RESUMO
Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We have identified three cell types that regulate aggression in Drosophila: one type is sexually shared, and the other two are sex specific. Shared common aggression-promoting (CAP) neurons mediate aggressive approach in both sexes, whereas functionally downstream dimorphic but homologous cell types, called male-specific aggression-promoting (MAP) neurons in males and fpC1 in females, control dimorphic attack. These symmetric circuits underlie the divergence of male and female aggressive behaviors, from their monomorphic appetitive/motivational to their dimorphic consummatory phases. The strength of the monomorphic â dimorphic functional connection is increased by social isolation in both sexes, suggesting that it may be a locus for isolation-dependent enhancement of aggression. Together, these findings reveal a circuit logic for the neural control of behaviors that include both sexually monomorphic and dimorphic actions, which may generalize to other organisms.
Assuntos
Agressão/fisiologia , Drosophila melanogaster/fisiologia , Lógica , Caracteres Sexuais , Comportamento Sexual Animal/fisiologia , Animais , Feminino , Masculino , Rede Nervosa/fisiologia , Neurônios/fisiologia , Isolamento Social , Taquicininas/metabolismoRESUMO
Neural activity underlying short-term memory is maintained by interconnected networks of brain regions. It remains unknown how brain regions interact to maintain persistent activity while exhibiting robustness to corrupt information in parts of the network. We simultaneously measured activity in large neuronal populations across mouse frontal hemispheres to probe interactions between brain regions. Activity across hemispheres was coordinated to maintain coherent short-term memory. Across mice, we uncovered individual variability in the organization of frontal cortical networks. A modular organization was required for the robustness of persistent activity to perturbations: each hemisphere retained persistent activity during perturbations of the other hemisphere, thus preventing local perturbations from spreading. A dynamic gating mechanism allowed hemispheres to coordinate coherent information while gating out corrupt information. Our results show that robust short-term memory is mediated by redundant modular representations across brain regions. Redundant modular representations naturally emerge in neural network models that learned robust dynamics.
Assuntos
Lobo Frontal/fisiologia , Rede Nervosa/fisiologia , Envelhecimento/fisiologia , Animais , Comportamento Animal , Cérebro/fisiologia , Comportamento de Escolha , Feminino , Luz , Masculino , Camundongos , Modelos Neurológicos , Córtex Motor/fisiologia , Neurônios/fisiologiaRESUMO
Jellyfish are radially symmetric organisms without a brain that arose more than 500 million years ago. They achieve organismal behaviors through coordinated interactions between autonomously functioning body parts. Jellyfish neurons have been studied electrophysiologically, but not at the systems level. We introduce Clytia hemisphaerica as a transparent, genetically tractable jellyfish model for systems and evolutionary neuroscience. We generate stable F1 transgenic lines for cell-type-specific conditional ablation and whole-organism GCaMP imaging. Using these tools and computational analyses, we find that an apparently diffuse network of RFamide-expressing umbrellar neurons is functionally subdivided into a series of spatially localized subassemblies whose synchronous activation controls directional food transfer from the tentacles to the mouth. These data reveal an unanticipated degree of structured neural organization in this species. Clytia affords a platform for systems-level studies of neural function, behavior, and evolution within a clade of marine organisms with growing ecological and economic importance.
Assuntos
Evolução Biológica , Hidrozoários/genética , Modelos Animais , Neurociências , Animais , Animais Geneticamente Modificados , Comportamento Animal , Comportamento Alimentar , Marcação de Genes , Hidrozoários/fisiologia , Modelos Biológicos , Rede Nervosa/fisiologia , Neurônios/metabolismo , Neuropeptídeos/metabolismoRESUMO
In motor neuroscience, state changes are hypothesized to time-lock neural assemblies coordinating complex movements, but evidence for this remains slender. We tested whether a discrete change from more autonomous to coherent spiking underlies skilled movement by imaging cerebellar Purkinje neuron complex spikes in mice making targeted forelimb-reaches. As mice learned the task, millimeter-scale spatiotemporally coherent spiking emerged ipsilateral to the reaching forelimb, and consistent neural synchronization became predictive of kinematic stereotypy. Before reach onset, spiking switched from more disordered to internally time-locked concerted spiking and silence. Optogenetic manipulations of cerebellar feedback to the inferior olive bi-directionally modulated neural synchronization and reaching direction. A simple model explained the reorganization of spiking during reaching as reflecting a discrete bifurcation in olivary network dynamics. These findings argue that to prepare learned movements, olivo-cerebellar circuits enter a self-regulated, synchronized state promoting motor coordination. State changes facilitating behavioral transitions may generalize across neural systems.
Assuntos
Movimento/fisiologia , Rede Nervosa/fisiologia , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Cerebelo/fisiologia , Sincronização Cortical , Membro Anterior/fisiologia , Interneurônios/fisiologia , Aprendizagem , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Atividade Motora/fisiologia , Núcleo Olivar/fisiologia , Optogenética , Células de Purkinje/fisiologia , Comportamento Estereotipado , Análise e Desempenho de TarefasRESUMO
Comprehensively resolving neuronal identities in whole-brain images is a major challenge. We achieve this in C. elegans by engineering a multicolor transgene called NeuroPAL (a neuronal polychromatic atlas of landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that resolves all neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. We showcase three applications that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding for these stimuli.
Assuntos
Atlas como Assunto , Mapeamento Encefálico , Encéfalo/fisiologia , Caenorhabditis elegans/fisiologia , Neurônios/fisiologia , Software , Algoritmos , Pontos de Referência Anatômicos , Animais , Corpo Celular/fisiologia , Linhagem da Célula , Drosophila/fisiologia , Mutação/genética , Rede Nervosa/fisiologia , Fenótipo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Neurotransmissores/metabolismo , Olfato/fisiologia , Paladar/fisiologia , Fatores de Transcrição/metabolismo , TransgenesRESUMO
Large scientific projects in genomics and astronomy are influential not because they answer any single question but because they enable investigation of continuously arising new questions from the same data-rich sources. Advances in automated mapping of the brain's synaptic connections (connectomics) suggest that the complicated circuits underlying brain function are ripe for analysis. We discuss benefits of mapping a mouse brain at the level of synapses.
Assuntos
Encéfalo/fisiologia , Conectoma/métodos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , CamundongosRESUMO
Sequential activation of neurons has been observed during various behavioral and cognitive processes, but the underlying circuit mechanisms remain poorly understood. Here, we investigate premotor sequences in HVC (proper name) of the adult zebra finch forebrain that are central to the performance of the temporally precise courtship song. We use high-density silicon probes to measure song-related population activity, and we compare these observations with predictions from a range of network models. Our results support a circuit architecture in which heterogeneous delays between sequentially active neurons shape the spatiotemporal patterns of HVC premotor neuron activity. We gauge the impact of several delay sources, and we find the primary contributor to be slow conduction through axonal collaterals within HVC, which typically adds between 1 and 7.5 ms for each link within the sequence. Thus, local axonal "delay lines" can play an important role in determining the dynamical repertoire of neural circuits.
Assuntos
Tentilhões/fisiologia , Prosencéfalo/fisiologia , Vocalização Animal/fisiologia , Comunicação Animal , Animais , Axônios , Masculino , Córtex Motor/fisiologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologiaRESUMO
Comprehensive analysis of neuronal networks requires brain-wide measurement of connectivity, activity, and gene expression. Although high-throughput methods are available for mapping brain-wide activity and transcriptomes, comparable methods for mapping region-to-region connectivity remain slow and expensive because they require averaging across hundreds of brains. Here we describe BRICseq (brain-wide individual animal connectome sequencing), which leverages DNA barcoding and sequencing to map connectivity from single individuals in a few weeks and at low cost. Applying BRICseq to the mouse neocortex, we find that region-to-region connectivity provides a simple bridge relating transcriptome to activity: the spatial expression patterns of a few genes predict region-to-region connectivity, and connectivity predicts activity correlations. We also exploited BRICseq to map the mutant BTBR mouse brain, which lacks a corpus callosum, and recapitulated its known connectopathies. BRICseq allows individual laboratories to compare how age, sex, environment, genetics, and species affect neuronal wiring and to integrate these with functional activity and gene expression.
Assuntos
Conectoma , Regulação da Expressão Gênica , Rede Nervosa/fisiologia , Neurônios/fisiologia , Análise de Sequência de DNA , Animais , Mapeamento Encefálico , Tomada de Decisões , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Reprodutibilidade dos Testes , Análise e Desempenho de TarefasRESUMO
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.
Assuntos
Comportamento Animal/fisiologia , Cognição/fisiologia , Tomada de Decisões/fisiologia , Hipocampo/fisiologia , Potenciais de Ação/fisiologia , Animais , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Ratos , Ratos Long-Evans , Ritmo Teta/fisiologiaRESUMO
Developing neurons connect in specific and stereotyped ways to form the complex circuits that underlie brain function. By comparison to earlier steps in neural development, progress has been slow in identifying the cell surface recognition molecules that mediate these synaptic choices, but new high-throughput imaging, genetic, and molecular methods are accelerating progress. Over the past decade, numerous large and small gene families have been implicated in target recognition, including members of the immunoglobulin, cadherin, and leucine-rich repeat superfamilies. We review these advances and propose ways in which combinatorial use of multifunctional recognition molecules enables the complex neuron-neuron interactions that underlie synaptic specificity.
Assuntos
Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Sinapses/metabolismo , Animais , Caderinas/genética , Comunicação Celular , Membrana Celular/metabolismo , Humanos , Neurogênese , Neurônios/metabolismo , Neurônios/fisiologia , Sinapses/fisiologiaRESUMO
Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.
Assuntos
Tomada de Decisões/fisiologia , Rede Nervosa/fisiologia , Pensamento/fisiologia , Animais , Encéfalo/fisiologia , Feminino , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Neurônios/metabolismo , Neurônios/fisiologia , Estudos Prospectivos , Adulto JovemRESUMO
Exploration of novel environments ensures survival and evolutionary fitness. It is expressed through exploratory bouts and arrests that change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase in momentary arrests in locations where animals arrested previously. Calcium imaging in freely exploring mice revealed a genetically and projection-defined neuronal ensemble in the basolateral amygdala that is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests during exploration. Projection-specific imaging and optogenetic experiments revealed that these arrests are effected by basolateral amygdala neurons projecting to the central amygdala, uncovering an amygdala circuit that mediates momentary arrests in familiar places but not avoidance or anxiety/fear-like behaviors.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Núcleo Central da Amígdala/fisiologia , Comportamento Exploratório/fisiologia , Rede Nervosa/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/diagnóstico por imagem , Comportamento Animal/fisiologia , Núcleo Central da Amígdala/diagnóstico por imagem , Feminino , Locomoção , Aprendizado de Máquina , Masculino , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Imagem ÓpticaRESUMO
Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids. Using rabies tracing, calcium imaging, and patch-clamp recordings, we show that corticofugal neurons project and connect with spinal spheroids, while spinal-derived motor neurons connect with muscle. Glutamate uncaging or optogenetic stimulation of cortical spheroids triggers robust contraction of 3D muscle, and assembloids are morphologically and functionally intact for up to 10 weeks post-fusion. Together, this system highlights the remarkable self-assembly capacity of 3D cultures to form functional circuits that could be used to understand development and disease.
Assuntos
Córtex Cerebral/fisiologia , Córtex Motor/fisiologia , Organoides/fisiologia , Animais , Cálcio/metabolismo , Diferenciação Celular , Células Cultivadas , Vértebras Cervicais , Regulação da Expressão Gênica , Glutamatos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Músculos/fisiologia , Mioblastos/metabolismo , Rede Nervosa/fisiologia , Optogenética , Organoides/ultraestrutura , Rombencéfalo/fisiologia , Esferoides Celulares/citologia , Medula Espinal/citologiaRESUMO
Hunger and thirst have distinct goals but control similar ingestive behaviors, and little is known about neural processes that are shared between these behavioral states. We identify glutamatergic neurons in the peri-locus coeruleus (periLCVGLUT2 neurons) as a polysynaptic convergence node from separate energy-sensitive and hydration-sensitive cell populations. We develop methods for stable hindbrain calcium imaging in free-moving mice, which show that periLCVGLUT2 neurons are tuned to ingestive behaviors and respond similarly to food or water consumption. PeriLCVGLUT2 neurons are scalably inhibited by palatability and homeostatic need during consumption. Inhibition of periLCVGLUT2 neurons is rewarding and increases consumption by enhancing palatability and prolonging ingestion duration. These properties comprise a double-negative feedback relationship that sustains food or water consumption without affecting food- or water-seeking. PeriLCVGLUT2 neurons are a hub between hunger and thirst that specifically controls motivation for food and water ingestion, which is a factor that contributes to hedonic overeating and obesity.
Assuntos
Regulação do Apetite/fisiologia , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/fisiologia , Locus Cerúleo/citologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Rombencéfalo/fisiologia , Análise de Célula Única/métodos , Animais , Apetite/fisiologia , Escala de Avaliação Comportamental , Retroalimentação , Comportamento Alimentar/fisiologia , Feminino , Glutamina/metabolismo , Glutamina/fisiologia , Homeostase/fisiologia , Fome/fisiologia , Masculino , Camundongos , Camundongos Knockout , Motivação/fisiologia , Neurônios/efeitos dos fármacos , Proteínas Recombinantes , Recompensa , Rombencéfalo/citologia , Rombencéfalo/diagnóstico por imagem , Paladar/fisiologia , Sede/fisiologiaRESUMO
What specific features should visual neurons encode, given the infinity of real-world images and the limited number of neurons available to represent them? We investigated neuronal selectivity in monkey inferotemporal cortex via the vast hypothesis space of a generative deep neural network, avoiding assumptions about features or semantic categories. A genetic algorithm searched this space for stimuli that maximized neuronal firing. This led to the evolution of rich synthetic images of objects with complex combinations of shapes, colors, and textures, sometimes resembling animals or familiar people, other times revealing novel patterns that did not map to any clear semantic category. These results expand our conception of the dictionary of features encoded in the cortex, and the approach can potentially reveal the internal representations of any system whose input can be captured by a generative model.
Assuntos
Rede Nervosa/fisiologia , Lobo Temporal/fisiologia , Percepção Visual/fisiologia , Algoritmos , Animais , Córtex Cerebral/fisiologia , Macaca mulatta/fisiologia , Masculino , Neurônios/metabolismo , Neurônios/fisiologiaRESUMO
Distributing learning across multiple layers has proven extremely powerful in artificial neural networks. However, little is known about how multi-layer learning is implemented in the brain. Here, we provide an account of learning across multiple processing layers in the electrosensory lobe (ELL) of mormyrid fish and report how it solves problems well known from machine learning. Because the ELL operates and learns continuously, it must reconcile learning and signaling functions without switching its mode of operation. We show that this is accomplished through a functional compartmentalization within intermediate layer neurons in which inputs driving learning differentially affect dendritic and axonal spikes. We also find that connectivity based on learning rather than sensory response selectivity assures that plasticity at synapses onto intermediate-layer neurons is matched to the requirements of output neurons. The mechanisms we uncover have relevance to learning in the cerebellum, hippocampus, and cerebral cortex, as well as in artificial systems.
Assuntos
Peixe Elétrico/fisiologia , Aprendizagem , Rede Nervosa/fisiologia , Potenciais de Ação/fisiologia , Estruturas Animais/citologia , Estruturas Animais/fisiologia , Animais , Axônios/metabolismo , Fenômenos Biofísicos , Peixe Elétrico/anatomia & histologia , Feminino , Masculino , Modelos Neurológicos , Plasticidade Neuronal , Comportamento Predatório , Sensação , Fatores de TempoRESUMO
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.
Assuntos
Tonsila do Cerebelo/fisiologia , Giro do Cíngulo/fisiologia , Neurônios/fisiologia , Adulto , Animais , Evolução Biológica , Criança , Pré-Escolar , Cognição/fisiologia , Emoções/fisiologia , Feminino , Humanos , Macaca , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Especificidade da EspécieRESUMO
Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with â¼3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.
Assuntos
Rede Nervosa/fisiologia , Comportamento Sexual Animal/fisiologia , Animais , Estrogênios/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônios Esteroides Gonadais/farmacologia , Hipotálamo Anterior/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ovário/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Receptores de Progesterona/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed â¼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.
Assuntos
Proteínas Aviárias , Galinhas/fisiologia , Evolução Molecular , Proteínas de Peixes , Proteínas de Homeodomínio , Rede Nervosa/fisiologia , Rajidae/fisiologia , Fatores de Transcrição , Caminhada/fisiologia , Peixe-Zebra/fisiologia , Nadadeiras de Animais/fisiologia , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Embrião de Galinha , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Músculo Esquelético/fisiologia , Natação/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
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.