figure 6. Although 20 sections were taken through each rat's hippocampus, only seven from each rat are shown in Figure 6. ...
Context 4
... [ 3 H]muscimol images overlaid on cresylviolet-stained sections from representative rats from each infusion-kill interval are shown in Figure 6. Although 20 sections were taken through each rat's hippocampus, only seven from each rat are shown in Figure 6. Visual inspection of the sections revealed that rats killed at 0, 20, and 60 min after infusion retained strong radioactive signal across many sections, whereas there was very little signal remaining 360 min after infusion. ...
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Citations
... Since DMS inactivation during fear extinction selectively altered the contextual modulation of fear extinction memory and not fear extinction per se, it seems likely that the DMS somehow contributes to contextual gating of fear extinction. Consistent with a primary role of the hippocampus in contextual processing, contextual modulation of fear extinction involves the hippocampus [41][42][43] and hippocampal projections to the amygdala [44,45]. If the hippocampus is the driver of contextual modulation of fear extinction, then what is the role of the DMS? Contextual learning has been reported to involve cooperation between the DMS and the hippocampus in a variety of paradigms [46][47][48][49][50][51]. ...
Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABA A /GABA B receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.
Highlights
Dorsolateral striatum D1 receptor signaling during fear extinction reduces renewal
Neural activity in the dorsomedial striatum during fear extinction permits renewal
Dorsal striatum subregions have opposing roles in contextual gating of fear extinction
Graphical Abstract
... are widely conceptualized as context-based relapse in which fear memory returns due to the physical, internal, and temporal context change from how extinction occurred (Bouton et al., 2006). Hippocampus is a well-studied region important for context learning (Kim and Fanselow, 1992;Lee et al., 2023), and its dysfunction during extinction can cause renewal (Corcoran et al., 2005). Hippocampus also changes rapidly during development and show sex-specific effects from infancy (Koss and Frick, 2016;Griffiths et al., 2019). ...
... Reappraisal, or the reinterpretation of a negative cue, is supported by hippocampal activation and neurogenesis, which have been shown to promote resiliency to aversive experiences and emotional regulation (Feder, Nestler, & Charney, 2009). Inactivation of the hippocampus disrupts the contextual encoding of fear extinction (Corcoran, Desmond, Frey, & Maren, 2005); the opposite may facilitate enhanced extinction learning, resiliency, and well-being (Liberzon & Abelson, 2016). The hippocampus also gates amygdala-related fear responses to the prefrontal cortex, which is critical for reappraisal during fear extinction learning (Maren et al., 2013;Sotres-Bayon, Sierra-Mercado, Pardilla-Delgado, & Quirk, 2012). ...
Background:
The ability to extinguish a maladaptive conditioned fear response is crucial for healthy emotional processing and resiliency to aversive experiences. Therefore, enhancing fear extinction learning has immense potential emotional and health benefits. Mindfulness training enhances both fear conditioning and recall of extinguished fear; however, its effects on fear extinction learning are unknown. Here we investigated the impact of mindfulness training on brain mechanisms associated with fear-extinction learning, compared to an exercise-based program.
Methods:
We investigated BOLD activations in response to a previously learned fear-inducing cue during an extinction paradigm, before and after an 8-week mindfulness-based stress reduction program (MBSR, n = 49) or exercise-based stress management education program (n = 27).
Results:
The groups exhibited similar reductions in stress, but the MBSR group was uniquely associated with enhanced activation of salience network nodes and increased hippocampal engagement.
Conclusions:
Our results suggest that mindfulness training increases attention to anticipatory aversive stimuli, which in turn facilitates decreased aversive subjective responses and enhanced reappraisal of the memory.
... Hippocampus: While the role of the hippocampus in mediating context specificity of fear extinction is well-established (Corcoran et al. 2005), the findings on PTSD-related alterations in hippocampal activity during this process are inconsistent. Specifically, while decreased activity of hippocampus during extinction has been reported (Knight et al. 2004), other groups failed to find any PTSD-related hippocampal alterations during this stage (Hoffman et al. 2014;Wicking et al. 2016). ...
Impairments in fear extinction processes have been implicated in the genesis and maintenance of debilitating psychopathologies, including Posttraumatic stress disorder (PTSD). PTSD, classified as a trauma- and stressor-related disorder, is characterized by four symptom clusters: intrusive recollections of trauma, avoidance of trauma-related stimuli, alterations in cognition and mood, and hyperarousal. One of the key pathological feature associated with the persistence of these symptoms is impaired fear extinction, as delineated in multiple studies employing Pavlovian fear-conditioning paradigms. These paradigms, comprising fear acquisition, extinction, extinction recall, and fear renewal phases, have illuminated the neurobiological substrates of PTSD. Dysfunctions in the neural circuits that mediate these fear learning and extinction processes can result in failure to extinguish fear responses and retain extinction memory, giving rise to enduring experience of fear and anxiety. The protective avoidance behaviors observed in individuals with PTSD further exacerbate intrusive symptoms and pose challenges to effective treatment strategies. A comprehensive analysis of fear conditioning and extinction processes, along with the underlying neurobiology, could significantly enhance our understanding of PTSD pathophysiology. This chapter delineates the role of fear extinction processes in PTSD, investigates the underlying neurobiological substrates, and underscores the therapeutic implications, while also identifying future research directions.
... Generally, after extinction training, rats showed lower freezing in the extinction situation and higher freezing outside the extinction situation. A study found that reversible inactivation of dHPC before extinction training significantly inhibited but did not completely block the acquisition of fear extinction memory in rats, showing a reduction in freezing (Corcoran et al., 2005). The reversible inactivation of dHPC during extinction training can disturb the situational coding of extinction memory, which is manifested by the impairment of fear extinction memory expression and the increase of freezing in rats no matter whether the extinction training occurs in the original conditioned situation or the second context (Corcoran et al., 2005). ...
... A study found that reversible inactivation of dHPC before extinction training significantly inhibited but did not completely block the acquisition of fear extinction memory in rats, showing a reduction in freezing (Corcoran et al., 2005). The reversible inactivation of dHPC during extinction training can disturb the situational coding of extinction memory, which is manifested by the impairment of fear extinction memory expression and the increase of freezing in rats no matter whether the extinction training occurs in the original conditioned situation or the second context (Corcoran et al., 2005). This suggests that dHPC is involved in the expression of context-dependent extinction memory and disrupts the renewal of fear extinction memory. ...
Fear refers to an adaptive response in the face of danger, and the formed fear memory acts as a warning when the individual faces a dangerous situation again, which is of great significance to the survival of humans and animals. Excessive fear response caused by abnormal fear memory can lead to neuropsychiatric disorders. Fear memory has been studied for a long time, which is of a certain guiding effect on the treatment of fear-related disorders. With continuous technological innovations, the study of fear has gradually shifted from the level of brain regions to deeper neural (micro) circuits between brain regions and even within single brain regions, as well as molecular mechanisms. This article briefly outlines the basic knowledge of fear memory and reviews the neurobiological mechanisms of fear extinction and relapse, which aims to provide new insights for future basic research on fear emotions and new ideas for treating trauma and fear-related disorders.
... Acquisition and expression of contextual fear recruit unique DG granule neuron ensembles to form engram of memory and activation of such engram is sufficient to induce freezing responses [15,16]. Intriguingly, distinct ensembles of DG granule neurons are activated during contextual fear extinction and inhibition of DG activity or silencing the extinction-recruited DG granule neuron ensembles significantly impairs contextual fear extinction [14,17,18], suggesting that neuronal activities in the DG are also required for memory extinction. Despite the important role of DG in regulating contextual fear, the regulatory mechanisms underlying such functions remain poorly understood. ...
... PPARα knockout reduces intrinsic excitability of granule neurons in the dentate gyrus DG granule neuron activity, particularly that of the memory engram cells, is crucial and delicately regulated during contextual fear extinction [14,17,38]. To explore the cellular mechanisms underlying PPARα regulation on contextual fear extinction, we tested whether PPARα modulates the intrinsic excitability of DG granule neurons. ...
The dentate gyrus (DG) of the hippocampus encodes contextual information associated with fear, and cell activity in the DG is required for acquisition and extinction of contextual fear. However, the underlying molecular mechanisms are not fully understood. Here we show that mice deficient for peroxisome proliferator-activated receptor-α (PPARα) exhibited a slower rate of contextual fear extinction. Furthermore, selective deletion of PPARα in the DG attenuated, while activation of PPARα in the DG by local infusion of aspirin facilitated extinction of contextual fear. The intrinsic excitability of DG granule neurons was reduced by PPARα deficiency but increased by activation of PPARα with aspirin. Using RNA-Seq transcriptome we found that the transcription level of neuropeptide S receptor 1 (Npsr1) was tightly correlated with PPARα activation. Our results provide evidence that PPARα plays an important role in regulating DG neuronal excitability and contextual fear extinction.
... The hippocampus is considered to play an important role in PTSD pathophysiology and treatment through its involvement in memory functions (42,43) and fear-related learning processes (44,45). The findings suggest that over the course of treatment, hippocampal volume may increase through neurogenesis or show greater density, which can potentially lead to greater functional connectivity to other brain areas (46,47). ...
Background
The hippocampus plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD) and its prognosis. Accumulating findings suggest that individuals with larger pretreatment hippocampal volume are more likely to benefit from PTSD treatment, but the mechanism underlying this effect is unknown. We investigated whether further increase in hippocampal volume during treatment explains the better prognosis of individuals with greater pretreatment hippocampal volume.
Methods
We collected structural magnetic resonance imagesfrom patients with PTSD before and after treatment. We examined whether larger hippocampal volume moderates the effect of increased hippocampal volume during treatment on symptom reduction. Given the relatively small sample sizes of treatment studies with pre- and posttreatment magnetic resonance imaging, we focused on effect sizes and sought to replicate findings in an external sample. We tested our hypothesis in study 1 (N = 38; prolonged exposure therapy) and then tested whether the results could be externally replicated in study 2 (N = 20; ketamine infusion followed by exposure therapy).
Results
Findings from study 1 revealed that increased right hippocampal volume during treatment was associated with greater PTSD symptom reduction only in patients with greater pretreatment right hippocampal volume (p = .03; η² = 0.13, a large effect). Findings were partially replicated in study 2 for depressive symptoms (p = .034; η² = 0.25, a very large effect) and for PTSD symptoms (p = .15; η² = 0.15, a large effect).
Conclusions
Elucidating increased hippocampal volume as one of the neural mechanisms predictive of therapeutic outcome for individuals with larger pretreatment hippocampal volume may help identify clinical targets for this subgroup.
... Prolonged exposure (PE) therapy, which is a well-established therapy for patients suffering from fear memory-associated disorders, like post-traumatic stress disorder (PTSD), takes advantage of the mechanism of fear extinction [4][5][6] . Studies have revealed some relevant brain areas and circuits involved in the extinction of fear memory [7][8][9][10][11][12][13][14][15][16] . ...
Repetitive exposure to fear-associated targets is a typical treatment for patients with panic or post-traumatic stress disorder (PTSD). The success of exposure therapy depends on the active exploration of a fear-eliciting target despite an innate drive to avoid it. Here, we found that a circuit running from CaMKIIα-positive neurons of the medial preoptic area to the ventral periaqueductal gray (MPA-vPAG) facilitates the exploration of a fear-conditioned zone and subsequent fear extinction in mice. Activation or inhibition of this circuit did not induce preference/avoidance of a specific zone. Repeated entries into the fear-conditioned zone, induced by the motivation to chase a head-mounted object due to MPA-vPAG circuit photostimulation, facilitated fear extinction. Our results show how the brain forms extinction memory against avoidance of a fearful target and suggest a circuit-based mechanism of exposure therapy.
... Future studies should aim to replicate these results using scopolamine infusion in the BLA. Together, our findings point to the critical role played by Ach HDB→BLA pathway during fear extinction, a role consistent with HDB connectivity to the BLA, the infralimbic cortex and the hippocampus, which are part of neuronal circuitry supporting extinction [5,12,[18][19][20][39][40][41][42][43]. ...
The basolateral amygdala (BLA) complex receives dense cholinergic projections from the nucleus basalis of Meynert (NBM) and the horizontal limb of the diagonal band of Broca (HDB). The present experiments examined whether these projections regulate the formation, extinction, and renewal of fear memories. This was achieved by employing a Pavlovian fear conditioning protocol and optogenetics in transgenic rats. Silencing NBM projections during fear conditioning weakened the fear memory produced by that conditioning and abolished its renewal after extinction. By contrast, silencing HDB projections during fear conditioning had no effect. Silencing NBM or HDB projections during extinction enhanced the loss of fear produced by extinction, but only HDB silencing prevented renewal. Next, we found that systemic blockade of nicotinic acetylcholine receptors during fear conditioning mimicked the effects produced by silencing NBM projections during fear conditioning. However, this blockade had no effect when given during extinction. These findings indicate that basal forebrain cholinergic signaling in the BLA plays a critical role in fear regulation by promoting strength and durability of fear memories. We concluded that cholinergic compounds may improve treatments for post-traumatic stress disorder by durably stripping fear memories from their fear-eliciting capacity.
... It is noteworthy to mention that A-CPP scores in controls (SS-infused vHp) implanted with a cannula are similar to those obtained in animals without surgery, indicating that the surgical trauma provoked by the cannula implantation does not, itself, modify the behavior evaluated. In this respect, it has been reported that the mere placement cannula in the dorsal hippocampus had no significant effect on behavior (Corcoran et al., 2005). ...
Inflammatory response in the Central Nervous System (CNS) induced by psychostimulants seems to be a crucial factor in the development and maintenance of drug addiction. The ventral hippocampus (vHp) is part of the reward system involved in substance addiction and expresses abundant G protein-coupled receptor 55 (GPR55). This receptor modulates the inflammatory response in vitro and in vivo, but there is no information regarding its anti-inflammatory effects and its impact on psychostimulant consumption. The aim of the present study was to investigate whether vHp GPR55 activation prevents both the inflammatory response induced by amphetamine (AMPH) in the vHp and the AMPH-induced conditioned place preference (A-CPP). Wistar adult male rats with a bilateral cannula into the vHp or intact males were subjected to A-CPP (5 mg/kg). Upon the completion of A-CPP, the vHp was dissected to evaluate IL-1β and IL-6 expression through RT-PCR, Western blot and immunofluorescence. Our results reveal that AMPH induces both A-CPP and an increase of IL-1β and IL-6 in the vHp. The GPR55 agonist lysophosphatidylinositol (LPI, 10 μM) infused into the vHp prevented A-CPP and the AMPH-induced IL-1β increase. CID 16020046 (CID, 10 μM), a selective GPR55 antagonist, abolished LPI effects. To evaluate the effect of the inflammatory response, lipopolysaccharide (LPS, 5 μg/μl) was infused bilaterally into the vHp during A-CPP acquisition. LPS strengthened A-CPP and increased IL-1β/IL-6 mRNA and protein levels in the vHp. LPS also increased CD68, Iba1, GFAP and vimentin expression. All LPS-induced effects were blocked by LPI. Our results suggest that GPR55 activation in the vHp prevents A-CPP while decreasing the local neuro-inflammatory response. These findings indicate that vHp GPR55 is a crucial factor in preventing the rewarding effects of AMPH due to its capacity to interfere with proinflammatory responses in the vHp.
