RESUMO
Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal sub-regions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype.
Assuntos
Síndrome de Down , Masculino , Feminino , Camundongos , Animais , Síndrome de Down/patologia , Trissomia/genética , Trissomia/patologia , Glutamina/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismo , Modelos Animais de DoençasRESUMO
Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process.
Assuntos
Doenças Neurodegenerativas , Doenças Priônicas , Camundongos , Animais , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neuroinflamatórias , Células Endoteliais/metabolismo , Receptores de GABA/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Macrófagos/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neurônios/metabolismo , Doenças Priônicas/metabolismo , Biomarcadores/metabolismoRESUMO
Ex vivo diffusion imaging can be used to study healthy and pathological tissue microstructure in the rodent brain with high resolution, providing a link between in vivo MRI and ex vivo microscopy techniques. Major challenges for the successful acquisition of ex vivo diffusion imaging data however are changes in the relaxivity and diffusivity of brain tissue following perfusion fixation. In this study we address this question by examining the combined effects of tissue preparation factors that influence signal-to-noise ratio (SNR) and consequently image quality, including fixative concentration, contrast agent concentration and tissue rehydration time. We present an optimization strategy combining these factors to manipulate the T 1 and T 2 of fixed tissue and maximize SNR efficiency. We apply this strategy in the rat brain, for a diffusion-weighted spin echo protocol with TE = 27 ms on a 9.4 T scanner with a 39 mm volume coil and 660 mT/m 114 mm gradient insert. We used a reduced fixative concentration of 2% paraformaldehyde (PFA), rehydration time more than 20 days, 15 mM Gd-DTPA in perfusate and TR 250 ms. This resulted in a doubling of SNR and an increase in SNR per unit time of 135% in cortical grey matter and 88% in white matter compared with 4% PFA and no contrast agent. This improved SNR efficiency enabled the acquisition of excellent-quality high-resolution (78 µ m isotropic voxel size) diffusion data with b = 4000 s/mm 2 , 30 diffusion directions and a field of view of 40 × 13 × 18 mm3 in less than 4 days. It was also possible to achieve comparable data quality for a standard resolution (150 µ m) diffusion dataset in 2 1 4 h. In conclusion, the tissue optimization strategy presented here may be used to improve SNR, increase spatial resolution and/or allow faster acquisitions in preclinical ex vivo diffusion MRI experiments.
Assuntos
Encéfalo , Imagem de Difusão por Ressonância Magnética , Fixadores , Imagem de Difusão por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Substância CinzentaRESUMO
Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice requires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target intervention. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery-brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.
Assuntos
Depressão , Comportamento de Doença , Humanos , Encéfalo , Transtornos do Humor , Fatores Imunológicos/uso terapêutico , InflamaçãoRESUMO
It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostly ex vivo and/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammation in vivo in a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n = 20) vs. vehicle-treated controls (n = 12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.
Assuntos
Imagem de Tensor de Difusão , Lipopolissacarídeos , Ratos , Animais , Imagem de Tensor de Difusão/métodos , Lipopolissacarídeos/farmacologia , Doenças Neuroinflamatórias , Imagem de Difusão por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
Dysfunctional mitochondria characterise Parkinson's Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy-lysosomal pathway during neurotoxicity.
Assuntos
Mitofagia , Síndromes Neurotóxicas , Receptores de GABA , Autofagia , Humanos , Lisossomos/metabolismo , Mitocôndrias , Síndromes Neurotóxicas/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismoRESUMO
The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain. The aim of the current study was to ascertain if TSPO PET imaging can be used to detect neuroinflammation induced by a peripheral treatment with a low dose of the endotoxin, lipopolysaccharide (LPS), in a rat model (ip LPS), and investigate the origin of TSPO signal changes in terms of their cellular sources and regional distribution. An initial pilot study utilising both [18F]DPA-714 and [11C]PK11195 TSPO radiotracers demonstrated [18F]DPA-714 to exhibit a significantly higher lesion-related signal in the intracerebral LPS rat model (ic LPS) than [11C]PK11195. Subsequently, [18F]DPA-714 was selected for use in the ip LPS study. Twenty-four hours after ip LPS, there was an increased uptake of [18F]DPA-714 across the whole brain. Further analyses of regions of interest, using immunohistochemistry and RNAscope Multiplex fluorescence V2 in situ hybridization technology, showed TSPO expression in microglia, monocyte derived-macrophages, astrocytes, neurons and endothelial cells. The expression of TSPO was significantly increased after ip LPS in a region-dependent manner: with increased microglia, monocyte-derived macrophages and astrocytes in the substantia nigra, in contrast to the hippocampus where TSPO was mostly confined to microglia and astrocytes. In summary, our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [18F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal increase arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages.
Assuntos
Células Endoteliais , Tomografia por Emissão de Pósitrons , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas de Transporte , Células Endoteliais/metabolismo , Microglia/metabolismo , Projetos Piloto , Ratos , Receptores de GABA/metabolismo , Receptores de GABA-ARESUMO
OBJECTIVE: Neurotrophin-3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke. METHODS: Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps. RESULTS: Radiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri-infarct blood oxygenation level-dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways. INTERPRETATION: Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke. ANN NEUROL 2019;85:32-46.
Assuntos
Neurotrofina 3/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Feminino , Injeções Intramusculares , Distribuição Aleatória , Ratos , Recuperação de Função Fisiológica/fisiologia , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/efeitos dos fármacos , Córtex Sensório-Motor/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoRESUMO
Ebselen, a potential new lithium-like drug, treatment reduced brain glutamate, as measured by PET imaging using the mGluR5 radioligand [18 F]FPEB in rats.
Assuntos
Azóis/farmacologia , Encéfalo/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Compostos Organosselênicos/farmacologia , Psicotrópicos/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Transmissão Sináptica , Animais , Encéfalo/diagnóstico por imagem , Isoindóis , Tomografia por Emissão de Pósitrons , Ligação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases.
Assuntos
Imidazóis/farmacologia , Microglia/efeitos dos fármacos , Piridinas/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Doença de Alzheimer/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Humanos , Imidazóis/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/fisiologia , Doenças Neurodegenerativas/tratamento farmacológico , Neurogênese , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Piridinas/metabolismo , Receptores de GABA/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Tauopatias/tratamento farmacológico , Proteínas tau/genéticaRESUMO
Exposure to early adversity is implicated in the development of aggressive behaviour later in life in some but not all individuals. The reasons for the variability in response to such experiences are not clear but may relate to pre-existing individual differences that influence their downstream effects. Applying structural magnetic resonance imaging (MRI) to a rat model of abnormal aggression induced by peripubertal stress, we examined whether individual differences in the development of an aggressive phenotype following stress exposure were underpinned by variation in the structure of aggression-associated, corticolimbic brain regions. We also assessed whether responsiveness of the hypothalamic-pituitary-adrenal axis to stress was associated with neurobehavioural outcome following adversity. A subset of the rats exposed to peripubertal stress developed an aggressive phenotype, while the remaining rats were affected in other behavioural domains, such as increased anxiety-like behaviours and reduced sociability. Peripubertal stress led to changes in tissue microstructure within prefrontal cortex, amygdala and hippocampal formation only in those individuals displaying an aggressive phenotype. Attenuated glucocorticoid response to stress during juvenility predicted the subsequent development of an aggressive phenotype in peripubertal stress-exposed rats. Our study establishes a link between peripubertal stress exposure in rats and structural deviations in brain regions linked to abnormal aggression and points towards low glucocorticoid responsiveness to stress as a potential underlying mechanism. We additionally highlight the importance of considering individual differences in behavioural response to stress when determining neurobiological correlates.
Assuntos
Agressão/fisiologia , Tonsila do Cerebelo/patologia , Comportamento Animal/fisiologia , Corticosterona/metabolismo , Hipocampo/patologia , Individualidade , Córtex Pré-Frontal/patologia , Estresse Psicológico , Fatores Etários , Tonsila do Cerebelo/diagnóstico por imagem , Animais , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Hipocampo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Ratos , Ratos Wistar , Comportamento Social , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.
Assuntos
Neurotrofina 3/administração & dosagem , Neurotrofina 3/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Adenoviridae , Fatores Etários , Animais , Endotelina-1/administração & dosagem , Feminino , Vetores Genéticos/administração & dosagem , Humanos , Injeções Intramusculares , Locomoção/efeitos dos fármacos , Imageamento por Ressonância Magnética , Microinjeções , Músculo Esquelético/metabolismo , Neuroimagem , Neurotrofina 3/sangue , Neurotrofina 3/metabolismo , Tratos Piramidais/efeitos dos fármacos , Ratos , Medula Espinal/metabolismo , Acidente Vascular Cerebral/induzido quimicamente , Fatores de TempoRESUMO
BACKGROUND: Understanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye-movement sleep [REMS] disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known. METHODS: In a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored posttraumatic stress disorder-related biobehavioral traits using ex vivo magnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined with in vivo photometric measurements. RESULTS: We showed that genetic selection for blunted glucocorticoid responsiveness led to a correlated multitrait response, including impaired fear extinction (observed in males but not in females), small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core posttraumatic stress disorder-related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reversed by postextinction corticosterone treatment. CONCLUSIONS: Our results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and they causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances that lead to fear extinction deficits.
Assuntos
Extinção Psicológica , Transtornos de Estresse Pós-Traumáticos , Masculino , Feminino , Ratos , Animais , Extinção Psicológica/fisiologia , Medo/fisiologia , Glucocorticoides/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/complicações , CorticosteronaRESUMO
BACKGROUND: The single pellet reaching and grasp (SPRG) task is a behavioural assay widely used to study motor learning, control and recovery after nervous system injury in animals. The manual training and assessment of the SPRG is labour intensive and time consuming and has led to the development of multiple devices which automate the SPRG task. NEW METHOD: Here, using robotics, computer vision, and machine learning analysis of videos, we describe a device that can be left unattended, presents pellets to mice, and, using two supervised learning algorithms, classifies the outcome of each trial with an accuracy of greater than 94% without the use of graphical processing units (GPUs). Our devices can also be operated using our cross-platform Graphical User Interface (GUI). RESULTS: We show that these devices train and assess mice in parallel. 21 out of 30 mice retrieved > 40% of pellets successfully following the training period. Following ischaemic stroke; some mice showed large persistent deficits whilst others showed only transient deficits. This highlights the heterogeneity in reaching outcomes following stroke. COMPARISON WITH EXISTING METHOD(S): Current state-of-the-art desktop methods either still require supervision, manual classification of trial outcome, or expensive locally-installed hardware such as graphical processing units (GPUs). CONCLUSIONS: ReachingBots successfully automated SPRG training and assessment and revealed the heterogeneity in reaching outcomes following stroke. We conjecture that reach-and-grasp is represented in motor cortex bilaterally but with greater asymmetry in some mice than in others.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Robótica , Acidente Vascular Cerebral , Camundongos , Animais , Força da MãoRESUMO
It is widely assumed that our actions shape our brains and that the resulting connections determine who we are. To test this idea in a reductionist setting, in which genes and environment are controlled, we investigated differences in neuroanatomy and structural covariance by ex vivo structural magnetic resonance imaging in mice whose behavioral activity was continuously tracked for 3 months in a large, enriched environment. We confirmed that environmental enrichment increases mouse hippocampal volumes. Stratifying the enriched group according to individual longitudinal behavioral trajectories, however, revealed striking differences in mouse brain structural covariance in continuously highly active mice compared to those whose trajectories showed signs of habituating activity. Network-based statistics identified distinct subnetworks of murine structural covariance underlying these differences in behavioral activity. Together, these results reveal that differentiated behavioral trajectories of mice in an enriched environment are associated with differences in brain connectivity.
An individual's experiences and behavior shape their brain, thereby building and refining a network of connections between neurons. This unique network may affect an individual's brain resilience in the face of aging, injury or disease. Understanding how individual experiences shape brain connections could help scientists develop personalized treatments. It may also have important implications for preventing brain disease. Studying mice can provide a window into some of these brain processes. By using inbred mice, scientists can rule out the role of genetics in brain differences. Scientists can also control the animals' environments and track the activity of individuals to study their behavior. Bogado Lopes et al. show that more active mice living in enriched environments have signs of more complex networks of brain connections. In the experiments, the researchers placed genetically identical mice in either standard laboratory mouse housing or in enriched environments. Mice in the enriched housing had access to multi-level enclosures connected with tubes and supplied with a rotating array of toys. A tiny tracking device was inserted under the skin of the mice to follow their movements. Finally, all mice underwent structural magnetic resonance imaging to assess their brain anatomy and connections. This revealed that the most active and adventurous mice in the enriched enclosures had the most robust signs of increased brain connectivity. However, mice with declining activity levels in the enriched enclosures had fewer brain connections. Brain connection patterns in these creatures of habit were nearly identical to the ones in mice housed in small unenriched enclosures. The results show that how individual mice respond to their environments affects their brain structure. More active behavior patterns lead to more robust networks of brain connections. Larger studies in mice could provide more about lifestyle-dependent brain resilience. It may also help scientists to develop individualized approaches to optimizing brain health.
Assuntos
Mapeamento Encefálico , Encéfalo , Camundongos , Animais , Encéfalo/anatomia & histologia , Mapeamento Encefálico/métodos , HipocampoRESUMO
Background: Past research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review, and to critically assess, contemporary evidence on sex and gender differences in alpha-synucleinopathies using a bench-to-bedside approach. Methods: In this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid. Results: One hundred sixty-two studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects. Conclusion: Future studies disentangling the underlying sex-specific mechanisms of alpha-synucleinopathies are urgently needed in order to enable novel sex-specific therapeutics.
RESUMO
Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p = 0.02) and rats (F(1,5)26.04, p = 0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p = 0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t = 2.6(16) p = 0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB's hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB's ability to enhance cerebral metabolism might be limited.
Assuntos
Encéfalo , Azul de Metileno , Humanos , Ratos , Animais , Azul de Metileno/farmacologia , Azul de Metileno/metabolismo , Encéfalo/irrigação sanguínea , Glucose/metabolismo , Oxigênio/metabolismo , Consumo de Oxigênio , Circulação CerebrovascularRESUMO
BACKGROUND AND HYPOTHESIS: Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. STUDY DESIGN: Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. RESULTS: Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. CONCLUSIONS: These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.
Assuntos
Glutamina , Transtornos Psicóticos , Camundongos , Animais , Glutamina/metabolismo , Parvalbuminas/metabolismo , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/metabolismo , Interneurônios/metabolismo , Fenótipo , Neuroimagem , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismoRESUMO
The brain is the central and most complex organ in the nervous system, comprising billions of neurons that constantly communicate through trillions of connections called synapses. Despite being formed mainly during prenatal and early postnatal development, synapses are continually refined and eliminated throughout life via complicated and hitherto incompletely understood mechanisms. Failure to correctly regulate the numbers and distribution of synapses has been associated with many neurological and psychiatric disorders, including autism, epilepsy, Alzheimer's disease, and schizophrenia. Therefore, measurements of brain synaptic density, as well as early detection of synaptic dysfunction, are essential for understanding normal and abnormal brain development. To date, multiple synaptic density markers have been proposed and investigated in experimental models of brain disorders. The majority of the gold standard methodologies (e.g., electron microscopy or immunohistochemistry) visualize synapses or measure changes in pre- and postsynaptic proteins ex vivo. However, the invasive nature of these classic methodologies precludes their use in living organisms. The recent development of positron emission tomography (PET) tracers [such as (18F)UCB-H or (11C)UCB-J] that bind to a putative synaptic density marker, the synaptic vesicle 2A (SV2A) protein, is heralding a likely paradigm shift in detecting synaptic alterations in patients. Despite their limited specificity, novel, non-invasive magnetic resonance (MR)-based methods also show promise in inferring synaptic information by linking to glutamate neurotransmission. Although promising, all these methods entail various advantages and limitations that must be addressed before becoming part of routine clinical practice. In this review, we summarize and discuss current ex vivo and in vivo methods of quantifying synaptic density, including an evaluation of their reliability and experimental utility. We conclude with a critical assessment of challenges that need to be overcome before successfully employing synaptic density biomarkers as diagnostic and/or prognostic tools in the study of neurological and neuropsychiatric disorders.
RESUMO
The difference between brain age predicted from MRI and chronological age (the so-called BrainAGE) has been proposed as an ageing biomarker. We analyse its cross-species potential by testing it on rats undergoing an ageing modulation intervention. Our rat brain age prediction model combined Gaussian process regression with a classifier and achieved a mean absolute error (MAE) of 4.87 weeks using cross-validation on a longitudinal dataset of 31 normal ageing rats. It was then tested on two groups of 24 rats (MAE = 9.89 weeks, correlation coefficient = 0.86): controls vs. a group under long-term environmental enrichment and dietary restriction (EEDR). Using a linear mixed-effects model, BrainAGE was found to increase more slowly with chronological age in EEDR rats (p=0.015 for the interaction term). Cox regression showed that older BrainAGE at 5 months was associated with higher mortality risk (p=0.03). Our findings suggest that lifestyle-related prevention approaches may help to slow down brain ageing in rodents and the potential of BrainAGE as a predictor of age-related health outcomes.