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The basal ganglia are known to influence action selection and modulation of movement vigor, but whether and how they contribute to specifying the kinematics of learned motor skills is not understood. Here, we probe this question by recording and manipulating basal ganglia activity in rats trained to generate complex task-specific movement patterns with rich kinematic structure. We find that the sensorimotor arm of the basal ganglia circuit is crucial for generating the detailed movement patterns underlying the acquired motor skills. Furthermore, the neural representations in the striatum, and the control function they subserve, do not depend on inputs from the motor cortex. Taken together, these results extend our understanding of the basal ganglia by showing that they can specify and control the fine-grained details of learned motor skills through their interactions with lower-level motor circuits. By recording and manipulating neural activity in rats performing a skilled behavior, the authors show that the basal ganglia control the detailed kinematics of learned skills and can do so independently of the motor cortex.

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits. Stimulus convergence and concomitant auditory cortex disinhibition are essential for fear learning. Sounds like fear It is generally recognized that learned behavioural responses, such as those associated with sound, involve changes within specific neural circuits. However, we are only beginning to understand how those changes are implemented and what interactions between different types of neurons within the circuits contribute to the learning process. Using classical sound-based fear-conditioning in mice as a model system, Andreas Lüthi and colleagues identify a distinct disinhibition-based circuit that is critical to learning. The neural circuit involved is not specific to auditory cortex, and may represent a general mechanism through which cholinergic neuromodulation gates cortical activity.

The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour. The neural circuitry of fear The central amygdala, composed mainly of GABAergic inhibitory neurons, is the part of the brain that processes Pavlovian conditioned fear. Two groups reporting in this issue of Nature use different yet complementary experimental approaches to arrive at similar conclusions about the functional architecture that underlies the conditioned fear response. They find that two microcircuits are involved, one required for fear acquisition and the other for conditioned fear responses. Haubensak et al . use genetically based functional manipulations to identify a subpopulation of GABAergic neurons that has a key role in gating learned fear. Ciocchi et al . use a combination of in vivo electrophysiological, optogenetic and pharmacological approaches in mice to identify three functionally distinct types of neurons that are embedded in a highly organized local disinhibitory network. The central amygdala relies on inhibitory circuitry to encode fear memories, but how this information is acquired and expressed in these connections is unknown. Two new papers use a combination of cutting-edge technologies to reveal two distinct microcircuits within the central amygdala, one required for fear acquisition and the other critical for conditioned fear responses. Understanding this architecture provides a strong link between activity in a specific circuit and particular behavioural consequences.

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The formation of extinction memories involves interactions between various corticolimbic structures, resulting in reduced central amygdala (CEA) output. Recent studies show, however, the CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. Here, by integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. Moreover, we show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. Our findings identify CEA inhibitory microcircuits that act as critical elements within the brain networks mediating fear extinction. The central amygdala inhibitory microcircuits mediate fear extinction by reversible, stimulus- and context-specific changes in neuronal responses. These alterations are absent when extinction is deficient and selective silencing of PKCδ neurons impairs fear extinction.

Through its widespread reciprocal connections with the cerebral cortex, the claustrum is implicated in sleep and waking cortical network states. Yet, basic knowledge of neuromodulation in this structure is lacking. The claustrum is richly innervated by serotonergic fibers, expresses serotonin receptors, and is suggested to play a role in the ability of psilocybin, which is metabolized to the non-specific serotonin receptor agonist psilocin, to disrupt cortex-wide network states. We therefore addressed the possible role of serotonin, and the classic psychedelic psilocybin, in modulating cortical signaling through the claustrum. We show that serotonin activates 5-HT 1B receptors on anterior cingulate cortex inputs – a primary driver of claustrum activity – to suppress signaling to parietal association cortex-projecting claustrum neurons. Additionally, we demonstrate that psilocybin injection also activates anterior cingulate cortex presynaptic 5-HT 1B receptors to suppress cortical signaling through the claustrum. Thus, serotonin, via 5-HT 1B , may provide gain-control of cortical input to the claustrum, a mechanism that may be directly targeted by psilocybin to modulate downstream cortical network states. Our basic understanding of neuromodulation in the claustrum remains limited. Here Madden et al., identify a key mechanism by which serotonin and the psychedelic psilocybin modulate cortical signalling through the claustrum, a brain region involved in regulating cognition and brain network states.

Rapid and reversible manipulations of neural activity in behaving animals are transforming our understanding of brain function. An important assumption underlying much of this work is that evoked behavioural changes reflect the function of the manipulated circuits. We show that this assumption is problematic because it disregards indirect effects on the independent functions of downstream circuits. Transient inactivations of motor cortex in rats and nucleus interface (Nif) in songbirds severely degraded task-specific movement patterns and courtship songs, respectively, which are learned skills that recover spontaneously after permanent lesions of the same areas. We resolve this discrepancy in songbirds, showing that Nif silencing acutely affects the function of HVC, a downstream song control nucleus. Paralleling song recovery, the off-target effects resolved within days of Nif lesions, a recovery consistent with homeostatic regulation of neural activity in HVC. These results have implications for interpreting transient circuit manipulations and for understanding recovery after brain lesions. Transient manipulation of neural activity is widely used to probe the function of specific circuits, yet such targeted perturbations could also have indirect effects on downstream circuits that implement separate and independent functions; a study to test this reveals that transient perturbations of specific circuits in mammals and songbirds severely impair learned skills that recover spontaneously after permanent lesions of the same brain areas. Confounding effects of optogenetics The development of optogenetics as a specific tool to probe the function of genetically defined neural circuits in the execution of specific behaviours has been a prominent field of recent growth in neuroscience. However, many of these studies disregard the potential for indirect effects of circuit manipulation on other downstream circuits operating independently in separate functions. Here, Bence Ölveczky and colleagues reveal how transient inactivation of specific circuits in mammals and songbirds can severely impair task-specific responses that otherwise spontaneously recover after permanent lesions of the same brain areas. This suggests that additional considerations must be taken into account when interpreting data from transient circuit manipulations of behaviour.

How an established behavior is retained and consistently produced by a nervous system in constant flux remains a mystery. One possible solution to ensure long-term stability in motor output is to fix the activity patterns of single neurons in the relevant circuits. Alternatively, activity in single cells could drift over time provided that the population dynamics are constrained to produce the same behavior. To arbitrate between these possibilities, we recorded single-unit activity in motor cortex and striatum continuously for several weeks as rats performed stereotyped motor behaviors—both learned and innate. We found long-term stability in single neuron activity patterns across both brain regions. A small amount of drift in neural activity, observed over weeks of recording, could be explained by concomitant changes in task-irrelevant aspects of the behavior. These results suggest that long-term stable behaviors are generated by single neuron activity patterns that are themselves highly stable.Using chronic neural recordings, the authors show that long-term stability in both skilled and natural behaviors is associated with stable single neuron activity patterns in relevant motor circuits.

Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV + interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM + interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV + and SOM + interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons. Plasticity within neuronal microcircuits is believed to be the substrate of learning, and this study identifies two distinct disinhibitory mechanisms involving interactions between PV + and SOM + interneurons that dynamically regulate principal neuron activity in the amygdala and thereby control auditory fear learning. Interneuron disinhibition in learning Experience-dependent plasticity within neuronal microcircuits is believed to be a crucial component in learning and memory, but only recently has it become possible to explore these circuits minutely. Using classical auditory fear conditioning in mice as a model system, Andreas Lüthi and colleagues identify two distinct learning-associated disinhibitory mechanisms involving distinct populations of interneurons. Targeting identified interneuron types for in vivo physiological and optogenetic analysis in freely moving mice, the authors demonstrate that parvalbumin-expressing interneurons disinhibit principal amygdala neurons by limiting the firing of a second population of interneurons (expressing somatostatin) known to directly synapse onto the principal neurons. The authors speculate that differential modulation of PV + and SOM + interneurons in this microcircuit may permit flexible regulation of learning according to the behavioural context and the animal's internal state.

Addressing how neural circuits underlie behavior is routinely done by measuring electrical activity from single neurons in experimental sessions. While such recordings yield snapshots of neural dynamics during specified tasks, they are ill-suited for tracking single-unit activity over longer timescales relevant for most developmental and learning processes, or for capturing neural dynamics across different behavioral states. Here we describe an automated platform for continuous long-term recordings of neural activity and behavior in freely moving rodents. An unsupervised algorithm identifies and tracks the activity of single units over weeks of recording, dramatically simplifying the analysis of large datasets. Months-long recordings from motor cortex and striatum made and analyzed with our system revealed remarkable stability in basic neuronal properties, such as firing rates and inter-spike interval distributions. Interneuronal correlations and the representation of different movements and behaviors were similarly stable. This establishes the feasibility of high-throughput long-term extracellular recordings in behaving animals.

Lesion verification and quantification is traditionally done via histological examination of sectioned brains, a time-consuming process that relies heavily on manual estimation. Such methods are particularly problematic in posterior cortical regions ( e . g . visual cortex), where sectioning leads to significant damage and distortion of tissue. Even more challenging is the post hoc localization of micro-electrodes, which relies on the same techniques, suffers from similar drawbacks and requires even higher precision. Here, we propose a new, simple method for quantitative lesion characterization and electrode localization that is less labor-intensive and yields more detailed results than conventional methods. We leverage staining techniques standard in electron microscopy with the use of commodity micro-CT imaging. We stain whole rat and zebra finch brains in osmium tetroxide, embed these in resin and scan entire brains in a micro-CT machine. The scans result in 3D reconstructions of the brains with section thickness dependent on sample size (12–15 and 5–6 microns for rat and zebra finch respectively) that can be segmented manually or automatically. Because the method captures the entire intact brain volume, comparisons within and across studies are more tractable, and the extent of lesions and electrodes may be studied with higher accuracy than with current methods.