Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice.

Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.

A multidimensional coding architecture of the vagal interoceptive system.

Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.

Immunogenic cell death (ICD) enhancers-Drugs that enhance the perception of ICD by dendritic cells.

The search for immunostimulatory drugs applicable to cancer immunotherapy may profit from target-agnostic methods in which agents are screened for their functional impact on immune cells cultured in vitro without any preconceived idea on their mode of action. We have built a synthetic mini-immune system in which stressed and dying cancer cells (derived from standardized cell lines) are confronted with dendritic cells (DCs, derived from immortalized precursors) and CD8+ T-cell hybridoma cells expressing a defined T-cell receptor. Using this system, we can identify three types of immunostimulatory drugs: (i) pharmacological agents that stimulate immunogenic cell death (ICD) of malignant cells; (ii) drugs that act on DCs to enhance their response to ICD; and (iii) drugs that act on T cells to increase their effector function. Here, we focus on strategies to develop drugs that enhance the perception of ICD by DCs and to which we refer as "ICD enhancers." We discuss examples of ICD enhancers, including ligands of pattern recognition receptors (exemplified by TLR3 ligands that correct the deficient function of DCs lacking FPR1) and immunometabolic modifiers (exemplified by hexokinase-2 inhibitors), as well as methods for target deconvolution applicable to the mechanistic characterization of ICD enhancers.

Sensory processing during sleep in Drosophila melanogaster.

During sleep, most animal species enter a state of reduced consciousness characterized by a marked sensory disconnect. Yet some processing of the external world must remain intact, given that a sleeping animal can be awoken by intense stimuli (for example, a loud noise or a bright light) or by soft but qualitatively salient stimuli (for example, the sound of a baby cooing or hearing one's own name1-3). How does a sleeping brain retain the ability to process the quality of sensory information? Here we present a paradigm to study the functional underpinnings of sensory discrimination during sleep in Drosophila melanogaster. We show that sleeping vinegar flies, like humans, discern the quality of sensory stimuli and are more likely to wake up in response to salient stimuli. We also show that the salience of a stimulus during sleep can be modulated by internal states. We offer a prototypical blueprint detailing a circuit involved in this process and its modulation as evidence that the system can be used to explore the cellular underpinnings of how a sleeping brain experiences the world.

A unified framework for perceived magnitude and discriminability of sensory stimuli.

The perception of sensory attributes is often quantified through measurements of sensitivity (the ability to detect small stimulus changes), as well as through direct judgments of appearance or intensity. Despite their ubiquity, the relationship between these two measurements remains controversial and unresolved. Here, we propose a framework in which they arise from different aspects of a common representation. Specifically, we assume that judgments of stimulus intensity (e.g., as measured through rating scales) reflect the mean value of an internal representation, and sensitivity reflects a combination of mean value and noise properties, as quantified by the statistical measure of Fisher information. Unique identification of these internal representation properties can be achieved by combining measurements of sensitivity and judgments of intensity. As a central example, we show that Weber's law of perceptual sensitivity can coexist with Stevens' power-law scaling of intensity ratings (for all exponents), when the noise amplitude increases in proportion to the representational mean. We then extend this result beyond the Weber's law range by incorporating a more general and physiology-inspired form of noise and show that the combination of noise properties and sensitivity measurements accurately predicts intensity ratings across a variety of sensory modalities and attributes. Our framework unifies two primary perceptual measurements-thresholds for sensitivity and rating scales for intensity-and provides a neural interpretation for the underlying representation.

Epistemic language in news headlines shapes readers' perceptions of objectivity.

How we reason about objectivity-whether an assertion has a ground truth-has implications for belief formation on wide-ranging topics. For example, if someone perceives climate change to be a matter of subjective opinion similar to the best movie genre, they may consider empirical claims about climate change as mere opinion and irrelevant to their beliefs. Here, we investigate whether the language employed by journalists might influence the perceived objectivity of news claims. Specifically, we ask whether factive verb framing (e.g., "Scientists know climate change is happening") increases perceived objectivity compared to nonfactive framing (e.g., "Scientists believe [...]"). Across eight studies (N = 2,785), participants read news headlines about unique, noncontroversial topics (studies 1a-b, 2a-b) or a familiar, controversial topic (climate change; studies 3a-b, 4a-b) and rated the truth and objectivity of the headlines' claims. Across all eight studies, when claims were presented as beliefs (e.g., "Tortoise breeders believe tortoises are becoming more popular pets"), people consistently judged those claims as more subjective than claims presented as knowledge (e.g., "Tortoise breeders know…"), as well as claims presented as unattributed generics (e.g., "Tortoises are becoming more popular pets"). Surprisingly, verb framing had relatively little, inconsistent influence over participants' judgments of the truth of claims. These results demonstrate how, apart from shaping whether we believe a claim is true or false, epistemic language in media can influence whether we believe a claim has an objective answer at all.

Cognition as a Window into Neuronal Population Space.

Understanding how cognitive processes affect the responses of sensory neurons may clarify the relationship between neuronal population activity and behavior. However, tools for analyzing neuronal activity have not kept up with technological advances in recording from large neuronal populations. Here, we describe prevalent hypotheses of how cognitive processes affect sensory neurons, driven largely by a model based on the activity of single neurons or pools of neurons as the units of computation. We then use simple simulations to expand this model to a new conceptual framework that focuses on subspaces of population activity as the relevant units of computation, uses comparisons between brain areas or to behavior to guide analyses of these subspaces, and suggests that population activity is optimized to decode the large variety of stimuli and tasks that animals encounter in natural behavior. This framework provides new ways of understanding the ever-growing quantity of recorded population activity data.

Untangling the cortico-thalamo-cortical loop: cellular pieces of a knotty circuit puzzle.

Functions of the neocortex depend on its bidirectional communication with the thalamus, via cortico-thalamo-cortical (CTC) loops. Recent work dissecting the synaptic connectivity in these loops is generating a clearer picture of their cellular organization. Here, we review findings across sensory, motor and cognitive areas, focusing on patterns of cell type-specific synaptic connections between the major types of cortical and thalamic neurons. We outline simple and complex CTC loops, and note features of these loops that appear to be general versus specialized. CTC loops are tightly interlinked with local cortical and corticocortical (CC) circuits, forming extended chains of loops that are probably critical for communication across hierarchically organized cerebral networks. Such CTC-CC loop chains appear to constitute a modular unit of organization, serving as scaffolding for area-specific structural and functional modifications. Inhibitory neurons and circuits are embedded throughout CTC loops, shaping the flow of excitation. We consider recent findings in the context of established CTC and CC circuit models, and highlight current efforts to pinpoint cell type-specific mechanisms in CTC loops involved in consciousness and perception. As pieces of the connectivity puzzle fall increasingly into place, this knowledge can guide further efforts to understand structure-function relationships in CTC loops.

Feedback information transfer in the human brain reflects bistable perception in the absence of report.

In the search for the neural basis of conscious experience, perception and the cognitive processes associated with reporting perception are typically confounded as neural activity is recorded while participants explicitly report what they experience. Here, we present a novel way to disentangle perception from report using eye movement analysis techniques based on convolutional neural networks and neurodynamical analyses based on information theory. We use a bistable visual stimulus that instantiates two well-known properties of conscious perception: integration and differentiation. At any given moment, observers either perceive the stimulus as one integrated unitary object or as two differentiated objects that are clearly distinct from each other. Using electroencephalography, we show that measures of integration and differentiation based on information theory closely follow participants' perceptual experience of those contents when switches were reported. We observed increased information integration between anterior to posterior electrodes (front to back) prior to a switch to the integrated percept, and higher information differentiation of anterior signals leading up to reporting the differentiated percept. Crucially, information integration was closely linked to perception and even observed in a no-report condition when perceptual transitions were inferred from eye movements alone. In contrast, the link between neural differentiation and perception was observed solely in the active report condition. Our results, therefore, suggest that perception and the processes associated with report require distinct amounts of anterior-posterior network communication and anterior information differentiation. While front-to-back directed information is associated with changes in the content of perception when viewing bistable visual stimuli, regardless of report, frontal information differentiation was absent in the no-report condition and therefore is not directly linked to perception per se.

Auditory cortex ensembles jointly encode sound and locomotion speed to support sound perception during movement.

The ability to process and act upon incoming sounds during locomotion is critical for survival and adaptive behavior. Despite the established role that the auditory cortex (AC) plays in behavior- and context-dependent sound processing, previous studies have found that auditory cortical activity is on average suppressed during locomotion as compared to immobility. While suppression of auditory cortical responses to self-generated sounds results from corollary discharge, which weakens responses to predictable sounds, the functional role of weaker responses to unpredictable external sounds during locomotion remains unclear. In particular, whether suppression of external sound-evoked responses during locomotion reflects reduced involvement of the AC in sound processing or whether it results from masking by an alternative neural computation in this state remains unresolved. Here, we tested the hypothesis that rather than simple inhibition, reduced sound-evoked responses during locomotion reflect a tradeoff with the emergence of explicit and reliable coding of locomotion velocity. To test this hypothesis, we first used neural inactivation in behaving mice and found that the AC plays a critical role in sound-guided behavior during locomotion. To investigate the nature of this processing, we used two-photon calcium imaging of local excitatory auditory cortical neural populations in awake mice. We found that locomotion had diverse influences on activity of different neurons, with a net suppression of baseline-subtracted sound-evoked responses and neural stimulus detection, consistent with previous studies. Importantly, we found that the net inhibitory effect of locomotion on baseline-subtracted sound-evoked responses was strongly shaped by elevated ongoing activity that compressed the response dynamic range, and that rather than reflecting enhanced "noise," this ongoing activity reliably encoded the animal's locomotion speed. Decoding analyses revealed that locomotion speed and sound are robustly co-encoded by auditory cortical ensemble activity. Finally, we found consistent patterns of joint coding of sound and locomotion speed in electrophysiologically recorded activity in freely moving rats. Together, our data suggest that rather than being suppressed by locomotion, auditory cortical ensembles explicitly encode it alongside sound information to support sound perception during locomotion.

Sensory processing in humans and mice fluctuates between external and internal modes.

Perception is known to cycle through periods of enhanced and reduced sensitivity to external information. Here, we asked whether such slow fluctuations arise as a noise-related epiphenomenon of limited processing capacity or, alternatively, represent a structured mechanism of perceptual inference. Using 2 large-scale datasets, we found that humans and mice alternate between externally and internally oriented modes of sensory analysis. During external mode, perception aligns more closely with the external sensory information, whereas internal mode is characterized by enhanced biases toward perceptual history. Computational modeling indicated that dynamic changes in mode are enabled by 2 interlinked factors: (i) the integration of subsequent inputs over time and (ii) slow antiphase oscillations in the impact of external sensory information versus internal predictions that are provided by perceptual history. We propose that between-mode fluctuations generate unambiguous error signals that enable optimal inference in volatile environments.

NMDA-driven dendritic modulation enables multitask representation learning in hierarchical sensory processing pathways.

While sensory representations in the brain depend on context, it remains unclear how such modulations are implemented at the biophysical level, and how processing layers further in the hierarchy can extract useful features for each possible contextual state. Here, we demonstrate that dendritic N-Methyl-D-Aspartate spikes can, within physiological constraints, implement contextual modulation of feedforward processing. Such neuron-specific modulations exploit prior knowledge, encoded in stable feedforward weights, to achieve transfer learning across contexts. In a network of biophysically realistic neuron models with context-independent feedforward weights, we show that modulatory inputs to dendritic branches can solve linearly nonseparable learning problems with a Hebbian, error-modulated learning rule. We also demonstrate that local prediction of whether representations originate either from different inputs, or from different contextual modulations of the same input, results in representation learning of hierarchical feedforward weights across processing layers that accommodate a multitude of contexts.

Impaired perception of temporal contiguity between action and effect is associated with disorders of agency in schizophrenia.

Delusions of control in schizophrenia are characterized by the striking feeling that one's actions are controlled by external forces. We here tested qualitative predictions inspired by Bayesian causal inference models, which suggest that such misattributions of agency should lead to decreased intentional binding. Intentional binding refers to the phenomenon that subjects perceive a compression of time between their intentional actions and consequent sensory events. We demonstrate that patients with delusions of control perceived less self-agency in our intentional binding task. This effect was accompanied by significant reductions of intentional binding as compared to healthy controls and patients without delusions. Furthermore, the strength of delusions of control tightly correlated with decreases in intentional binding. Our study validated a critical prediction of Bayesian accounts of intentional binding, namely that a pathological reduction of the prior likelihood of a causal relation between one's actions and consequent sensory events-here captured by delusions of control-should lead to lesser intentional binding. Moreover, our study highlights the import of an intact perception of temporal contiguity between actions and their effects for the sense of agency.

Internal feedback in the cortical perception-action loop enables fast and accurate behavior.

Animals move smoothly and reliably in unpredictable environments. Models of sensorimotor control, drawing on control theory, have assumed that sensory information from the environment leads to actions, which then act back on the environment, creating a single, unidirectional perception-action loop. However, the sensorimotor loop contains internal delays in sensory and motor pathways, which can lead to unstable control. We show here that these delays can be compensated by internal feedback signals that flow backward, from motor toward sensory areas. This internal feedback is ubiquitous in neural sensorimotor systems, and we show how internal feedback compensates internal delays. This is accomplished by filtering out self-generated and other predictable changes so that unpredicted, actionable information can be rapidly transmitted toward action by the fastest components, effectively compressing the sensory input to more efficiently use feedforward pathways: Tracts of fast, giant neurons necessarily convey less accurate signals than tracts with many smaller neurons, but they are crucial for fast and accurate behavior. We use a mathematically tractable control model to show that internal feedback has an indispensable role in achieving state estimation, localization of function (how different parts of the cortex control different parts of the body), and attention, all of which are crucial for effective sensorimotor control. This control model can explain anatomical, physiological, and behavioral observations, including motor signals in the visual cortex, heterogeneous kinetics of sensory receptors, and the presence of giant cells in the cortex of humans as well as internal feedback patterns and unexplained heterogeneity in neural systems.

Antigen perception in T cells by long-term Erk and NFAT signaling dynamics.

Immune system threat detection hinges on T cells' ability to perceive varying peptide-major histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs but diverge only over longer (9+ h) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception and establish a framework for understanding T cell responses under diverse contexts.

Specific and Nonuniform Brain States during Cold Perception in Mice.

The quest to decode the complex supraspinal mechanisms that integrate cutaneous thermal information in the central system is still ongoing. The dorsal horn of the spinal cord is the first hub that encodes thermal input which is then transmitted to brain regions via the spinothalamic and thalamocortical pathways. So far, our knowledge about the strength of the interplay between the brain regions during thermal processing is limited. To address this question, we imaged the brains of adult awake male mice in resting state using functional ultrasound imaging during plantar exposure to constant and varying temperatures. Our study reveals for the first time the following: (1) a dichotomy in the response of the somatomotor-cingulate cortices and the hypothalamus, which was never described before, due to the lack of appropriate tools to study such regions with both good spatial and temporal resolutions. (2) We infer that cingulate areas may be involved in the affective responses to temperature changes. (3) Colder temperatures (ramped down) reinforce the disconnection between the somatomotor-cingulate and hypothalamus networks. (4) Finally, we also confirm the existence in the mouse brain of a brain mode characterized by low cognitive strength present more frequently at resting neutral temperature. The present study points toward the existence of a common hub between somatomotor and cingulate regions, whereas hypothalamus functions are related to a secondary network.

Forms of prediction in the nervous system.

The idea that predictions shape how we perceive and comprehend the world has become increasingly influential in the field of systems neuroscience. It also forms an important framework for understanding neuropsychiatric disorders, which are proposed to be the result of disturbances in the mechanisms through which prior information influences perception and belief, leading to the production of suboptimal models of the world. There is a widespread tendency to conceptualize the influence of predictions exclusively in terms of 'top-down' processes, whereby predictions generated in higher-level areas exert their influence on lower-level areas within an information processing hierarchy. However, this excludes from consideration the predictive information embedded in the 'bottom-up' stream of information processing. We describe evidence for the importance of this distinction and argue that it is critical for the development of the predictive processing framework and, ultimately, for an understanding of the perturbations that drive the emergence of neuropsychiatric symptoms and experiences.

Mechanisms underlying gain modulation in the cortex.

Cortical gain regulation allows neurons to respond adaptively to changing inputs. Neural gain is modulated by internal and external influences, including attentional and arousal states, motor activity and neuromodulatory input. These influences converge to a common set of mechanisms for gain modulation, including GABAergic inhibition, synaptically driven fluctuations in membrane potential, changes in cellular conductance and changes in other biophysical neural properties. Recent work has identified GABAergic interneurons as targets of neuromodulatory input and mediators of state-dependent gain modulation. Here, we review the engagement and effects of gain modulation in the cortex. We highlight key recent findings that link phenomenological observations of gain modulation to underlying cellular and circuit-level mechanisms. Finally, we place these cellular and circuit interactions in the larger context of their impact on perception and cognition.

Auditory aversive generalization learning prompts threat-specific changes in alpha-band activity.

Pairing a neutral stimulus with aversive outcomes prompts neurophysiological and autonomic changes in response to the conditioned stimulus (CS+), compared to cues that signal safety (CS-). One of these changes-selective amplitude reduction of parietal alpha-band oscillations-has been reliably linked to processing of visual CS+. It is, however, unclear to what extent auditory conditioned cues prompt similar changes, how these changes evolve as learning progresses, and how alpha reduction in the auditory domain generalizes to similar stimuli. To address these questions, 55 participants listened to three sine wave tones, with either the highest or lowest pitch (CS+) being associated with a noxious white noise burst. A threat-specific (CS+) reduction in occipital-parietal alpha-band power was observed similar to changes expected for visual stimuli. No evidence for aversive generalization to the tone most similar to the CS+ was observed in terms of alpha-band power changes, aversiveness ratings, or pupil dilation. By-trial analyses found that selective alpha-band changes continued to increase as aversive conditioning continued, beyond when participants reported awareness of the contingencies. The results support a theoretical model in which selective alpha power represents a cross-modal index of continuous aversive learning, accompanied by sustained sensory discrimination of conditioned threat from safety cues.