Area-Specificity and Plasticity of History-Dependent Value Coding During Learning.

Decision making is often driven by the subjective value of available options, a value which is formed through experience. To support this fundamental behavior, the brain must encode and maintain the subjective value. To investigate the area specificity and plasticity of value coding, we trained mice in a value-based decision task and imaged neural activity in 6 cortical areas with cellular resolution. History- and value-related signals were widespread across areas, but their strength and temporal patterns differed. In expert mice, the retrosplenial cortex (RSC) uniquely encoded history- and value-related signals with persistent population activity patterns across trials. This unique encoding of RSC emerged during task learning with a strong increase in more distant history signals. Acute inactivation of RSC selectively impaired the reward-history-based behavioral strategy. Our results indicate that RSC flexibly changes its history coding and persistently encodes value-related signals to support adaptive behaviors.

A Tradeoff in the Neural Code across Regions and Species.

Many evolutionary years separate humans and macaques, and although the amygdala and cingulate cortex evolved to enable emotion and cognition in both, an evident functional gap exists. Although they were traditionally attributed to differential neuroanatomy, functional differences might also arise from coding mechanisms. Here we find that human neurons better utilize information capacity (efficient coding) than macaque neurons in both regions, and that cingulate neurons are more efficient than amygdala neurons in both species. In contrast, we find more overlap in the neural vocabulary and more synchronized activity (robustness coding) in monkeys in both regions and in the amygdala of both species. Our findings demonstrate a tradeoff between robustness and efficiency across species and regions. We suggest that this tradeoff can contribute to differential cognitive functions between species and underlie the complementary roles of the amygdala and the cingulate cortex. In turn, it can contribute to fragility underlying human psychopathologies.

Neuronal prediction of opponent's behavior during cooperative social interchange in primates.

A cornerstone of successful social interchange is the ability to anticipate each other's intentions or actions. While generating these internal predictions is essential for constructive social behavior, their single neuronal basis and causal underpinnings are unknown. Here, we discover specific neurons in the primate dorsal anterior cingulate that selectively predict an opponent's yet unknown decision to invest in their common good or defect and distinct neurons that encode the monkey's own current decision based on prior outcomes. Mixed population predictions of the other was remarkably near optimal compared to behavioral decoders. Moreover, disrupting cingulate activity selectively biased mutually beneficial interactions between the monkeys but, surprisingly, had no influence on their decisions when no net-positive outcome was possible. These findings identify a group of other-predictive neurons in the primate anterior cingulate essential for enacting cooperative interactions and may pave a way toward the targeted treatment of social behavioral disorders.

Monkeys in a prisoner's dilemma.

Haroush and Williams trained pairs of monkeys to play in a prisoner's dilemma game, a model of social interactions. Recording from the dorsal anterior cingulate cortex (dACC), they find neurons whose activity reflects the anticipation of the opponent's yet unknown choice, which may be important in guiding animals' performance in the game.

A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict.

A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival.

Cortical regulation of helping behaviour towards others in pain.

Humans and animals exhibit various forms of prosocial helping behaviour towards others in need1-3. Although previous research has investigated how individuals may perceive others' states4,5, the neural mechanisms of how they respond to others' needs and goals with helping behaviour remain largely unknown. Here we show that mice engage in a form of helping behaviour towards other individuals experiencing physical pain and injury-they exhibit allolicking (social licking) behaviour specifically towards the injury site, which aids the recipients in coping with pain. Using microendoscopic imaging, we found that single-neuron and ensemble activity in the anterior cingulate cortex (ACC) encodes others' state of pain and that this representation is different from that of general stress in others. Furthermore, functional manipulations demonstrate a causal role of the ACC in bidirectionally controlling targeted allolicking. Notably, this behaviour is represented in a population code in the ACC that differs from that of general allogrooming, a distinct type of prosocial behaviour elicited by others' emotional stress. These findings advance our understanding of the neural coding and regulation of helping behaviour.

Neural circuit basis of placebo pain relief.

Placebo effects are notable demonstrations of mind-body interactions1,2. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain-a phenomenon known as placebo analgesia3-6. However, despite the strength of placebo effects and their impact on everyday human experience and the failure of clinical trials for new therapeutics7, the neural circuit basis of placebo effects has remained unclear. Here we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn)-a precerebellar nucleus with no established function in pain. We created a behavioural assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain-relief expectation, providing cellular-level evidence for a role of the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain.

Behavioral variability through stochastic choice and its gating by anterior cingulate cortex.

Behavioral choices that ignore prior experience promote exploration and unpredictability but are seemingly at odds with the brain's tendency to use experience to optimize behavioral choice. Indeed, when faced with virtual competitors, primates resort to strategic counter prediction rather than to stochastic choice. Here, we show that rats also use history- and model-based strategies when faced with similar competitors but can switch to a "stochastic" mode when challenged with a competitor that they cannot defeat by counter prediction. In this mode, outcomes associated with an animal's actions are ignored, and normal engagement of anterior cingulate cortex (ACC) is suppressed. Using circuit perturbations in transgenic rats, we demonstrate that switching between strategic and stochastic behavioral modes is controlled by locus coeruleus input into ACC. Our findings suggest that, under conditions of uncertainty about environmental rules, changes in noradrenergic input alter ACC output and prevent erroneous beliefs from guiding decisions, thus enabling behavioral variation. PAPERCLIP:

A cortico-collicular circuit for orienting to shelter during escape.

When faced with predatory threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. Animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions1,2. Although previous work has identified neural mechanisms of escape initiation3,4, it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that the mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes the shelter-direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP-SC pathway disrupts the orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network because of higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter-direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically constrained spiking network model in which RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP-SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible.

Molecular features driving cellular complexity of human brain evolution.

Human-specific genomic changes contribute to the unique functionalities of the human brain1-5. The cellular heterogeneity of the human brain6,7 and the complex regulation of gene expression highlight the need to characterize human-specific molecular features at cellular resolution. Here we analysed single-nucleus RNA-sequencing and single-nucleus assay for transposase-accessible chromatin with sequencing datasets for human, chimpanzee and rhesus macaque brain tissue from posterior cingulate cortex. We show a human-specific increase of oligodendrocyte progenitor cells and a decrease of mature oligodendrocytes across cortical tissues. Human-specific regulatory changes were accelerated in oligodendrocyte progenitor cells, and we highlight key biological pathways that may be associated with the proportional changes. We also identify human-specific regulatory changes in neuronal subtypes, which reveal human-specific upregulation of FOXP2 in only two of the neuronal subtypes. We additionally identify hundreds of new human accelerated genomic regions associated with human-specific chromatin accessibility changes. Our data also reveal that FOS::JUN and FOX motifs are enriched in the human-specifically accessible chromatin regions of excitatory neuronal subtypes. Together, our results reveal several new mechanisms underlying the evolutionary innovation of human brain at cell-type resolution.

A tripartite view of the posterior cingulate cortex.

The posterior cingulate cortex (PCC) is one of the least understood regions of the cerebral cortex. By contrast, the anterior cingulate cortex has been the subject of intensive investigation in humans and model animal systems, leading to detailed behavioural and computational theoretical accounts of its function. The time is right for similar progress to be made in the PCC given its unique anatomical and physiological properties and demonstrably important contributions to higher cognitive functions and brain diseases. Here, we describe recent progress in understanding the PCC, with a focus on convergent findings across species and techniques that lay a foundation for establishing a formal theoretical account of its functions. Based on this converging evidence, we propose that the broader PCC region contains three major subregions - the dorsal PCC, ventral PCC and retrosplenial cortex - that respectively support the integration of executive, mnemonic and spatial processing systems. This tripartite subregional view reconciles inconsistencies in prior unitary theories of PCC function and offers promising new avenues for progress.

Prefrontal feature representations drive memory recall.

Memory formation involves binding of contextual features into a unitary representation1-4, whereas memory recall can occur using partial combinations of these contextual features. The neural basis underlying the relationship between a contextual memory and its constituent features is not well understood; in particular, where features are represented in the brain and how they drive recall. Here, to gain insight into this question, we developed a behavioural task in which mice use features to recall an associated contextual memory. We performed longitudinal imaging in hippocampus as mice performed this task and identified robust representations of global context but not of individual features. To identify putative brain regions that provide feature inputs to hippocampus, we inhibited cortical afferents while imaging hippocampus during behaviour. We found that whereas inhibition of entorhinal cortex led to broad silencing of hippocampus, inhibition of prefrontal anterior cingulate led to a highly specific silencing of context neurons and deficits in feature-based recall. We next developed a preparation for simultaneous imaging of anterior cingulate and hippocampus during behaviour, which revealed robust population-level representation of features in anterior cingulate, that lag hippocampus context representations during training but dynamically reorganize to lead and target recruitment of context ensembles in hippocampus during recall. Together, we provide the first mechanistic insights into where contextual features are represented in the brain, how they emerge, and how they access long-range episodic representations to drive memory recall.

Frontal neurons driving competitive behaviour and ecology of social groups.

Competitive interactions have a vital role in the ecology of most animal species1-3 and powerfully influence the behaviour of groups4,5. To succeed, individuals must exert effort based on not only the resources available but also the social rank and behaviour of other group members2,6,7. The single-cellular mechanisms that precisely drive competitive interactions or the behaviour of social groups, however, remain poorly understood. Here we developed a naturalistic group paradigm in which large cohorts of mice competitively foraged for food as we wirelessly tracked neuronal activities across thousands of unique interactions. By following the collective behaviour of the groups, we found neurons in the anterior cingulate that adaptively represented the social rank of the animals in relation to others. Although social rank was closely behaviourally linked to success, these cells disambiguated the relative rank of the mice from their competitive behaviour, and incorporated information about the resources available, the environment, and past success of the mice to influence their decisions. Using multiclass models, we show how these neurons tracked other individuals within the group and accurately predicted upcoming success. Using neuromodulation techniques, we also show how the neurons conditionally influenced competitive effort-increasing the effort of the animals only when they were more dominant to their groupmates and decreasing it when they were subordinate-effects that were not observed in other frontal lobe areas. Together, these findings reveal cingulate neurons that serve to adaptively drive competitive interactions and a putative process that could intermediate the social and economic behaviour of groups.

The anterior cingulate cortex controls the hyperactivity in subthalamic neurons in male mice with comorbid chronic pain and depression.

Neurons in the subthalamic nucleus (STN) become hyperactive following nerve injury and promote pain-related responses in mice. Considering that the anterior cingulate cortex (ACC) is involved in pain and emotion processing and projects to the STN, we hypothesize that ACC neurons may contribute to hyperactivity in STN neurons in chronic pain. In the present study, we showed that ACC neurons enhanced activity in response to noxious stimuli and to alterations in emotional states and became hyperactive in chronic pain state established by spared nerve injury of the sciatic nerve (SNI) in mice. In naïve mice, STN neurons were activated by noxious stimuli, but not by alterations in emotional states. Pain responses in STN neurons were attenuated in both naïve and SNI mice when ACC neurons were inhibited. Furthermore, optogenetic activation of the ACC-STN pathway induced bilateral hyperalgesia and depression-like behaviors in naive mice; conversely, inhibition of this pathway is sufficient to attenuate hyperalgesia and depression-like behaviors in SNI mice and naïve mice subjected to stimulation of STN neurons. Finally, mitigation of pain-like and depression-like behaviors in SNI mice by inhibition of the ACC-STN projection was eliminated by activation of STN neurons. Our results demonstrate that hyperactivity in the ACC-STN pathway may be an important pathophysiology in comorbid chronic pain and depression. Thus, the ACC-STN pathway may be an intervention target for the treatment of the comorbid chronic pain and depression.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Space wandering in the rodent default mode network.

The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here, we use multisite GCaMP (a genetically encoded calcium indicator) fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats. We examined neural dynamics in three core DMN nodes-the retrosplenial cortex, cingulate cortex, and prelimbic cortex-as well as the anterior insula node of the salience network, and their association with the rats' spatial exploration behaviors. We found that DMN nodes displayed a hierarchical functional organization during spatial exploration, characterized by stronger coupling with each other than with the anterior insula. Crucially, these DMN nodes encoded the kinematics of spatial exploration, including linear and angular velocity. Additionally, we identified latent brain states that encoded distinct patterns of time-varying exploration behaviors and found that higher linear velocity was associated with enhanced DMN activity, heightened synchronization among DMN nodes, and increased anticorrelation between the DMN and anterior insula. Our findings highlight the involvement of the DMN in collectively and dynamically encoding spatial exploration in a real-world setting. Our findings challenge the notion that the DMN is primarily a "task-negative" network disengaged from the external world. By illuminating the DMN's role in naturalistic behaviors, our study underscores the importance of investigating brain network function in ecologically valid contexts.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age.

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

Brain decoding of spontaneous thought: Predictive modeling of self-relevance and valence using personal narratives.

The contents and dynamics of spontaneous thought are important factors for personality traits and mental health. However, assessing spontaneous thoughts is challenging due to their unconstrained nature, and directing participants' attention to report their thoughts may fundamentally alter them. Here, we aimed to decode two key content dimensions of spontaneous thought-self-relevance and valence-directly from brain activity. To train functional MRI-based predictive models, we used individually generated personal stories as stimuli in a story-reading task to mimic narrative-like spontaneous thoughts (n = 49). We then tested these models on multiple test datasets (total n = 199). The default mode, ventral attention, and frontoparietal networks played key roles in the predictions, with the anterior insula and midcingulate cortex contributing to self-relevance prediction and the left temporoparietal junction and dorsomedial prefrontal cortex contributing to valence prediction. Overall, this study presents brain models of internal thoughts and emotions, highlighting the potential for the brain decoding of spontaneous thought.

Dynamics of retrieval strategies for remote memories.

Prevailing theory suggests that long-term memories are encoded via a two-phase process requiring early involvement of the hippocampus followed by the neocortex. Contextual fear memories in rodents rely on the hippocampus immediately following training but are unaffected by hippocampal lesions or pharmacological inhibition weeks later. With fast optogenetic methods, we examine the real-time contribution of hippocampal CA1 excitatory neurons to remote memory and find that contextual fear memory recall, even weeks after training, can be reversibly abolished by temporally precise optogenetic inhibition of CA1. When this inhibition is extended to match the typical time course of pharmacological inhibition, remote hippocampus dependence converts to hippocampus independence, suggesting that long-term memory retrieval normally depends on the hippocampus but can adaptively shift to alternate structures. Further revealing the plasticity of mechanisms required for memory recall, we confirm the remote-timescale importance of the anterior cingulate cortex (ACC) and implicate CA1 in ACC recruitment for remote recall.

Shared yet dissociable neural codes across eye gaze, valence and expectation.

The direction of the eye gaze of others is a prominent social cue in primates and is important for communication1-11. Although gaze can signal threat and elicit anxiety6,12,13, it remains unclear whether it shares neural circuitry with stimulus value. Notably, gaze not only has valence, but can also serve as a predictor of the outcome of a social encounter, which can be either negative or positive2,8,12,13. Here we show that the neural codes for gaze and valence overlap in primates and that they involve two different mechanisms: one for the outcome and another for its expectation. Monkeys participated in the human intruder test13,14, in which a human participant had either a direct or averted gaze, interleaved with blocks of aversive and appetitive conditioning. We find that single neurons in the amygdala encode gaze15, whereas neurons in the anterior cingulate cortex encode the social context16, but not gaze. We identify a shared population in the amygdala for which the neural responses to direct and averted gaze parallel the responses to aversive and appetitive stimulus, respectively. Furthermore, we distinguish between two neural mechanisms-an overall-activity scheme that is used for gaze and the unconditioned stimulus, and a correlated-selectivity scheme that is used for gaze and the conditioned stimulus. These findings provide insights into the origins of the neural mechanisms that underlie the computations of both social interactions and valence, and could help to shed light on mechanisms that underlie social anxiety and the comorbidity between anxiety and impaired social interactions.