Highlights • Oxytocin has been suggested to facilitate approach-related processing. • We tested if oxytocin reduces or enhances amygdala responses during threat approach. • Oxytocin decreased ...amygdala activation specifically during threat approach. • This neuroendocrine mechanism is in line with oxytocin’s social anxiolytic effects.
In the process of neuronal wiring, axons derived from the same functional group typically extend together, resulting in fascicle formation. How these axons communicate with one another remains ...largely unknown. Here, we show that protocadherin-17 (Pcdh17) supports this group extension by recruiting actin polymerization regulators to interaxonal contact sites. Pcdh17 is expressed by a subset of amygdala neurons, and it accumulates at axon-axon boundaries because of homophilic binding. Pcdh17 knockout in mice suppressed the extension of these axons. Ectopically expressed Pcdh17 altered the pattern of axon extension. In in vitro cultures, wild-type growth cones normally migrate along other axons, whereas Pcdh17 null growth cones do not. Pcdh17 recruits the WAVE complex, Lamellipodin, and Ena/VASP to cell-cell contacts, converting these sites into motile structures. We propose that, through these mechanisms, Pcdh17 maintains the migration of growth cones that are in contact with other axons, thereby supporting their collective extension.
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•Amygdala axons fail to grow normally in the absence of protocadherin-17 (Pcdh17)•Amygdala axons expressing ectopic Pcdh17 are misrouted during extension•Pcdh17 recruits the WAVE complex, Lamellipodin, and Ena/VASP to axon-axon contacts•The Pcdh17-mediated recruitment of actin regulators enhances cell motility
Axons arising from functionally related groups of neurons often advance together, but how they communicate with one another remains unknown. Hayashi et al. now show that protocadherin-17 accumulates at interaxonal contact sites and coordinates collective axonal extension by recruiting actin polymerization regulators, such as the WAVE complex, Lamellipodin, and Ena/VASP.
•Juvenile chlorpyrifos exposure induced persistent changes in the amygdala proteome.•These changes occurred in proteins related to GABA and glutamate systems.•Similar changes were observed with ...chlorpyrifos and the FAAH inhibitor PF-04457845.•Inhibition of FAAH by chlorpyrifos leads to alterations in endocannabinoid signaling.•Altered endocannabinoid signaling may be responsible for these persistent changes.
Chlorpyrifos (CPF) remains one of the most widely used organophosphorus insecticides (OPs) despite the concerns about its developmental neurotoxicity. Developmental exposure to CPF has long-lasting negative impacts, including abnormal emotional behaviors. These negative impacts are observed at exposure levels do not cause inhibition of acetylcholinesterase, the canonical target of OPs. Exposure to CPF at these levels inhibits the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) but it is not clear what the persistent effects of this inhibition are. To investigate this, male rat pups were exposed orally to either corn oil, 0.75 mg/kg CPF, or 0.02 mg/kg PF-04457845 (PF; a specific inhibitor of FAAH) daily from postnatal day 10 (PND10) - PND16. This dosage of CPF does not inhibit brain cholinesterase activity but inhibits FAAH activity. On PND38 (adolescence), the protein expression in the amygdala was determined using a label-free shotgun proteomic approach. The analysis of control vs CPF and control vs PF led to the identification of 44 and 142 differentially regulated proteins, respectively. Gene ontology enrichment analysis revealed that most of the proteins with altered expression in both CPF and PF treatment groups were localized in the synapse-related regions, such as presynaptic membrane, postsynaptic density, and synaptic vesicle. The different biological processes affected by both treatment groups included persistent synaptic potentiation, glutamate receptor signaling, protein phosphorylation, and chemical synaptic transmission. These results also indicated disturbances in the balance between glutamatergic (↓ Glutamate AMPA receptor 2, ↓ Excitatory amino acid transporter 2, and ↑ vesicular glutamate transporter 2) and GABAergic signaling (↑ GABA transporter 3 and ↑ glutamate decarboxylase 2). This imbalance could play a role in the abnormal emotional behavior that we have previously reported. These results suggest that there is a similar pattern of expression between CPF and PF, and both these chemicals can persistently alter emotional behavior as a consequence of inhibition of FAAH.
Enriched environments elicit brain plasticity in animals. In humans it is unclear which environment is enriching. Living in a city has been associated with increased amygdala activity in a stress ...paradigm, and being brought up in a city with increased pregenual anterior cingulate cortex (pACC) activity. We set out to identify geographical characteristics that constitute an enriched environment affecting the human brain. We used structural equation modelling on 341 older adults to establish three latent brain factors (amygdala, pACC and dorsolateral prefrontal cortex (DLPFC)) to test the effects of forest, urban green, water and wasteland around the home address. Our results reveal a significant positive association between the coverage of forest and amygdala integrity. We conclude that forests may have salutogenic effects on the integrity of the amygdala. Since cross-sectional data does not allow causal inference it could also be that individuals with high structural integrity choose to live closer to forest.
Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low ...within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test–retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies.
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•We assessed within-subject reliability of amygdala habituation measures.•Amygdala habituation is a considerably more reliable index than the mean amplitude.•Amygdala habituation is a robust endpoint for within-subject designs.
The persecutory delusion is the most common symptom of psychosis, yet its underlying neurobiological mechanisms are poorly understood. Prior studies have suggested that abnormalities in medial ...temporal lobe-dependent associative learning may contribute to this symptom. In the current study, this hypothesis was tested in a non-clinical sample of young adults without histories of psychiatric treatment (n = 64), who underwent classical Pavlovian fear conditioning while fMRI data were collected. During the fear conditioning procedure, participants viewed images of faces which were paired (the CS+) or not paired (the CS-) with an aversive stimulus (a mild electrical shock). Fear conditioning-related neural responses were measured in two medial temporal lobe regions, the amygdala and hippocampus, and in other closely connected brain regions of the salience and default networks. The participants without persecutory beliefs (n = 43) showed greater responses to the CS- compared to the CS+ in the right amygdala and hippocampus, while the participants with persecutory beliefs (n = 21) failed to exhibit this response. These between-group differences were not accounted for by symptoms of depression, anxiety or a psychosis risk syndrome. However, the severity of subclinical psychotic symptoms overall was correlated with the level of this aberrant response in the amygdala (p = .013) and hippocampus (p = .033). Thus, these findings provide evidence for a disruption of medial temporal lobe-dependent associative learning in young people with subclinical psychotic symptoms, specifically persecutory thinking.
Growing evidence indicates a critical role of astrocytes in learning and memory. However, little is known about the role of basolateral amygdala complex (BLA-C) astrocytes in contextual fear ...conditioning (CFC), a paradigm relevant to understand and generate treatments for fear- and anxiety-related disorders. To get insights on the involvement of BLA-C astrocytes in fear memory, fluorocitrate (FLC), a reversible astroglial metabolic inhibitor, was applied at critical moments of the memory processing in order to target the acquisition, consolidation, retrieval and reconsolidation process of the fear memory. Adult Wistar male rats were bilaterally cannulated in BLA-C. Ten days later they were infused with different doses of FLC (0.5 or 1 nmol/0.5 µl) or saline before or after CFC and before or after retrieval. FLC impaired fear memory expression when administered before and shortly after CFC, but not one hour later. Infusion of FLC prior and after retrieval did not affect the memory. Our findings suggest that BLA-C astrocytes are critically involved in the acquisition/early consolidation of fear memory but not in the retrieval and reconsolidation. Furthermore, the extinction process was presumably not affected (considering that peri-retrieval administration could also affect this process).
•The DSub-BLA disconnection by using NMDA blockade impairs the CFC consolidation;•This same disconnection does not affect the TFC consolidation;•This suggests that the CFC effect is probably due to ...related spatial processing;•This study helps to filling a gap of works exploring the DSub in fear conditioning.
Fear conditioning tasks enable us to explore the neural basis of adaptative and maladaptive behaviors related to aversive memories. Recently, we provided the first evidence of the dorsal subiculum (DSub) involvement in contextual fear conditioning (CFC) consolidation by showing that the post-training bilateral NMDA (N-methyl-D-aspartate) receptor blockade in DSub impaired the performance of animals in the test session. As the memory consolidation process depends on the coordinated engagement of different brain regions, and the DSub share reciprocal projections with the basolateral amygdala (BLA), which is also involved in CFC, it is possible that the functional interaction between these sites can be relevant for the consolidation of this task. In this sense, the present study aimed to explore the effects of the functional disconnection of the DSub and BLA in the CFC consolidation after NMDA post-training blockade. In addition, to verify if the observed effects were due to spatial representation processes mediated by the DSub, we employed a hippocampal-independent procedure: tone fear conditioning (TFC). Results showed that the functional disconnection of these regions by post-training NMDA blockade impaired CFC consolidation, whereas there was no impairment in TFC. Altogether, the present data suggest that the DSub and BLA would functionally interact through NMDA-related synaptic plasticity to support CFC consolidation probably due to DSub-related spatial processing showing that the TFC consolidation was not disrupted. This work contributes to filling a gap of studies exploring the DSub involvement in fear conditioning by providing a broad framework of the subicular-amygdaloid connection functionality.
There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders, such as post-traumatic stress disorder. However, its applicability is restricted by ...reconsolidation-resistant boundary conditions that constrain the initial memory destabilization. In this study, we investigated whether the induction of synaptic protein degradation through autophagy modulation, a major protein degradation pathway, can enhance memory destabilization upon retrieval and whether it can be used to overcome these conditions. Here, using male mice in an auditory fear reconsolidation model, we showed that autophagy contributes to memory destabilization and its induction can be used to enhance erasure of a reconsolidation-resistant auditory fear memory that depended on AMPAR endocytosis. Using male mice in a contextual fear reconsolidation model, autophagy induction in the amygdala or in the hippocampus enhanced fear or contextual memory destabilization, respectively. The latter correlated with AMPAR degradation in the spines of the contextual memory-ensemble cells. Using male rats in an
LTP reconsolidation model, autophagy induction enhanced synaptic destabilization in an NMDAR-dependent manner. These data indicate that induction of synaptic protein degradation can enhance both synaptic and memory destabilization upon reactivation and that autophagy inducers have the potential to be used as a therapeutic tool in the treatment of anxiety disorders.
It has been reported that inhibiting synaptic protein degradation prevents memory destabilization. However, whether the reverse relation is true and whether it can be used to enhance memory destabilization are still unknown. Here we addressed this question on the behavioral, molecular, and synaptic levels, and showed that induction of autophagy, a major protein degradation pathway, can enhance memory and synaptic destabilization upon reactivation. We also show that autophagy induction can be used to overcome a reconsolidation-resistant memory, suggesting autophagy inducers as a potential therapeutic tool in the treatment of anxiety disorders.
Facilitation of social attraction and bonding by the evolutionarily conserved neuropeptide oxytocin is well-established in female mammals. However, accumulating behavioral evidence suggests that ...oxytocin may have evolved sex-specific functional roles in the domain of human social cognition. A critical question is how oxytocin differentially modulates neural processing of social information in men and women, leading to divergent behavioral responses. Here we show that intranasal oxytocin treatment produces sex- and valence-dependent increases in amygdala activation when women view individuals identified as praising others but in men those who criticize them. Women subsequently show increased liking for the faces of these individuals, whereas in men it is reduced. Thus, oxytocin may act differentially via the amygdala to enhance the salience of positive social attributes in women but negative ones in men. We hypothesize that oxytocin may have evolved different but complementary roles to help ensure successful reproduction by encouraging mothers to promote a prosocial rearing environment for offspring and fathers to protect against antisocial influences.
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