RESUMEN
The cerebral cortex is the brain's outermost layer. It is responsible for processing motor and sensory information that support high-level cognitive abilities and shape personality. Its development and functional organization strongly rely on cell communication that is established via an intricate system of diffusible signals and physical contacts during development. Interfering with this cellular crosstalk can cause neurodevelopmental disorders. Here, we review how crosstalk between migrating cells and their environment influences cerebral cortex development, ranging from neurogenesis to synaptogenesis and assembly of cortical circuits.
Asunto(s)
Corteza Cerebral , Neurogénesis , Comunicación Celular , CogniciónRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Anciano , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Cognición , Disfunción Cognitiva/metabolismo , Neuronas/metabolismoRESUMEN
Cognitive flexibility, the ability to alter strategy according to changing stimulus-response-reward relationships, is critical for updating learned behavior. Attentional set-shifting, a test of cognitive flexibility, depends on the activity of prefrontal cortex (PFC). It remains unclear, however, what role PFC neurons play to support set-shifting. Using optogenetics and two-photon calcium imaging, we demonstrate that medial PFC activity does not bias sensorimotor responses during set-shifting, but rather enables set-shifting by encoding trial feedback information, a role it has been known to play in other contexts. Unexpectedly, the functional properties of PFC cells did not vary with their efferent projection targets. Instead, representations of trial feedback formed a topological gradient, with cells more strongly selective for feedback information located further from the pial surface, where afferent input from the anterior cingulate cortex was denser. These findings identify a critical role for deep PFC projection neurons in enabling set-shifting through behavioral feedback monitoring.
Asunto(s)
Cognición/fisiología , Neurorretroalimentación , Neuronas/fisiología , Corteza Prefrontal/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Single-cell transcriptomics has been widely applied to classify neurons in the mammalian brain, while systems neuroscience has historically analyzed the encoding properties of cortical neurons without considering cell types. Here we examine how specific transcriptomic types of mouse prefrontal cortex (PFC) projection neurons relate to axonal projections and encoding properties across multiple cognitive tasks. We found that most types projected to multiple targets, and most targets received projections from multiple types, except PFCâPAG (periaqueductal gray). By comparing Ca2+ activity of the molecularly homogeneous PFCâPAG type against two heterogeneous classes in several two-alternative choice tasks in freely moving mice, we found that all task-related signals assayed were qualitatively present in all examined classes. However, PAG-projecting neurons most potently encoded choice in cued tasks, whereas contralateral PFC-projecting neurons most potently encoded reward context in an uncued task. Thus, task signals are organized redundantly, but with clear quantitative biases across cells of specific molecular-anatomical characteristics.
Asunto(s)
Cognición/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Análisis y Desempeño de Tareas , Animales , Calcio/metabolismo , Conducta de Elección , Señales (Psicología) , Imagenología Tridimensional , Integrasas/metabolismo , Ratones Endogámicos C57BL , Odorantes , Optogenética , Sustancia Gris Periacueductal/fisiología , Recompensa , Análisis de la Célula Individual , Transcriptoma/genéticaRESUMEN
Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.
Asunto(s)
Cognición/fisiología , Suturas Craneales/fisiopatología , Craneosinostosis/fisiopatología , Regeneración/fisiología , Cráneo/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Craneosinostosis/genética , Duramadre/patología , Duramadre/fisiopatología , Gelatina/farmacología , Perfilación de la Expresión Génica , Fuerza de la Mano , Presión Intracraneal/efectos de los fármacos , Presión Intracraneal/fisiología , Locomoción/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Metacrilatos/farmacología , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Regeneración/efectos de los fármacos , Cráneo/patología , Proteína 1 Relacionada con Twist/metabolismo , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The type I interferon (IFN) response is the body's typical immune defense against viruses. Previous studies linked high expression of genes encoding type I IFNs in the brain's choroid plexus to cognitive decline under virus-free conditions in aging and neurodegeneration. Multiple reports have documented persisting cognitive symptoms following recovery from COVID-19. Cumulative evidence shows that the choroid plexus is one of the brain regions most vulnerable to infection with the coronavirus SARS-CoV-2, and manifests increased expression of genes encoding type I IFNs even in the absence of viral traces within the brain. In this Perspective, we propose that the type I IFN defensive immune response to SARS-CoV-2 infection in the choroid plexus poses a risk to cognitive function if not resolved in a timely manner.
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COVID-19 , Interferón Tipo I , Humanos , COVID-19/metabolismo , Interferón Tipo I/metabolismo , SARS-CoV-2/fisiología , Plexo Coroideo/metabolismo , Cognición , Antivirales/metabolismo , Interferones/metabolismoRESUMEN
Cognitive faculties such as imagination, planning, and decision-making entail the ability to represent hypothetical experience. Crucially, animal behavior in natural settings implies that the brain can represent hypothetical future experience not only quickly but also constantly over time, as external events continually unfold. To determine how this is possible, we recorded neural activity in the hippocampus of rats navigating a maze with multiple spatial paths. We found neural activity encoding two possible future scenarios (two upcoming maze paths) in constant alternation at 8 Hz: one scenario per â¼125-ms cycle. Further, we found that the underlying dynamics of cycling (both inter- and intra-cycle dynamics) generalized across qualitatively different representational correlates (location and direction). Notably, cycling occurred across moving behaviors, including during running. These findings identify a general dynamic process capable of quickly and continually representing hypothetical experience, including that of multiple possible futures.
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Conducta Animal/fisiología , Cognición/fisiología , Toma de Decisiones/fisiología , Hipocampo/fisiología , Potenciales de Acción/fisiología , Animales , Locomoción/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Ratas , Ratas Long-Evans , Ritmo Teta/fisiologíaRESUMEN
Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (>10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.
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Cerebelo/fisiología , Toma de Decisiones/fisiología , Tiempo de Reacción/fisiología , Pez Cebra/fisiología , Animales , Conducta Animal/fisiología , Mapeo Encefálico/métodos , Cerebro/fisiología , Cognición/fisiología , Condicionamiento Operante/fisiología , Objetivos , Habénula/fisiología , Calor , Larva/fisiología , Actividad Motora/fisiología , Movimiento , Neuronas/fisiología , Desempeño Psicomotor/fisiología , Rombencéfalo/fisiologíaRESUMEN
Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.
Asunto(s)
Células T Invariantes Asociadas a Mucosa , Animales , Ratones , Encéfalo , Meninges , Cognición , Estrés OxidativoRESUMEN
We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.
Asunto(s)
Estimulación Acústica/métodos , Enfermedad de Alzheimer/terapia , Cognición/fisiología , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Percepción Auditiva/fisiología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ritmo Gamma/fisiología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Placa Amiloide/metabolismoRESUMEN
Many evolutionary years separate humans and macaques, and although the amygdala and cingulate cortex evolved to enable emotion and cognition in both, an evident functional gap exists. Although they were traditionally attributed to differential neuroanatomy, functional differences might also arise from coding mechanisms. Here we find that human neurons better utilize information capacity (efficient coding) than macaque neurons in both regions, and that cingulate neurons are more efficient than amygdala neurons in both species. In contrast, we find more overlap in the neural vocabulary and more synchronized activity (robustness coding) in monkeys in both regions and in the amygdala of both species. Our findings demonstrate a tradeoff between robustness and efficiency across species and regions. We suggest that this tradeoff can contribute to differential cognitive functions between species and underlie the complementary roles of the amygdala and the cingulate cortex. In turn, it can contribute to fragility underlying human psychopathologies.
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Amígdala del Cerebelo/fisiología , Giro del Cíngulo/fisiología , Neuronas/fisiología , Adulto , Animales , Evolución Biológica , Niño , Preescolar , Cognición/fisiología , Emociones/fisiología , Femenino , Humanos , Macaca , Macaca mulatta , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/metabolismo , Red Nerviosa/fisiología , Corteza Prefrontal/fisiología , Especificidad de la EspecieRESUMEN
Psychiatric genetic studies have drawn associations between human cognitive traits and noncoding genomic variants. However, the mechanistic effects of these variants are unclear. By weaving in strands of genomic data from developing human brains, de la Torre-Ubieta et al. tie disease-associated loci to functional enhancers, target genes, and putatively affected cell types.
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Cromatina , Estudio de Asociación del Genoma Completo , Cognición , Humanos , Neurogénesis , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
The activity patterns of grid cells form distinctively regular triangular lattices over the explored spatial environment and are largely invariant to visual stimuli, animal movement, and environment geometry. These neurons present numerous fascinating challenges to the curious (neuro)scientist: What are the circuit mechanisms responsible for creating spatially periodic activity patterns from the monotonic input-output responses of single neurons? How and why does the brain encode a local, nonperiodic variable-the allocentric position of the animal-with a periodic, nonlocal code? And, are grid cells truly specialized for spatial computations? Otherwise, what is their role in general cognition more broadly? We review efforts in uncovering the mechanisms and functional properties of grid cells, highlighting recent progress in the experimental validation of mechanistic grid cell models, and discuss the coding properties and functional advantages of the grid code as suggested by continuous attractor network models of grid cells.
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Cognición , Células de Red , Modelos Neurológicos , Animales , Cognición/fisiología , Células de Red/fisiología , Humanos , Percepción Espacial/fisiología , Red Nerviosa/fisiología , Encéfalo/fisiología , Neuronas/fisiologíaRESUMEN
The cerebral cortex performs computations via numerous six-layer modules. The operational dynamics of these modules were studied primarily in early sensory cortices using bottom-up computation for response selectivity as a model, which has been recently revolutionized by genetic approaches in mice. However, cognitive processes such as recall and imagery require top-down generative computation. The question of whether the layered module operates similarly in top-down generative processing as in bottom-up sensory processing has become testable by advances in the layer identification of recorded neurons in behaving monkeys. This review examines recent advances in laminar signaling in these two computations, using predictive coding computation as a common reference, and shows that each of these computations recruits distinct laminar circuits, particularly in layer 5, depending on the cognitive demands. These findings highlight many open questions, including how different interareal feedback pathways, originating from and terminating at different layers, convey distinct functional signals.
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Corteza Cerebral , Cognición , Animales , Cognición/fisiología , Corteza Cerebral/fisiología , Humanos , Neuronas/fisiología , Modelos Neurológicos , Vías Nerviosas/fisiología , Red Nerviosa/fisiología , Transducción de Señal/fisiologíaRESUMEN
The increasing burden in dementia-related disorders has necessitated improved understanding of cognitive decline. In a recent issue of Nature, Schroer et al. demonstrate that platelet factor 4 in young blood reduces age-related hippocampal dysfunction and improves cognition in aged mice.
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Encéfalo , Cognición , Animales , RatonesRESUMEN
The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (3D) epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal-activity-regulated genes, thus influencing their expression. It also alters A/B compartments, topologically associating domains, and frequently interacting regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with a SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence, and schizophrenia. Our data establish SATB2 as a cell-type-specific 3D genome modulator, which operates both independently and in cooperation with CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.
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Proteínas de Unión a la Región de Fijación a la Matriz , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neuronas/metabolismo , Factor de Unión a CCCTC/metabolismo , Cromatina/genética , Cromatina/metabolismo , Genoma , Cognición , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismoRESUMEN
Rapid advances in the neural control of social behavior highlight the role of interconnected nodes engaged in differential information processing to generate behavior. Many innate social behaviors are essential to reproductive fitness and therefore fundamentally different in males and females. Programming these differences occurs early in development in mammals, following gonadal differentiation and copious androgen production by the fetal testis during a critical period. Early-life programming of social behavior and its adult manifestation are separate but yoked processes, yet how they are linked is unknown. This review seeks to highlight that gap by identifying four core mechanisms (epigenetics, cell death, circuit formation, and adult hormonal modulation) that could connect developmental changes to the adult behaviors of mating and aggression. We further propose that a unique social behavior, adolescent play, bridges the preweaning to the postpubertal brain by engaging the same neural networks underpinning adult reproductive and aggressive behaviors.
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Agresión , Conducta Social , Masculino , Animales , Femenino , Encéfalo , Conducta Sexual Animal , Cognición , MamíferosRESUMEN
Primates have evolved diverse cognitive capabilities to navigate their complex social world. To understand how the brain implements critical social cognitive abilities, we describe functional specialization in the domains of face processing, social interaction understanding, and mental state attribution. Systems for face processing are specialized from the level of single cells to populations of neurons within brain regions to hierarchically organized networks that extract and represent abstract social information. Such functional specialization is not confined to the sensorimotor periphery but appears to be a pervasive theme of primate brain organization all the way to the apex regions of cortical hierarchies. Circuits processing social information are juxtaposed with parallel systems involved in processing nonsocial information, suggesting common computations applied to different domains. The emerging picture of the neural basis of social cognition is a set of distinct but interacting subnetworks involved in component processes such as face perception and social reasoning, traversing large parts of the primate brain.
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Encéfalo , Cognición Social , Animales , Encéfalo/fisiología , Primates/fisiología , Percepción Social , Cognición/fisiologíaRESUMEN
Examination of cognition has historically been approached from language and introspection. However, human language-dependent definitions ignore the evolutionary roots of brain mechanisms and constrain their study in experimental animals. We promote an alternative view, namely that cognition, including memory, can be explained by exaptation and expansion of the circuits and algorithms serving bodily functions. Regulation and protection of metabolic and energetic processes require time-evolving brain computations enabling the organism to prepare for altered future states. Exaptation of such circuits was likely exploited for exploration of the organism's niche. We illustrate that exploration gives rise to a cognitive map, and in turn, environment-disengaged computation allows for mental travel into the past (memory) and the future (planning). Such brain-body interactions not only occur during waking but also persist during sleep. These exaptation steps are illustrated by the dual, endocrine-homeostatic and memory, contributions of the hippocampal system, particularly during hippocampal sharp-wave ripples.
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Hipocampo , Sueño , Animales , Humanos , Hipocampo/fisiología , Sueño/fisiología , CogniciónRESUMEN
In mammals, the activity of neurons in the entorhinal-hippocampal network is modulated by the animal's position and its movement through space. At multiple stages of this distributed circuit, distinct populations of neurons can represent a rich repertoire of navigation-related variables like the animal's location, the speed and direction of its movements, or the presence of borders and objects. Working together, spatially tuned neurons give rise to an internal representation of space, a cognitive map that supports an animal's ability to navigate the world and to encode and consolidate memories from experience. The mechanisms by which, during development, the brain acquires the ability to create an internal representation of space are just beginning to be elucidated. In this review, we examine recent work that has begun to investigate the ontogeny of circuitry, firing patterns, and computations underpinning the representation of space in the mammalian brain.