RESUMO
The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2-/- model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2-/- mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2-/- mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.
Assuntos
Microbioma Gastrointestinal , Locomoção , Comportamento Social , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores , Transplante de Microbiota Fecal , Fezes/microbiologia , Limosilactobacillus reuteri/metabolismo , Limosilactobacillus reuteri/fisiologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/microbiologia , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/terapia , Análise de Componente Principal , Agitação Psicomotora/patologia , Transmissão SinápticaRESUMO
Neural circuit plasticity and sensory response dynamics depend on forming new synaptic connections. Despite recent advances toward understanding the consequences of circuit plasticity, the mechanisms driving circuit plasticity are unknown. Adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and circuit integration. We and others have shown that efficient adult-born neuron circuit integration hinges on presynaptic activity in the form of diverse signaling peptides. Here, we demonstrate a novel oxytocin-dependent mechanism of adult-born neuron synaptic maturation and circuit integration. We reveal spatial and temporal enrichment of oxytocin receptor expression within adult-born neurons in the murine olfactory bulb, with oxytocin receptor expression peaking during activity-dependent integration. Using viral labeling, confocal microscopy, and cell type-specific RNA-seq, we demonstrate that oxytocin receptor signaling promotes synaptic maturation of newly integrating adult-born neurons by regulating their morphological development and expression of mature synaptic AMPARs and other structural proteins.
Assuntos
Ocitocina , Receptores de Ocitocina , Camundongos , Animais , Ocitocina/metabolismo , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Neurônios/fisiologia , Bulbo Olfatório/metabolismo , NeurogêneseRESUMO
The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.
Assuntos
Fator 4 Ativador da Transcrição , Memória de Longo Prazo , Neurônios , Animais , Camundongos , Fator 4 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/genética , Astrócitos/metabolismo , Potenciação de Longa Duração , Memória de Longo Prazo/fisiologia , Camundongos Knockout , Neurônios/metabolismo , Prosencéfalo/metabolismo , MasculinoRESUMO
Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L. reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Criança , Camundongos , Animais , Humanos , Transtorno Autístico/terapia , Transtorno do Espectro Autista/terapia , Comportamento Social , Resultado do Tratamento , Método Duplo-CegoRESUMO
Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA neurons following BFc circuit manipulations. Furthermore, in vivo acetylcholine sensor and genetically encoded calcium indicator imaging within the BLA (using GACh3 and GCaMP, respectively) revealed selective response patterns of activity during feeding. Finally, through optogenetic manipulations in vivo, we found that increased cholinergic signaling from the BFc to the BLA suppresses appetite and food intake. Together, these data support a model in which cholinergic signaling from the BFc to the BLA directly influences appetite and feeding behavior.
Assuntos
Prosencéfalo Basal , Complexo Nuclear Basolateral da Amígdala , Camundongos , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Prosencéfalo Basal/fisiologia , Neurônios Colinérgicos/fisiologia , Colinérgicos , Ingestão de Alimentos/fisiologiaRESUMO
Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration- and European Medicines Agency-approved drug, dequalinium chloride (DEQ), that inhibits activation of the Escherichia coli general stress response, which promotes ciprofloxacin-induced (stress-induced) mutagenic DNA break repair. We uncover the step in the pathway inhibited: activation of the upstream "stringent" starvation stress response, and find that DEQ slows evolution without favoring proliferation of DEQ-resistant mutants. Furthermore, we demonstrate stress-induced mutagenesis during mouse infections and its inhibition by DEQ. Our work provides a proof-of-concept strategy for drugs to slow evolution in bacteria and generally.
Assuntos
Antibacterianos , Escherichia coli , Animais , Camundongos , Preparações Farmacêuticas/metabolismo , Mutagênese , Mutação , Escherichia coli/metabolismo , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Resistência Microbiana a Medicamentos/genéticaRESUMO
Gut microbes can modulate almost all aspects of host physiology throughout life. As a result, specific microbial interventions are attracting considerable attention as potential therapeutic strategies for treating a variety of conditions. Nonetheless, little is known about the mechanisms through which many of these microbes work. Recently, we and others have found that the commensal bacterium Limosilactobacillus reuteri (formerly Lactobacillus reuteri) reverses social deficits in several mouse models (genetic, environmental, and idiopathic) for neurodevelopmental disorders in a vagus nerve-, oxytocin-, and biopterin-dependent manner. Given that gut microbes can signal to the brain through the immune system and L. reuteri promotes wound healing via the adaptive immune response, we sought to determine whether the prosocial effect mediated by L. reuteri also depends on adaptive immunity. Here, we found that the effects of L. reuteri on social behavior and related changes in synaptic function are independent of the mature adaptive immune system. Interestingly, these findings indicate that the same microbe (L. reuteri) can affect different host phenotypes through distinct mechanisms. IMPORTANCE Because preclinical animal studies support the idea that gut microbes could represent novel therapeutics for brain disorders, it is essential to fully understand the mechanisms by which gut microbes affect their host's physiology. Previously, we discovered that treatment with Limosilactobacillus reuteri selectively improves social behavior in different mouse models for autism spectrum disorder through the vagus nerve, oxytocin reward signaling in the brain, and biopterin metabolites (BH4) in the gut. However, given that (i) the immune system remains a key pathway for host-microbe interactions and that (ii) L. reuteri has been shown to facilitate wound healing through the adaptive immune system, we examined here whether the prosocial effects of L. reuteri require immune signaling. Unexpectedly, we found that the mature adaptive immune system (i.e., conventional B and T cells) is not required for L. reuteri to reverse social deficits and related changes in synaptic function. Overall, these findings add new insight into the mechanism through which L. reuteri modulates brain function and behavior. More importantly, they highlight that a given bacterial species can modulate different phenotypes (e.g., wound healing versus social behavior) through separate mechanisms.
Assuntos
Transtorno do Espectro Autista , Limosilactobacillus reuteri , Camundongos , Animais , Ocitocina/metabolismo , Comportamento Social , Sistema Imunitário/metabolismoRESUMO
Environmental cues and internal states such as mood, reward, or aversion directly influence feeding behaviors beyond homeostatic necessity. The hypothalamus has been extensively investigated for its role in homeostatic feeding. However, many of the neural circuits that drive more complex, non-homeostatic feeding that integrate valence and sensory cues (such as taste and smell) remain unknown. Here, we describe a basal forebrain (BF)-to-lateral habenula (LHb) circuit that directly modulates non-homeostatic feeding behavior. Using viral-mediated circuit mapping, we identified a population of glutamatergic neurons within the BF that project to the LHb, which responds to diverse sensory cues, including aversive and food-related odors. Optogenetic activation of BF-to-LHb circuitry drives robust, reflexive-like aversion. Furthermore, activation of this circuitry suppresses the drive to eat in a fasted state. Together, these data reveal a role of basal forebrain glutamatergic neurons in modulating LHb-associated aversion and feeding behaviors by sensing environmental cues.
Assuntos
Prosencéfalo Basal , Habenula , Habenula/fisiologia , Prosencéfalo Basal/fisiologia , Afeto , Hipotálamo/fisiologia , Comportamento Alimentar , Vias Neurais/fisiologiaRESUMO
Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.
Assuntos
Transtorno do Espectro Autista/complicações , Limosilactobacillus reuteri/fisiologia , Transtornos do Comportamento Social/etiologia , Transtornos do Comportamento Social/terapia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/genética , Benzoxazinas/administração & dosagem , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Exploratório/fisiologia , Microbioma Gastrointestinal/fisiologia , Humanos , Relações Interpessoais , Limosilactobacillus reuteri/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Picrotoxina/farmacologia , Piperidinas/administração & dosagem , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Olfato/fisiologia , Ácido Valproico/toxicidadeRESUMO
Down syndrome (DS) is the most common genetic cause of intellectual disability. Protein homeostasis is essential for normal brain function, but little is known about its role in DS pathophysiology. In this study, we found that the integrated stress response (ISR)-a signaling network that maintains proteostasis-was activated in the brains of DS mice and individuals with DS, reprogramming translation. Genetic and pharmacological suppression of the ISR, by inhibiting the ISR-inducing double-stranded RNA-activated protein kinase or boosting the function of the eukaryotic translation initiation factor eIF2-eIF2B complex, reversed the changes in translation and inhibitory synaptic transmission and rescued the synaptic plasticity and long-term memory deficits in DS mice. Thus, the ISR plays a crucial role in DS, which suggests that tuning of the ISR may provide a promising therapeutic intervention.
Assuntos
Síndrome de Down/fisiopatologia , Síndrome de Down/psicologia , Plasticidade Neuronal , Proteostase/fisiologia , Estresse Fisiológico/fisiologia , Transmissão Sináptica , Animais , Encéfalo/fisiopatologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Memória de Longo Prazo , Camundongos , Camundongos Mutantes , Biossíntese de Proteínas , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
Why ketogenic diet (KD) effectively controls seizures in some people with epilepsy is unclear. In a recent issue of Cell, Olson et al. (2018) showed that KD prevents seizures by upregulating key bacterial species (Akkermansia muciniphila and Parabacteroides merdae). These bacteria synergize to decrease gammaglutamylation of amino acids, increase hippocampal GABA/Glutamate ratios, and, ultimately, prevent seizures.