RESUMO
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
CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease.
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Adult neurogenesis has fascinated the field of neuroscience for decades given the prospects of harnessing mechanisms that facilitate the rewiring and/or replacement of adult brain tissue. The subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle are the two main areas in the brain that exhibit ongoing neurogenesis. Of these, 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 continued circuit integration within adult brain tissue. This review focuses on some of the recognized molecular and signaling mechanisms underlying activity-dependent adult-born neuron development. Notably, olfactory activity and behavioral states contribute to adult-born neuron plasticity through sensory and centrifugal inputs, in which calcium-dependent transcriptional programs, local translation, and neuropeptide signaling play important roles. This review also highlights areas of needed continued investigation to better understand the remarkable phenomenon of adult-born neuron integration.
Assuntos
Neurônios , Bulbo Olfatório , Camundongos , Animais , Bulbo Olfatório/fisiologia , Neurônios/fisiologia , Neurogênese/fisiologia , EncéfaloRESUMO
Co-transmission, meaning the release of multiple neurotransmitters from one synapse, allows for increased diversity of signaling in the brain. Dopamine (DA) and γ-Aminobutyric acid (GABA) are known to co-express in many regions such as the olfactory bulb and the ventral tegmental area. Tuberoinfundibular dopaminergic neurons (TIDA) in the arcuate nucleus of the hypothalamus (Arc) project to the median eminence (ME) and regulate prolactin release from the pituitary, and prior work suggests dopaminergic Arc neurons also co-transmit GABA. However, the extent of co-transmission, and the projection patterns of these neurons have not been fully revealed. Here we used a genetic intersectional reporter expression approach to selectively label cells that express both tyrosine hydroxylase (TH), and vesicular GABA transporter (Vgat). Through this approach, we identified cells capable of both dopamine (DA) and GABA co-transmission in the Arc, periventricular (Pe), paraventricular (Pa), ventromedial, and the dorsolateral hypothalamic nuclei, in addition to a novel population in the caudate putamen. The highest density of labeled cells was in the Arc, 6.68% of DAPI-labeled cells at -2.06mm Bregma, and in the Pe, 2.83% of DAPI-labeled cells at -1.94mm Bregma. Next, we evaluated the projections of these DA/GABA cells by injecting an mCherry virus that fluoresces in DA/GABA cells. We observed a co-transmitting DA/GABA population, with projections within the Arc, and to the Pa and ME. These data suggest DA/GABA Arc neurons are involved in prolactin release as a subset of TIDA neurons. Further investigation will elucidate the interactions of dopamine and GABA in the hypothalamus.
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Astrocytes display extraordinary morphological complexity that is essential to support brain circuit development and function. Formin proteins are key regulators of the cytoskeleton; however, their role in astrocyte morphogenesis across diverse brain regions and neural circuits is unknown. Here, we show that loss of the formin protein Daam2 in astrocytes increases morphological complexity in the cortex and olfactory bulb, but elicits opposing effects on astrocytic calcium dynamics. These differential physiological effects result in increased excitatory synaptic activity in the cortex and increased inhibitory synaptic activity in the olfactory bulb, leading to altered olfactory behaviors. Proteomic profiling and immunoprecipitation experiments identify Slc4a4 as a binding partner of Daam2 in the cortex, and combined deletion of Daam2 and Slc4a4 restores the morphological alterations seen in Daam2 mutants. Our results reveal new mechanisms regulating astrocyte morphology and show that congruent changes in astrocyte morphology can differentially influence circuit function.
Assuntos
Astrócitos , Proteínas dos Microfilamentos/genética , Proteínas rho de Ligação ao GTP/genética , Forminas , Morfogênese , Bulbo Olfatório/metabolismo , Proteômica , Simportadores de Sódio-BicarbonatoRESUMO
BACKGROUND: The functional understanding of genetic interaction networks and cellular mechanisms governing health and disease requires the dissection, and multifaceted study, of discrete cell subtypes in developing and adult animal models. Recombinase-driven expression of transgenic effector alleles represents a significant and powerful approach to delineate cell populations for functional, molecular, and anatomical studies. In addition to single recombinase systems, the expression of two recombinases in distinct, but partially overlapping, populations allows for more defined target expression. Although the application of this method is becoming increasingly popular, its experimental implementation has been broadly restricted to manipulations of a limited set of common alleles that are often commercially produced at great expense, with costs and technical challenges associated with production of intersectional mouse lines hindering customized approaches to many researchers. Here, we present a simplified CRISPR toolkit for rapid, inexpensive, and facile intersectional allele production. RESULTS: Briefly, we produced 7 intersectional mouse lines using a dual recombinase system, one mouse line with a single recombinase system, and three embryonic stem (ES) cell lines that are designed to study the way functional, molecular, and anatomical features relate to each other in building circuits that underlie physiology and behavior. As a proof-of-principle, we applied three of these lines to different neuronal populations for anatomical mapping and functional in vivo investigation of respiratory control. We also generated a mouse line with a single recombinase-responsive allele that controls the expression of the calcium sensor Twitch-2B. This mouse line was applied globally to study the effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on calcium release in the ovarian follicle. CONCLUSIONS: The lines presented here are representative examples of outcomes possible with the successful application of our genetic toolkit for the facile development of diverse, modifiable animal models. This toolkit will allow labs to create single or dual recombinase effector lines easily for any cell population or subpopulation of interest when paired with the appropriate Cre and FLP recombinase mouse lines or viral vectors. We have made our tools and derivative intersectional mouse and ES cell lines openly available for non-commercial use through publicly curated repositories for plasmid DNA, ES cells, and transgenic mouse lines.
Assuntos
Cálcio , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Animais , Feminino , Integrases/genética , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Recombinases/genética , Recombinases/metabolismoRESUMO
The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here, we found that HFD feeding blunted PVH CRH neuron response to nutritional challenges as well as stress stimuli and dexamethesone, which normally produce rapid activation and inhibition on these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which showed HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models developed rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rhythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity and may also contribute to stress-induced obesity.
Assuntos
Obesidade , Hormônios Liberadores de Hormônios Hipofisários , Animais , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Camundongos , Neurônios/metabolismo , Obesidade/etiologiaRESUMO
Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.
Assuntos
Regulação do Apetite/fisiologia , Prosencéfalo Basal/citologia , Prosencéfalo Basal/fisiologia , Neurônios Colinérgicos/metabolismo , Comportamento Alimentar/fisiologia , Resposta de Saciedade/fisiologia , Acetilcolina/metabolismo , Animais , Peso Corporal/fisiologia , Morte Celular , Colina O-Acetiltransferase/deficiência , Agonistas Colinérgicos , Neurônios Colinérgicos/patologia , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Feminino , Homeostase , Hiperfagia/enzimologia , Hiperfagia/genética , Hiperfagia/patologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Knockout , Modelos Neurológicos , Nicotina/metabolismo , Obesidade/enzimologia , Obesidade/genética , Obesidade/patologia , Receptores Colinérgicos/metabolismoRESUMO
Astrocytes are the most abundant glial cell in the central nervous system. They modulate synaptic function through a variety of mechanisms, and yet remain relatively understudied with respect to overall neuronal circuit function. Exploiting the tractability of the mouse olfactory system, we manipulated astrocyte activity and examined how astrocytes modulate olfactory bulb responses. Toward this, we genetically targeted both astrocytes and neurons for in vivo widefield imaging of Ca2+ responses to odor stimuli. We found that astrocytes exhibited odor response maps that overlap with excitatory neuronal activity. By manipulating Ca2+ activity in astrocytes using chemical genetics we found that odor-evoked neuronal activity was reciprocally affected, suggesting that astrocyte activation inhibits neuronal odor responses. Subsequently, behavioral experiments revealed that astrocyte manipulations affect both odor detection threshold and discrimination, suggesting that astrocytes play an active role in olfactory sensory processing circuits. Together, these studies show that astrocyte calcium signaling contributes to olfactory behavior through modulation of sensory circuits.
Assuntos
Astrócitos/fisiologia , Sinalização do Cálcio/fisiologia , Bulbo Olfatório/fisiologia , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Odorantes , Bulbo Olfatório/metabolismo , Condutos Olfatórios/fisiologiaRESUMO
The mouse olfactory bulb (OB) features continued, activity-dependent integration of adult-born neurons, providing a robust model with which to examine mechanisms of plasticity in the adult brain. We previously reported that local OB interneurons secrete the neuropeptide corticotropin-releasing hormone (CRH) in an activity-dependent manner onto adult-born granule neurons and that local CRH signaling promotes expression of synaptic machinery in the bulb. This effect is mediated via activation of the CRH receptor 1 (CRHR1), which is developmentally regulated during adult-born neuron maturation. CRHR1 is a GS-protein-coupled receptor that activates CREB-dependent transcription in the presence of CRH. Therefore, we hypothesized that locally secreted CRH activates CRHR1 to initiate circuit plasticity programs. To identify such programs, we profiled gene expression changes associated with CRHR1 activity in adult-born neurons of the OB. Here, we show that CRHR1 activity influences expression of the brain-specific Homeobox-containing transcription factor POU Class 6 Homeobox 1 (POU6f1). To elucidate the contributions of POU6f1 toward activity-dependent circuit remodeling, we targeted CRHR1+ neurons in male and female mice for cell-type-specific manipulation of POU6f1 expression. Whereas loss of POU6f1 in CRHR1+ neurons resulted in reduced dendritic complexity and decreased synaptic connectivity, overexpression of POU6f1 in CRHR1+ neurons promoted dendritic outgrowth and branching and influenced synaptic function. Together, these findings suggest that the transcriptional program directed by POU6f1 downstream of local CRH signaling in adult-born neurons influences circuit dynamics in response to activity-dependent peptide signaling in the adult brain.SIGNIFICANCE STATEMENT Elucidating mechanisms of plasticity in the adult brain is helpful for devising strategies to understand and treat neurodegeneration. Circuit plasticity in the adult mouse olfactory bulb is exemplified by both continued cell integration and synaptogenesis. We previously reported that these processes are influenced by local neuropeptide signaling in an activity-dependent manner. Here, we show that local corticotropin-releasing hormone (CRH) signaling induces dynamic gene expression changes in CRH receptor expressing adult-born neurons, including altered expression of the transcription factor POU6f1 We further show that POU6f1 is necessary for proper dendrite specification and patterning, as well as synapse development and function in adult-born neurons. Together, these findings reveal a novel mechanism by which peptide signaling modulates adult brain circuit plasticity.
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Encéfalo/fisiologia , Plasticidade Neuronal/fisiologia , Neuropeptídeos/fisiologia , Fator 3 de Transcrição de Octâmero/fisiologia , Animais , Comportamento Animal/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Feminino , Técnicas de Introdução de Genes , Masculino , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Neurônios/ultraestrutura , Fator 3 de Transcrição de Octâmero/genética , Bulbo Olfatório/citologia , Bulbo Olfatório/fisiologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Olfato/fisiologiaRESUMO
UNLABELLED: Elucidating patterns of functional synaptic connectivity and deciphering mechanisms of how plasticity influences such connectivity is essential toward understanding brain function. In the mouse olfactory bulb (OB), principal neurons (mitral/tufted cells) make reciprocal connections with local inhibitory interneurons, including granule cells (GCs) and external plexiform layer (EPL) interneurons. Our current understanding of the functional connectivity between these cell types, as well as their experience-dependent plasticity, remains incomplete. By combining acousto-optic deflector-based scanning microscopy and genetically targeted expression of Channelrhodopsin-2, we mapped connections in a cell-type-specific manner between mitral cells (MCs) and GCs or between MCs and EPL interneurons. We found that EPL interneurons form broad patterns of connectivity with MCs, whereas GCs make more restricted connections with MCs. Using an olfactory associative learning paradigm, we found that these circuits displayed differential features of experience-dependent plasticity. Whereas reciprocal connectivity between MCs and EPL interneurons was nonplastic, the connections between GCs and MCs were dynamic and adaptive. Interestingly, experience-dependent plasticity of GCs occurred only in certain stages of neuronal maturation. We show that different interneuron subtypes form distinct connectivity maps and modes of experience-dependent plasticity in the OB, which may reflect their unique functional roles in information processing. SIGNIFICANCE STATEMENT: Deducing how specific interneuron subtypes contribute to normal circuit function requires understanding the dynamics of their connections. In the olfactory bulb (OB), diverse interneuron subtypes vastly outnumber principal excitatory cells. By combining acousto-optic deflector-based scanning microscopy, electrophysiology, and genetically targeted expression of Channelrhodopsin-2, we mapped the functional connectivity between mitral cells (MCs) and OB interneurons in a cell-type-specific manner. We found that, whereas external plexiform layer (EPL) interneurons show broadly distributed patterns of stable connectivity with MCs, adult-born granule cells show dynamic and plastic patterns of synaptic connectivity with task learning. Together, these findings reveal the diverse roles for interneuons within sensory circuits toward information learning and processing.
Assuntos
Aprendizagem por Associação/fisiologia , Mapeamento Encefálico , Interneurônios/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Bulbo Olfatório/citologia , Análise de Variância , Animais , Channelrhodopsins , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/genética , Potenciais Pós-Sinápticos Inibidores/fisiologia , Interneurônios/classificação , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Luz , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Inibição Neural/genética , Inibição Neural/fisiologia , Plasticidade Neuronal/genética , Odorantes , Optogenética , Técnicas de Patch-Clamp , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
UNLABELLED: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Severe breathing abnormalities are common in RTT and are reproduced in mouse models of RTT. Previously, we found that removing MeCP2 from the brainstem and spinal cord in mice caused early lethality and abnormal breathing. To determine whether loss of MeCP2 in functional components of the respiratory network causes specific breathing disorders, we used the Cre/LoxP system to differentially manipulate MeCP2 expression throughout the brainstem respiratory network, specifically within HoxA4-derived tissues, which include breathing control circuitry within the nucleus tractus solitarius and the caudal part of ventral respiratory column but do not include more rostral parts of the breathing control circuitry. To determine whether respiratory phenotypes manifested in animals with MeCP2 removed from specific pons medullary respiratory circuits, we performed whole-body plethysmography and electrophysiological recordings from in vitro brainstem slices from mice lacking MeCP2 in different circuits. Our results indicate that MeCP2 expression in the medullary respiratory network is sufficient for normal respiratory rhythm and preventing apnea. However, MeCP2 expression within components of the breathing circuitry rostral to the HoxA4 domain are neither sufficient to prevent the hyperventilation nor abnormal hypoxic ventilatory response. Surprisingly, we found that MeCP2 expression in the HoxA4 domain alone is critical for survival. Our study reveals that MeCP2 is differentially required in select respiratory components for different aspects of respiratory functions, and collectively for the integrity of this network functions to maintain proper respiration. SIGNIFICANCE STATEMENT: Breathing abnormalities are a significant clinical feature in Rett syndrome and are robustly reproduced in the mouse models of this disease. Previous work has established that alterations in the function of MeCP2, the protein encoded by the gene mutated in Rett syndrome, within the hindbrain are critical for control of normal breathing. Here we show that MeCP2 function plays distinct roles in specific brainstem regions in the genesis of various aspects of abnormal breathing. This provides insight into the pathogenesis of these breathing abnormalities in Rett syndrome, which could be used to target treatments to improve these symptoms. Furthermore, it provides further knowledge about the fundamental neural circuits that control breathing.
Assuntos
Bulbo/fisiologia , Proteína 2 de Ligação a Metil-CpG/genética , Respiração , Síndrome de Rett/fisiopatologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Homeodomínio , Masculino , Bulbo/metabolismo , Proteína 2 de Ligação a Metil-CpG/deficiência , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Síndrome de Rett/genética , Fatores de TranscriçãoRESUMO
Physiological and behavioral evidence supports that dopamine (DA) receptor signaling influences hippocampal function. While several recent studies examined how DA influences CA1 plasticity and learning, there are fewer studies investigating the influence of DA signaling to the dentate gyrus. The dentate gyrus receives convergent cortical input through the perforant path fiber tracts and has been conceptualized to detect novelty in spatial memory tasks. To test whether DA-receptor activity influences novelty-detection, we used a novel object recognition (NOR) task where mice remember previously presented objects as an indication of learning. Although DA innervation arises from other sources and the main DA signaling may be from those sources, our molecular approaches verified that midbrain dopaminergic fibers also sparsely innervate the dentate gyrus. During the NOR task, wild-type mice spent significantly more time investigating novel objects rather than previously observed objects. Dentate granule cells in slices cut from those mice showed an increased AMPA/NMDA-receptor current ratio indicative of potentiated synaptic transmission. Post-training injection of a D1-like receptor antagonist not only effectively blocked the preference for the novel objects, but also prevented the increased AMPA/NMDA ratio. Consistent with that finding, neither NOR learning nor the increase in the AMPA/NMDA ratio were observed in DA-receptor KO mice under the same experimental conditions. The results indicate that DA-receptor signaling contributes to the successful completion of the NOR task and to the associated synaptic plasticity of the dentate gyrus that likely contributes to the learning.
Assuntos
Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Receptores Dopaminérgicos/metabolismo , Reconhecimento Psicológico/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Dopamina/metabolismo , Potenciais Pós-Sinápticos Excitadores/genética , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos Knockout , Plasticidade Neuronal/genética , Receptores Dopaminérgicos/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Lesions of the lateral hypothalamus (LH) cause hypophagia. However, activation of glutamatergic neurons in LH inhibits feeding. These results suggest a potential importance for other LH neurons in stimulating feeding. Our current study in mice showed that disruption of GABA release from adult LH GABAergic neurons reduced feeding. LH GABAergic neurons project extensively to the paraventricular hypothalamic nucleus (PVH), and optogenetic stimulation of GABAergic LH â PVH fibers induced monosynaptic IPSCs in PVH neurons, and potently increased feeding, which depended on GABA release. In addition, disruption of GABA-A receptors in the PVH reduced feeding. Thus, we have identified a new feeding pathway in which GABAergic projections from the LH to the PVH promote feeding.
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Ingestão de Alimentos/fisiologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Animais , Neurônios GABAérgicos/metabolismo , Região Hipotalâmica Lateral/citologia , Potenciais Pós-Sinápticos Inibidores , Camundongos , Vias Neurais/citologia , Vias Neurais/fisiologia , Núcleo Hipotalâmico Paraventricular/citologiaRESUMO
Recent studies have found that those who suffer from posttraumatic stress disorder (PTSD) are more likely to experience dementia as they age, most often Alzheimer's disease (AD). These findings suggest that the symptoms of PTSD might have an exacerbating effect on AD progression. AD and PTSD might also share common susceptibility factors such that those who experience trauma-induced disease were already more likely to succumb to dementia with age. Here, we explored these two hypotheses using a mouse model of PTSD in wild-type and AD model animals. We found that expression of human familial AD mutations in amyloid precursor protein and presenilin 1 leads to sensitivity to trauma-induced PTSD-like changes in behavioral and endocrine stress responses. PTSD-like induction, in turn, chronically elevates levels of CSF ß-amyloid (Aß), exacerbating ongoing AD pathogenesis. We show that PTSD-like induction and Aß elevation are dependent on corticotropin-releasing factor (CRF) receptor 1 signaling and an intact hypothalamic-pituitary-adrenal axis. Furthermore, we show that Aß species can hyperexcite CRF neurons, providing a mechanism by which Aß influences stress-related symptoms and PTSD-like phenotypes. Consistent with Aß causing excitability of the stress circuitry, we attenuate PTSD-like phenotypes in vivo by lowering Aß levels during PTSD-like trauma exposure. Together, these data demonstrate that exposure to PTSD-like trauma can drive AD pathogenesis, which directly perturbs CRF signaling, thereby enhancing chronic PTSD symptoms while increasing risk for AD-related dementia.
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Peptídeos beta-Amiloides/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Neurônios/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/metabolismo , Corticosteroides/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Comportamento Animal , Células CHO , Cricetulus , Técnicas de Introdução de Genes , Camundongos , Cultura Primária de Células , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/psicologiaRESUMO
When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical-genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression.
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Desamparo Aprendido , Córtex Pré-Frontal/fisiopatologia , Resiliência Psicológica , Estresse Psicológico/fisiopatologia , Sinapses/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Córtex Pré-Frontal/patologia , Estresse Psicológico/patologia , Sinapses/patologiaRESUMO
Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS, therefore it is critical to understand how the factors associated with the various regulatory layers of this complex pathway contribute to these processes. Recently, Apcdd1 was identified as a negative regulator of proximal Wnt signaling, however its role in oligodendrocyte (OL) differentiation and reymelination in the CNS remain undefined. Analysis of Apcdd1 expression revealed dynamic expression during OL development, where its expression is upregulated during differentiation. Functional studies using ex vivo and in vitro OL systems revealed that Apcdd1 promotes OL differentiation, suppresses Wnt signaling, and associates with ß-catenin. Application of these findings to white matter injury (WMI) models revealed that Apcdd1 similarly promotes OL differentiation after gliotoxic injury in vivo and acute hypoxia ex vivo. Examination of Apcdd1 expression in white matter lesions from neonatal WMI and adult multiple sclerosis revealed its expression in subsets of oligodendrocyte (OL) precursors. These studies describe, for the first time, the role of Apcdd1 in OLs after WMI and reveal that negative regulators of the proximal Wnt pathway can influence regenerative myelination, suggesting a new therapeutic strategy for modulating Wnt signaling and stimulating repair after WMI.
Assuntos
Diferenciação Celular/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Oligodendroglia/fisiologia , Doença do Músculo Branco/patologia , Fatores Etários , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hipóxia/complicações , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lisofosfatidilcolinas/toxicidade , Proteínas de Membrana/genética , Camundongos , Técnicas de Cultura de Órgãos , Medula Espinal/patologia , Células-Tronco/metabolismo , Células-Tronco/fisiologia , Doença do Músculo Branco/induzido quimicamente , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismoRESUMO
Brain function emerges from the morphologies, spatial organization and patterns of connectivity established between diverse sets of neurons. Historically, the notion that neuronal structure predicts function stemmed from classic histological staining and neuronal tracing methods. Recent advances in molecular genetics and imaging technologies have begun to reveal previously unattainable details about patterns of functional circuit connectivity and the subcellular organization of synapses in the living brain. This sophisticated molecular and genetic 'toolbox', coupled with new methods in optical and electron microscopy, provides an expanding array of techniques for probing neural anatomy and function.
Assuntos
Biologia Molecular/métodos , Vias Neurais/fisiologia , Neuroanatomia/métodos , Animais , Encéfalo/ultraestrutura , Vias Neurais/ultraestrutura , Sinapses/metabolismo , Sinapses/ultraestruturaRESUMO
Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF â VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of anxiety, all hallmarks of typical anorexia symptoms. Importantly, activation of BF glutamatergic terminals in the VTA reduced dopamine release in the nucleus accumbens. Collectively, our results point to overactivation of the glutamatergic BF â VTA circuit as a potential cause of anorexia-like phenotypes involving reduced dopamine release.
Assuntos
Prosencéfalo Basal , Área Tegmentar Ventral , Camundongos , Animais , Área Tegmentar Ventral/fisiologia , Dopamina/fisiologia , Anorexia , Fenótipo , Neurônios Dopaminérgicos/fisiologiaRESUMO
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.