Populations Of Cortical Neurons Research Articles

MULTIPLE DISTINCT TIMESCALES OF RAPID SENSORY ADAPATION IN THE THALAMOCORTICAL CIRCUIT.

Numerous studies have shown that neuronal representations in sensory pathways are far from static but are instead strongly shaped by the complex properties of the sensory inputs they receive. Adaptation dynamically shapes the neural signaling that underlies our perception of the world yet remains poorly understood. We investigated rapid adaptation across timescales from hundreds of milliseconds to seconds through simultaneous multi-electrode recordings from the ventro-posteromedial nucleus of the thalamus (VPm) and layer 4 of the primary somatosensory cortex (S1) in male and female anesthetized mice in response to controlled, persistent whisker stimulation. Observations in VPm and S1 reveal a degree of adaptation that progresses through the pathway. Signatures of two distinct timescales of rapid adaptation in the firing rates of both thalamic and cortical neuronal populations were revealed, also reflected in the synchrony of the thalamic population and in the thalamocortical synaptic efficacy that was measured in putatively monosynaptically connected thalamocortical pairs. Controlled optogenetic activation of VPm further demonstrated that the longer timescale adaptation observed in S1 is likely inherited from slow decreases in thalamic firing rate and synchrony. Despite the degraded sensory responses, adaptation resulted in a shift in coding strategy that favors theoretical discrimination over detection across the observed timescales of adaptation. Overall, although multiple mechanisms contribute to rapid adaptation at distinct timescales, they support a unifying framework on the role of adaptation in sensory processing.

Focal seizures induce spatiotemporally organized spiking activity in the human cortex

Epileptic seizures are debilitating because of the clinical symptoms they produce. These symptoms, in turn, may stem directly from disruptions in neural coding. Recent evidence has suggested that the specific temporal order, or sequence, of spiking across a population of cortical neurons may encode information. Here, we investigate how seizures disrupt neuronal spiking sequences in the human brain by recording multi-unit activity from the cerebral cortex in five male participants undergoing monitoring for seizures. We find that pathological discharges during seizures are associated with bursts of spiking activity across a population of cortical neurons. These bursts are organized into highly consistent and stereotyped temporal sequences. As the seizure evolves, spiking sequences diverge from the sequences observed at baseline and become more spatially organized. The direction of this spatial organization matches the direction of the ictal discharges, which spread over the cortex as traveling waves. Our data therefore suggest that seizures can entrain cortical spiking sequences by changing the spatial organization of neuronal firing, providing a possible mechanism by which seizures create symptoms.

Generation of contractile forces by three-dimensional bundled axonal tracts in micro-tissue engineered neural networks.

Axonal extension and retraction are ongoing processes that occur throughout all developmental stages of an organism. The ability of axons to produce mechanical forces internally and respond to externally generated forces is crucial for nervous system development, maintenance, and plasticity. Such axonal mechanobiological phenomena have typically been evaluated in vitro at a single-cell level, but these mechanisms have not been studied when axons are present in a bundled three-dimensional (3D) form like in native tissue. In an attempt to emulate native cortico-cortical interactions under in vitro conditions, we present our approach to utilize previously described micro-tissue engineered neural networks (micro-TENNs). Here, micro-TENNs were comprised of discrete populations of rat cortical neurons that were spanned by 3D bundled axonal tracts and physically integrated with each other. We found that these bundled axonal tracts inherently exhibited an ability to generate contractile forces as the microtissue matured. We therefore utilized this micro-TENN testbed to characterize the intrinsic contractile forces generated by the integrated axonal tracts in the absence of any external force. We found that contractile forces generated by bundled axons were dependent on microtubule stability. Moreover, these intra-axonal contractile forces could simultaneously generate tensile forces to induce so-called axonal "stretch-growth" in different axonal tracts within the same microtissue. The culmination of axonal contraction generally occurred with the fusion of both the neuronal somatic regions along the axonal tracts, therefore perhaps showing the innate tendency of cortical neurons to minimize their wiring distance, a phenomenon also perceived during brain morphogenesis. In future applications, this testbed may be used to investigate mechanisms of neuroanatomical development and those underlying certain neurodevelopmental disorders.

Long-range inhibitory neurons mediate cortical neurovascular coupling

To meet the high energy demands of brain function, cerebral blood flow (CBF) parallels changes in neuronal activity by a mechanism known as neurovascular coupling (NVC). However, which neurons play a role in mediating NVC is not well understood. Here, we identify in mice and humans a specific population of cortical GABAergic neurons that co-express neuronal nitric oxide synthase and tachykinin receptor 1 (Tacr1). Through whole-tissue clearing, we demonstrate that Tacr1 neurons extend local and long-range projections across functionally connected cortical areas. We show that whisker stimulation elicited Tacr1 neuron activity in the barrel cortex through feedforward excitatory pathways. Additionally, through optogenetic experiments, we demonstrate that Tacr1 neurons are instrumental in mediating CBF through the relaxation of mural cells in a similar fashion to whisker stimulation. Finally, by electron microscopy, we observe that Tacr1 processes contact astrocytic endfeet. These findings suggest that Tacr1 neurons integrate cortical activity to mediate NVC.

Neuronal models of TDP-43 proteinopathy display reduced axonal translation, increased oxidative stress, and defective exocytosis.

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, an RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt mRNA transport and localization. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two cellular models, consisting of virtually pure populations of primary mouse cortical neurons expressing a human TDP-43 fusion protein, wt or carrying an ALS mutation. Both forms facilitate cytoplasmic aggregate formation, unlike the corresponding native proteins, giving rise to bona fide primary culture models of TDP-43 proteinopathy. Neurons expressing TDP-43 fusion proteins exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation of axonal levels of polysome-engaged mRNAs playing relevant roles in the same processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS.

Is song processing distinct and special in the auditory cortex?

Is the singing voice processed distinctively in the human brain? In this Perspective, we discuss what might distinguish song processing from speech processing in light of recent work suggesting that some cortical neuronal populations respond selectively to song and we outline the implications for our understanding of auditory processing. We review the literature regarding the neural and physiological mechanisms of song production and perception and show that this provides evidence for key differences between song and speech processing. We conclude by discussing the significance of the notion that song processing is special in terms of how this might contribute to theories of the neurobiological origins of vocal communication and to our understanding of the neural circuitry underlying sound processing in the human cortex.

In Utero Electroporated Neurons for Medium-Throughput Screening of Compounds Regulating Neuron Morphology.

Several neurodevelopmental disorders are associated with increased mTOR activity that results in pathogenic neuronal dysmorphogenesis (i.e., soma and dendrite overgrowth), leading to circuit alterations associated with epilepsy and neurologic disabilities. Although an mTOR analog is approved for the treatment of epilepsy in one of these disorders, it has limited efficacy and is associated with a wide range of side effects. There is a need to develop novel agents for the treatment of mTOR-pathway related disorders. Here, we developed a medium-throughput phenotypic assay to test drug efficacy on neurite morphogenesis of mouse neurons in a hyperactive mTOR condition. Our assay involved in utero electroporation (IUE) of a selective population of cortical pyramidal neurons with a plasmid encoding the constitutively active mTOR activator, Rheb, and tdTomato. Labeled neurons from the somatosensory cortex (SSC) were cultured onto 96-well plates and fixed at various days in vitro or following Torin 1 treatment. Automated systems were used for image acquisition and neuron morphologic measurements. We validated our automated approach using traditional manual methods of neuron morphologic assessment. Both automated and manual analyses showed increased neurite length and complexity over time, and decreased neurite overgrowth and soma size with Torin 1. These data validate the accuracy of our automated approach that takes hours compared with weeks when using traditional manual methods. Taken together, this assay can be scaled to screen 32 compounds simultaneously in two weeks, highlighting its robustness and efficiency for medium-throughput screening of candidate therapeutics on a defined population of wild-type or diseased neurons.

Synaptic zinc potentiates AMPA receptor function in mouse auditory cortex

Synaptic zinc signaling modulates synaptic activity and is present in specific populations of cortical neurons, suggesting that synaptic zinc contributes to the diversity of intracortical synaptic microcircuits and their functional specificity. To understand the role of zinc signaling in the cortex, we performed whole-cell patch-clamp recordings from intratelencephalic (IT)-type neurons and pyramidal tract (PT)-type neurons in layer 5 of the mouse auditory cortex during optogenetic stimulation of specific classes of presynaptic neurons. Our results show that synaptic zinc potentiates AMPA receptor (AMPAR) function in a synapse-specific manner. We performed invivo 2-photon calcium imaging of the same classes of neurons in awake mice and found that changes in synaptic zinc can widen or sharpen the sound-frequency tuning bandwidth of IT-type neurons but only widen the tuning bandwidth of PT-type neurons. These results provide evidence for synapse- and cell-type-specific actions of synaptic zinc in the cortex.

Pharmacological profiling identifies divergent chemosensitivities of differentiating and maturing iPSC-derived human cortical neuron populations.

Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small compound library comprising FDA-approved and investigational drugs. Using a neurotoxicity assay format, both respective neuronal population-based screening campaigns performed robustly (Z-factors = 0.7-0.8), although the hit rate for the differentiating neurons (2.8%) was slightly higher than for maturing neurons (1.9%). While the majority of hits were toxic to both neuronal populations, these hits predominantly represented promiscuous drugs. Other drugs were selectively neurotoxic, with receptor tyrosine kinase inhibitors disproportionally represented after confirmation. Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Chemoinformatic analyses confirmed differences in potential drug targets that may be differentially expressed during neuronal development. Subsequent studies demonstrated neuronal expression of AXL, an amuvatinib target, in both neuronal populations. However, functional AXL activity was confirmed only in the maturing neuronal population as determined by AXL phosphorylation in response to GAS6, the cognate ligand of AXL, and concurrent STAT3Y705 phosphorylation. Differentiating neurons were unresponsive to the effects of GAS6 suggesting that the AXL-STAT3 signaling axis was nonfunctional. Amuvatinib treatment of maturing neuronal cultures significantly reduced pAXL levels. These studies indicate that neuronal developmental states may exhibit unique chemosensitivities and that drugs may have different neuro-inhibitory effects depending upon the developmental stage of the neuronal population.

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model.

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Hippocampal and Medial Prefrontal Cortex Fractal Spiking Patterns Encode Episodes and Rules

A central question in neuroscience is how the brain represents and processes information to guide behavior. The principles that organize brain computations are not fully known, and could include scale-free, or fractal patterns of neuronal activity. Scale-free brain activity may be a natural consequence of the relatively small subsets of neuronal populations that respond to task features, i.e., sparse coding. The size of the active subsets constrains the possible sequences of inter-spike intervals (ISI), and selecting from this limited set may produce firing patterns across wide-ranging timescales that form fractal spiking patterns. To investigate the extent to which fractal spiking patterns corresponded with task features, we analyzed ISIs in simultaneously recorded populations of CA1 and medial prefrontal cortical (mPFC) neurons in rats performing a spatial memory task that required both structures. CA1 and mPFC ISI sequences formed fractal patterns that predicted memory performance. CA1 pattern duration, but not length or content, varied with learning speed and memory performance whereas mPFC patterns did not. The most common CA1 and mPFC patterns corresponded with each region's cognitive function: CA1 patterns encoded behavioral episodes which linked the start, choice, and goal of paths through the maze whereas mPFC patterns encoded behavioral “rules” which guided goal selection. mPFC patterns predicted changing CA1 spike patterns only as animals learned new rules. Together, the results suggest that CA1 and mPFC population activity may predict choice outcomes by using fractal ISI patterns to compute task features.

Saying goodbye to an unwelcome guest: Towards robust methods for controlling multi-sensory confounds in TMS-EEG research.

Saying goodbye to an unwelcome guest: Towards robust methods for controlling multi-sensory confounds in TMS-EEG research.

Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development

BackgroundLoss-of-function mutations in the contactin-associated protein-like 2 (CNTNAP2) gene are causal for neurodevelopmental disorders, including autism, schizophrenia, epilepsy, and intellectual disability. CNTNAP2 encodes CASPR2, a single-pass transmembrane protein that belongs to the neurexin family of cell adhesion molecules. These proteins have a variety of functions in developing neurons, including connecting presynaptic and postsynaptic neurons, and mediating signaling across the synapse. MethodsTo study the effect of loss of CNTNAP2 function on human cerebral cortex development, and how this contributes to the pathogenesis of neurodevelopmental disorders, we generated human induced pluripotent stem cells from one neurotypical control donor null for full-length CNTNAP2, modeling cortical development from neurogenesis through to neural network formation in vitro. ResultsCNTNAP2 is particularly highly expressed in the first two populations of early-born excitatory cortical neurons, and loss of CNTNAP2 shifted the relative proportions of these two neuronal types. Live imaging of excitatory neuronal growth showed that loss of CNTNAP2 reduced neurite branching and overall neuronal complexity. At the network level, developing cortical excitatory networks null for CNTNAP2 had complex changes in activity compared with isogenic controls: an initial period of relatively reduced activity compared with isogenic controls, followed by a lengthy period of hyperexcitability, and then a further switch to reduced activity. ConclusionsComplete loss of CNTNAP2 contributes to the pathogenesis of neurodevelopmental disorders through complex changes in several aspects of human cerebral cortex excitatory neuron development that culminate in aberrant neural network formation and function.

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping.

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.

Generation and Co-culture of Cortical Glutamatergic and GABAergic-Induced Neuronal Cells.

The study of neurological disorders requires experimentation on human neurons throughout their development. Primary neurons can be difficult to obtain, and animal models may not fully recapitulate phenotypes observed in human neurons. Human neuronal culturing schemes which contain a balanced mixture of excitatory and inhibitory neurons that resemble physiological ratios seen in vivo will be useful to probe the neurological basis of excitation-inhibition (E-I) balance. Here, we describe a method for directly inducing a homogenous population of cortical excitatory neurons and cortical interneurons from human pluripotent stem cells, as well as the generation of mixed cultures using these induced neurons. The obtained cells display robust neuronal synchronous network activity as well as complex morphologies that are amenable to studies probing the molecular and cellular basis of disease mutations or other aspects of neuronal and synaptic development.

Automated Image Analysis Reveals Different Localization of Synaptic Gephyrin C4 Splice Variants.

Postsynaptic scaffolding proteins function as central organization hubs, ensuring the synaptic localization of neurotransmitter receptors, trans-synaptic adhesion proteins, and signaling molecules. Gephyrin is the major postsynaptic scaffolding protein at glycinergic and a subset of GABAergic inhibitory synapses. In contrast to cells outside the CNS, where one gephyrin isoform is predominantly expressed, neurons express different splice variants. In this study, we characterized the expression and scaffolding of neuronal gephyrin isoforms differing in the inclusion of the C4 cassettes located in the central C-domain. In hippocampal and cortical neuronal populations, gephyrin P1, lacking additional cassettes, is the most abundantly expressed isoform. In addition, alternative splicing generated isoforms carrying predominantly C4a, and minor amounts of C4c or C4d cassettes. We detected no striking difference in C4 isoform expression between different neuron types and a single neuron can likely express all C4 isoforms. To avoid the cytosolic aggregates that are commonly observed upon exogenous gephyrin expression, we used adeno-associated virus (AAV)-mediated expression to analyze the scaffolding behavior of individual C4 isoforms in murine dissociated hippocampal glutamatergic neurons. While all isoforms showed similar clustering at GABAergic synapses, a thorough quantitative analysis revealed localization differences for the C4c isoform (also known as P2). Specifically, synaptic C4c isoform clusters showed a more distal dendritic localization and reduced occurrence at P1-predominating synapses. Additionally, inhibitory currents displayed faster decay kinetics in the presence of gephyrin C4c compared with P1. Therefore, inhibitory synapse heterogeneity may be influenced, at least in part, by mechanisms relating to C4 cassette splicing.

Pulse flows of cork neuron populations under microwave irradiation of different intensity

The one-minute effects of the microwave field (wavelength 37.5 cm, power density 0.2-0.3; 0.4; 0.5, and 40 mW/cm2) on the impulse flows of cortical neurons of awake non-immobilized rabbits were investigated. Interpulse intervals were considered within a minute before exposure, during exposure and within one minute after. The changes that occurred on the side of the interspike intervals as a result of these impacts were analyzed. It was found that in the case of irradiation intensities of 0.2-0.3 and 0.4 mW/cm2, the average values of interspike intervals predominantly decreased, and at irradiation intensities of 0.5 and 40 mW/cm2 shifts in the values of interspike intervals of the opposite direction prevailed. The smallest changes in interspike intervals were observed at an intensity of 0.4 mW/cm2. The work shows that microwave irradiation with a one-minute exposure causes rearrangements in the impulse flows of populations of cortical neurons. The rearrangements of neuronal activity that occur under the influence of one-minute microwave irradiation consist of visually predominantly separate shifts during and after exposure with additional fluctuations and indicators within these periods, which is similar to the encephalograms we studied earlier. The studies carried out are necessary for understanding the electromagnetic situation on the Earth and for the analysis of the corresponding space-related problems.

A Redundant Cortical Code for Speech Envelope.

Animal communication sounds exhibit complex temporal structure because of the amplitude fluctuations that comprise the sound envelope. In human speech, envelope modulations drive synchronized activity in auditory cortex (AC), which correlates strongly with comprehension (Giraud and Poeppel, 2012; Peelle and Davis, 2012; Haegens and Zion Golumbic, 2018). Studies of envelope coding in single neurons, performed in nonhuman animals, have focused on periodic amplitude modulation (AM) stimuli and use response metrics that are not easy to juxtapose with data from humans. In this study, we sought to bridge these fields. Specifically, we looked directly at the temporal relationship between stimulus envelope and spiking, and we assessed whether the apparent diversity across neurons' AM responses contributes to the population representation of speech-like sound envelopes. We gathered responses from single neurons to vocoded speech stimuli and compared them to sinusoidal AM responses in auditory cortex (AC) of alert, freely moving Mongolian gerbils of both sexes. While AC neurons displayed heterogeneous tuning to AM rate, their temporal dynamics were stereotyped. Preferred response phases accumulated near the onsets of sinusoidal AM periods for slower rates (<8 Hz), and an over-representation of amplitude edges was apparent in population responses to both sinusoidal AM and vocoded speech envelopes. Crucially, this encoding bias imparted a decoding benefit: a classifier could discriminate vocoded speech stimuli using summed population activity, while higher frequency modulations required a more sophisticated decoder that tracked spiking responses from individual cells. Together, our results imply that the envelope structure relevant to parsing an acoustic stream could be read-out from a distributed, redundant population code.SIGNIFICANCE STATEMENT Animal communication sounds have rich temporal structure and are often produced in extended sequences, including the syllabic structure of human speech. Although the auditory cortex (AC) is known to play a crucial role in representing speech syllables, the contribution of individual neurons remains uncertain. Here, we characterized the representations of both simple, amplitude-modulated sounds and complex, speech-like stimuli within a broad population of cortical neurons, and we found an overrepresentation of amplitude edges. Thus, a phasic, redundant code in auditory cortex can provide a mechanistic explanation for segmenting acoustic streams like human speech.

The study of visual evoked potentials in children with retinopathy of prematurity

Visual functions in children after retinopathy of prematurity depend not only on the degree of residual clinical changes in the fundus and structural features of the retina, but also on the state of the pathways and higher parts of the visual analyzer, which can be investigated by recording visual evoked potentials. This examination method involves recording the overall response of large populations of cortical neurons to the synchronous flow of impulses coming to them, arising in response to an afferent stimulus and reflecting mainly the electrical activity of the macular area. The registration of visual evoked potentials in the retinopathy of prematurity has an important diagnostic value for identifying the level and degree of damage to the pathways and higher parts of the visual analyzer. This literature review presents the data of foreign and domestic authors on the state of the pathways and higher parts of the visual analyzer in premature babies and children with retinopathy of prematurity using the registration of visual evoked potentials. It has been noted that the magnocellular system, which is activated in response to motor stimuli, is affected to a greater extent in preterm infants than the parvocellular system, which functions in response to pattern stimuli. A comprehensive ophthalmological examination with the registration of visual evoked potentials on the presentation of pattern-reversing stimuli and/or on a flash stimulus should be carried out in children with cicatricial stages of retinopathy of prematurity, in order to identify and confirm the concomitant pathology of the optic nerve. It has been established that the frequency of registration of pathologically altered visual evoked potentials as the severity of retinopathy of prematurity increases, indicating an increase in pathway dysfunction. The effect of laser coagulation of the retina and the volume of its implementation in retinopathy of prematurity on the functional state of the visual analyzer was studied.

Precise movement-based predictions in the mouse auditory cortex

Many of the sensations experienced by an organism are caused by their own actions, and accurately anticipating both the sensory features and timing of self-generated stimuli is crucial to a variety of behaviors. In the auditory cortex, neural responses to self-generated sounds exhibit frequency-specific suppression, suggesting that movement-based predictions may be implemented early in sensory processing. However, it remains unknown whether this modulation results from a behaviorally specific and temporally precise prediction, nor is it known whether corresponding expectation signals are present locally in the auditory cortex. To address these questions, we trained mice to expect the precise acoustic outcome of a forelimb movement using a closed-loop sound-generating lever. Dense neuronal recordings in the auditory cortex revealed suppression of responses to self-generated sounds that was specific to the expected acoustic features, to a precise position within the movement, and to the movement that was coupled to sound during training. Prediction-based suppression was concentrated in L2/3 and L5, where deviations from expectation also recruited a population of prediction-error neurons that was otherwise unresponsive. Recording in the absence of sound revealed abundant movement signals in deep layers that were biased toward neurons tuned to the expected sound, as well as expectation signals that were present throughout the cortex and peaked at the time of expected auditory feedback. Together, these findings identify distinct populations of auditory cortical neurons with movement, expectation, and error signals consistent with a learned internal model linking an action to its specific acoustic outcome.