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•Modafinil shapes the thalamo-cortical functional connectivity in a specific manner.•The medial pulvinar increased connectivity with Sensorimotor/Attention Networks.•The anterior + inferior pulvinar enhanced connectivity with the Attention Network.•Ventral complex increased connectivity with the Default Mode/FrontoParietal Networks.•Connectivity changes overlap with the expression of 5-HT, mGluR5 receptors, and NET. Modafinil promotes wakefulness and enhances cognitive function through mechanisms and neural effects that are still partially unknown. Several studies have shown that the compound alters the functional cortical architecture. In contrast, its influence on subcortical regions and thalamocortical connections, which are crucial for modulating neocortical connectivity, remains unexplored. The acute modulation of thalamo-cortical connectivity was assessed in two groups of participants who received either a single 100 mg dose of modafinil (N = 25) or a placebo (N = 25). Magnetic Resonance Imaging (MRI) was used to parcel the thalamus into its constituent nuclei, which served as seeds for voxel-wise resting state functional connectivity analyses. Additionally, maps of nuclei-specific functional reorganization were compared to those of receptor/transporter expression to assess their spatial overlaps. Modafinil, but not placebo, altered the connectivity of three thalamic nuclei. Specifically, the medial pulvinar nuclei showed increased connectivity with cortical regions of the Sensorimotor and Salience/Ventral Attention (SVAN) Networks. These functional changes spatially overlapped with the distribution of the norepinephrine transporter (NET). Additionally, the anterior and inferior pulvinar complex exhibited enhanced connectivity with the insular and supramarginal regions of the SVAN and superior frontal area of the Default Mode Network (DMN). However, unlike the medial pulvinar, these effects were not spatially linked to the expression of any specific receptor or transporter. Finally, the ventro-lateral anterior complex exhibited increased connectivity with the posterior region of the DMN and the Fronto-Parietal Control Network, along with decreased connectivity to the premotor cortex. The topography of these functional modifications mainly overlaps with the distribution of glutamatergic and serotonergic receptors. In summary, our findings highlight modafinil's influence on thalamocortical circuits, emphasizing the role of higher-order pulvinar nuclei and ventro-lateral anterior complex.

The complementary learning systems account of declarative memory suggests two distinct memory networks, a fast-mapping, episodic system involving the hippocampus, and a slower semantic memory system distributed across the neocortex in which new information is gradually integrated with existing representations. In this study, we investigated the extent to which these two networks are involved in the integration of novel words into the lexicon after extensive learning, and how the involvement of these networks changes after 24h. In particular, we explored whether having richer information at encoding influences the lexicalization trajectory. We trained participants with two sets of novel words, one where exposure was only to the words' phonological forms (the form-only condition), and one where pictures of unfamiliar objects were associated with the words' phonological forms (the picture-associated condition). A behavioral measure of lexical competition (indexing lexicalization) indicated stronger competition effects for the form-only words. Imaging (fMRI) results revealed greater involvement of phonological lexical processing areas immediately after training in the form-only condition, suggesting that tight connections were formed between novel words and existing lexical entries already at encoding. Retrieval of picture-associated novel words involved the episodic/hippocampal memory system more extensively. Although lexicalization was weaker in the picture-associated condition, overall memory strength was greater when tested after a 24hour delay, probably due to the availability of both episodic and lexical memory networks to aid retrieval. It appears that, during lexicalization of a novel word, the relative involvement of different memory networks differs according to the richness of the information about that word available at encoding. •Novel words are better remembered if associated with pictorial information.•Novel words with pictures involved the hippocampal memory system at retrieval.•Neocortical activation for novel words with pictures increased with consolidation.•Novel words without pictures showed increased lexical competition after 24h.•Novel words without pictures involved more phonological processing.

The active electrical properties of dendrites shape neuronal input and output and are fundamental to brain function. However, our knowledge of active dendrites has been almost entirely acquired from studies of rodents. In this work, we investigated the dendrites of layer 2 and 3 (L2/3) pyramidal neurons of the human cerebral cortex ex vivo. In these neurons, we discovered a class of calcium-mediated dendritic action potentials (dCaAPs) whose waveform and effects on neuronal output have not been previously described. In contrast to typical all-or-none action potentials, dCaAPs were graded; their amplitudes were maximal for threshold-level stimuli but dampened for stronger stimuli. These dCaAPs enabled the dendrites of individual human neocortical pyramidal neurons to classify linearly nonseparable inputs—a computation conventionally thought to require multilayered networks.

Harris and Shepherd review our knowledge of input and output patterns for different classes of cortical cells. They propose that cortex, like other parts of the body, has a serially homologous organization, featuring area- and species-specific variations on a basic theme, that allows different types of function to emerge. Similarities in neocortical circuit organization across areas and species suggest a common strategy to process diverse types of information, including sensation from diverse modalities, motor control and higher cognitive processes. Cortical neurons belong to a small number of main classes. The properties of these classes, including their local and long-range connectivity, developmental history, gene expression, intrinsic physiology and in vivo activity patterns, are remarkably similar across areas. Each class contains subclasses; for a rapidly growing number of these, conserved patterns of input and output connections are also becoming evident. The ensemble of circuit connections constitutes a basic circuit pattern that appears to be repeated across neocortical areas, with area- and species-specific modifications. Such 'serially homologous' organization may adapt individual neocortical regions to the type of information each must process.

How are behaviorally relevant representations of the outside world initiated and manifested in the mammalian brain? Marshel et al. combined a channelrhodopsin with an improved holographic stimulation technique to examine activity in the mouse visual cortex, including its deep layers. Optogenetic stimulation of neurons previously activated by natural visual stimuli recreated the original activity and behavior. Neuronal population activity typically propagated from cortical layer 2/3 to layer 5 rather than in the reverse direction. Stimulation of a larger number of cells was required to initiate activity in layer 2/3 than in layer 5. This indicates differences in ensemble coding between the two layers. Science , this issue p. eaaw5202 An optical neural interface reveals the dynamics of cortical network activity underlying mammalian behavior. Perceptual experiences may arise from neuronal activity patterns in mammalian neocortex. We probed mouse neocortex during visual discrimination using a red-shifted channelrhodopsin (ChRmine, discovered through structure-guided genome mining) alongside multiplexed multiphoton-holography (MultiSLM), achieving control of individually specified neurons spanning large cortical volumes with millisecond precision. Stimulating a critical number of stimulus-orientation-selective neurons drove widespread recruitment of functionally related neurons, a process enhanced by (but not requiring) orientation-discrimination task learning. Optogenetic targeting of orientation-selective ensembles elicited correct behavioral discrimination. Cortical layer–specific dynamics were apparent, as emergent neuronal activity asymmetrically propagated from layer 2/3 to layer 5, and smaller layer 5 ensembles were as effective as larger layer 2/3 ensembles in eliciting orientation discrimination behavior. Population dynamics emerging after optogenetic stimulation both correctly predicted behavior and resembled natural internal representations of visual stimuli at cellular resolution over volumes of cortex.

Hattori et al . review the recent advances in our understanding of the roles of inhibitory neuron subtypes in shaping the activity and plasticity states of neocortical circuits, how neuromodulators control inhibitory neuron subtypes, and the role of inhibitory neuron dysfunction in neurological disorders. Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

Myelin is a defining feature of the vertebrate nervous system. Variability in the thickness of the myelin envelope is a structural feature affecting the conduction of neuronal signals. Conversely, the distribution of myelinated tracts along the length of axons has been assumed to be uniform. Here, we traced high-throughput electron microscopy reconstructions of single axons of pyramidal neurons in the mouse neocortex and built high-resolution maps of myelination. We find that individual neurons have distinct longitudinal distribution of myelin. Neurons in the superficial layers displayed the most diversified profiles, including a new pattern where myelinated segments are interspersed with long, unmyelinated tracts. Our data indicate that the profile of longitudinal distribution of myelin is an integral feature of neuronal identity and may have evolved as a strategy to modulate long-distance communication in the neocortex.

Key Points The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation, forming distinct functional areas within the tangential expanse of the neocortex. This collection of specialized neurons is produced by various progenitors with distinct morphological and molecular properties and with distinct patterns of cell division. The lineages leading from progenitor cells to specific neuronal subtypes and the molecular mechanisms that determine the fixed order in which neuronal subtypes are generated remain largely unknown. Recent work suggests that some subtypes of neurons are produced by lineage-committed progenitors, although a number of models of lineage commitment can be entertained on the basis of current evidence. Area identity acquisition is initiated by diffusible factors released from the periphery of the neocortical domain and subsequent induction of graded expression of arealizing transcription factors in ventricular zone progenitors. These progenitor-based controls establish a coordinate system of positional information that anchors area identity to specific rostrocaudal and mediolateral positions, which must then be transmitted to their neuronal progeny to be interpreted by a second network of transcription factors that direct postmitotic acquisition of area identity. Projection neuron subtype identity is progressively established by extensive transcriptional cross-repression between genetic programmes driving the development of one subtype of projection neuron and those driving the development of alternative subtypes. These competing regulators sort newly postmitotic projection neurons into one of three broad subtype identities: corticothalamic, subcerebral and callosal. Postmitotic regulators, including Lmo4 (LIM domain only 4) and Bhlhb5 (basic helix–loop–helix domain-containing, class B5), transform continuous gradients of positional information inherited from progenitors into sharp areal boundaries, instruct the formation of sensory maps and direct projection neurons to acquire areally appropriate phenotypic characteristics. Over the course of evolution, a growing number of transcription factors were progressively recruited to control cortical development, gradually adding layers of neuronal diversity and areal specialization to a simpler ancestral framework. The emerging understanding of the expression and function of key molecular regulators is beginning to illuminate a molecular logic underlying subtype and area identity acquisition. We propose that the order- and dose-dependent nature of projection neuron identity specification can be formalized by analogy to first-order Boolean logic, with decision points represented by 'molecular logic gates'. Understanding how each of the many diverse subtypes of neurons that make up the cortex are specified during development presents a continuing challenge for developmental neurobiologists. Macklis and colleagues describe recent advances in our understanding of the specification of cortical projection neuron subtype and area identity. The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation. In recent years, several key controls over the specification and differentiation of neocortical projection neurons have been identified. This work provides substantial insight into the 'molecular logic' underlying cortical development and increasingly supports a model in which individual progenitor-stage and postmitotic regulators are embedded within highly interconnected networks that gate sequential developmental decisions. Here, we provide an integrative account of the molecular controls that direct the progressive development and delineation of subtype and area identity of neocortical projection neurons.

With advances in connectomics, transcriptome and neurophysiological technologies, the neuroscience of brain-wide neural circuits is poised to take off. A major challenge is to understand how a vast diversity of functions is subserved by parcellated areas of mammalian neocortex composed of repetitions of a canonical local circuit. Areas of the cerebral cortex differ from each other not only in their input–output patterns but also in their biological properties. Recent experimental and theoretical work has revealed that such variations are not random heterogeneities; rather, synaptic excitation and inhibition display systematic macroscopic gradients across the entire cortex, and they are abnormal in mental illness. Quantitative differences along these gradients can lead to qualitatively novel behaviours in non-linear neural dynamical systems, by virtue of a phenomenon mathematically described as bifurcation. The combination of macroscopic gradients and bifurcations, in tandem with biological evolution, development and plasticity, provides a generative mechanism for functional diversity among cortical areas, as a general principle of large-scale cortical organization.Certain biological properties vary across different areas of the cerebral cortex. In this Perspective, Xiao-Jing Wang proposes that macroscopic gradients in some properties align with functional hierarchy and can lead to qualitative differences in function.

Despite the importance of the brain's neocortex, we still do not completely understand the diversity and functional connections of its cell types. Jiang et al. recorded, labeled, and classified over 1200 interneurons and more than 400 pyramidal neurons in the mature mouse visual cortex. Fifteen major classes of interneurons fell into three types: some connect to all neurons, some connect to other interneurons, and some form synapses with pyramidal neurons. Science , this issue p. 10.1126/science.aac9462 The connections between more than 10,000 pairs of individually classified neurons in the visual cortex of adult mice are mapped. Since the work of Ramón y Cajal in the late 19th and early 20th centuries, neuroscientists have speculated that a complete understanding of neuronal cell types and their connections is key to explaining complex brain functions. However, a complete census of the constituent cell types and their wiring diagram in mature neocortex remains elusive. By combining octuple whole-cell recordings with an optimized avidin-biotin-peroxidase staining technique, we carried out a morphological and electrophysiological census of neuronal types in layers 1, 2/3, and 5 of mature neocortex and mapped the connectivity between more than 11,000 pairs of identified neurons. We categorized 15 types of interneurons, and each exhibited a characteristic pattern of connectivity with other interneuron types and pyramidal cells. The essential connectivity structure of the neocortical microcircuit could be captured by only a few connectivity motifs.