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Amygdala memory trace activity is functionally coupled to the fear network in the brain after normal memory reconsolidation but not after disrupted reconsolidation. The connectivity analysis, using BOLD activity in the amygdala from areas representing memory trace activity in the 6 hours group as a seed of interest, demonstrated stronger functional couplings in the 6 hours than in the 10 min group in structures forming the fear-circuit of the brain, including the midline anterior cingulate cortex ( A and B ) ( x , y , z = – 9, 47, 13; Z = 3.14; 5994 mm 3 ), bilateral insula ( A and C ) ( x , y , z = 33, 20, 7; Z = 3.28; 1890 mm 3 ; x , y , z = – 27, 29, 10; Z = 2.95; 4077 mm 3 ), and bilateral hippocampus (C), although only the right hippocampus is illustrated ( x , y , z = – 27, – 13, – 14; Z = 2.51; 297 mm 3 ; x , y , z = 30, – 25, – 8; Z = 2.51; total 675 mm 3 ).
Source publication
Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting
reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was
formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predic...
Context in source publication
Context 1
... disorders are common, and they A cause costs ( 1 great ). The suffering etiology involves and high amygdala- societal dependent memory mechanisms that link stress- ful events to previously neutral stimuli ( 2 ), and the amygdala has been demonstrated to be hy- perresponsive across the anxiety disorders ( 3 ). Pharmacological and behavioral treatments of anxiety reduce symptomatology and amygdala activity ( 4 ) but have limited success because re- lapses occur ( 5 ). However, fear memories may be erased by recalling them and preventing their reconsolidation ( 6 , 7 ). In rodents, the amygdala seems vital for fear memory reconsolidation ( 7 , 8 ), but this has not been investigated in humans. Fear conditioning, in which a previously neutral stimulus turns into a conditioned stimulus (CS) through pairings with an aversive stimulus, forms a memory trace in the amygdala ( 2 ). Memory activation produces behavioral ( 2 , 9 ) and autonomic fear reactions, such as skin conduct- ance responses (SCRs) ( 10 – 12 ), frequently used to measure fear learning. Studies in animals ( 13 ) and anxiety patients ( 14 ) demonstrate that extinction weakens, but does not erase, fear memories. In rodents ( 13 ) and humans ( 15 ) alike, extinction attenuates conditioned fear expression through prefrontal inhibition. Fear can return after stress, be renewed when altering the envi- ronmental context, or reoccur with the passage of time ( 16 ). By activating memories and disrupting their reconsolidation, through protein synthesis block- ade local in the amygdala ( 8 ) or through systemic administration of b -adrenergic receptor antago- nists ( 17 , 18 ), fear memories are inhibited. Fear memory reconsolidation can also be disrupted behaviorally ( 6 , 7 , 19 ). In rodents, extinction of fear conditioning performed 10 or 60 min after presenting a reminder of the conditioned fear, but not after 6 or 24 hours, inhibited fear expression ( 7 ). Fear did not return in a new context, after shock exposure, or with time. Thus, extinction conducted within, but not outside, the reconsolidation window resulted in permanent attenuation of the fear memory ( 7 ). In humans, extinction performed within the reconsolidation interval also inhibited fear, whereas extinction training performed outside of the reconsolidation interval spared the memory and fear returned ( 6 ). In animals, the neu- ral functions enabling fear memory formation and reconsolidation are located in the amygdala ( 2 , 7 – 9 , 20 ). In humans, lesion ( 21 ) and brain imaging studies ( 10 – 12 , 22 ) confirm that the amygdala is a key area for fear memory en- coding. To test the hypothesis that reconsolidation in humans is amygdala-mediated and that disruption of reconsolidation inactivates a memory trace in the basolateral amygdala, we performed a study combining brain imaging with a physiological measure of fear. On day 1, twenty-two subjects (11 women) aged 24.0 T 0.48 (mean T SEM) underwent fear conditioning to establish an associative fear memory (Fig. 1A and fig. S1). On day 2, the fear memory was reactivated by presenting the cue previously paired with the shock (CS+) for 2 min. Subjects were randomized into two groups. One group received extinction, consisting of repeated CS presentations with the shock withheld, 10 min after reactivation and thus within the reconsolidation interval. The other group received extinction 6 hours after the reactivation — i.e., outside of the interval. Fear expression was measured using SCRs ( 6 , 19 ). On day 3, a renewal session was performed in a new environment, a magnetic resonance scanner, where shock electrodes were at- tached, although no shocks were delivered. SCRs were not measured for technical reasons. On day 5, subjects were exposed to unsignaled shocks and then re-exposed to CS+. Return of fear was defined as the increase in SCR from the last extinction trial on day 2 to the first reinstatement trial on day 5 (Fig. 1B) ( 6 ). First, we evaluated if the predicted behavioral reinstatement effect was present on day 5. Con- firming this, increased fear responding was ob- served in the 6 hours, but not the 10 min group (Fig. 1B, right panel). Groups were indistinguish- able in acquisition and extinction (Fig. 1B and fig. S1). Next, we tested the hypothesis that the fear memory representation is localized to the amygdala. Significantly greater activity was evident bilaterally in the basolateral amygdala in the 6 hours group as compared with the 10 min group (Fig. 1B). We then tested if the amygdala-localized memory predicted return of fear. Positive correlations were present between return of fear and blood oxygen level – dependent (BOLD) activity bilaterally in the basolateral amygdala in the 6 hours group (Fig. 2A). In the 10 min group, a cluster in the right claustrum extending into the amygdala correlated significantly with SCRs (Fig. 2A). BOLD activity reflecting the amygdala-localized memory trace also correlated with fear recall during extinction the previous day in the 6 hours, but not the 10 min, group (Fig. 2B). Amygdala areas harboring the memory trace (Fig. 1B) and areas covarying with return of fear (Fig. 2A) overlapped in the 6 hours group only (Fig. 3A). Moreover, the memory trace was colocalized to areas involved in fear memory recall during extinction (Fig. 3B). Finally, all these areas overlapped with each other only in the 6 hours group (Fig. 3C). Thus, the localization of the memory trace in the amygdala overlapped bilaterally with areas related both to recall of fear during extinction and return of fear during reinstatement. The hypothesis that memory was not erased, but only suppressed, by extinction- mediated prefrontal inhibition was not supported because the theoretically predicted ( 13 , 15 ) neg- ative coupling between activity in the ventro- medial prefrontal cortex (vmPFC) and return of fear was absent because vmPFC activity did not correlate negatively with fear in either group ( Z -scores of <1). Finally, we evaluated if activation of the fear memory in the amygdala was linked to activity in other nodes of the fear network ( 23 ) by calcu- lating the covariation between memory-associated amygdala activity and activity in the remaining network. Our amygdala seed of interest correlated strongly with activity bilaterally in the insula, hippocampus, and the midline anterior cingulate cortex and significantly more so in the 6 hours than in the 10 min group (Fig. 4). No clusters showed a better correlation with the amygdala seed in the 10 min group. This suggests that the amygdala could be the primary site of memory plasticity, but also influence reconsolidation by affecting other regions of the fear network. The amygdala could thus play a modulatory, rather than a solitary, role in human fear reconsolidation processes. In summary, whereas the amygdala memory representation after activation and undisrupted reconsolidation predicted return of fear and was functionally coupled to other nodes of the brain ’ s fear network, disruption of reconsolidation significantly weakened the amygdala memory and its coupling, rendering it unrelated to both recall and return of fear. We conclude that extinction training initiated during reconsolidation abolishes fear expression by erasing a memory trace in the amygdala. Reactivated fear memories are sensi- tive to behavioral disruption ( 6 , 7 , 19 ), and the amygdala proves to be a key neurobiological substrate for this process also in humans. This mechanism holds great clinical promise in anxiety treatment ( 6 , 17 – 19 ) in order to dissociate fear from cognitive ...
Citations
... In this paradigm, an isolated retrieval trial is presented; then, after sufficient time has elapsed for the memory to destabilize, extinction training is introduced. This has been successful in some studies with rodents and humans (e.g., Agren et al., 2012;Rao-Ruiz et al., 2011), and translated with some success in clinical and analog samples (e.g., Lancaster, Monfils, and Telch 2020). One advantage of reconsolidation-based approaches is that they are theoretically less susceptible to return of fear (Monfils and Holmes, 2018)-and unlike extinction, need not engage the prefrontal cortex (Agren et al., 2012). ...
... This has been successful in some studies with rodents and humans (e.g., Agren et al., 2012;Rao-Ruiz et al., 2011), and translated with some success in clinical and analog samples (e.g., Lancaster, Monfils, and Telch 2020). One advantage of reconsolidation-based approaches is that they are theoretically less susceptible to return of fear (Monfils and Holmes, 2018)-and unlike extinction, need not engage the prefrontal cortex (Agren et al., 2012). They could thus prove effective in treating populations in which engaging the prefrontal cortex proves challenging (e.g., individuals with traumatic brain injury, or youth). ...
Anxiety and related disorders are a significant public-health burden with rising prevalence in the wake of the COVID-19 pandemic. As demand for effective anxiety treatment increases, so too does the need for strategies to bolster treatment outcomes. Research on the mechanisms of exposure therapy, the frontline behavioral treatment, will be critically important for optimizing clinical outcomes. We outline an initial agenda for future research on the mechanisms of change of exposure therapy, developed in collaboration with a large international team of researchers through the Exposure Therapy Consortium. Key questions and recommendations for future research focus on four priority areas: conceptualization, measurement, study design/analysis, and individual/contextual differences. Rising to the challenge of addressing these questions will require coordinated action and availability of centralized tools that can be used across trials, settings, and research groups.
... Given the role of hippocampal SWRs in the generalization of cued fear memories, we decided to perform a CL stimulation of BLA and hippocampus. In the subsequent series of experiments, we decided to target the reconsolidation, a second strategy that has been proposed to modify memory traces in a persistent manner 8,36 . We hypothesized that if SWRs play a dedicate role during the discrimination process, the emotional updating of memory via CL stimulation after reactivation might modify the reconsolidation of cued fear memories. ...
... While early interventions aiming to update the emotional content or prevent the overconsolidation of aversive memories offered a strategy to reduce the likelihood of PTSD development 52,53 , neuromodulation systems using electrical stimulation must be readily adaptable to any given moment to ensure feasibility. Memory reconsolidation has been described as a plasticity process that allows previously consolidated memories to be updated 37,54 , enhanced 55 , or suppressed 36,56 . In the case of aversive responses, fear memories suppressed through this reconsolidation method were more resistant to recovery than traditional extinction procedures 57,58 . ...
The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD.
... After retrieval, reactivated memories are sensitive to various manipulations, ranging from new learning experiences (22,(25)(26)(27) to pharmacological interventions (21, 28) or electroconvulsive shock (29). Of particular relevance for memory in the context of eyewitness testimony or mental disorders are the effects of acute stress on memory updating. ...
Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown. In a 3-day functional magnetic resonance imaging study, we show that post-retrieval stress impairs subsequent memory depending on the strength of neural reinstatement of the original memory trace during reactivation, driven by the hippocampus and its cross-talk with neocortical representation areas. Comparison of neural patterns during immediate and final memory testing further revealed that successful retrieval was linked to pattern-dissimilarity in controls, suggesting the use of a different trace, whereas stressed participants relied on the original memory representation. These representation changes were again dependent on neocortical reinstatement during reactivation. Our findings show disruptive stress effects on the consolidation of retrieval-related memory traces that support future remembering.
... However, despite early replications (Bjorkstrand et al. 2016;Agren et al. 2012;Schiller et al. 2013;Johnson and Casey 2015), the robustness and generalizability of the superior effect of post-retrieval extinction training in humans are facing challenges. Evidence suggests that a simple CS + reminder before extinction training may not effectively prevent fear relapse for fear-relevant stimuli (Fricchione et al. 2016;Golkar et al. 2017Golkar et al. , 2012 or in more generalized situations (Kroes et al. 2017;Drexler et al. 2014;Soeter and Kindt 2011). ...
The post-retrieval extinction paradigm, rooted in reconsolidation theory, holds promise for enhancing extinction learning and addressing anxiety and trauma-related disorders. This study investigates the impact of two reminder types, mild US-reminder (US-R) and CS-reminder (CS-R), along with a no-reminder extinction, on fear recovery prevention in a categorical fear conditioning paradigm. Scalp EEG recordings during reminder and extinction processes were conducted in a three-day design. Results show that the US-R group exhibits a distinctive extinction learning pattern, characterized by a slowed-down yet successful process and pronounced theta-alpha desynchronization (source-located in the prefrontal cortex) during CS processing, followed by enhanced synchronization (source-located in the anterior cingulate) after shock cancellation in extinction trials. These neural dynamics correlate with the subtle advantage of US-R in the Day 3 recovery test, presenting faster spontaneous recovery fading and generally lower fear reinstatement responses. Conversely, the CS reminder elicits CS-specific effects in later episodic tests. The unique neural features of the US-R group suggest a larger prediction error and subsequent effortful conflict learning processes, warranting further exploration.
... Targeting the proteins or pathways involved in the memory reconsolidation process within the limited time window to disrupt the reconsolidation process has been proposed as a potential strategy to impair problematic memories (27), including fear conditioning memory (51,52), posttraumatic stress disorder (53), and drug addiction (54,55). Since mTOR pathway, ERK pathway, and BDNF are indispensable for reconsolidation of CSM, we explored whether blockade of these pathways during the reconsolidation time window can attenuate CSM (Fig. 4A). ...
... Our study consistently demonstrated that targeting any of these pathways within specific time window leads to impaired memory reconsolidation of seizure memory. In recent years, interventions based on memory reconsolidation theory have been widely applied in various pathological memory disorders, including fear conditioning memory (51,52), posttraumatic stress disorder (53), hyperalgesia (69), and drug addiction (54,55). ...
Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin–brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.
... Retrieval-extinction first opens the reconsolidation window that renders the fear memory labile and then updates it with the CS-noUS association. Retrieval-extinction effectively prevents the return of fear in both rodents and humans and does so via mechanisms that are distinct from, but overlap with, extinction (19)(20)(21)(22)(23)(24)(25)(26)(27) [see (28) for review]. We should note that not all studies have successfully replicated this effect (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44), and there has been relatively little research conducted on individual differences or predictors of retrieval-extinction responding (38,(45)(46)(47)(48). ...
Background
Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction.
Methods
Male rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test.
Results
We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree.
Conclusions
CO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.
... Memory reconsolidation theory posits that when the memory is reactivated, the memory trace becomes temporarily malleable, allowing it to be modified [11,12]. Therefore, if the fear memory is reactivated with a reminder of the CS, it becomes labile and subject to disruption during the reconsolidation window, i.e., 10 minutes to 6 hours after memory reactivation [12][13][14][15]. ...
... The authors demonstrated that a single brief exposure of a non-reinforced CS+ (a colored blue/yellow square paired with mild electric shock) used for memory reactivation just before extinction training could prevent the return of fear. These findings have important implications in the treatment of anxiety disorder; therefore, it has been further replicated in many other studies [13,[22][23][24][25][26]. ...
... The entire experiment was divided into five phases, i.e., habituation, acquisition, extinction, re-extinction, and reinstatement of fear. Differential SCR values (CS+ minus CS-) were calculated for each experimental phase (habituation, acquisition, extinction, and re-extinction) to evaluate fear conditioning [13]. A repeated measures ANOVA with phase (habituation, acquisition, and extinction) as the within-subject factor and intervention group (standard extinction, reactivation-extinction, and music reactivation-extinction) as the within-group factor was performed. ...
In several research studies, the reactivation extinction paradigm did not effectively prevent the return of fear if administered without any intervention technique. Therefore, in this study, the authors hypothesized that playing music (high valence, low arousal) during the reconsolidation window may be a viable intervention technique for eliminating fear-related responses. A three-day auditory differential fear conditioning paradigm was used to establish fear conditioning. Participants were randomly assigned into three groups, i.e., one control group, standard extinction (SE), and two experimental groups, reactivation extinction Group (RE) and music reactivation extinction (MRE), of twenty participants in each group. Day 1 included the habituation and fear acquisition phases; on Day 2 (after 24 hours), the intervention was conducted, and re-extinction took place on Day 3. Skin conductance responses were used as the primary outcome measure. Results indicated that the MRE group was more effective in reducing fear response than the RE and SE groups in the re-extinction phase. Furthermore, there was no significant difference observed between SE and RE groups. This is the first study known to demonstrate the effectiveness of music intervention in preventing the return of fear in a healthy individual. Therefore, it might also be employed as an intervention strategy (non-pharmacological approach) for military veterans, in emotion regulation, those diagnosed with post-traumatic stress disorder, and those suffering from specific phobias.
... The state of neural activation in the target region seems important for the efficacy of TMS (Silvanto et al., 2008)-the current TMS treatment protocol for the treatment of OCD that is approved by the U.S. Food and Drug Administration applies symptom provocation before each stimulation session to elicit a moderate level of obsessional distress reported by patients (Food and Drug Administration, 2020). The underlying (although untested) assumption for the application of symptom provocation before treatment is that symptom provocation induces the reconsolidation of fear and distressing memories into longterm memories, which can be disrupted by neural stimulation during this susceptible period (Forcato et al., 2007;Agren et al., 2012;Schiller et al., 2013). Symptom provocation is believed to activate the cortico-striato-thalamo-cortical circuitry, mainly in the right hemisphere, which can be targeted by TMS (Saxena et al., 2001). ...
Symptom provocation is a well-established component of psychiatric research and therapy. It is hypothesized that specific activation of those brain circuits involved in the symptomatic expression of a brain pathology makes the relevant neural substrate accessible as a target for therapeutic interventions. For example, in the treatment of obsessive-compulsive disorder (OCD), symptom provocation is an important part of psychotherapy and is also performed prior to therapeutic brain stimulation with transcranial magnetic stimulation (TMS). Here, we discuss the potential of symptom provocation to isolate neurophysiological biomarkers reflecting the fluctuating activity of relevant brain networks with the goal of subsequently using these markers as targets to guide therapy. We put forward a general experimental framework based on the rapid switching between psychiatric symptom states. This enable neurophysiological measures to be derived from EEG and/or TMS-evoked EEG measures of brain activity during both states. By subtracting the data recorded during the baseline state from that recorded during the provoked state, the resulting contrast would ideally isolate the specific neural circuits differentially activated during the expression of symptoms. A similar approach enables the design of effective classifiers of brain activity from EEG data in Brain-Computer Interfaces (BCI). To obtain reliable contrast data, psychiatric state switching needs to be achieved multiple times during a continuous recording so that slow changes of brain activity affect both conditions equally. This is achieved easily for conditions that can be controlled intentionally, such as motor imagery, attention, or memory retention. With regard to psychiatric symptoms, an increase can often be provoked effectively relatively easily, however, it can be difficult to reliably and rapidly return to a baseline state. Here, we review different approaches to return from a provoked state to a baseline state and how these may be applied to different symptoms occurring in different psychiatric disorders.
... Psychologically, conditioned taste aversion (CTA) is a type of classical conditioning that strongly induces negative emotions, and the incidence of CTA is higher when the interval between food consumption and onset of illness is shorter than when the interval is longer [38]. Simultaneously, fear memories are attenuated by distraction during the consolidation process [39]. Therefore, our results may be explained by the difference in timing of symptom onset between FD and IBS and the mechanism of taste aversive learning. ...
Background:
Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are caused and exacerbated by consumption of fatty foods. However, no study has evaluated brain activity in response to food images in patients with disorders of gut-brain interaction (DGBI). This study aimed to compare food preference and brain activity when viewing food images between patients with DGBI and healthy controls.
Methods:
FD and IBS were diagnosed using the ROME IV criteria. Food preference was assessed using a visual analog scale (VAS). Brain activity in the prefrontal cortex (PFC) in response to food images was investigated using functional near-infrared spectroscopy (fNIRS).
Results:
Forty-one patients were enrolled, including 25 with DGBI. The mean VAS scores for all foods (controls vs. FD vs. IBS: 69.1 ± 3.3 vs. 54.8 ± 3.8 vs. 62.8 ± 3.7, p = 0.02), including fatty foods (78.1 ± 5.4 vs. 43.4 ± 6.3 vs. 64.7 ± 6.1, p < 0.01), were the lowest in patients with FD among all groups. Patients with FD had significantly higher brain activity in the left PFC than those with IBS and healthy controls (mean z-scores in controls vs. FD vs. IBS: - 0.077 ± 0.03 vs. 0.125 ± 0.04 vs. - 0.002 ± 0.03, p < 0.001).
Conclusions:
Patients with DGBI, particularly those with FD, disliked fatty foods. The brain activity in patients with DGBI differed from that in healthy controls. Increased activity in the PFC of patients with FD was confirmed.
... The amygdala is a central region responsible for fear and anxiety 14 , as evident from studies of fear circuits in animals 6,15,16 . Consistent with these findings, functional imaging studies in humans have reported activation of the amygdala during conditioned fear acquisition and extinction 17,18 . The amygdala consists of multiple subdivisions such as the basolateral amygdala (BLA), the basomedial amygdala (BMA), the central amygdala (CeA), the medial amygdala (MeA), and the cortical amygdala (CoA), of which the BLA and CeA are particularly important in anxiety and fear processing 19,20 . ...
Synucleinopathies are neurodegenerative disorders characterized by alpha-synuclein (αSyn) accumulation in neurons or glial cells, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). αSyn-related pathology plays a critical role in the pathogenesis of synucleinopathies leading to the progressive loss of neuronal populations in specific brain regions and the development of motor and non-motor symptoms. Anxiety is among the most frequent non-motor symptoms in patients with PD, but it remains underrecognized and undertreated, which significantly reduces the quality of life for patients. Anxiety is defined as a neuropsychiatric complication with characteristics such as nervousness, loss of concentration, and sweating due to the anticipation of impending danger. In patients with PD, neuropathology in the amygdala, a central region in the anxiety and fear circuitry, may contribute to the high prevalence of anxiety. Studies in animal models reported αSyn pathology in the amygdala together with alteration of anxiety or fear learning response. Therefore, understanding the progression, extent, and specifics of pathology in the anxiety and fear circuitry in synucleinopathies will suggest novel approaches to the diagnosis and treatment of neuropsychiatric symptoms. Here, we provide an overview of studies that address neuropsychiatric symptoms in synucleinopathies. We offer insights into anxiety and fear circuitry in animal models and the current implications for therapeutic intervention. In summary, it is apparent that anxiety is not a bystander symptom in these disorders but reflects early pathogenic mechanisms in the cortico-limbic system which may even contribute as a driver to disease progression.
