Differential behavioral engagement of inhibitory interneuron subtypes in the zebra finch brain.

Inhibitory interneurons are highly heterogeneous circuit elements often characterized by cell biological properties, but how these factors relate to specific roles underlying complex behavior remains poorly understood. Using chronic silicon probe recordings, we demonstrate that distinct interneuron groups perform different inhibitory roles within HVC, a song production circuit in the zebra finch forebrain. To link these functional subtypes to molecular identity, we performed two-photon targeted electrophysiological recordings of HVC interneurons followed by post hoc immunohistochemistry of subtype-specific markers.

Pyramidal neurons proportionately alter the identity and survival of specific cortical interneuron subtypes.

The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes.

Pyramidal neurons proportionately alter the identity and survival of specific cortical interneuron subtypes.

The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood.

Interneuron Diversity: How Form Becomes Function.

A persistent question in neuroscience is how early neuronal subtype identity is established during the development of neuronal circuits. Despite significant progress in the transcriptomic characterization of cortical interneurons, the mechanisms that control the acquisition of such identities as well as how they relate to function are not clearly understood. Accumulating evidence indicates that interneuron identity is achieved through the interplay of intrinsic genetic and activity-dependent programs.

Neurogliaform Cells Exhibit Laminar-specific Responses in the Visual Cortex and Modulate Behavioral State-dependent Cortical Activity.

Neurogliaform cells are a distinct type of GABAergic cortical interneurons known for their 'volume transmission' output property. However, their activity and function within cortical circuits remain unclear. Here, we developed two genetic tools to target these neurons and examine their function in the primary visual cortex.

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.

Neurogliaform Cells Exhibit Laminar-specific Responses in the Visual Cortex and Modulate Behavioral State-dependent Cortical Activity.

Neurogliaform cells are a distinct type of GABAergic cortical interneurons known for their "volume transmission" output property. However, their activity and function within cortical circuits remain unclear. Here, we developed two genetic tools to target these neurons and examine their function in the primary visual cortex.

Disruption of Cholinergic Retinal Waves Alters Visual Cortex Development and Function.

Retinal waves represent an early form of patterned spontaneous neural activity in the visual system. These waves originate in the retina before eye-opening and propagate throughout the visual system, influencing the assembly and maturation of subcortical visual brain regions. However, because it is technically challenging to ablate retina-derived cortical waves without inducing compensatory activity, the role these waves play in the development of the visual cortex remains unclear.

Developmental trajectories of GABAergic cortical interneurons are sequentially modulated by dynamic expression levels.

GABAergic inhibitory interneurons, originating from the embryonic ventral forebrain territories, traverse a convoluted migratory path to reach the neocortex. These interneuron precursors undergo sequential phases of tangential and radial migration before settling into specific laminae during differentiation. Here, we show that the developmental trajectory of expression is dynamically controlled in these interneuron precursors at critical junctures of migration.

An Anatomical and Physiological Basis for Flexible Coincidence Detection in the Auditory System.

Animals navigate the auditory world by recognizing complex sounds, from the rustle of a predator to the call of a potential mate. This ability depends in part on the octopus cells of the auditory brainstem, which respond to multiple frequencies that change over time, as occurs in natural stimuli. Unlike the average neuron, which integrates inputs over time on the order of tens of milliseconds, octopus cells must detect momentary coincidence of excitatory inputs from the cochlea during an ongoing sound on both the millisecond and submillisecond time scale.

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development.

Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), μ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development.

Layer 1 neocortex: Gating and integrating multidimensional signals.

Layer 1 (L1) of the neocortex acts as a nexus for the collection and processing of widespread information. By integrating ascending inputs with extensive top-down activity, this layer likely provides critical information regulating how the perception of sensory inputs is reconciled with expectation. This is accomplished by sorting, directing, and integrating the complex network of excitatory inputs that converge onto L1.

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.

Cortical somatostatin interneuron subtypes form cell-type-specific circuits.

The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. Although there is evidence that this diversity is functionally relevant, the circuit implications of this diversity are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes and found that each subtype possesses a unique laminar organization and stereotyped axonal projection pattern.

Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing.

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons in mouse somatosensory cortex is activity dependent.

FACS-Based Neuronal Cell Type-Specific RNA Isolation and Alternative Splicing Analysis.

Alternative splicing of pre-mRNAs expands the coding abilities of genomes by generating distinct transcription variants from individual genes. It contributes to the marvelous complexity of the transcriptome in neurons. Given the differential expression of alternative splicing regulators and diversity in alternative splicing programs in neuronal subpopulations, it is urgent and necessary to develop methods to efficiently isolate diverse subgroups of neurons and analyze their transcriptomic diversity.

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.

Basic science under threat: Lessons from the Skirball Institute.

Support for basic science has been eclipsed by initiatives aimed at specific medical problems. The latest example is the dismantling of the Skirball Institute at NYU School of Medicine. Here, we reflect on the achievements and mission underlying the Skirball to gain insight into the dividends of maintaining a basic science vision within the academic enterprises.

Single-cell delineation of lineage and genetic identity in the mouse brain.

During neurogenesis, mitotic progenitor cells lining the ventricles of the embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia. The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progenitors to track clonal relationships and transcriptomic signatures during mouse forebrain development.

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.

Genetic and epigenetic coordination of cortical interneuron development.

One of the hallmarks of the cerebral cortex is the extreme diversity of interneurons. The two largest subtypes of cortical interneurons, parvalbumin- and somatostatin-positive cells, are morphologically and functionally distinct in adulthood but arise from common lineages within the medial ganglionic eminence. This makes them an attractive model for studying the generation of cell diversity.