Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development.

During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian "fire together, wire together" precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies in mice. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this process impacts the development of normal exploratory behaviors of adult mice.

Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development.

During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian "fire together, wire together" precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this developmental process impacts the development of normal exploratory behaviors of adult mice.

A versatile viral toolkit for functional discovery in the nervous system.

The ability to precisely control transgene expression is essential for basic research and clinical applications. Adeno-associated viruses (AAVs) are non-pathogenic and can be used to drive stable expression in virtually any tissue, cell type, or species, but their limited genomic payload results in a trade-off between the transgenes that can be incorporated and the complexity of the regulatory elements controlling their expression. Resolving these competing imperatives in complex experiments inevitably results in compromises. Here, we assemble an optimized viral toolkit (VTK) that addresses these limitations and allows for efficient combinatorial targeting of cell types. Moreover, their modular design explicitly enables further refinements. We achieve this in compact vectors by integrating structural improvements of AAV vectors with innovative molecular tools. We illustrate the potential of this approach through a systematic demonstration of their utility for targeting cell types and querying their biology using a wide array of genetically encoded tools.

The organization and development of cortical interneuron presynaptic circuits are area specific.

Parvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.

Bottom-up inputs are required for establishment of top-down connectivity onto cortical layer 1 neurogliaform cells.

Higher-order projections to sensory cortical areas converge on layer 1 (L1), the primary site for integration of top-down information via the apical dendrites of pyramidal neurons and L1 GABAergic interneurons. Here we investigated the contribution of early thalamic inputs onto L1 interneurons for establishment of top-down connectivity in the primary visual cortex. We find that bottom-up thalamic inputs predominate during L1 development and preferentially target neurogliaform cells. We show that these projections are critical for the subsequent strengthening of top-down inputs from the anterior cingulate cortex onto L1 neurogliaform cells. Sensory deprivation or selective removal of thalamic afferents blocked this phenomenon. Although early activation of the anterior cingulate cortex resulted in premature strengthening of these top-down afferents, this was dependent on thalamic inputs. Our results demonstrate that proper establishment of top-down connectivity in the visual cortex depends critically on bottom-up inputs from the thalamus during postnatal development.

A transient postnatal quiescent period precedes emergence of mature cortical dynamics.

Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synaptic and cellular activity patterns across development using high spatiotemporal resolution in vivo electrophysiology in immature mice. We reveal that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the second postnatal week of rodent development. The transition is characterized by relative neural quiescence, after which spatially distributed, temporally precise, and internally organized activity occurs. We demonstrate a similar developmental trajectory in humans, suggesting an evolutionarily conserved mechanism that could facilitate a transition in network operation. We hypothesize that this transient quiescent period is a requisite for the subsequent emergence of coordinated cortical networks.

It can take several months, or even years, for the brain of a young animal to develop and refine the complex neural networks which underpin cognitive abilities such as memory, planning, and decision making. While the properties that support these functions have been well-documented, less is known about how they emerge during development. Domínguez, Ma, Yu et al. therefore set out to determine when exactly these properties began to take shape in mice, using lightweight nets of electrodes to record brain activity in sleeping newborn pups. The nets were designed to avoid disturbing the animals or damaging their fragile brains. The recordings showed that patterns of brain activity similar to those seen in adults emerged during the first couple of weeks after birth. Just before, however, the brains of the pups went through a brief period of reduced activity: this lull seemed to mark a transition from an immature to a more mature mode of operation. After this pause, neurons in the mouse brains showed coordinated patterns of firing reminiscent of those seen in adults. By monitoring the brains of human babies using scalp sensors, Domínguez, Ma, Yu et al. showed that a similar transition also occurs in infants during their first few months of life, suggesting that brains may mature via a process retained across species. Overall, the relative lull in activity before transition may mark when neural networks gain mature properties; in the future, it could therefore potentially be used to diagnose and monitor individuals with delayed cognitive development.

Input-dependent regulation of excitability controls dendritic maturation in somatosensory thalamocortical neurons.

Input from the sensory organs is required to pattern neurons into topographical maps during development. Dendritic complexity critically determines this patterning process; yet, how signals from the periphery act to control dendritic maturation is unclear. Here, using genetic and surgical manipulations of sensory input in mouse somatosensory thalamocortical neurons, we show that membrane excitability is a critical component of dendritic development. Using a combination of genetic approaches, we find that ablation of N-methyl-D-aspartate (NMDA) receptors during postnatal development leads to epigenetic repression of Kv1.1-type potassium channels, increased excitability, and impaired dendritic maturation. Lesions to whisker input pathways had similar effects. Overexpression of Kv1.1 was sufficient to enable dendritic maturation in the absence of sensory input. Thus, Kv1.1 acts to tune neuronal excitability and maintain it within a physiological range, allowing dendritic maturation to proceed. Together, these results reveal an input-dependent control over neuronal excitability and dendritic complexity in the development and plasticity of sensory pathways.

A cross-modal genetic framework for the development and plasticity of sensory pathways.

Modality-specific sensory inputs from individual sense organs are processed in parallel in distinct areas of the neocortex. For each sensory modality, input follows a cortico-thalamo-cortical loop in which a 'first-order' exteroceptive thalamic nucleus sends peripheral input to the primary sensory cortex, which projects back to a 'higher order' thalamic nucleus that targets a secondary sensory cortex. This conserved circuit motif raises the possibility that shared genetic programs exist across sensory modalities. Here we report that, despite their association with distinct sensory modalities, first-order nuclei in mice are genetically homologous across somatosensory, visual, and auditory pathways, as are higher order nuclei. We further reveal peripheral input-dependent control over the transcriptional identity and connectivity of first-order nuclei by showing that input ablation leads to induction of higher-order-type transcriptional programs and rewiring of higher-order-directed descending cortical input to deprived first-order nuclei. These findings uncover an input-dependent genetic logic for the design and plasticity of sensory pathways, in which conserved developmental programs lead to conserved circuit motifs across sensory modalities.

Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons.

During development, thalamocortical (TC) input has a critical role in the spatial delineation and patterning of cortical areas, yet the underlying cellular and molecular mechanisms that drive cortical neuron differentiation are poorly understood. In the primary (S1) and secondary (S2) somatosensory cortex, layer 4 (L4) neurons receive mutually exclusive input originating from two thalamic nuclei: the ventrobasalis (VB), which conveys tactile input, and the posterior nucleus (Po), which conveys modulatory and nociceptive input. Recently, we have shown that L4 neuron identity is not fully committed postnatally, implying a capacity for TC input to influence differentiation during cortical circuit assembly. Here we investigate whether the cell-type-specific molecular and functional identity of L4 neurons is instructed by the origin of their TC input. Genetic ablation of the VB at birth resulted in an anatomical and functional rewiring of Po projections onto L4 neurons in S1. This induced acquisition of Po input led to a respecification of postsynaptic L4 neurons, which developed functional molecular features of Po-target neurons while repressing VB-target traits. Respecified L4 neurons were able to respond both to touch and to noxious stimuli, in sharp contrast to the normal segregation of these sensory modalities in distinct cortical circuits. These findings reveal a behaviourally relevant TC-input-type-specific control over the molecular and functional differentiation of postsynaptic L4 neurons and cognate intracortical circuits, which instructs the development of modality-specific neuronal and circuit properties during corticogenesis.

Retinal input directs the recruitment of inhibitory interneurons into thalamic visual circuits.

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Nurturing the cortex's thalamic nature.

PURPOSE OF REVIEW: Neocortical and thalamic interactions are necessary for the execution of complex sensory-motor tasks and associated cognitive processes. Investigation of thalamocortical circuit development is therefore critical to understand developmental disorders involving abnormal cortical function. Here, we review recent advances in our understanding of thalamus-dependent cortical patterning and cortical neuron differentiation. RECENT FINDINGS: Although the principles of cortical map patterning are increasingly understood, the extent to which thalamocortical inputs contribute to cortical neuron differentiation is still unclear. The recent development of genetic models allowing cell-type-specific dissection of cortical input pathways has shed light on some of the input-dependent and activity-dependent processes occurring during cortical development, which are discussed here. SUMMARY: These recent studies have revealed interwoven links between thalamic and cortical neurons, in which cell intrinsic differentiation programs are tightly regulated by synaptic input during a prolonged period of development. Challenges in the years to come will be to identify the mechanisms underlying the reciprocal interactions between intrinsic and extrinsic differentiation programs, and their contribution to neurodevelopmental disorders and neuropsychiatric disorders at large.

Patterning of pre-thalamic somatosensory pathways.

The topographical mapping of input is a fundamental organizing principle of sensory pathways. In the somatosensory system, a precise topographical representation of the face is first generated in the brainstem and then faithfully replicated in the thalamus and cortex. Although our knowledge of the distinct polysynaptic pathways that link cutaneous mechanoreceptors of the face with neocortical neurons has recently expanded, the molecular mechanisms controlling their neuron-type-specific assembly during development remain poorly understood. The increasing availability of genetic tools that enable manipulation of these developing circuits with cellular resolution now opens new perspectives in our understanding of the molecular mechanisms through which input from the periphery is converted into patterned central pathways.