RESUMO
Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory, and excitatory neurons suggests that each circuit motif may be controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several local and long-range sources. In vivo photometry and CRISPR-Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.
Assuntos
Córtex Auditivo/metabolismo , Bombesina/metabolismo , Medo/fisiologia , Memória/fisiologia , Rede Nervosa/metabolismo , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Condicionamento Clássico , Peptídeo Liberador de Gastrina/química , Peptídeo Liberador de Gastrina/metabolismo , Regulação da Expressão Gênica , Genes Precoces , Células HEK293 , Humanos , Espaço Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Receptores da Bombesina/metabolismo , Som , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and in vitro and in vivo serotonin detection, respectively.
Assuntos
Evolução Molecular Direcionada , Aprendizado de Máquina , Serotonina/metabolismo , Algoritmos , Sequência de Aminoácidos , Tonsila do Cerebelo/fisiologia , Animais , Comportamento Animal , Sítios de Ligação , Encéfalo/metabolismo , Células HEK293 , Humanos , Cinética , Modelos Lineares , Camundongos , Camundongos Endogâmicos C57BL , Fótons , Ligação Proteica , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sono/fisiologia , Vigília/fisiologiaRESUMO
Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Reação de Fuga , Adulto , Animais , Medo , Feminino , Reação de Congelamento Cataléptica , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto , Especificidade da EspécieRESUMO
Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function and suggest potential new therapeutic applications for Nk3R antagonists.
Assuntos
Encéfalo/metabolismo , Neurocinina B/metabolismo , Precursores de Proteínas/metabolismo , Isolamento Social , Estresse Psicológico , Taquicininas/metabolismo , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neurocinina B/genética , Neurônios/citologia , Neurônios/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Precursores de Proteínas/antagonistas & inibidores , Precursores de Proteínas/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de Taquicininas/antagonistas & inibidores , Receptores de Taquicininas/metabolismo , Taquicininas/antagonistas & inibidores , Taquicininas/genética , Regulação para Cima/efeitos dos fármacosRESUMO
Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments.
Assuntos
Potenciação de Longa Duração , Memória , Neurônios/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Hipocampo/citologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Optogenética , Técnicas de Patch-Clamp , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico , Potenciais Sinápticos/efeitos dos fármacosRESUMO
Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACCâBLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACCâBLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACCâBLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. VIDEO ABSTRACT.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Córtex Cerebral/fisiologia , Aprendizagem/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Comportamento Animal , Condicionamento Clássico , Fenômenos Eletrofisiológicos , Medo , Luz , Masculino , Memória/fisiologia , Camundongos , Vias Neurais/fisiologia , Neurônios/fisiologia , Optogenética , Córtex Pré-Frontal/fisiologiaRESUMO
Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility.
Assuntos
Tonsila do Cerebelo/fisiologia , Hipocampo/fisiologia , Memória , Vias Neurais , Animais , Condicionamento Psicológico , Fenômenos Eletrofisiológicos , Medo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/fisiologia , Optogenética , Vírus da Raiva/genética , SinapsesRESUMO
We show that nocturnal aversive stimuli presented to mice while they are eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We also show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus, the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our findings support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders are, in part, the output of a fear-entrained clock, and provide a mechanistic insight into this clock.
Assuntos
Relógios Circadianos , Camundongos , Animais , Relógios Circadianos/genética , Núcleo Supraquiasmático , Ritmo Circadiano , MedoRESUMO
Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry.
Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Animais , HumanosRESUMO
Recently, social media platforms are heavily moderated to prevent the spread of online hate speech, which is usually fertile in toxic words and is directed toward an individual or a community. Owing to such heavy moderation, newer and more subtle techniques are being deployed. One of the most striking among these is fear speech. Fear speech, as the name suggests, attempts to incite fear about a target community. Although subtle, it might be highly effective, often pushing communities toward a physical conflict. Therefore, understanding their prevalence in social media is of paramount importance. This article presents a large-scale study to understand the prevalence of 400K fear speech and over 700K hate speech posts collected from Gab.com. Remarkably, users posting a large number of fear speech accrue more followers and occupy more central positions in social networks than users posting a large number of hate speech. They can also reach out to benign users more effectively than hate speech users through replies, reposts, and mentions. This connects to the fact that, unlike hate speech, fear speech has almost zero toxic content, making it look plausible. Moreover, while fear speech topics mostly portray a community as a perpetrator using a (fake) chain of argumentation, hate speech topics hurl direct multitarget insults, thus pointing to why general users could be more gullible to fear speech. Our findings transcend even to other platforms (Twitter and Facebook) and thus necessitate using sophisticated moderation policies and mass awareness to combat fear speech.
Assuntos
Mídias Sociais , Humanos , Fala , Medo , Fertilidade , ÓdioRESUMO
Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.
Assuntos
Condicionamento Clássico , Medo , Humanos , Camundongos , Animais , Medo/fisiologia , Condicionamento Clássico/fisiologia , Aprendizagem da Esquiva , Estresse Psicológico/genética , Afeto , Extinção Psicológica/fisiologiaRESUMO
Freezing is a defensive behavior commonly examined during hippocampal-mediated fear engram reactivation. How these cellular populations engage the brain and modulate freezing across varying environmental demands is unclear. To address this, we optogenetically reactivated a fear engram in the dentate gyrus subregion of the hippocampus across three distinct contexts in male mice. We found that there were differential amounts of light-induced freezing depending on the size of the context in which reactivation occurred: mice demonstrated robust light-induced freezing in the most spatially restricted of the three contexts but not in the largest. We then utilized graph theoretical analyses to identify brain-wide alterations in cFos expression during engram reactivation across the smallest and largest contexts. Our manipulations induced positive interregional cFos correlations that were not observed in control conditions. Additionally, regions spanning putative "fear" and "defense" systems were recruited as hub regions in engram reactivation networks. Lastly, we compared the network generated from engram reactivation in the small context with a natural fear memory retrieval network. Here, we found shared characteristics such as modular composition and hub regions. By identifying and manipulating the circuits supporting memory function, as well as their corresponding brain-wide activity patterns, it is thereby possible to resolve systems-level biological mechanisms mediating memory's capacity to modulate behavioral states.
Assuntos
Hipocampo , Memória , Masculino , Camundongos , Animais , Hipocampo/fisiologia , Memória/fisiologia , Medo/fisiologia , Neurônios/fisiologiaRESUMO
It is widely accepted that fear memories are consolidated through protein synthesis-dependent changes in the basolateral amygdala complex (BLA). However, recent studies show that protein synthesis is not required to consolidate the memory of a new dangerous experience when it is similar to a prior experience. Here, we examined whether the protein synthesis requirement for consolidating the new experience varies with its spatial and temporal distance from the prior experience. Female and male rats were conditioned to fear a stimulus (S1, e.g., light) paired with shock in stage 1 and a second stimulus (S2, e.g., tone) that preceded additional S1-shock pairings (S2-S1-shock) in stage 2. The latter stage was followed by a BLA infusion of a protein synthesis inhibitor, cycloheximide, or vehicle. Subsequent testing with S2 revealed that protein synthesis in the BLA was not required to consolidate fear to S2 when the training stages occurred 48â h apart in the same context; was required when they were separated by 14â d or occurred in different contexts; but was again not required if S1 was re-presented after the delay or in the different context. Similarly, protein synthesis in the BLA was not required to reconsolidate fear to S2 when the training stages occurred 48â h apart but was required when they occurred 14â d apart. Thus, the protein synthesis requirement for consolidating/reconsolidating fear memories in the BLA is determined by similarity between present and past experiences, the time and place in which they occur, and reminders of the past experiences.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Consolidação da Memória , Ratos , Masculino , Feminino , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Consolidação da Memória/fisiologia , Inibidores da Síntese de Proteínas/farmacologia , Cicloeximida/farmacologia , Medo/fisiologiaRESUMO
Foraging decisions involve assessing potential risks and prioritizing food sources, which can be challenging when confronted with changing and conflicting circumstances. A crucial aspect of this decision-making process is the ability to actively overcome defensive reactions to threats and focus on achieving specific goals. The ventral pallidum (VP) and basolateral amygdala (BLA) are two brain regions that play key roles in regulating behavior motivated by either rewards or threats. However, it is unclear whether these regions are necessary in decision-making processes involving competing motivational drives during conflict. Our aim was to investigate the requirements of the VP and BLA for foraging choices in conflicts involving overcoming defensive responses. Here, we used a novel foraging task and pharmacological techniques to inactivate either the VP or BLA or to disconnect these brain regions before conducting a conflict test in male rats. Our findings showed that BLA is necessary for making risky choices during conflicts, whereas VP is necessary for invigorating the drive to obtain food, regardless of the presence of conflict. Importantly, our research revealed that the connection between VP and BLA is critical in controlling risky food-seeking choices during conflict situations. This study provides a new perspective on the collaborative function of VP and BLA in driving behavior, aimed at achieving goals in the face of dangers.
Assuntos
Tonsila do Cerebelo , Prosencéfalo Basal , Recompensa , Animais , Masculino , Ratos , Prosencéfalo Basal/fisiologia , Tonsila do Cerebelo/fisiologia , Conflito Psicológico , Complexo Nuclear Basolateral da Amígdala/fisiologia , Assunção de Riscos , Ratos Long-Evans , Comportamento Alimentar/fisiologia , Medo/fisiologiaRESUMO
Activity in the basolateral amygdala complex (BLA) is needed to encode fears acquired through contact with both innate sources of danger (i.e., things that are painful) and learned sources of danger (e.g., being threatened with a gun). However, within the BLA, the molecular processes required to consolidate the two types of fear are not the same: protein synthesis is needed to consolidate the first type of fear (so-called first-order fear) but not the latter (so-called second-order fear). The present study examined why first- and second-order fears differ in this respect. Specifically, it used a range of conditioning protocols in male and female rats, and assessed the effects of a BLA infusion of the protein synthesis inhibitor, cycloheximide, on first- and second-order conditioned fear. The results revealed that the differential protein synthesis requirements for consolidation of first- and second-order fears reflect differences in what is learned in each case. Protein synthesis in the BLA is needed to consolidate fears that result from encoding of relations between stimuli in the environment (stimulus-stimulus associations, typical for first-order fear) but is not needed to consolidate fears that form when environmental stimuli associate directly with fear responses emitted by the animal (stimulus-response associations, typical for second-order fear). Thus, the substrates of Pavlovian fear conditioning in the BLA depend on the way that the environment impinges upon the animal. This is discussed with respect to theories of amygdala function in Pavlovian fear conditioning, and ways in which stimulus-response associations might be consolidated in the brain.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Aprendizagem , Feminino , Ratos , Masculino , Animais , Tonsila do Cerebelo/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologiaRESUMO
Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.
Assuntos
Ansiedade , Vias Neurais , Córtex Pré-Frontal , Estresse Psicológico , Animais , Ansiedade/psicologia , Ansiedade/fisiopatologia , Masculino , Estresse Psicológico/psicologia , Estresse Psicológico/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/fisiologia , Camundongos , Medo/fisiologia , Medo/psicologia , Camundongos Endogâmicos C57BL , Área Tegmentar Ventral/fisiopatologia , Tálamo/fisiopatologia , Núcleo Mediodorsal do Tálamo/fisiologia , Núcleo Mediodorsal do Tálamo/fisiopatologiaRESUMO
Neuroticism/negative emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and well-being. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are nonfungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for refining mechanistic research.
Assuntos
Tonsila do Cerebelo , Emoções , Imageamento por Ressonância Magnética , Neuroticismo , Núcleos Septais , Núcleos Septais/fisiologia , Núcleos Septais/diagnóstico por imagem , Humanos , Masculino , Feminino , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/diagnóstico por imagem , Adulto Jovem , Neuroticismo/fisiologia , Adulto , Emoções/fisiologia , Incerteza , Medo/fisiologia , Medo/psicologia , AdolescenteRESUMO
The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified. Employing a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are synchronously activated during social fear expression. Moreover, optogenetic inhibition of the mPFC-LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal-habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear. These results unravel a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptom often observed in many psychiatric disorders.
RESUMO
This study aimed to investigate network-level brain functional changes in breast cancer patients and their relationship with fear of cancer recurrence (FCR). Resting-state functional MRI was collected from 43 patients with breast cancer and 40 healthy controls (HCs). Graph theory analyses, whole-brain voxel-wise functional connectivity strength (FCS) analyses and seed-based functional connectivity (FC) analyses were performed to identify connection alterations in breast cancer patients. Correlations between brain functional connections (i.e. FCS and FC) and FCR level were assessed to further reveal the neural mechanisms of FCR in breast cancer patients. Graph theory analyses indicated a decreased clustering coefficient in breast cancer patients compared to HCs (P = 0.04). Patients with breast cancer exhibited significantly higher FCS in both higher-order function networks (frontoparietal, default mode, and dorsal attention systems) and primary somatomotor networks. Among the hyperconnected regions in breast cancer, the left inferior frontal operculum demonstrated a significant positive correlation with FCR. Our findings suggest that breast cancer patients exhibit less segregation of brain function, and the left inferior frontal operculum is a key region associated with FCR. This study offers insights into the neural mechanisms of FCR in breast cancer patients at the level of brain connectome.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Conectoma , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , MedoRESUMO
The MAP kinase ERK is important for neuronal plasticity underlying associative learning, yet specific molecular pathways for neuronal ERK activation are undetermined. RapGEF2 is a neuron-specific cAMP sensor that mediates ERK activation. We investigated whether it is required for cAMP-dependent ERK activation leading to other downstream neuronal signaling events occurring during associative learning, and if RapGEF2-dependent signaling impairments affect learned behavior. Camk2α-cre+/-::RapGEF2fl/fl mice with depletion of RapGEF2 in hippocampus and amygdala exhibit impairments in context- and cue-dependent fear conditioning linked to corresponding impairment in Egr1 induction in these two brain regions. Camk2α-cre+/-::RapGEF2fl/fl mice show decreased RapGEF2 expression in CA1 and dentate gyrus associated with abolition of pERK and Egr1, but not of c-Fos induction, following fear conditioning, impaired freezing to context after fear conditioning, and impaired cAMP-dependent long-term potentiation at perforant pathway and Schaffer collateral synapses in hippocampal slices ex vivo. RapGEF2 expression is largely eliminated in basolateral amygdala, also involved in fear memory, in Camk2α-cre+/-::RapGEF2fl/fl mice. Neither Egr1 nor c-fos induction in BLA after fear conditioning, nor cue-dependent fear learning, are affected by ablation of RapGEF2 in BLA. However, Egr1 induction (but not that of c-fos) in BLA is reduced after restraint stress-augmented fear conditioning, as is freezing to cue after restraint stress-augmented fear conditioning, in Camk2α-cre+/-::RapGEF2fl/fl mice. Cyclic AMP-dependent GEFs have been genetically associated as risk factors for schizophrenia, a disorder associated with cognitive deficits. Here we show a functional link between one of them, RapGEF2, and cognitive processes involved in associative learning in amygdala and hippocampus.