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Hemispheric brain asymmetry is a basic organizational principle of the human brain and has been implicated in various psychiatric conditions, including autism spectrum disorder. Brain asymmetry is not a uniquely human feature and is observed in other species such as the mouse. Yet, asymmetry patterns are generally nuanced, and substantial sample sizes are required to detect these patterns. In this pre-registered study, we use a mouse dataset from the Province of Ontario Neurodevelopmental Network, which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse. Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain, such as larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole, opposite to what has been shown in humans. This suggests the existence of species-specific traits. Further clustering analysis identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. Our study shows potential for the use of mouse models to understand the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.
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Functional magnetic resonance imaging in rodents holds great potential for advancing our understanding of brain networks. Unlike the human community, there remains no standardized resource in rodents for image processing, analysis and quality control, posing significant reproducibility limitations. Our software platform, Rodent Automated Bold Improvement of EPI Sequences, is a pipeline designed to address these limitations for preprocessing, quality control, and confound correction, along with best practices for reproducibility and transparency. We demonstrate the robustness of the preprocessing workflow by validating performance across multiple acquisition sites and both mouse and rat data. Building upon a thorough investigation into data quality metrics across acquisition sites, we introduce guidelines for the quality control of network analysis and offer recommendations for addressing issues. Taken together, this software platform will allow the emerging community to adopt reproducible practices and foster progress in translational neuroscience.
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Encéfalo , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Programas Informáticos , Animales , Imagen por Resonancia Magnética/métodos , Ratas , Ratones , Procesamiento de Imagen Asistido por Computador/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Reproducibilidad de los Resultados , Exactitud de los Datos , Mapeo Encefálico/métodos , Masculino , Control de CalidadRESUMEN
The subdivisions of the extended cingulate cortex of the human brain are implicated in a number of high-level behaviors and affected by a range of neuropsychiatric disorders. Its anatomy, function, and response to therapeutics are often studied using non-human animals, including the mouse. However, the similarity of human and mouse frontal cortex, including cingulate areas, is still not fully understood. Some accounts emphasize resemblances between mouse cingulate cortex and human cingulate cortex while others emphasize similarities with human granular prefrontal cortex. We use comparative neuroimaging to study the connectivity of the cingulate cortex in the mouse and human, allowing comparisons between mouse 'gold standard' tracer and imaging data, and, in addition, comparison between the mouse and the human using comparable imaging data. We find overall similarities in organization of the cingulate between species, including anterior and midcingulate areas and a retrosplenial area. However, human cingulate contains subareas with a more fine-grained organization than is apparent in the mouse and it has connections to prefrontal areas not present in the mouse. Results such as these help formally address between-species brain organization and aim to improve the translation from preclinical to human results.
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While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.
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Corteza Motora , Humanos , Corteza Motora/fisiología , Animales , Ratones , Masculino , Ratones Endogámicos C57BL , Adulto , Femenino , Mapeo EncefálicoRESUMEN
Fueled by the recent and controversial brain-wide association studies in humans, the animal neuroimaging community has also begun questioning whether using larger sample sizes is necessary for ethical and effective scientific progress. In this opinion piece, we illustrate two opposing views on sample size extremes in MRI-based animal neuroimaging.
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Imagen por Resonancia Magnética , Neuroimagen , Animales , Humanos , Neuroimagen/métodos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagenRESUMEN
Imaging awake animals is quickly gaining traction in neuroscience as it offers a means to eliminate the confounding effects of anesthesia, difficulties of inter-species translation (when humans are typically imaged while awake), and the inability to investigate the full range of brain and behavioral states in unconscious animals. In this systematic review, we focus on the development of awake mouse blood oxygen level dependent functional magnetic resonance imaging (fMRI). Mice are widely used in research due to their fast-breeding cycle, genetic malleability, and low cost. Functional MRI yields whole-brain coverage and can be performed on both humans and animal models making it an ideal modality for comparing study findings across species. We provide an analysis of 30 articles (years 2011-2022) identified through a systematic literature search. Our conclusions include that head-posts are favorable, acclimation training for 10-14 d is likely ample under certain conditions, stress has been poorly characterized, and more standardization is needed to accelerate progress. For context, an overview of awake rat fMRI studies is also included. We make recommendations that will benefit a wide range of neuroscience applications.
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Anestesia , Imagen por Resonancia Magnética , Humanos , Ratones , Ratas , Animales , Imagen por Resonancia Magnética/métodos , Vigilia , Encéfalo/diagnóstico por imagen , Mapeo EncefálicoRESUMEN
Brain communication, defined as information transmission through white-matter connections, is at the foundation of the brain's computational capacities that subtend almost all aspects of behavior: from sensory perception shared across mammalian species, to complex cognitive functions in humans. How did communication strategies in macroscale brain networks adapt across evolution to accomplish increasingly complex functions? By applying a graph- and information-theory approach to assess information-related pathways in male mouse, macaque and human brains, we show a brain communication gap between selective information transmission in non-human mammals, where brain regions share information through single polysynaptic pathways, and parallel information transmission in humans, where regions share information through multiple parallel pathways. In humans, parallel transmission acts as a major connector between unimodal and transmodal systems. The layout of information-related pathways is unique to individuals across different mammalian species, pointing at the individual-level specificity of information routing architecture. Our work provides evidence that different communication patterns are tied to the evolution of mammalian brain networks.
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Macaca , Sustancia Blanca , Humanos , Masculino , Ratones , Animales , Encéfalo , Cognición , Sensación , Imagen por Resonancia Magnética , Red Nerviosa , MamíferosRESUMEN
The complex symbiotic relationship between the mammalian body and gut microbiome plays a critical role in the health outcomes of offspring later in life. The gut microbiome modulates virtually all physiological functions through direct or indirect interactions to maintain physiological homeostasis. Previous studies indicate a link between maternal/early-life gut microbiome, brain development, and behavioral outcomes relating to social cognition. Here we present direct evidence of the role of the gut microbiome in brain development. Through magnetic resonance imaging (MRI), we investigated the impact of the gut microbiome on brain organization and structure using germ-free (GF) mice and conventionalized mice, with the gut microbiome reintroduced after weaning. We found broad changes in brain volume in GF mice that persist despite the reintroduction of gut microbes at weaning. These data suggest a direct link between the maternal gut or early-postnatal microbe and their impact on brain developmental programming.
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Microbioma Gastrointestinal , Ratones , Animales , Microbioma Gastrointestinal/fisiología , Encéfalo , Cabeza , MamíferosRESUMEN
Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.
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Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.
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Mapeo Encefálico , Encéfalo , Ratas , Animales , Mapeo Encefálico/métodos , Consenso , Neuroimagen , Imagen por Resonancia Magnética/métodosRESUMEN
The central serotoninergic system is critical for stress responsivity and social behavior, and its dysregulations have been centrally implicated in virtually all neuropsychiatric disorders. Genetic serotonin depletion animal models could provide a tool to elucidate the causes and mechanisms of diseases and to develop new treatment approaches. Previously, mice lacking tryptophan hydroxylase 2 (Tph2) have been developed, showing altered behaviors and neurotransmission. However, the effect of congenital serotonin deficiency on emotional and social behavior in rats is still largely unknown, as are the underlying mechanisms. In this study, we used a Tph2 knockout (Tph2-/-) male rat model to study how the lack of serotonin in the rat brain affects anxiety-like and social behaviors. Since oxytocin is centrally implicated in these behaviors, we furthermore explored whether the effects of Tph2 knockout on behavior would relate to changes in the oxytocin system. We show that Tph2-/- rats display reduced anxiety-like behavior and a high level of aggression in social interactions. In addition, oxytocin receptor expression was increased in the infralimbic and prelimbic cortices, paraventricular nucleus, dorsal raphe nucleus, and some subregions of the hippocampus, which was paralleled by increased levels of oxytocin in the medial frontal cortex and paraventricular nucleus but not the dorsal raphe nucleus, central amygdala, and hippocampus. In conclusion, our study demonstrated reduced anxiety but exaggerated aggression in Tph2-/- male rats and reveals for the first time a potential involvement of altered oxytocin system function. Meanwhile, the research of oxytocin could be distinguished in almost any psychiatric disorder including anxiety and mental disorders. This research potentially proposes a new target for the treatment of such disorders, from a genetic serotonin deficiency aspect.
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Oxitocina , Triptófano Hidroxilasa , Animales , Masculino , Ratones , Ratas , Agresión , Ansiedad/metabolismo , Ratones Noqueados , Receptores de Oxitocina/genética , Serotonina/metabolismo , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismoRESUMEN
Functional network activity alterations are one of the earliest hallmarks of Alzheimer's disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice, thus, reveal a dichotomic hypo-connected:resting versus hyper-responsive:active phenotype. This strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related, early-AD deficits in humans.
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Enfermedad de Alzheimer , Tauopatías , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Corteza Entorrinal , Humanos , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
INTRODUCTION: Impaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased cerebral blood flow (CBF) during hypoglycemia appear to be involved in the pathogenesis of impaired awareness of hypoglycemia. Here we examine the effect of lactate on CBF during hypoglycemia. RESEARCH DESIGN AND METHODS: Nine people with type 1 diabetes and normal awareness of hypoglycemia underwent two hyperinsulinemic euglycemic-hypoglycemic (3.0 mmol/L) glucose clamps in a 3T MR system, once with sodium lactate infusion and once with sodium chloride infusion. Global and regional changes in CBF were determined using pseudocontinuous arterial spin labeling. RESULTS: Lactate (3.3±0.6 vs 0.9±0.2 mmol/L during lactate infusion vs placebo infusion, respectively) suppressed the counter-regulatory hormone responses to hypoglycemia. Global CBF increased considerably in response to intravenous lactate infusion but did not further increase during hypoglycemia. Lactate also blunted the hypoglycemia-induced regional redistribution of CBF towards the thalamus. CONCLUSIONS: Elevated lactate levels enhance global CBF and blunt the thalamic CBF response during hypoglycemia in patients with type 1 diabetes, mimicking observations of impaired awareness of hypoglycemia. These findings suggest that alteration of CBF associated with lactate may play a role in some aspects of the development of impaired awareness of hypoglycemia. TRIAL REGISTRATION NUMBER: NCT03730909.
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Diabetes Mellitus Tipo 1 , Hipoglucemia , Circulación Cerebrovascular/fisiología , Diabetes Mellitus Tipo 1/complicaciones , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemia/inducido químicamente , Ácido Láctico/efectos adversosRESUMEN
The triple-network model of psychopathology is a framework to explain the functional and structural neuroimaging phenotypes of psychiatric and neurological disorders. It describes the interactions within and between three distributed networks: the salience, default-mode, and central executive networks. These have been associated with brain disorder traits in patients. Homologous networks have been proposed in animal models, but their integration into a triple-network organization has not yet been determined. Using resting-state datasets, we demonstrate conserved spatio-temporal properties between triple-network elements in human, macaque, and mouse. The model predictions were also shown to apply in a mouse model for depression. To validate spatial homologies, we developed a data-driven approach to convert mouse brain maps into human standard coordinates. Finally, using high-resolution viral tracers in the mouse, we refined an anatomical model for these networks and validated this using optogenetics in mice and tractography in humans. Unexpectedly, we find serotonin involvement within the salience rather than the default-mode network. Our results support the existence of a triple-network system in the mouse that shares properties with that of humans along several dimensions, including a disease condition. Finally, we demonstrate a method to humanize mouse brain networks that opens doors to fully data-driven trans-species comparisons.
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Imagen por Resonancia Magnética , Red Nerviosa , Animales , Encéfalo , Mapeo Encefálico/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Ratones , Vías NerviosasRESUMEN
Stimulation of glucagon-like peptide-1 (GLP-1) receptors increases the insulin release in the pancreas during high glucose levels, and also stimulates a feeling of satiety. Likewise, synthetic GLP-1 receptor agonists derived from exendin are used successfully in the treatment of type-2 diabetes mellitus and obesity. Interestingly, preclinical and clinical studies further suggest that GLP-1 receptor agonists may decrease motor, behavioral, and cognitive symptoms in (animal models) Parkinson's disease and Alzheimer's disease and may slow down neurodegeneration. These observations suggest stimulation of GLP-1 receptors in the brain. The GLP-1 positron emission tomography (PET) tracer 68Ga-NODAGA-exendin-4 has been developed and successfully used for imaging in humans. In an ongoing study on the effects of bariatric surgery on GLP-1 receptor expression, we performed 68Ga-NODAGA-exendin-4 PET in obese subjects. Here we evaluated whether GLP-1 receptor binding could be visualized in the central nervous system in 10 obese subjects (seven woman; body mass index: mean ± SD: 39 ± 4.4 kg/m2) before bariatric surgery. Although we observed clear uptake in the pituitary area (mean SUVmax 4.3 ± 2.3), we found no significant uptake in other parts of the brain. We conclude that 68Ga-NODAGA-exendin-4 PET cannot be used to analyze GLP-1 receptors in the brain of obese subjects.
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Human neuroimaging studies have shown that, during cognitive processing, the brain undergoes dynamic transitions between multiple, frequency-tuned states of activity. Although different states may emerge from distinct sources of neural activity, it remains unclear whether single-area neuronal spiking can also drive multiple dynamic states. In mice, we ask whether frequency modulation of the entorhinal cortex activity causes dynamic states to emerge and whether these states respond to distinct stimulation frequencies. Using hidden Markov modeling, we perform unsupervised detection of transient states in mouse brain-wide fMRI fluctuations induced via optogenetic frequency modulation of excitatory neurons. We unveil the existence of multiple, frequency-dependent dynamic states, invisible through standard static fMRI analyses. These states are linked to different anatomical circuits and disrupted in a frequency-dependent fashion in a transgenic model of cognitive disease directly related to entorhinal cortex dysfunction. These findings provide cross-scale insight into basic neuronal mechanisms that may underpin flexibility in brain-wide dynamics.
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Conducta Animal , Cognición , Corteza Entorrinal/fisiología , Neuronas/fisiología , Ritmo Teta , Adaptación Psicológica , Animales , Mapeo Encefálico , Corteza Entorrinal/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Cadenas de Markov , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Neurológicos , Optogenética , Factores de TiempoRESUMEN
Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised.
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Experimentación Animal , Encéfalo , Neurociencias , AnimalesRESUMEN
BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT-/-) is one of the animal models used to investigate the underlying molecular mechanisms of depression in humans. They present decreased BDNF levels, and anxiety- and depression-like behavior. To investigate whether upregulating BDNF would ameliorate the phenotype of SERT-/- rats, we overexpressed BDNF locally into the ventral hippocampus and submitted the animals to behavioral testing. The results showed that BDNF overexpression in the vHIP of SERT-/- rats promoted higher sucrose preference and sucrose intake; on the first day of the sucrose consumption test it decreased immobility time in the forced swim test and increased the time spent in the center of a novel environment. Furthermore, BDNF overexpression altered social behavior in SERT-/- rats, which presented increased passive contact with test partner and decreased solitary behavior. Finally, it promoted decrease in plasma corticosterone levels 60 min after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT-/- rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential target to new therapeutic approaches to improve depressive symptoms.