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Using a combination of optogenetics, single-cell molecular profiling and paired electrophysiological recordings in the mouse visual cortex, Pfeffer and colleagues derived the connectivity matrix of three major classes of interneurons with their post-synaptic GABAergic targets. This study provides a comprehensive overview of the wiring rules of the inhibition of inhibition in the cortex. Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we describe a simple and complementary interaction scheme between three large, molecularly distinct interneuron populations in mouse visual cortex: parvalbumin-expressing interneurons strongly inhibit one another but provide little inhibition to other populations. In contrast, somatostatin-expressing interneurons avoid inhibiting one another yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide–expressing interneurons preferentially inhibit somatostatin-expressing interneurons. This scheme occurs in supragranular and infragranular layers, suggesting that inhibitory networks operate similarly at the input and output of the visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons.

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells. Sleep contributes to the strengthening of memories. During non-dreaming sleep, neurons in regions of the brain that form and store memories – such as the hippocampus and prefrontal cortex – fire in rhythmic waves. The neurons in the hippocampus tend to fire during a wave that repeats up to 250 times per second, called sharp-wave ripples. Meanwhile, in the prefrontal cortex, the neurons tend to fire during a lower frequency wave that repeats 12 to 15 times per second, called spindles. During sleep and quiet wakefulness, hippocampal ripples often synchronize with prefrontal spindles; that is, both waves tend to occur at approximately the same time. Many neuroscientists think this allows the brain regions to better communicate with one another, which in turn should help the brain to strengthen memories. Consistent with this possibility, rodents that learn a new task show more synchrony between ripples and spindles afterwards. But no one had actually tested whether this increase in ripple-spindle synchrony does strengthen the rodent’s memory of the task. It was also unclear how the brain achieves such an increase. Xia et al. suspected that this process involved a group of inhibitory brain cells called parvalbumin-positive interneurons. These cells act like timekeepers, and help to synchronize the firing of groups of neurons. Xia et al. now show that training mice to associate an environment with a mild electric shock made it more likely that the animals would show ripple-spindle synchrony. Yet, inhibiting the activity of parvalbumin-positive interneurons in either the hippocampus or prefrontal cortex blocked this effect. It also prevented sleep from strengthening the animals’ memory of the link between the environment and the shock. Patients with Alzheimer’s disease have fewer parvalbumin-positive interneurons. By showing that these neurons help strengthen new memories, these findings may explain why losing them can impair memory. Restoring or replacing interneuron activity could be a promising therapeutic avenue to explore.

In the hippocampus, each memory trace is encoded by a specific subset of pyramidal cells. The other pyramidal cells must be actively excluded from the memory encoding process by inhibition, which is done by selective dendrite-targeting interneurons. Szőnyi et al. found that γ-aminobutyric acid–releasing (GABAergic) cells located in a small region in the brain stem called the nucleus incertus project to the hippocampus. The nucleus incertus again is innervated by several regions that respond to salient stimuli. Its GABAergic cells preferentially inhibit the dendrite-targeting interneurons in the hippocampus. The nucleus incertus is thus a central mediator between brain regions that are highly responsive to salient stimuli and the hippocampal circuitry involved in memory formation. Science , this issue p. eaaw0445 A brainstem regulatory mechanism for the selection of hippocampal neuronal assemblies during contextual learning is described. Hippocampal pyramidal cells encode memory engrams, which guide adaptive behavior. Selection of engram-forming cells is regulated by somatostatin-positive dendrite-targeting interneurons, which inhibit pyramidal cells that are not required for memory formation. Here, we found that γ-aminobutyric acid (GABA)–releasing neurons of the mouse nucleus incertus (NI) selectively inhibit somatostatin-positive interneurons in the hippocampus, both monosynaptically and indirectly through the inhibition of their subcortical excitatory inputs. We demonstrated that NI GABAergic neurons receive monosynaptic inputs from brain areas processing important environmental information, and their hippocampal projections are strongly activated by salient environmental inputs in vivo. Optogenetic manipulations of NI GABAergic neurons can shift hippocampal network state and bidirectionally modify the strength of contextual fear memory formation. Our results indicate that brainstem NI GABAergic cells are essential for controlling contextual memories.

The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level.

Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.

Bidirectional manipulations – activation and inactivation – are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is the notion that tonic activation and inactivation will both produce valid, internally consistent insights into interneurons’ computational roles. Here, using single-unit recordings in auditory cortex of awake mice, we show that this may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed that Sst+ inactivation increased response gain, while Pvalb+ inactivation weakened tuning and decreased information transfer, implying that these neurons support delineable computational functions. But activating Sst+ and Pvalb+ interneurons revealed no such differences. We used a simple network model to understand this asymmetry, and showed how relatively small changes in key parameters, such as spontaneous activity or strength of the light manipulation, determined whether activation and inactivation would produce consistent or paradoxical conclusions regarding interneurons’ computational functions. The brain processes information through the activity of many different types of neurons. A common assumption is that we can work out the role of each type of neuron by increasing or decreasing its activity experimentally and observing the consequences. Imagine, for example, that increasing the activity of a group of neurons boosts the formation of memories, whereas decreasing their activity has the opposite effect. Can we conclude that the natural role of those neurons is to support memory formation? This question has become increasingly pertinent in recent years, as advances in molecular genetic techniques such as optogenetics have made it easier to experimentally manipulate the activity of neurons. However, the ease with which these experiments can be done masks how difficult it can be to interpret the results. To test the assumption that dialing a neuron’s activity up or down provides a straightforward readout of its role in the brain, Phillips and Hasenstaub used optogenetics to inactivate two types of neurons in an area of the mouse brain responsible for processing sound. Inactivating each cell type produced different outcomes. The standard way of interpreting these results is to conclude that the neurons must therefore have different, separable roles. However, using optogenetics to increase the activity of the neurons revealed no such differences in the neurons’ roles. Using a computer model, Phillips and Hasenstaub showed that relatively small changes in factors such as the spontaneous activity of the neurons can affect the outcome of the experiments. Under certain circumstances, the two types of neurons respond in the same way to activation and inactivation; under other circumstances, they respond differently. The results presented by Phillips and Hasenstaub remind us that the conclusions we draw about a neuron’s role can be sensitive to how the cell was manipulated. Future studies should address how other aspects of experimental manipulations, such as their timing or pattern, affect the apparent behavior of neurons.

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance in human circuit function. In this study, we focus on neurogliaform cells, that possess specialized physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms underlying human cognitive processing and behavior.

Purkinje cells (PCs) in Crus 1 represent whisker movement via linear changes in firing rate, but the circuit mechanisms underlying this coding scheme are unknown. Here we examine the role of upstream inputs to PCs—excitatory granule cells (GCs) and inhibitory molecular layer interneurons—in processing of whisking signals. Patch clamp recordings in GCs reveal that movement is accompanied by changes in mossy fibre input rate that drive membrane potential depolarisation and high-frequency bursting activity at preferred whisker angles. Although individual GCs are narrowly tuned, GC populations provide linear excitatory drive across a wide range of movement. Molecular layer interneurons exhibit bidirectional firing rate changes during whisking, similar to PCs. Together, GC populations provide downstream PCs with linear representations of volitional movement, while inhibitory networks invert these signals. The exquisite sensitivity of neurons at each processing stage enables faithful propagation of kinematic representations through the cerebellum. Cerebellar Purkinje cells (PCs) linearly encode whisker position but the precise circuit mechanisms that generate these signals are not well understood. Here the authors use patch clamp recordings to show that selective tuning of granule cell inputs and bidirectional tuning of interneuron inputs are required to generate the kinematic representations in PCs.

CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8–15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells’ whole transcriptome, can determine cell-type identity.

Orientation in space is a fundamental cognitive process relying on brain-wide neuronal circuits. Many neurons in the presubiculum in the parahippocampal region encode head direction and each head direction cell selectively discharges when the animal faces a specific direction. Here, we attempt to link the current knowledge of afferent and efferent connectivity of the presubiculum to the processing of the head direction signal. We describe the cytoarchitecture of the presubicular six-layered cortex and the morphological and electrophysiological intrinsic properties of principal neurons and interneurons. While the presubicular head direction signal depends on synaptic input from thalamus, the intra- and interlaminar information flow in the microcircuit of the presubiculum may contribute to refine directional tuning. The interaction of a specific interneuron type, the Martinotti cells, with the excitatory pyramidal cells may maintain the head direction signal in the presubiculum with attractor-like properties.