Sustained behaviour: Encoding of cumulative experience in the anterior cingulate.

Time is a ubiquitous dimension of behaviour. A new study demonstrates that low-dimensional temporal drift in rodent anterior cingulate ensembles encodes cumulative experience. These data provide fresh insight into how neurons encode extended periods of time to guide high-level behaviours.

Understanding Others' Distress Through Past Experiences: The Role of Memory Engram Cells in Observational Fear.

For individuals to survive and function in society, it is essential that they recognize, interact with, and learn from other conspecifics. Observational fear (OF) is the well-conserved empathic ability of individuals to understand the other's aversive situation. While it is widely known that factors such as prior similar aversive experience and social familiarity with the demonstrator facilitate OF, the neural circuit mechanisms that explicitly regulate experience-dependent OF (Exp OF) were unclear. In this review, we examine the neural circuit mechanisms that regulate OF, with an emphasis on rodent models, and then discuss emerging evidence for the role of fear memory engram cells in the regulation of Exp OF. First, we examine the neural circuit mechanisms that underlie Naive OF, which is when an observer lacks prior experiences relevant to OF. In particular, the anterior cingulate cortex to basolateral amygdala (BLA) neural circuit is essential for Naive OF. Next, we discuss a recent study that developed a behavioral paradigm in mice to examine the neural circuit mechanisms that underlie Exp OF. This study found that fear memory engram cells in the BLA of observers, which form during a prior similar aversive experience with shock, are reactivated by ventral hippocampal neurons in response to shock delivery to the familiar demonstrator to elicit Exp OF. Finally, we discuss the implications of fear memory engram cells in Exp OF and directions of future research that are of both translational and basic interest.

Shifts in attention drive context-dependent subspace encoding in anterior cingulate cortex in mice during decision making.

Attention supports decision making by selecting the features that are relevant for decisions. Selective enhancement of the relevant features and inhibition of distractors has been proposed as potential neural mechanisms driving this selection process. Yet, how attention operates when relevance cannot be directly determined, and the attention signal needs to be internally constructed is less understood. Here we recorded from populations of neurons in the anterior cingulate cortex (ACC) of mice in an attention-shifting task where relevance of stimulus modalities changed across blocks of trials. In contrast with V1 recordings, decoding of the irrelevant modality gradually declined in ACC after an initial transient. Our analytical proof and a recurrent neural network model of the task revealed mutually inhibiting connections that produced context-gated suppression as observed in mice. Using this RNN model we predicted a correlation between contextual modulation of individual neurons and their stimulus drive, which we confirmed in ACC but not in V1.

Long-range inhibition from prelimbic to cingulate areas of the medial prefrontal cortex enhances network activity and response execution.

It is well established that the medial prefrontal cortex (mPFC) exerts top-down control of many behaviors, but little is known regarding how cross-talk between distinct areas of the mPFC influences top-down signaling. We performed virus-mediated tracing and functional studies in male mice, homing in on GABAergic projections whose axons are located mainly in layer 1 and that connect two areas of the mPFC, namely the prelimbic area (PrL) with the cingulate area 1 and 2 (Cg1/2). We revealed the identity of the targeted neurons that comprise two distinct types of layer 1 GABAergic interneurons, namely single-bouquet cells (SBCs) and neurogliaform cells (NGFs), and propose that this connectivity links GABAergic projection neurons with cortical canonical circuits. In vitro electrophysiological and in vivo calcium imaging studies support the notion that the GABAergic projection neurons from the PrL to the Cg1/2 exert a crucial role in regulating the activity in the target area by disinhibiting layer 5 output neurons. Finally, we demonstrated that recruitment of these projections affects impulsivity and mechanical responsiveness, behaviors which are known to be modulated by Cg1/2 activity.

Beta activity in human anterior cingulate cortex mediates reward biases.

The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.

Electrocortical theta activity may reflect sensory prediction errors during adaptation to a gradual gait perturbation.

Locomotor adaptation to abrupt and gradual perturbations are likely driven by fundamentally different neural processes. The aim of this study was to quantify brain dynamics associated with gait adaptation to a gradually introduced gait perturbation, which typically results in smaller behavioral errors relative to an abrupt perturbation. Loss of balance during standing and walking elicits transient increases in midfrontal theta oscillations that have been shown to scale with perturbation intensity. We hypothesized there would be no significant change in anterior cingulate theta power (4-7 Hz) with respect to pre-adaptation when a gait perturbation is introduced gradually because the gradual perturbation acceleration and stepping kinematic errors are small relative to an abrupt perturbation. Using mobile electroencephalography (EEG), we measured gait-related spectral changes near the anterior cingulate, posterior cingulate, sensorimotor, and posterior parietal cortices as young, neurotypical adults (n = 30) adapted their gait to an incremental split-belt treadmill perturbation. Most cortical clusters we examined (>70%) did not exhibit changes in electrocortical activity between 2-50 Hz. However, we did observe gait-related theta synchronization near the left anterior cingulate cortex during strides with the largest errors, as measured by step length asymmetry. These results suggest gradual adaptation with small gait asymmetry and perturbation magnitude may not require significant cortical resources beyond normal treadmill walking. Nevertheless, the anterior cingulate may remain actively engaged in error monitoring, transmitting sensory prediction error information via theta oscillations.

Unveiling the axonal connectivity between the precuneus and temporal pole: Structural evidence from the cingulum pathways.

Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.

The Granular Retrosplenial Cortex Is Necessary in Male Rats for Object-Location Associative Learning and Memory, But Not Spatial Working Memory or Visual Discrimination and Reversal, in the Touchscreen Operant Chamber.

The retrosplenial cortex (RSC) is a hub of diverse afferent and efferent projections thought to be involved in associative learning. RSC shows early pathology in mild cognitive impairment and Alzheimer's disease (AD), which impairs associative learning. To understand and develop therapies for diseases such as AD, animal models are essential. Given the importance of human RSC in object-location associative learning and the success of object-location associative paradigms in human studies and in the clinic, it would be of considerable value to establish a translational model of object-location learning for the rodent. For this reason, we sought to test the role of RSC in object-location learning in male rats using the object-location paired-associates learning (PAL) touchscreen task. First, increased cFos immunoreactivity was observed in granular RSC following PAL training when compared with extended pretraining controls. Following this, RSC lesions following PAL acquisition were used to explore the necessity of the RSC in object-location associative learning and memory and two tasks involving only one modality: trial-unique nonmatching-to-location for spatial working memory and pairwise visual discrimination/reversal. RSC lesions impaired both memory for learned paired-associates and learning of new object-location associations but did not affect performance in either the spatial or visual single-modality tasks. These findings provide evidence that RSC is necessary for object-location learning and less so for learning and memory involving the individual modalities therein.

Claustrum neurons projecting to the anterior cingulate restrict engagement during sleep and behavior.

The claustrum has been linked to attention and sleep. We hypothesized that this reflects a shared function, determining responsiveness to stimuli, which spans the axis of engagement. To test this hypothesis, we recorded claustrum population dynamics from male mice during both sleep and an attentional task ('ENGAGE'). Heightened activity in claustrum neurons projecting to the anterior cingulate cortex (ACCp) corresponded to reduced sensory responsiveness during sleep. Similarly, in the ENGAGE task, heightened ACCp activity correlated with disengagement and behavioral lapses, while low ACCp activity correlated with hyper-engagement and impulsive errors. Chemogenetic elevation of ACCp activity reduced both awakenings during sleep and impulsive errors in the ENGAGE task. Furthermore, mice employing an exploration strategy in the task showed a stronger correlation between ACCp activity and performance compared to mice employing an exploitation strategy which reduced task complexity. Our results implicate ACCp claustrum neurons in restricting engagement during sleep and goal-directed behavior.

Microstructural differences in the cingulum and the inferior longitudinal fasciculus are associated with (extinction) learning.

Cognitive functions, such as learning and memory processes, depend on effective communication between brain regions which is facilitated by white matter tracts (WMT). We investigated the microstructural properties and the contribution of WMT to extinction learning and memory in a predictive learning task. Forty-two healthy participants completed an extinction learning paradigm without a fear component. We examined differences in microstructural properties using diffusion tensor imaging to identify underlying neural connectivity and structural correlates of extinction learning and their potential implications for the renewal effect. Participants with good acquisition performance exhibited higher fractional anisotropy (FA) in WMT including the bilateral inferior longitudinal fasciculus (ILF) and the right temporal part of the cingulum (CNG). This indicates enhanced connectivity and communication between brain regions relevant to learning and memory resulting in better learning performance. Our results suggest that successful acquisition and extinction performance were linked to enhanced structural connectivity. Lower radial diffusivity (RD) in the right ILF and right temporal part of the CNG was observed for participants with good acquisition learning performance. This observation suggests that learning difficulties associated with increased RD may potentially be due to less myelinated axons in relevant WMT. Also, participants with good acquisition performance were more likely to show a renewal effect. The results point towards a potential role of structural integrity in extinction-relevant WMT for acquisition and extinction.

Top-down brain circuits for operant bradycardia.

Heart rate (HR) can be voluntarily regulated when individuals receive real-time feedback. In a rat model of HR biofeedback, the neocortex and medial forebrain bundle were stimulated as feedback and reward, respectively. The rats reduced their HR within 30 minutes, achieving a reduction of approximately 50% after 5 days of 3-hour feedback. The reduced HR persisted for at least 10 days after training while the rats exhibited anxiolytic behavior and an elevation in blood erythrocyte count. This bradycardia was prevented by inactivating anterior cingulate cortical (ACC) neurons projecting to the ventromedial thalamic nucleus (VMT). Theta-rhythm stimulation of the ACC-to-VMT pathway replicated the bradycardia. VMT neurons projected to the dorsomedial hypothalamus (DMH) and DMH neurons projected to the nucleus ambiguus, which innervates parasympathetic neurons in the heart.

Prefrontal coding of learned and inferred knowledge during REM and NREM sleep.

Idling brain activity has been proposed to facilitate inference, insight, and innovative problem-solving. However, it remains unclear how and when the idling brain can create novel ideas. Here, we show that cortical offline activity is both necessary and sufficient for building unlearned inferential knowledge from previously acquired information. In a transitive inference paradigm, male C57BL/6J mice gained the inference 1 day after, but not shortly after, complete training. Inhibiting the neuronal computations in the anterior cingulate cortex (ACC) during post-learning either non-rapid eye movement (NREM) or rapid eye movement (REM) sleep, but not wakefulness, disrupted the inference without affecting the learned knowledge. In vivo Ca2+ imaging suggests that NREM sleep organizes the scattered learned knowledge in a complete hierarchy, while REM sleep computes the inferential information from the organized hierarchy. Furthermore, after insufficient learning, artificial activation of medial entorhinal cortex-ACC dialog during only REM sleep created inferential knowledge. Collectively, our study provides a mechanistic insight on NREM and REM coordination in weaving inferential knowledge, thus highlighting the power of idling brain in cognitive flexibility.

Inhibition of cortical synaptic transmission, behavioral nociceptive, and anxiodepressive-like responses by arecoline in adult mice.

Areca nut, the seed of Areca catechu L., is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. The major effective constituent of A. catechu, arecoline, has been reported to affect the central nervous system. Less is known if it may affect pain and its related emotional responses. In this study, we found that oral application of arecoline alleviated the inflammatory pain and its induced anxiolytic and anti-depressive-like behavior. Arecoline also increased the mechanical nociceptive threshold and alleviated depression-like behavior in naïve mice. In the anterior cingulate cortex (ACC), which acts as a hinge of nociception and its related anxiety and depression, by using the multi-electrode field potential recording and whole-cell patch-clamp recording, we found that the evoked postsynaptic transmission in the ACC of adult mice has been inhibited by the application of arecoline. The muscarinic receptor is the major receptor of the arecoline in the ACC. Our results suggest that arecoline alleviates pain, anxiety, and depression-like behavior in both physiological and pathological conditions, and this new mechanism may help to treat patients with chronic pain and its related anxiety and disorder in the future.

Enhanced long-term potentiation in the anterior cingulate cortex of tree shrew.

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

General mechanisms of task engagement in the primate frontal cortex.

Staying engaged is necessary to maintain goal-directed behaviors. Despite this, engagement exhibits continuous, intrinsic fluctuations. Even in experimental settings, animals, unlike most humans, repeatedly and spontaneously move between periods of complete task engagement and disengagement. We, therefore, looked at behavior in male macaques (macaca mulatta) in four tasks while recording fMRI signals. We identified consistent autocorrelation in task disengagement. This made it possible to build models capturing task-independent engagement. We identified task general patterns of neural activity linked to impending sudden task disengagement in mid-cingulate gyrus. By contrast, activity centered in perigenual anterior cingulate cortex (pgACC) was associated with maintenance of performance across tasks. Importantly, we carefully controlled for task-specific factors such as the reward history and other motivational effects, such as response vigor, in our analyses. Moreover, we showed pgACC activity had a causal link to task engagement: transcranial ultrasound stimulation of pgACC changed task engagement patterns.

Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis.

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.

Task-induced deactivation dysfunction during reward processing is associated with low self-esteem in a possible subtype of major depression.

INTRODUCTION: Low self-esteem is a frequent symptom in major depressive disorder (MDD). This functional magnetic resonance imaging study investigated whether MDD patients with low self-esteem show a distinct neural pathophysiology. Previous studies linked low self-esteem to reduced task-induced deactivation of the pregenual anterior cingulate cortex (pgACC) as a part of the default mode network, and to reduced connectivity between pgACC and reward system. Goya-Maldonado et al. identified an MDD subtype with pgACC and ventral striatal overactivations during reward processing. We hypothesized that this subtype might be characterized by low self-esteem. METHODS: Eighty-three MDD patients performed the desire-reason dilemma task and completed the Rosenberg Self-Esteem Scale (RSES). Brain activity during bottom-up reward processing was regressed upon the RSES scores, controlling for depression severity measured by the Montgomery-Åsberg Depression Rating Scale. To corroborate the findings, we compared self-esteem scores between patient subgroups with impaired task-induced deactivation (n = 31) and with preserved task-induced deactivation (n = 31) of the pgACC. RESULTS: Consistent with our a priori hypothesis, activity in a bilateral fronto-striatal network including pgACC and ventral striatum correlated negatively with RSES scores, also when controlling for depression severity. In the additional analysis, patients with impaired task-induced pgACC deactivation showed lower self-esteem (t (52.82) = -2.27; p = .027, d = 0.58) compared to those with preserved task-induced pgACC deactivation. CONCLUSIONS: We conclude that low self-esteem in MDD patients is linked to a task-induced deactivation dysfunction of the pgACC. Our findings suggest that a previously described possible subtype of MDD with pgACC and ventral striatal overactivations during reward processing is clinically characterized by low self-esteem.

Neural mechanisms underpinning metacognitive shifts driven by non-informative predictions.

Humans constantly make predictions and such predictions allow us to prepare for future events. Yet, such benefits may come with drawbacks as premature predictions may potentially bias subsequent judgments. Here we examined how prediction influences our perceptual decisions and subsequent confidence judgments, on scenarios where the predictions were arbitrary and independent of the identity of the upcoming stimuli. We defined them as invalid and non-informative predictions. Behavioral results showed that, such non-informative predictions biased perceptual decisions in favor of the predicted choice, and such prediction-induced perceptual bias further increased the metacognitive efficiency. The functional MRI results showed that activities in the medial prefrontal cortex (mPFC) and subgenual anterior cingulate cortex (sgACC) encoded the response consistency between predictions and perceptual decisions. Activity in mPFC predicted the strength of this congruency bias across individuals. Moreover, the parametric encoding of confidence in putamen was modulated by prediction-choice consistency, such that activity in putamen was negatively correlated with confidence rating after inconsistent responses. These findings suggest that predictions, while made arbitrarily, orchestrate the neural representations of choice and confidence judgment.

Negative emotionality shapes the modulatory effects of ketamine and lamotrigine in subregions of the anterior cingulate cortex.

Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine's antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.

Intracranial EEG signals disentangle multi-areal neural dynamics of vicarious pain perception.

Empathy enables understanding and sharing of others' feelings. Human neuroimaging studies have identified critical brain regions supporting empathy for pain, including the anterior insula (AI), anterior cingulate (ACC), amygdala, and inferior frontal gyrus (IFG). However, to date, the precise spatio-temporal profiles of empathic neural responses and inter-regional communications remain elusive. Here, using intracranial electroencephalography, we investigated electrophysiological signatures of vicarious pain perception. Others' pain perception induced early increases in high-gamma activity in IFG, beta power increases in ACC, but decreased beta power in AI and amygdala. Vicarious pain perception also altered the beta-band-coordinated coupling between ACC, AI, and amygdala, as well as increased modulation of IFG high-gamma amplitudes by beta phases of amygdala/AI/ACC. We identified a necessary combination of neural features for decoding vicarious pain perception. These spatio-temporally specific regional activities and inter-regional interactions within the empathy network suggest a neurodynamic model of human pain empathy.