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1.
Behav Brain Res ; 427: 113868, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35364111

RESUMO

Associative learning and memory mechanisms drive interoceptive signaling along the gut-brain axis, thus shaping affective-emotional reactions and behavior. Specifically, learning to predict potentially harmful, visceral pain is assumed to succeed within very few trials. However, the temporal dynamics of cerebellar and cerebral fMRI signal changes underlying early acquisition and extinction of learned fear signals and the concomitant evolvement of safety learning remain incompletely understood. 3 T fMRI data of healthy individuals from three studies were uniformly processed across the whole brain and the cerebellum. All studies employed differential delay conditioning (N = 94) with one visual cue (CS+) being repeatedly paired with visceral pain as unconditioned stimulus (US) while a second cue remained unpaired (CS-). During subsequent extinction (N = 51), all CS were presented without US. Behavioral results revealed increased CS+-aversiveness and CS--pleasantness after conditioning and diminished valence ratings for both CS following extinction. During early acquisition, the CS- induced linearly increasing neural activation in the insula, midcingulate cortex, hippocampus, precuneus as well as cerebral and cerebellar somatomotor regions. The comparison between acquisition and extinction phases yielded a CS--induced linear increase in the posterior cingulate cortex and precuneus during early acquisition, while there was no evidence for linear fMRI signal changes for the CS+ during acquisition and for both CS during extinction. Based on theoretical accounts of discrimination and temporal difference learning, these results suggest a gradual evolvement of learned safety cues that engage emotional arousal, memory, and cortical modulatory networks. As safety signals are presumably more difficult to learn and to discriminate from learned threat cues, the underlying temporal dynamics may reflect enhanced salience and prediction processing as well as increasing demands for attentional resources and the integration of multisensory information. Maladaptive responses to learned safety signals are a clinically relevant phenotype in multiple conditions, including chronic visceral pain, and can be exceptionally resistant to modification or extinction. Through sustained hypervigilance, safety seeking constitutes one key component in pain and stress-related avoidance behavior, calling for future studies targeting the mechanisms of safety learning and extinction to advance current cognitive-behavioral treatment approaches.


Assuntos
Imageamento por Ressonância Magnética , Dor Visceral , Aprendizagem da Esquiva , Mapeamento Encefálico/métodos , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos , Transtornos Fóbicos
2.
Brain Nerve ; 74(4): 377-384, 2022 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-35437290

RESUMO

Fear memory is defined as the associative (fear-conditioned) memory between the context of a fear experience (conditioned stimulus) and fear itself (unconditioned stimulus). Re-exposure to the conditioned context retrieves the fear memory and triggers a fear response. Fear memories have been observed in both nematodes and humans, suggesting common neural mechanisms. Studies using rodents and other animal models have identified the mechanisms of fear memory processes, such as consolidation, retrieval, reconsolidation, destabilization, and extinction, at the molecular, cellular, circuit, and behavioral levels. This review introduces fear memory processes and their mechanisms.


Assuntos
Extinção Psicológica , Medo , Animais , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos , Memória/fisiologia
3.
Nat Commun ; 13(1): 1799, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379803

RESUMO

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.


Assuntos
Mapeamento Encefálico , Memória , Animais , Encéfalo , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Camundongos
4.
Biosensors (Basel) ; 12(4)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35448253

RESUMO

Defense is the basic survival mechanism of animals when facing dangers. Previous studies have shown that the midbrain periaqueduct gray (PAG) was essential for the production of defense responses. However, the correlation between the endogenous neuronal activities of the dorsal PAG (dPAG) and different defense behaviors was still unclear. In this article, we designed and manufactured microelectrode arrays (MEAs) whose detection sites were arranged to match the shape and position of dPAG in rats, and modified it with platinum-black nanoparticles to improve the detection performance. Subsequently, we successfully recorded the electrophysiological activities of dPAG neurons via designed MEAs in freely behaving rats before and after exposure to the potent analog of predator odor 2-methyl-2-thiazoline (2-MT). Results demonstrated that 2-MT could cause strong innate fear and a series of defensive behaviors, accompanied by the significantly increased average firing rate and local field potential (LFP) power of neurons in dPAG. We also observed that dPAG participated in different defense behaviors with different degrees of activation, which was significantly stronger in the flight stage. Further analysis showed that the neuronal activities of dPAG neurons were earlier than flight, and the intensity of activation was inversely proportional to the distance from predator odor. Overall, our results indicate that dPAG neuronal activities play a crucial role in controlling different types of predator odor-evoked innate fear/defensive behaviors, and provide some guidance for the prediction of defense behavior.


Assuntos
Medo , Substância Cinzenta Periaquedutal , Animais , Medo/fisiologia , Microeletrodos , Neurônios , Substância Cinzenta Periaquedutal/fisiologia , Ratos
5.
Science ; 376(6590): eabf7052, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35420958

RESUMO

Experience-dependent changes in behavior are mediated by long-term functional modifications in brain circuits. Activity-dependent plasticity of synaptic input is a major underlying cellular process. Although we have a detailed understanding of synaptic and dendritic plasticity in vitro, little is known about the functional and plastic properties of active dendrites in behaving animals. Using deep brain two-photon Ca2+ imaging, we investigated how sensory responses in amygdala principal neurons develop upon classical fear conditioning, a form of associative learning. Fear conditioning induced differential plasticity in dendrites and somas regulated by compartment-specific inhibition. Our results indicate that learning-induced plasticity can be uncoupled between soma and dendrites, reflecting distinct synaptic and microcircuit-level mechanisms that increase the computational capacity of amygdala circuits.


Assuntos
Tonsila do Cerebelo , Condicionamento Clássico , Tonsila do Cerebelo/fisiologia , Animais , Condicionamento Clássico/fisiologia , Medo/fisiologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia
6.
Sci Rep ; 12(1): 7016, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488117

RESUMO

Postnatal hippocampal neurogenesis has been demonstrated to affect learning and memory in numerous ways. Several studies have now demonstrated that increased neurogenesis can induce forgetting of memories acquired prior to the manipulation of neurogenesis and, as a result of this forgetting can also facilitate new learning. However, the mechanisms mediating neurogenesis-induced forgetting are not well understood. Here, we used a subregion-based analysis of the immediate early gene c-Fos as well as in vivo fiber photometry to determine changes in activity corresponding with neurogenesis induced forgetting. We found that increasing neurogenesis led to reduced CA1 activity during context memory retrieval. We also demonstrate here that perineuronal net expression in areas CA1 is bidirectionally altered by the levels or activity of postnatally generated neurons in the dentate gyrus. These results suggest that neurogenesis may induce forgetting by disrupting perineuronal nets in CA1 which may otherwise protect memories from degradation.


Assuntos
Memória , Neurogênese , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia
7.
Behav Brain Res ; 428: 113862, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35405547

RESUMO

Emotional learning and memory are affected in numerous psychiatric disorders. At a systems level, however, the underlying neural circuitry is not well defined. Rodent fear conditioning (FC) provides a translational model to study the networks underlying associative memory retrieval. In the current study, functional connectivity among regions related to the cue associative fear network were investigated using functional ultrasound (fUS), a novel imaging technique with great potential for detecting neural activity through cerebral blood flow. Behavioral fear expression and fUS imaging were performed one and thirty-one days after FC to assess recent and remote memory recall. Cue-evoked increases in functional connectivity were detected throughout the amygdala, with the lateral (LA) and central (CeA) amygdalar nuclei emerging as major hubs of connectivity, although CeA connectivity was reduced during remote recall. Hippocampal and sensory cortical regions displayed heightened connectivity with the LA during remote recall, whereas interconnectivity between the primary auditory cortex and temporal association areas was reduced. Subregions of the prefrontal cortex exhibited variable changes, where prelimbic connectivity with the amygdala was refined while specific connections between the infralimbic cortex and amygdalar subregions emerged during remote memory retrieval, a signature of extinction memory. Moreover, freezing behavior positively correlated with functional connectivity between hubs of the associative fear network, suggesting that emotional response intensity reflected the strength of the cue-evoked functional network. Overall, our data provide evidence of the functionality of fUS imaging to investigate the neural dynamics of memory retrieval, applicable in the development of innovative treatments for affective disorders.


Assuntos
Núcleo Central da Amígdala , Condicionamento Clássico , Animais , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos , Memória de Longo Prazo/fisiologia , Rememoração Mental/fisiologia , Camundongos , Redes Neurais de Computação , Córtex Pré-Frontal/fisiologia , Ultrassonografia
8.
Elife ; 112022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35420543

RESUMO

Preys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behavior is implemented at the circuit level. Here, using adult male mice, we show that the anterior hypothalamic nucleus (AHN) is best positioned to control this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system. Selective optogenetic stimulation and inhibition of hippocampal inputs to the AHN revealed that the HPC→AHN pathway not only mediates the contextual memory of predator threats but also controls the goal-directed escape by transmitting information about the surrounding environment. These results reveal a new mechanism for experience-dependent, top-down control of innate defensive behaviors.


Assuntos
Comportamento Animal , Medo , Animais , Comportamento Animal/fisiologia , Medo/fisiologia , Hipocampo , Hipotálamo/fisiologia , Instinto , Masculino , Camundongos , Vias Neurais/fisiologia
9.
Neuropharmacology ; 211: 109048, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35364101

RESUMO

After experiencing a traumatic event people often turn to alcohol to cope with symptoms. In those with post-traumatic stress disorder (PTSD) and a co-occurring alcohol use disorder (AUD), PTSD symptoms can worsen, suggesting that alcohol changes how traumatic memory is expressed. The objective of this series of experiments is to identify how alcohol drinking (EtOH), following cued fear conditioning and extinction, impacts fear expression in mice. Molecular (activity-regulated cytoskeleton-associated protein, Arc/arg3.1) and structural (dendrite and spine morphometry) markers of neuronal plasticity were measured following remote extinction retrieval. Mouse age (adolescent and adult) and sex were included as interacting variables in a full factorial design. Females drank more EtOH than males and adolescents drank more EtOH than adults. Adolescent females escalated EtOH intake across drinking days. Adolescent drinkers exhibited more conditioned freezing during extinction retrieval, an effect that persisted for at least 20 days. Heightened cued freezing in the adolescent group was associated with greater Arc/arg3.1 expression in layer (L) 2/3 prelimbic (PL) cortex, greater spine density, and reduced basal dendrite complexity. In adults, drinking was associated with reduced L2/3 infralimbic (IL) Arc expression but no behavioral differences. Few sex interactions were uncovered throughout. Overall, these data identify prolonged age-related differences in alcohol-induced fear extinction impairment and medial prefrontal cortex neuroadaptations.


Assuntos
Medo , Transtornos de Estresse Pós-Traumáticos , Adolescente , Animais , Etanol/metabolismo , Etanol/farmacologia , Extinção Psicológica , Medo/fisiologia , Feminino , Humanos , Masculino , Camundongos , Córtex Pré-Frontal , Transtornos de Estresse Pós-Traumáticos/metabolismo
10.
Dev Psychobiol ; 64(4): e22242, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35452541

RESUMO

The Generalized Unsafety Theory of Stress posits that low heart rate variability contributes to a perception of "generalized unsafety" (i.e., constantly perceiving oneself to be unsafe), independent of stressful events or stress-related symptomatology. We tested this claim by examining if resting heart rate variability, trait worry, posttraumatic stress symptoms, trauma history, and age of onset predicted fear inhibition, a measure of generalized unsafety. A Pavlovian discriminant conditioning paradigm was used to assess fear inhibition level by comparing eyeblink startle potentiation to a threat cue (presented with air blast) with startle potentiation to a safety signal (never presented with air blast). Survey and laboratory responses were collected from 42 adults who were 20 years old on average, 86% Women, and 76% White. Heart rate variability did not independently predict variation in fear inhibition, as hypothesized. Rather, higher levels of posttraumatic stress symptoms and greater cumulative interpersonal trauma predicted lower fear inhibition. Individuals reporting childhood trauma had higher trait worry, which predicted more severe posttraumatic stress symptoms. These findings highlight the role of attenuated inhibitory learning in stress-related symptomatology and developmentally disruptive trauma. Ability to distinguish threat from safety is a plausible biobehavioral mechanism by which adversity impacts development.


Assuntos
Experiências Adversas da Infância , Transtornos de Estresse Pós-Traumáticos , Adulto , Ansiedade , Condicionamento Clássico/fisiologia , Medo/fisiologia , Feminino , Humanos , Inibição Psicológica , Masculino , Reflexo de Sobressalto/fisiologia , Adulto Jovem
11.
Physiol Behav ; 251: 113802, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35398091

RESUMO

Fear conditioning paradigms are frequently used in the translational study of anxiety and fear-related disorders. Accordingly, it is important to understand whether the measurement of fear conditioning responses is systematically influenced by an individual's race. Studies have found increased pain sensitivity and smaller physiological startle responses in Asian individuals, compared to White individuals; to our knowledge, no studies have evaluated whether skin conductance response (SCR) outcomes differ between Asian and White individuals. In a series of secondary data analyses, we investigated potential differences in skin conductance level (SCL), orienting SCR, unconditioned SCR, SCR to CS+ and CS-, differential SCR, and differential SCR non-responder status. In sample 1, Asian participants (n = 97) demonstrated a significantly smaller mean differential SCR compared to White participants (n = 86). No other between group differences were observed. In sample 2, there was no difference in mean differential SCR between Asian (n = 52) and White (n = 62) participants, although more Asian participants failed to show adequate skin conductance levels for study entry. To our knowledge, this is the first study to evaluate differences between Asian and White samples using skin conductance outcomes in a fear conditioning paradigm. We detected only subtle evidence for SCR differences between Asian and White samples, unlikely to reach significance outside large studies.


Assuntos
Condicionamento Clássico , Resposta Galvânica da Pele , Transtornos de Ansiedade , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos , Reflexo de Sobressalto/fisiologia
12.
Sci Rep ; 12(1): 6504, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35444205

RESUMO

Anxiety disorders, such as post-traumatic stress disorder (PTSD), are thought to occur by dysfunction in the fear and anxiety-related brain circuit, however, the exact mechanisms remain unknown. Recent human studies have shown that the right anterior insular cortex (aIC) activity is positively correlated with the severity of PTSD symptoms. Understanding the role of the aIC in fear and anxiety may provide insights into the etiology of anxiety disorders. We used a modified shock-probe defensive burying behavioral test, which utilizes the natural propensity of rodents to bury potentially dangerous objects, to test the role of aIC in fear. Mice exposed to restraint stress exhibited burying of the restrainer-resembling object, indicative of defensive behavior. Electrolytic ablation of the aIC significantly diminished this defensive burying behavior, suggesting the involvement of the aIC. Single-unit recording of pyramidal neurons in the aIC showed that a proportion of neurons which increased activity in the presence of a restrainer-resembling object was significantly correlated with the defensive burying behavior. This correlation was only present in mice exposed to restraint stress. These results suggest that altered neuronal representation in the aIC may regulate fear and anxiety after exposure to a traumatic event. Overall, our result demonstrates that the aIC mediates fear and anxiety and that it could be a potential target for treating anxiety disorders.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Animais , Ansiedade , Medo/fisiologia , Camundongos , Restrição Física
13.
Int J Mol Sci ; 23(7)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35408943

RESUMO

Fear memory helps animals and humans avoid harm from certain stimuli and coordinate adaptive behavior. However, excessive consolidation of fear memory, caused by the dysfunction of cellular mechanisms and neural circuits in the brain, is responsible for post-traumatic stress disorder and anxiety-related disorders. Dysregulation of specific brain regions and neural circuits, particularly the hippocampus, amygdala, and medial prefrontal cortex, have been demonstrated in patients with these disorders. These regions are involved in learning, memory, consolidation, and extinction. These are also the brain regions where new neurons are generated and are crucial for memory formation and integration. Therefore, these three brain regions and neural circuits have contributed greatly to studies on neural plasticity and structural remodeling in patients with psychiatric disorders. In this review, we provide an understanding of fear memory and its underlying cellular mechanisms and describe how neural circuits are involved in fear memory. Additionally, we discuss therapeutic interventions for these disorders based on their proneurogenic efficacy and the neural circuits involved in fear memory.


Assuntos
Condicionamento Clássico , Extinção Psicológica , Animais , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Humanos , Córtex Pré-Frontal/fisiologia
14.
Prog Brain Res ; 271(1): 51-69, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35397895

RESUMO

Innate fear-related behavioral responses have evolved as strategies for survival. The neural circuits responsible for defensive responses, studied mainly in rodents, have been substantially preserved across evolution. Amygdala collects sensory information (visual, auditory and olfactory) in the cortical division and conveys it to the striatal output division. Distinct amygdala nuclei/subnuclei are activated by different fearful stimuli, such as exposure to a predator or to an aggressive conspecific. The same stimuli segregation is observed in downstream structures, i.e., hypothalamus and PAG. In guinea pigs, the circuits underlying Tonic Immobility (TI) and freezing in response to a natural predator, have been mapped in different subnuclei of the same amygdala area. In the PAG circuits, defensive responses are differentially represented along the dorso-ventral and rostro-caudal axis. The coordination of behavioral, anti-nociceptive and autonomic responses is due to the overlapping of the involved neurons in longitudinal columns.


Assuntos
Tonsila do Cerebelo , Medo , Tonsila do Cerebelo/fisiologia , Animais , Comportamento Animal/fisiologia , Medo/fisiologia , Cobaias , Humanos , Neurônios , Substância Cinzenta Periaquedutal/fisiologia
15.
Prog Brain Res ; 271(1): 71-99, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35397896

RESUMO

The hypothesis that fear is involved in the mechanisms of tonic immobility (TI) has been supported by early studies conducted in newborn and adult chickens. The susceptibility to TI changes during development in parallel to other fear responses. TI duration increases following exposure before induction to threatening stimuli such as electric shock, loud sound, stuffed sparrow hawk, as well as in unfamiliar conditions applied before and/or during testing. TI duration and susceptibility are increased by prey/predator eye contact and inversely related with the predator distance. TI duration increases following exposure before induction to threatening stimuli such as electric shock, loud sound, stuffed sparrow hawk, as well as in unfamiliar conditions applied before and/or during testing. The fact that the experimenter presence or the experimenter eye visibility represent a potential source of fear like a natural predator in chicks and in adult hens is controversial. The likely explanations for the contradictory results are discussed in the text. The rearing conditions, for instance, seem to be critical: repeated handling in the first days after hatching reduces the fear of human beings, decreasing TI duration in adulthood with a parallel increase in proximity scores to the experimenter. In chicks, exposure to withdrawal from a positive imprinting stimulus increases and decreases TI duration, respectively.


Assuntos
Galinhas , Medo , Adulto , Animais , Galinhas/fisiologia , Medo/fisiologia , Feminino , Humanos , Som
16.
Biol Psychol ; 170: 108311, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35288212

RESUMO

Here, we tested the feasibility of a new paradigm developed to investigate the mechanisms of exposure-therapy. The protocol was previously developed for the use with adults and optimized to closely model the mechanisms underlying exposure, i.e. extinction learning. We adapted this paradigm for the use with children, and tested its feasibility in children and adult participants. We used an aversive acoustic unconditioned stimulus (US), picture-based rating scales and a child-oriented instruction/practice procedure. Results indicate robust fear acquisition, extinction and reinstatement on a self-report (US-expectancy) and on a physiological (startle reflex) level. We found evidence for the paradigms sensitivity to age and anxiety-dependent individual differences in fear-learning and extinction. We conclude that the present paradigm is capable of modeling the key mechanisms of exposure-therapy, that is extinction-learning, and can be accomplished with children, adolescents and adults, rendering it promising to bridge the gap between experimental protocols and treatment across the lifespan.


Assuntos
Extinção Psicológica , Longevidade , Adolescente , Adulto , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos , Aprendizagem , Reflexo de Sobressalto/fisiologia
17.
Biol Psychol ; 170: 108314, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35301083

RESUMO

This study examined associations between anxiety symptomatology and cognitive and physiological threat responses during threat learning in a large sample of children and adolescents. Anxiety symptomatology severity along different dimensions (generalized anxiety, separation anxiety, social anxiety, and panic symptoms) was measured using parental and self-reports. Participants completed differential threat acquisition and extinction using an age-appropriate threat conditioning task. They then returned to the lab after 7-10 days to complete an extinction recall task that also assessed threat generalization. Results indicated that more severe overall anxiety was associated with greater cognitive and physiological threat responses during acquisition, extinction, and extinction recall. During acquisition and extinction, all anxiety dimensions manifested greater cognitive threat responses, while panic, separation anxiety, and social anxiety symptoms, but not generalized anxiety, were related to heightened physiological threat responses. In contrast, when we assessed generalization of cognitive threat responses, we found only generalized anxiety symptoms were associated with greater threat response generalization. The study provides preliminary evidence of specificity in threat responses during threat learning across youth with different anxiety symptoms.


Assuntos
Transtornos de Ansiedade , Extinção Psicológica , Adolescente , Ansiedade , Criança , Cognição , Extinção Psicológica/fisiologia , Medo/fisiologia , Humanos
18.
Mol Autism ; 13(1): 13, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35303947

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms-social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non-Shank-related mouse model of ASD-mice with Tbr1 haploinsufficiency. METHODS: We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1+/- mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with Sídák's post hoc test and one-way ANOVA with Tukey's post hoc multiple comparisons were performed for statistical analysis. RESULTS: Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1+/- mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1+/- mice. LIMITATIONS: The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined. CONCLUSIONS: Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD.


Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/genética , Suplementos Nutricionais , Modelos Animais de Doenças , Medo/fisiologia , Humanos , Camundongos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato , Sinapses/metabolismo , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/farmacologia , Zinco/metabolismo , Zinco/farmacologia
19.
Neuroimage ; 253: 119080, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35276369

RESUMO

The cerebellum is involved in the acquisition and consolidation of learned fear responses. Knowledge about its contribution to extinction learning, however, is sparse. Extinction processes likely involve erasure of memories, but there is ample evidence that at least part of the original memory remains. We asked the question whether memory persists within the cerebellum following extinction training. The renewal effect, that is the reoccurrence of the extinguished fear memory during recall in a context different from the extinction context, constitutes one of the phenomena indicating that memory of extinguished learned fear responses is not fully erased during extinction training. We performed a differential AB-A/B fear conditioning paradigm in a 7-Tesla (7T) MRI system in 31 young and healthy men. On day 1, fear acquisition training was performed in context A and extinction training in context B. On day 2, recall was tested in contexts A and B. As expected, participants learned to predict that the CS+ was followed by an aversive electric shock during fear acquisition training. Skin conductance responses (SCRs) were significantly higher to the CS+ compared to the CS- at the end of acquisition. Differences in SCRs vanished in extinction and reoccurred in the acquisition context during recall indicating renewal. Fitting SCR data, a deep neural network model was trained to predict the correct shock value for a given stimulus and context. Event-related fMRI analysis with model-derived prediction values as parametric modulations showed significant effects on activation of the posterolateral cerebellum (lobules VI and Crus I) during recall. Since the prediction values differ based on stimulus (CS+ and CS-) and context during recall, data provide support that the cerebellum is involved in context-related recall of learned fear associations. Likewise, mean ß values were highest in lobules VI and Crus I bilaterally related to the CS+ in the acquisition context during early recall. A similar pattern was seen in the vermis, but only on a trend level. Thus, part of the original memory likely remains within the cerebellum following extinction training. We found cerebellar activations related to the CS+ and CS- during fear acquisition training which likely reflect associative and non-associative aspects of the task. Cerebellar activations, however, were not significantly different for CS+ and CS-. Since the CS- was never followed by an electric shock, the cerebellum may contribute to associative learning related to the CS, for example as a safety cue.


Assuntos
Extinção Psicológica , Medo , Mapeamento Encefálico , Cerebelo/diagnóstico por imagem , Cerebelo/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Resposta Galvânica da Pele , Humanos , Imageamento por Ressonância Magnética , Masculino
20.
Cell Rep ; 38(12): 110546, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35320727

RESUMO

Here, we used RNA capture-seq to identify a large population of lncRNAs that are expressed in the infralimbic prefrontal cortex of adult male mice in response to fear-related learning. Combining these data with cell-type-specific ATAC-seq on neurons that had been selectively activated by fear extinction learning, we find inducible 434 lncRNAs that are derived from enhancer regions in the vicinity of protein-coding genes. In particular, we discover an experience-induced lncRNA we call ADRAM (activity-dependent lncRNA associated with memory) that acts as both a scaffold and a combinatorial guide to recruit the brain-enriched chaperone protein 14-3-3 to the promoter of the memory-associated immediate-early gene Nr4a2 and is required fear extinction memory. This study expands the lexicon of experience-dependent lncRNA activity in the brain and highlights enhancer-derived RNAs (eRNAs) as key players in the epigenomic regulation of gene expression associated with the formation of fear extinction memory.


Assuntos
Medo , RNA Longo não Codificante , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Animais , Extinção Psicológica/fisiologia , Medo/fisiologia , Masculino , Camundongos , Córtex Pré-Frontal/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
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