A thalamic-primary auditory cortex circuit mediates resilience to stress.

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Control of mammalian locomotion by ventral spinocerebellar tract neurons.

Locomotion is a complex behavior required for animal survival. Vertebrate locomotion depends on spinal interneurons termed the central pattern generator (CPG), which generates activity responsible for the alternation of flexor and extensor muscles and the left and right side of the body. It is unknown whether multiple or a single neuronal type is responsible for the control of mammalian locomotion. Here, we show that ventral spinocerebellar tract neurons (VSCTs) drive generation and maintenance of locomotor behavior in neonatal and adult mice. Using mouse genetics, physiological, anatomical, and behavioral assays, we demonstrate that VSCTs exhibit rhythmogenic properties and neuronal circuit connectivity consistent with their essential role in the locomotor CPG. Importantly, optogenetic activation and chemogenetic silencing reveals that VSCTs are necessary and sufficient for locomotion. These findings identify VSCTs as critical components for mammalian locomotion and provide a paradigm shift in our understanding of neural control of complex behaviors.

A neural circuit state change underlying skilled movements.

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.

Functionally Distinct Neuronal Ensembles within the Memory Engram.

Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.

All-Optical Electrophysiology Reveals the Role of Lateral Inhibition in Sensory Processing in Cortical Layer 1.

Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs. VIDEO ABSTRACT.

A Hippocampus-Accumbens Tripartite Neuronal Motif Guides Appetitive Memory in Space.

Retrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior.

Nonoscillatory Phase Coding and Synchronization in the Bat Hippocampal Formation.

Hippocampal theta oscillations were proposed to be important for multiple functions, including memory and temporal coding of position. However, previous findings from bats have questioned these proposals by reporting absence of theta rhythmicity in bat hippocampal formation. Does this mean that temporal coding is unique to rodent hippocampus and does not generalize to other species? Here, we report that, surprisingly, bat hippocampal neurons do exhibit temporal coding similar to rodents, albeit without any continuous oscillations at the 1-20 Hz range. Bat neurons exhibited very strong locking to the non-rhythmic fluctuations of the field potential, such that neurons were synchronized together despite the absence of oscillations. Further, some neurons exhibited "phase precession" and phase coding of the bat's position-with spike phases shifting earlier as the animal moved through the place field. This demonstrates an unexpected type of neural coding in the mammalian brain-nonoscillatory phase coding-and highlights the importance of synchrony and temporal coding for hippocampal function across species.

Visual Projection Neurons Mediating Directed Courtship in Drosophila.

Many animals rely on vision to detect, locate, and track moving objects. In Drosophila courtship, males primarily use visual cues to orient toward and follow females and to select the ipsilateral wing for courtship song. Here, we show that the LC10 visual projection neurons convey essential visual information during courtship. Males with LC10 neurons silenced are unable to orient toward or maintain proximity to the female and do not predominantly use the ipsilateral wing when singing. LC10 neurons preferentially respond to small moving objects using an antagonistic motion-based center-surround mechanism. Unilateral activation of LC10 neurons recapitulates the orienting and ipsilateral wing extension normally elicited by females, and the potency with which LC10 induces wing extension is enhanced in a state of courtship arousal controlled by male-specific P1 neurons. These data suggest that LC10 is a major pathway relaying visual input to the courtship circuits in the male brain.

Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations.

Many human spinal cord injuries are anatomically incomplete but exhibit complete paralysis. It is unknown why spared axons fail to mediate functional recovery in these cases. To investigate this, we undertook a small-molecule screen in mice with staggered bilateral hemisections in which the lumbar spinal cord is deprived of all direct brain-derived innervation, but dormant relay circuits remain. We discovered that a KCC2 agonist restored stepping ability, which could be mimicked by selective expression of KCC2, or hyperpolarizing DREADDs, in the inhibitory interneurons between and around the staggered spinal lesions. Mechanistically, these treatments transformed this injury-induced dysfunctional spinal circuit to a functional state, facilitating the relay of brain-derived commands toward the lumbar spinal cord. Thus, our results identify spinal inhibitory interneurons as a roadblock limiting the integration of descending inputs into relay circuits after injury and suggest KCC2 agonists as promising treatments for promoting functional recovery after spinal cord injury.

Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making.

Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.

Spinal Interneurons: Diversity and Connectivity in Motor Control.

The spinal cord is home to the intrinsic networks for locomotion. An animal in which the spinal cord has been fully severed from the brain can still produce rhythmic, patterned locomotor movements as long as some excitatory drive is provided, such as physical, pharmacological, or electrical stimuli. Yet it remains a challenge to define the underlying circuitry that produces these movements because the spinal cord contains a wide variety of neuron classes whose patterns of interconnectivity are still poorly understood. Computational models of locomotion accordingly rely on untested assumptions about spinal neuron network element identity and connectivity. In this review, we consider the classes of spinal neurons, their interconnectivity, and the significance of their circuit connections along the long axis of the spinal cord. We suggest several lines of analysis to move toward a definitive understanding of the spinal network.

Neural Circuit to Integrate Opposing Motions in the Visual Field.

When navigating in their environment, animals use visual motion cues as feedback signals that are elicited by their own motion. Such signals are provided by wide-field neurons sampling motion directions at multiple image points as the animal maneuvers. Each one of these neurons responds selectively to a specific optic flow-field representing the spatial distribution of motion vectors on the retina. Here, we describe the discovery of a group of local, inhibitory interneurons in the fruit fly Drosophila key for filtering these cues. Using anatomy, molecular characterization, activity manipulation, and physiological recordings, we demonstrate that these interneurons convey direction-selective inhibition to wide-field neurons with opposite preferred direction and provide evidence for how their connectivity enables the computation required for integrating opposing motions. Our results indicate that, rather than sharpening directional selectivity per se, these circuit elements reduce noise by eliminating non-specific responses to complex visual information.

Protracted neuronal recruitment in the temporal lobes of young children.

The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs1-4. The human EC continues to develop during childhood5, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+RELN+ cells6,7. Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood.

Neurons and behavior: ex uno, plures.

Li et al. demonstrate that a single interneuron can regulate analog- and digital-like behaviors guided by two different postsynaptic neurons. Releasing a single neurotransmitter onto downstream neurons that express receptors with distinct biophysical properties enables a small set of neurons to direct a range of functional responses.

Encoding of both analog- and digital-like behavioral outputs by one C. elegans interneuron.

Model organisms usually possess a small nervous system but nevertheless execute a large array of complex behaviors, suggesting that some neurons are likely multifunctional and may encode multiple behavioral outputs. Here, we show that the C. elegans interneuron AIY regulates two distinct behavioral outputs: locomotion speed and direction-switch by recruiting two different circuits. The "speed" circuit is excitatory with a wide dynamic range, which is well suited to encode speed, an analog-like output. The "direction-switch" circuit is inhibitory with a narrow dynamic range, which is ideal for encoding direction-switch, a digital-like output. Both circuits employ the neurotransmitter ACh but utilize distinct postsynaptic ACh receptors, whose distinct biophysical properties contribute to the distinct dynamic ranges of the two circuits. This mechanism enables graded C. elegans synapses to encode both analog- and digital-like outputs. Our studies illustrate how an interneuron in a simple organism encodes multiple behavioral outputs at the circuit, synaptic, and molecular levels.

Neurogenesis in the striatum of the adult human brain.

In most mammals, neurons are added throughout life in the hippocampus and olfactory bulb. One area where neuroblasts that give rise to adult-born neurons are generated is the lateral ventricle wall of the brain. We show, using histological and carbon-14 dating approaches, that in adult humans new neurons integrate in the striatum, which is adjacent to this neurogenic niche. The neuronal turnover in the striatum appears restricted to interneurons, and postnatally generated striatal neurons are preferentially depleted in patients with Huntington's disease. Our findings demonstrate a unique pattern of neurogenesis in the adult human brain.

Interneuron Types as Attractors and Controllers.

Cortical interneurons display striking differences in shape, physiology, and other attributes, challenging us to appropriately classify them. We previously suggested that interneuron types should be defined by their role in cortical processing. Here, we revisit the question of how to codify their diversity based upon their division of labor and function as controllers of cortical information flow. We suggest that developmental trajectories provide a guide for appreciating interneuron diversity and argue that subtype identity is generated using a configurational (rather than combinatorial) code of transcription factors that produce attractor states in the underlying gene regulatory network. We present our updated three-stage model for interneuron specification: an initial cardinal step, allocating interneurons into a few major classes, followed by definitive refinement, creating subclasses upon settling within the cortex, and lastly, state determination, reflecting the incorporation of interneurons into functional circuit ensembles. We close by discussing findings indicating that major interneuron classes are both evolutionarily ancient and conserved. We propose that the complexity of cortical circuits is generated by phylogenetically old interneuron types, complemented by an evolutionary increase in principal neuron diversity. This suggests that a natural neurobiological definition of interneuron types might be derived from a match between their developmental origin and computational function.

The plasticitome of cortical interneurons.

Hebb postulated that, to store information in the brain, assemblies of excitatory neurons coding for a percept are bound together via associative long-term synaptic plasticity. In this view, it is unclear what role, if any, is carried out by inhibitory interneurons. Indeed, some have argued that inhibitory interneurons are not plastic. Yet numerous recent studies have demonstrated that, similar to excitatory neurons, inhibitory interneurons also undergo long-term plasticity. Here, we discuss the many diverse forms of long-term plasticity that are found at inputs to and outputs from several types of cortical inhibitory interneuron, including their plasticity of intrinsic excitability and their homeostatic plasticity. We explain key plasticity terminology, highlight key interneuron plasticity mechanisms, extract overarching principles and point out implications for healthy brain functionality as well as for neuropathology. We introduce the concept of the plasticitome - the synaptic plasticity counterpart to the genome or the connectome - as well as nomenclature and definitions for dealing with this rich diversity of plasticity. We argue that the great diversity of interneuron plasticity rules is best understood at the circuit level, for example as a way of elucidating how the credit-assignment problem is solved in deep biological neural networks.

System-wide rewiring underlies behavioral differences in predatory and bacterial-feeding nematodes.

The relationship between neural circuit function and patterns of synaptic connectivity is poorly understood, in part due to a lack of comparative data for larger complete systems. We compare system-wide maps of synaptic connectivity generated from serial transmission electron microscopy for the pharyngeal nervous systems of two nematodes with divergent feeding behavior: the microbivore Caenorhabditis elegans and the predatory nematode Pristionchus pacificus. We uncover a massive rewiring in a complex system of identified neurons, all of which are homologous based on neurite anatomy and cell body position. Comparative graph theoretical analysis reveals a striking pattern of neuronal wiring with increased connectional complexity in the anterior pharynx correlating with tooth-like denticles, a morphological feature in the mouth of P. pacificus. We apply focused centrality methods to identify neurons I1 and I2 as candidates for regulating predatory feeding and predict substantial divergence in the function of pharyngeal glands.