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
Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.
Assuntos
Medo/fisiologia , Memória/fisiologia , Neurônios/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Encéfalo/fisiologia , Giro Denteado/fisiologia , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.
Assuntos
Matriz Extracelular/metabolismo , Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Envelhecimento , Animais , Medo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Transdução de SinaisRESUMO
Social isolation is a stressful condition that often leads to maladaptive behaviors. In this issue of Cell, Zelikowsky et al. find that chronic social isolation stress triggers an increase in neuronal tachykinin signaling across distinct brain regions that mediate fear and aggression, elucidating the neural basis of these maladaptive responses.
Assuntos
Agressão , Isolamento Social , Encéfalo , Medo , NeuropeptídeosRESUMO
Learning theorists long hypothesized that appetitive and aversive motivational states influence one another antagonistically. Here, Felsenberg et al. show that the activity of neurons in Drosophila known to be important in appetitive conditioning is necessary for the extinction of aversive conditioning, thereby uncovering biological evidence for this opponent-process.
Assuntos
Condicionamento Psicológico , Medo , Animais , Aprendizagem , Memória , RecompensaRESUMO
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
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
Context plays a foundational role in determining how to interpret potentially fear-producing stimuli, yet the precise neurobiological substrates of context are poorly understood. In this issue of Cell, Xu et al. elegantly show that parallel neuronal circuits are necessary for two distinct roles of context in fear conditioning.
Assuntos
Medo , Memória , Condicionamento Clássico , Condicionamento Psicológico , HumanosRESUMO
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
Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.
Assuntos
Neurônios Colinérgicos/metabolismo , Medo/fisiologia , Habenula/fisiologia , Memória/fisiologia , Receptores de GABA-B/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais , Neurotransmissores/metabolismo , Transmissão SinápticaRESUMO
Fear is induced by innate and learned mechanisms involving separate pathways. Here, we used an olfactory-mediated innate-fear versus learned-fear paradigm to investigate how these pathways are integrated. Notably, prior presentation of innate-fear stimuli inhibited learned-freezing response, but not vice versa. Whole-brain mapping and pharmacological screening indicated that serotonin-2A receptor (Htr2a)-expressing cells in the central amygdala (CeA) control both innate and learned freezing, but in opposing directions. In vivo fiber photometry analyses in freely moving mice indicated that innate but not learned-fear stimuli suppressed the activity of Htr2a-expressing CeA cells. Artificial inactivation of these cells upregulated innate-freezing response and downregulated learned-freezing response. Thus, Htr2a-expressing CeA cells serve as a hierarchy generator, prioritizing innate fear over learned fear.
Assuntos
Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Vias Neurais , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Medo/classificação , Integrases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substância Cinzenta Periaquedutal/fisiologia , Receptor 5-HT2A de Serotonina/genética , OlfatoRESUMO
Animals can learn about sources of danger while minimizing their own risk by observing how others respond to threats. However, the distinct neural mechanisms by which threats are learned through social observation (known as observational fear learning1-4 (OFL)) to generate behavioural responses specific to such threats remain poorly understood. The dorsomedial prefrontal cortex (dmPFC) performs several key functions that may underlie OFL, including processing of social information and disambiguation of threat cues5-11. Here we show that dmPFC is recruited and required for OFL in mice. Using cellular-resolution microendoscopic calcium imaging, we demonstrate that dmPFC neurons code for observational fear and do so in a manner that is distinct from direct experience. We find that dmPFC neuronal activity predicts upcoming switches between freezing and moving state elicited by threat. By combining neuronal circuit mapping, calcium imaging, electrophysiological recordings and optogenetics, we show that dmPFC projections to the midbrain periaqueductal grey (PAG) constrain observer freezing, and that amygdalar and hippocampal inputs to dmPFC opposingly modulate observer freezing. Together our findings reveal that dmPFC neurons compute a distinct code for observational fear and coordinate long-range neural circuits to select behavioural responses.
Assuntos
Sinais (Psicologia) , Medo , Vias Neurais , Córtex Pré-Frontal , Aprendizado Social , Animais , Camundongos , Tonsila do Cerebelo/fisiologia , Cálcio/metabolismo , Eletrofisiologia , Medo/fisiologia , Hipocampo/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Optogenética , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/fisiologia , Estimulação Luminosa , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Aprendizado Social/fisiologia , Reação de Congelamento Cataléptica/fisiologiaRESUMO
To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.
Assuntos
Agressão , Aprendizagem da Esquiva , Hipotálamo , Vias Neurais , Neurônios , Ocitocina , Aprendizado Social , Animais , Camundongos , Agressão/fisiologia , Aprendizagem da Esquiva/fisiologia , Sinais (Psicologia) , Medo/fisiologia , Hipotálamo/citologia , Hipotálamo/metabolismo , Vias Neurais/fisiologia , Neurônios/metabolismo , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , Comportamento Social , Aprendizado Social/fisiologia , Núcleo Supraóptico/citologia , Núcleo Supraóptico/metabolismo , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Plasticidade NeuronalRESUMO
As hippocampal neurons respond to diverse types of information1, a subset assembles into microcircuits representing a memory2. Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage3-5. Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes6. Neuron-specific knockdown of Tlr9 impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets. We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits. With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders. Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits.
Assuntos
Região CA1 Hipocampal , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Inflamação , Memória , Receptor Toll-Like 9 , Animais , Feminino , Masculino , Camundongos , Envelhecimento/genética , Envelhecimento/patologia , Região CA1 Hipocampal/fisiologia , Centrossomo/metabolismo , Disfunção Cognitiva/genética , Condicionamento Clássico , Matriz Extracelular/metabolismo , Medo , Instabilidade Genômica/genética , Histonas/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Memória/fisiologia , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Doenças Neuroinflamatórias/genética , Neurônios/metabolismo , Neurônios/patologia , Membrana Nuclear/patologia , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismoRESUMO
T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1-/- mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1-/- T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.
Assuntos
Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Medo/fisiologia , Ativação Linfocitária/imunologia , Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Aminoácidos/sangue , Animais , Encéfalo/metabolismo , Dopamina/deficiência , Interferon gama/sangue , Cinurenina/sangue , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/deficiência , Serotonina/deficiência , Linfócitos T/metabolismo , Triptofano/metabolismo , Tirosina/metabolismoRESUMO
Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.
Assuntos
Medo , Memória de Longo Prazo , Plasticidade Neuronal , Animais , Epigênese Genética , Hipocampo/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , TranscriptomaRESUMO
The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.
Assuntos
Encéfalo , Medo , Leucócitos , Neurônios Motores , Vias Neurais , Estresse Psicológico , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Encéfalo/citologia , Encéfalo/fisiologia , COVID-19/imunologia , Quimiocinas/imunologia , Suscetibilidade a Doenças , Medo/fisiologia , Glucocorticoides/metabolismo , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Camundongos , Monócitos/citologia , Monócitos/imunologia , Neurônios Motores/citologia , Neurônios Motores/fisiologia , Neutrófilos/citologia , Neutrófilos/imunologia , Optogenética , Infecções por Orthomyxoviridae/imunologia , Núcleo Hipotalâmico Paraventricular/fisiologia , SARS-CoV-2/imunologia , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologiaRESUMO
Animals have sophisticated mechanisms for coping with danger. Freezing is a unique state that, upon threat detection, allows evidence to be gathered, response possibilities to be previsioned and preparations to be made for worst-case fight or flight. We propose that - rather than reflecting a passive fear state - the particular somatic and cognitive characteristics of freezing help to conceal overt responses, while optimizing sensory processing and action preparation. Critical for these functions are the neurotransmitters noradrenaline and acetylcholine, which modulate neural information processing and also control the sympathetic and parasympathetic branches of the autonomic nervous system. However, the interactions between autonomic systems and the brain during freezing, and the way in which they jointly coordinate responses, remain incompletely explored. We review the joint actions of these systems and offer a novel computational framework to describe their temporally harmonized integration. This reconceptualization of freezing has implications for its role in decision-making under threat and for psychopathology.
Assuntos
Sistema Nervoso Autônomo , Medo , Adaptação Psicológica , Animais , Sistema Nervoso Autônomo/fisiologia , Medo/fisiologiaRESUMO
Over-generalized fear is a maladaptive response to harmless stimuli or situations characteristic of posttraumatic stress disorder (PTSD) and other anxiety disorders. The dorsal dentate gyrus (dDG) contains engram cells that play a crucial role in accurate memory retrieval. However, the coordination mechanism of neuronal subpopulations within the dDG network during fear generalization is not well understood. Here, with the Tet-off system combined with immunostaining and two-photon calcium imaging, we report that dDG fear engram cells labeled in the conditioned context constitutes a significantly higher proportion of dDG neurons activated in a similar context where mice show generalized fear. The activation of these dDG fear engram cells encoding the conditioned context is both sufficient and necessary for inducing fear generalization in the similar context. Activities of mossy cells in the ventral dentate gyrus (vMCs) are significantly suppressed in mice showing fear generalization in a similar context, and activating the vMCs-dDG pathway suppresses generalized but not conditioned fear. Finally, modifying fear memory engrams in the dDG with "safety" signals effectively rescues fear generalization. These findings reveal that the competitive advantage of dDG engram cells underlies fear generalization, which can be rescued by activating the vMCs-dDG pathway or modifying fear memory engrams, and provide novel insights into the dDG network as the neuronal basis of fear generalization.