Distinct Neuronal Populations Research Articles

Two inhibitory neuronal classes govern acquisition and recall of spinal sensorimotor adaptation.

Spinal circuits are central to movement adaptation, yet the mechanisms within the spinal cord responsible for acquiring and retaining behavior upon experience remain unclear. Using a simple conditioning paradigm, we found that dorsal inhibitory neurons are indispensable for adapting protective limb-withdrawal behavior by regulating the transmission of a specific set of somatosensory information to enhance the saliency of conditioning cues associated with limb position. By contrast, maintaining previously acquired motor adaptation required the ventral inhibitory Renshaw cells. Manipulating Renshaw cells does not affect the adaptation itself but flexibly alters the expression of adaptive behavior. These findings identify a circuit basis involving two distinct populations of spinal inhibitory neurons, which enables lasting sensorimotor adaptation independently from the brain.

Distinct lateral hypothalamic CaMKIIα neuronal populations regulate wakefulness and locomotor activity

For nearly a century, evidence has accumulated indicating that the lateral hypothalamus (LH) contains neurons essential to sustain wakefulness. While lesion or inactivation of LH neurons produces a profound increase in sleep, stimulation of inhibitory LH neurons promotes wakefulness. To date, the primary wake-promoting cells that have been identified in the LH are the hypocretin/orexin (Hcrt) neurons, yet these neurons have little impact on total sleep or wake duration across the 24-h period. Recently, we and others have identified other LH populations that increase wakefulness. In the present study, we conducted microendoscopic calcium imaging in the LH concomitant with EEG and locomotor activity (LMA) recordings and found that a subset of LH neurons that express Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) are preferentially active during wakefulness. Chemogenetic activation of these neurons induced sustained wakefulness and greatly increased LMA even in the absence of Hcrt signaling. Few LH CaMKIIα-expressing neurons are hypocretinergic or histaminergic while a small but significant proportion are GABAergic. Ablation of LH inhibitory neurons followed by activation of the remaining LH CaMKIIα neurons induced similar levels of wakefulness but blunted the LMA increase. Ablated animals showed no significant changes in sleep architecture but both spontaneous LMA and high theta (8 to 10 Hz) power during wakefulness were reduced. Together, these findings indicate the existence of two subpopulations of LH CaMKIIα neurons: an inhibitory population that promotes locomotion without affecting sleep architecture and an excitatory population that promotes prolonged wakefulness even in the absence of Hcrt signaling.

Chemosensory detection of polyamine metabolites guides C. elegans to nutritive microbes.

Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm Caenorhabditis elegans is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by C. elegans to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive Escherichia coli and pathogenic Enterococcus faecalis, and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by E. coli activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.

Excitatory spinal Lhx9-derived interneurons modulate locomotor frequency in mice.

Locomotion allows us to move and interact with our surroundings. Spinal networks that control locomotion produce rhythm, left-right and flexor-extensor coordination. Several glutamatergic populations, Shox2 non-V2a, Hb9-derived interneurons and recently, spinocerebellar neurons have been proposed to be involved in the mouse rhythm generating networks. However, these cells make up only a smaller fraction of the excitatory cells in the ventral spinal cord. Here we set out to identify additional populations of excitatory spinal neurons that may be involved in rhythm generation or other functions in the locomotor network. For this, we use RNA-sequencing from glutamatergic, non-glutamatergic, and Shox2 cells in the neonatal mice from both sexes followed by differential gene expression analyses. These analyses identified transcription factors that are highly expressed by glutamatergic spinal neurons and differentially expressed between Shox2 neurons and glutamatergic neurons. From this latter category, we identified the Lhx9-derived neurons that have a restricted spinal expression pattern and do not overlap with Shox2 neurons. They are purely glutamatergic and ipsilaterally projecting. Ablation of the glutamatergic transmission or acute inactivation of the neuronal activity of Lhx9-derived neurons lead to a decrease in the frequency of locomotor-like activity with no change in coordination pattern. Optogenetic activation of Lhx9-derived neurons promotes locomotor-like activity and modulates the frequency of the ongoing drug-induced locomotor activity. Calcium activities of Lhx9-derived neurons in the upper lumbar cord show strong left-right out of phase rhythmicity during locomotor-like activity. Our study identifies a distinct population of spinal excitatory neurons that regulates the frequency of locomotor output with a suggested role in rhythm-generation in the mouse alongside other spinal populations.Significance Statement Ipsilaterally-projecting excitatory interneurons play a crucial role in the generation of locomotor rhythms in the vertebrate spinal cord. While the Shox2, Hb9, and spinocerebellar tract neurons are known components involved in this behavior they represent only a fraction of the entire excitatory population in the spinal cord. In this study, we identify additional excitatory spinal populations that could be essential contributors to the locomotor circuitry and shed light on a new population of ipsilaterally-projecting excitatory neurons expressing the transcription factor Lhx9. Our findings show that this newly identified population has the capacity to modulate the locomotor frequency, suggesting a potential involvement in the rhythm generating network along other spinal neuronal populations.

VEGF expression disparities in brainstem motor neurons of the SOD1G93A ALS model: Correlations with neuronal vulnerability

Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration. In this study, we investigated the survival of ocular, facial, and hypoglossal motor neurons utilizing the murine SOD1G93A ALS model at various stages of the disease. Our primary objective was to determine whether the survival of the different brainstem motor neurons was linked to disparate VEGF expression levels in resilient and susceptible motor neurons throughout neurodegeneration. Our findings revealed a selective loss of motor neurons exclusively within the vulnerable nuclei. Furthermore, a significantly higher level of VEGF was detected in the more resistant motor neurons, the extraocular ones. We also examined whether TDP-43 dynamics in the brainstem motor neuron of SOD mice was altered. Our data suggests that the increased VEGF levels observed in extraocular motor neurons may potentially underlie their resistance during the neurodegenerative processes in ALS in a TDP-43-independent manner. Our work might help to better understand the underlying mechanisms of selective vulnerability of motor neurons in ALS.

Retinal vascular pathology in a mouse model of Lafora progressive myoclonus epilepsy

Neurodegenerative diseases (ND) affect distinct populations of neurons and manifest various clinical and pathological symptoms. A subset of ND prognoses has been linked to vascular risk factors. Consequently, the current study investigated retinal vascular abnormalities in a murine model of Lafora neurodegenerative disease (LD), a fatal and genetic form of progressive myoclonus epilepsy that affects children. Here, arterial rigidity was evaluated by measuring pulse wave velocity and vasculature deformations in the retina. Our findings in the LD mouse model indicate altered pulse wave velocity, retinal vascular thinning, and convoluted retinal arteries.

Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons.

Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can 'learn' the association between a naive tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24 hr later (recall). In the NBM/SIp cholinergic neurons express the immediate early gene, Fos following both training and memory recall. Cholinergic neurons that express Fos following memory recall display increased intrinsic excitability. Chemogenetic silencing of these learning-activated cholinergic neurons prevents expression of the defensive behavior to the tone. In contrast, we show that NBM/SIp cholinergic neurons are not activated by an innately threatening stimulus (predator odor). Instead, VP/SIa cholinergic neurons are activated and contribute to defensive behaviors in response to predator odor, an innately threatening stimulus. Taken together, we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli, demonstrating functionally refined organization of specific types of memory within the cholinergic basal forebrain of mice.

Molecular diversity and functional dynamics in the central amygdala.

The central amygdala (CeA) is crucial in integrating sensory and associative information to mediate adaptive responses to emotional stimuli. Recent advances in genetic techniques like optogenetics and chemogenetics have deepened our understanding of distinct neuronal populations within the CeA, particularly those involved in fear learning and memory consolidation. However, challenges remain due to overlapping genetic markers complicating neuron identification. Furthermore, a comprehensive understanding of molecularly defined cell types and their projection patterns, which are essential for elucidating functional roles, is still developing. Recent advancements in transcriptomics are starting to bridge these gaps, offering new insights into the functional dynamics of CeA neurons. In this review, we provide an overview of the expanding genetic markers for amygdala research, encompassing recent developments and current trends. We also discuss how novel transcriptomic approaches are redefining cell types in the CeA and setting the stage for comprehensive functional studies.

Midbrain neurons important for the production of mouse ultrasonic vocalizations are not required for distress calls

A fundamental feature of vocal communication is that animals produce vocalizations with different acoustic features in different behavioral contexts (contact calls, territorial calls, courtship calls, etc.). The midbrain periaqueductal gray (PAG) is a key region that regulates vocal production, and artificial activation of the PAG can elicit the production of multiple species-typical vocalization types.1,2,3,4,5,6,7,8,9 How PAG circuits are organized to regulate the production of different vocalization types remains unknown. On the one hand, studies have found that partial PAG lesions abolish the production of some vocalization types while leaving others intact,3,8,10,11 suggesting that different populations of PAG neurons might control the production of different vocalization types. On the other hand, electrophysiological recordings have revealed individual PAG neurons that increase their activity during the production of multiple vocalization types,12,13,14 suggesting that some PAG neurons may regulate the production of more than one vocalization type. To test whether a single population of midbrain neurons regulates the production of different vocalization types, we applied intersectional methods to selectively ablate a population of midbrain neurons important for the production of ultrasonic vocalizations (USVs) in mice. We find that, although ablation of these PAG-USV neurons blocks USV production in both males and females, these neurons are not required for the production of distress calls. Our findings suggest that distinct populations of midbrain neurons control the production of different vocalization types.

Conscious Experience of Stimulus Presence and Absence Is Actively Encoded by Neurons in the Crow Brain.

The emergence of consciousness from brain activity constitutes one of the great riddles in biology. It is commonly assumed that only the conscious perception of the presence of a stimulus elicits neuronal activation to signify a "neural correlate of consciousness," whereas the subjective experience of the absence of a stimulus is associated with a neuronal resting state. Here, we demonstrate that the two subjective states "stimulus present" and "stimulus absent" are represented by two specialized neuron populations in crows, corvid birds. We recorded single-neuron activity from the nidopallium caudolaterale of crows trained to report the presence or absence of images presented near the visual threshold. Because of the task design, neuronal activity tracking the conscious "present" versus "absent" percept was dissociated from that involved in planning a motor response. Distinct neuron populations signaled the subjective percepts of "present" and "absent" by increases in activation. The response selectivity of these two neuron populations was similar in strength and time course. This suggests a balanced code for subjective "presence" versus "absence" experiences, which might be beneficial when both conscious states need to be maintained active in the service of goal-directed behavior.

Differential Regulation of Neurotrophic Factors During Pathogenic Tau-Aggregation in a Tau Transgenic Mouse Model for Alzheimer's Disease: A Protocol for Double-Labeling mRNA by In Situ Hybridization and Protein Epitopes by Immunohistochemistry.

Alzheimer's disease (AD), most tauopathies, and other neurodegenerative diseases are highly associated to impaired neurotrophin regulation and imbalanced neurotrophin transport and distribution. Neurotrophins are crucial for the survival and maintenance of distinct neuronal population therefore their supply is essential for a healthy brain. Tau phosphorylation occurs at different sites of the tau protein and some phospho-epitopes are highly associated to AD (e.g., abnormally phosphorylated tau at Thr212/Ser214). Though the importance of neurotrophins is well known, their analysis in tissue is not trivial and needs careful consideration. Here a detailed protocol is presented, which combines in situ hybridization (ISH) with immunohistochemistry (IHC) to analyze neurotrophin mRNA expression during tau neuropathology and the results were confirmed by immunological methods.With this protocol, it was demonstrated that Brain-Derived Neurotrophic Factor (BDNF) and its receptor Tropomyosin receptor kinase B (TrkB) were significantly decreased in tau-transgenic mice compared to their age-matched littermates. Neurotrophin-3 (NT-3) and its receptor TrkC were not altered with statistical significance, but a tendency for decreased NT-3 and slightly increased TrkC expression was observed in tau transgenic mice. The loss of BDNF-ISH signal was predominantly observed in hippocampus (CA1 and CA3) and cortex (layer II-VI) and verified by BDNF-immunoreactivity. Decreased BDNF and TrkB mRNA was negatively correlated with abnormal tau phosphorylation at Thr212/Ser214 in cortical neurons in transgenic mice. Strikingly, no correlation was observed with age-related phospho-epitopes such as Ser202/Thr205. Interestingly, both, the mRNA and protein levels of Nerve Growth Factor (NGF) were significantly increased in hippocampal neurons in the tau models as demonstrated by ISH, immunofluorescence, and Western Blotting. Here, some co-localization of NGF mRNA and phospho-tau (Thr212/Ser214) was observed but was a rare event. Since there is growing evidence for the relevance of neurotrophic factor distribution in the pathogenesis of neurodegeneration, this technique is a useful tool to investigate the underlying mechanisms and potential therapeutic intervention.

Two parabrachial Cck neurons involved in the feedback control of thirst or salt appetite

Thirst and salt appetite are temporarily suppressed after water and salt ingestion, respectively, before absorption; however, the underlying neural mechanisms remain unclear. The parabrachial nucleus (PBN) is the relay center of ingestion signals from the digestive organs. We herein identify two distinct neuronal populations expressing cholecystokinin (Cck) mRNA in the lateral PBN that are activated in response to water and salt intake, respectively. The two Cck neurons in the dorsal-lateral compartment of the PBN project to the median preoptic nucleus and ventral part of the bed nucleus of the stria terminalis, respectively. The optogenetic stimulation of respective Cck neurons suppresses thirst or salt appetite under water- or salt-depleted conditions. The combination of optogenetics and invivo Ca2+ imaging during ingestion reveals that both Cck neurons control GABAergic neurons in their target nuclei. These findings provide the feedback mechanisms for the suppression of thirst and salt appetite after ingestion.

Cannabis Sativa targets mediobasal hypothalamic neurons to stimulate appetite

The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis.

Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward.

Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. They function as signaling hubs, enriched with a diverse array of G-protein coupled receptors (GPCRs), including several associated with motivation and drug-related behaviors. However, our understanding of how cilia regulate neuronal function and behavior is still limited. The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons showed no difference in locomotor sensitization to cocaine compared to wild-type (WT) littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 and 30 mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to WT littermates. Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell- and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

Superior colliculus bidirectionally modulates choice activity in frontal cortex

Action selection occurs through competition between potential choice options. Neural correlates of choice competition are observed across frontal cortex and downstream superior colliculus (SC) during decision-making, yet how these regions interact to mediate choice competition remains unresolved. Here we report that SC can bidirectionally modulate choice competition and drive choice activity in frontal cortex. In the mouse, topographically matched regions of frontal cortex and SC formed a descending motor pathway for directional licking and a re-entrant loop via the thalamus. During decision-making, distinct neuronal populations in both frontal cortex and SC encoded opposing lick directions and exhibited competitive interactions. SC GABAergic neurons encoded ipsilateral choice and locally inhibited glutamatergic neurons that encoded contralateral choice. Activating or suppressing these cell types could bidirectionally drive choice activity in frontal cortex. These results thus identify SC as a major locus to modulate choice competition within the broader action selection network.

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.

A novel proneural function of Asense is integrated with the sequential actions of Delta-Notch, L'sc and Su(H) to promote the neuroepithelial to neuroblast transition.

In order for neural progenitors (NPs) to generate distinct populations of neurons at the right time and place during CNS development, they must switch from undergoing purely proliferative, self-renewing divisions to neurogenic, asymmetric divisions in a tightly regulated manner. In the developing Drosophila optic lobe, neuroepithelial (NE) cells of the outer proliferation center (OPC) are progressively transformed into neurogenic NPs called neuroblasts (NBs) in a medial to lateral proneural wave. The cells undergoing this transition express Lethal of Scute (L'sc), a proneural transcription factor (TF) of the Acheate Scute Complex (AS-C). Here we show that there is also a peak of expression of Asense (Ase), another AS-C TF, in the cells neighboring those with transient L'sc expression. These peak of Ase cells help to identify a new transitional stage as they have lost NE markers and L'sc, they receive a strong Notch signal and barely exhibit NB markers. This expression of Ase is necessary and sufficient to promote the NE to NB transition in a more robust and rapid manner than that of l'sc gain of function or Notch loss of function. Thus, to our knowledge, these data provide the first direct evidence of a proneural role for Ase in CNS neurogenesis. Strikingly, we found that strong Delta-Notch signaling at the lateral border of the NE triggers l'sc expression, which in turn induces ase expression in the adjacent cells through the activation of Delta-Notch signaling. These results reveal two novel non-conventional actions of Notch signaling in driving the expression of proneural factors, in contrast to the repression that Notch signaling exerts on them during classical lateral inhibition. Finally, Suppressor of Hairless (Su(H)), which seems to be upregulated late in the transitioning cells and in NBs, represses l'sc and ase, ensuring their expression is transient. Thus, our data identify a key proneural role of Ase that is integrated with the sequential activities of Delta-Notch signaling, L'sc, and Su(H), driving the progressive transformation of NE cells into NBs.

Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons.

Insulin is a peptide hormone that regulates post-prandial physiology, and it is well known that insulin controls homeostasis at least in part via the central nervous system. In particular, insulin alters the activity of neurons within the autonomic nervous system. However, currently available data are mostly from unidentified brainstem neurons of the dorsal motor nucleus of the vagus nerve (DMV). In this study, we used several genetically engineered mouse models to label distinct populations of neurons within the brainstem and the spinal cord for whole-cell patch clamp recordings and to assess several in vivo metabolic functions. We first confirmed that insulin directly inhibited cholinergic (parasympathetic preganglionic) neurons in the DMV. We also found inhibitory effects of insulin on both the excitatory and inhibitory postsynaptic currents recorded in DMV cholinergic neurons. In addition, GABAergic neurons of the DMV and nucleus tractus solitarius were inhibited by insulin. However, insulin had no effects on the cholinergic sympathetic preganglionic neurons of the spinal cord. Finally, we obtained results suggesting that the insulininduced inhibition of parasympathetic preganglionic neurons may not play a critical role in the regulation of glucose homeostasis and gastrointestinal motility. Our results demonstrate that insulin inhibits parasympathetic neuronal circuitry in the brainstem, while not affecting sympathetic neuronal activity in the spinal cord.

CA3 Principal Cell Activation Triggers Hypersynchronous-Onset Seizures in a Mouse Model of Mesial Temporal Lobe Epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF), and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in non-stimulated CaMKII-ChR2 (n= 6) and stimulated CaMKII-Cre (n= 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n= 5), triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal period. These results provide firm evidence that in MTLE spontaneous seizures in MTLE with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.

Stimulus-Specific Prediction Error Neurons in Mouse Auditory Cortex.

Comparing expectation with experience is an important neural computation performed throughout the brain and is a hallmark of predictive processing. Experiments that alter the sensory outcome of an animal's behavior reveal enhanced neural responses to unexpected self-generated stimuli, indicating that populations of neurons in sensory cortex may reflect prediction errors (PEs), mismatches between expectation and experience. However, enhanced neural responses to self-generated stimuli could also arise through nonpredictive mechanisms, such as the movement-based facilitation of a neuron's inherent sound responses. If sensory prediction error neurons exist in sensory cortex, it is unknown whether they manifest as general error responses, or respond with specificity to errors in distinct stimulus dimensions. To answer these questions, we trained mice of either sex to expect the outcome of a simple sound-generating behavior and recorded auditory cortex activity as mice heard either the expected sound or sounds that deviated from expectation in one of multiple distinct dimensions. Our data reveal that the auditory cortex learns to suppress responses to self-generated sounds along multiple acoustic dimensions simultaneously. We identify a distinct population of auditory cortex neurons that are not responsive to passive sounds or to the expected sound but that encode prediction errors. These prediction error neurons are abundant only in animals with a learned motor-sensory expectation, and encode one or two specific violations rather than a generic error signal. Together, these findings reveal that cortical predictions about self-generated sounds have specificity in multiple simultaneous dimensions and that cortical prediction error neurons encode specific violations from expectation.SIGNIFICANCE STATEMENT Audette et. al record neural activity in the auditory cortex while mice perform a sound-generating forelimb movement and measure neural responses to sounds that violate an animal's expectation in different ways. They find that predictions about self-generated sounds are highly specific across multiple stimulus dimensions and that a population of typically nonsound-responsive neurons respond to sounds that violate an animal's expectation in a specific way. These results identify specific prediction error (PE) signals in the mouse auditory cortex and suggest that errors may be calculated early in sensory processing.