Assessment of cFos labeling in the hippocampus and anterior cingulate cortex following recent and remote re-exposure to an unreinforced open field in preadolescent and postadolescent rats.

Spatial tasks are often goal-directed or reward-facilitated confounding the assessment of "pure" recent and remote spatial memories. The current work re-exposed preadolescent and postadolescent male rats to a non-reinforced, free exploration task to investigate cFos patterns within the hippocampus and anterior cingulate cortex (ACC) associated with recent and remote periods. Male rats were exposed to an open field task for one, 30 min session on postnatal day (P) 20, 25, or 50 and re-exposed for 30 min at either a recent (24 hours) or remote (3 weeks) timepoint. Distance traveled in the open field was measured as well as cFos labeling. In the P20 age group, there was elevated exploration at the 24-hour and 3-week tests compared to training and compared to the other age groups. In the hippocampus CA1, cFos levels were higher after the remote test than the recent test in the P20 group but higher after the recent test than remote test in the P25 and P50 groups. cFos labeling in the ACC was higher in all remote-tested groups compared to the recent-tested groups across all ages. In the P20, the 24-hour test was associated with less CA1 activity than the other age groups supporting the hypothesis that the hippocampus is not fully developed at this time point. In the P20 group, the remote representation of this task did not seem to be complete as there continued to be CA1 activity along with ACC activity following the remote test associated with elevated exploration. These results indicate the utility of unreinforced spatial navigation tasks for exploring systems consolidation processes over the lifespan and show that a fully developed hippocampus is required for optimal systems consolidation.

Distinct Roles of Medial Prefrontal Cortex Subregions in the Consolidation and Recall of Remote Spatial Memories.

It is a common belief that memories, over time, become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence showing that prefrontal cortex (PFC) manipulations impair the retrieval of remote memories, while hippocampal inhibition does not. More controversial is whether activity in the medial PFC is required immediately after learning to initiate consolidation. Another question concerns functional differences among PFC subregions in forming and storing remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the anterior cingulate cortex (aCC) and the ventromedial PFC, which includes the infralimbic (IL) and prelimbic (PL) cortices, before testing and immediately after training on the ability of CD1 mice to recall the hidden platform location in the Morris water maze. We injected an AAV carrying the hM4Di receptor into the PL-IL or aCC. Interestingly, pretest administrations of clozapine-N-oxide (CNO; 3 mg/kg) revealed that the aCC, but not the PL-IL, was necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO impaired memory recall at remote, but not recent, time points in both groups. These findings revealed a functional dissociation between the two prefrontal areas, demonstrating that both the PL-IL and the aCC are involved in early consolidation of remote spatial memories, but only the aCC is engaged in their recall.

Neural activity for complex sounds in the marmoset anterior cingulate cortex.

Vocalizations play an important role in the daily life of nonhuman primates and are likely precursors of human language. Recent functional imaging studies in the highly vocal common marmoset (Callithrix jacchus) have suggested that anterior cingulate cortex (ACC) area 32 may be a part of a vocalization-processing network but the response properties of area 32 neurons to auditory stimuli remain unknown. Here we perform electrophysiological recordings in area 32 in marmosets with high-density Neuropixels probes and characterize neuronal responses to a variety of sounds including conspecific vocalizations. Nearly half of the neurons in area 32 respond to conspecific vocalizations and other complex auditory stimuli. These responses exhibit dynamics consisting of an initially non-selective reduction in neural activity, followed by an increase in activity that immediately conveys sound selectivity. Our findings demonstrate that primate ACC area 32 processes species-specific and biologically relevant sounds.

Electroacupuncture inhibited carrageenan-induced pain aversion by activating GABAergic neurons in the ACC.

Pain aversion is an avoidance response to painful stimuli. Previous research has indicated that the anterior cingulate cortex (ACC) is involved in pain aversion processing. However, as interneurons, the role of GABAergic neurons in the ACC (GABAACC neurons) in pain aversion is still unclear. Electroacupuncture (EA) has been shown to ameliorate pain aversion, but the mechanism is not clarified. The present study provided evidence that inhibition of GABAACC neurons contributed to pain aversion. EA alleviated pain aversion by activating GABAACC neurons in an intensity-dependent manner. Specifically, 0.3 mA EA stimulation showed better effects on pain aversion than 0.1 mA stimulation, which could be reversed by chemical genetic inhibition of GABAACC neurons. These results provide a novel mechanism by which EA alleviates pain aversion by reversing GABAACC neurons.

Food Avoidance and Aversive Goal Value Computation in Anorexia Nervosa.

Anorexia nervosa (AN) is associated with food restriction and significantly low body weight, but the neurobiology of food avoidance in AN is unknown. Animal research suggests that food avoidance can be triggered by conditioned fear that engages the anterior cingulate and nucleus accumbens. We hypothesized that the neural activation during food avoidance in AN could be modeled based on aversive goal value processing. Nineteen females with AN and thirty healthy controls matched for age underwent functional magnetic resonance brain imaging while conducting a food avoidance task. During active control free-bid and computer-generated forced-bid trials, participants bid money to avoid eating food items. Brain activation was parametrically modulated with the trial-by-trial placed bids. During free-bid trials, the AN group engaged the caudate nucleus, nucleus accumbens, ventral anterior cingulate, and inferior and medial orbitofrontal cortex more than the control group. High- versus low-bid trials in the AN group were associated with higher caudate nucleus response. Emotion dysregulation and intolerance of uncertainty scores were inversely associated with nucleus accumbens free-bid trial brain response in AN. This study supports the idea that food avoidance behavior in AN involves aversive goal value computation in the nucleus accumbens, caudate nucleus, anterior cingulate, and orbitofrontal cortex.

Cingulate to septal circuitry facilitates the preference to affiliate with large peer groups.

Despite the prevalence of large-group living across the animal kingdom, no studies have examined the neural mechanisms that make group living possible. Spiny mice, Acomys, have evolved to live in large groups and exhibit a preference to affiliate with large over small groups. Here, we determine the neural circuitry that facilitates the drive to affiliate with large groups. We first identify an anterior cingulate cortex (ACC) to lateral septum (LS) circuit that is more responsive to large than small groups of novel same-sex peers. Using chemogenetics, we then demonstrate that this circuit is necessary for both male and female group investigation preferences but only males' preference to affiliate with larger peer groups. Furthermore, inhibition of the ACC-LS circuit specifically impairs social, but not nonsocial, affiliative grouping preferences. These findings reveal a key circuit for the regulation of mammalian peer group affiliation.

Cognitive benefits of higher cardiorespiratory fitness in preadolescent children are associated with increased connectivity within the cingulo-opercular network.

Higher cardiorespiratory fitness has been associated with improved cognitive control in preadolescent children, with various studies highlighting related brain health benefits. This cross-sectional study aimed to provide novel insights into the fitness-cognition relationship by investigating task-related changes in effective connectivity within two brain networks involved in cognitive control: the cingulo-opercular and fronto-parietal networks. Twenty-four higher-fit and twenty-four lower-fit preadolescent children completed a modified flanker task that modulated inhibitory control demand while their EEG and task performance were concurrently recorded. Effective connectivity for correct trials in the theta band was estimated using directed transfer function. The results indicate that children with higher fitness levels demonstrated greater connectivity in specific directions within the cingulo-opercular network (average effect size, d = 0.72). Brain-behavior correlations demonstrated a positive association between the majority of these connections and general task accuracy, which was also higher in higher fit children (average correlation coefficient, ρ = 0.34). The findings further support a positive relationship between fitness and cognitive performance in children. EEG findings offer novel insights into the potential brain mechanisms underlying the fitness-cognition relationship. The study suggests that increased task-related connectivity within the cingulo-opercular network may mediate the cognitive benefits associated with higher fitness levels in preadolescent children.

The relationship between structural properties of frontal cortical regions and response inhibition in 6-14-year-old children.

Development of attentional skills and inhibitory control rely on maturational changes in the brain across childhood and youth. However, both brain anatomy and different components of attention and inhibition show notable individual variation. Research on ADHD and inhibitory training and control have shown that variations in the thickness and surface area of particularly inferior cortical structures are associated with attentional control. However, the intricacies of how the development of inhibitory control is associated with the anatomical variations beyond the general age- and gender-dependent differences have not been resolved. Here, we sought to address these questions by quantifying the cortical thickness and surface area in frontal cortical regions and inhibitory control using the stop signal task performance in 6-14-year-old children. Our results showed that the thickness of the left medial orbitofrontal cortex and the surface area of the left caudal anterior cingulate were associated with the inhibitory performance, beyond the variance that could be explained by the subjects' age and gender. The results highlight the importance of factoring in anatomical variations when following attentional development and the importance of evaluating multiple anatomical measures when aiming to link the properties of cortical structures with variations in cognitive performance.

The oxytocinergic system and racial ingroup bias in empathic neural activity.

Studies have indicated that the human brain exhibits a more robust neural empathic response towards individuals of the same racial ingroup than those of the outgroup. However, the impact of the oxytocinergic system on the dynamic connectivity between brain regions involved in racial ingroup bias in empathy (RIBE) and its implications for real-life social interaction intention remains unclear. To address this gap, we employed functional magnetic resonance imaging (fMRI) to investigate RIBE-modulated neural activities and the influence of the oxytocinergic system at both neural and behavioral levels. Participants homozygous for the A/A and G/G genotypes of the oxytocin receptor gene (OXTR) rs53576 polymorphism underwent scanning while making judgments about painful versus non-painful stimuli in same-race versus other-race scenarios following either oxytocin (OT) or placebo treatment. The results revealed greater activity in the anterior cingulate cortex (ACC) and anterior insula (AI) in response to same-race compared to other-race models in the G/G group but not in the A/A group. RIBE also modulated the connections between bilateral AI and the ACC, and the effect of OT on this modulatory effect was moderated by genotype rs53576 and interpersonal trust. Moreover, more extensive changes in AI-ACC connections were associated with higher levels of revenge intention in the low interpersonal trust group. Overall, our findings suggest a pivotal role of the oxytocinergic system in the RIBE-modulated neural activities and revenge intention in human interactions with the modulatory effect of interpersonal trust. This article is part of the Special Issue on "Empathic Pain".

Conjunctive processing of spatial border and locomotion in retrosplenial cortex during spatial navigation.

Spatial information and dynamic locomotor behaviours are equally important for achieving locomotor goals during spatial navigation. However, it remains unclear how spatial and locomotor information is integrated during the processing of self-initiated spatial navigation. Anatomically, the retrosplenial cortex (RSC) has reciprocal connections with brain regions related to spatial processing, including the hippocampus and para-hippocampus, and also receives inputs from the secondary motor cortex. In addition, RSC is functionally associated with allocentric and egocentric spatial targets and head-turning. So, RSC may be a critical region for integrating spatial and locomotor information. In this study, we first examined the role of RSC in spatial navigation using the Morris water maze and found that mice with inactivated RSC took a longer time and distance to reach their destination. Then, by imaging neuronal activity in freely behaving mice within two open fields of different sizes, we identified a large proportion of border cells, head-turning cells and locomotor speed cells in the superficial layer of RSC. Interestingly, some RSC neurons exhibited conjunctive coding for both spatial and locomotor signals. Furthermore, these conjunctive neurons showed higher prediction accuracy compared with simple spatial or locomotor neurons in special navigator scenes using the border, turning and positive-speed conjunctive cells. Our study reveals that the RSC is an important conjunctive brain region that processes spatial and locomotor information during spatial navigation. KEY POINTS: Retrosplenial cortex (RSC) is indispensable during spatial navigation, which was displayed by the longer time and distance of mice to reach their destination after the inactivation of RSC in a water maze. The superficial layer of RSC has a larger population of spatial-related border cells, and locomotion-related head orientation and speed cells; however, it has few place cells in two-dimensional spatial arenas. Some RSC neurons exhibited conjunctive coding for both spatial and locomotor signals, and the conjunctive neurons showed higher prediction accuracy compared with simple spatial or locomotor neurons in special navigation scenes. Our study reveals that the RSC is an important conjunctive brain region that processes both spatial and locomotor information during spatial navigation.

Rat anterior cingulate neurons responsive to rule or strategy changes are modulated by the hippocampal theta rhythm and sharp-wave ripples.

To better understand neural processing during adaptive learning of stimulus-response-reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y-maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule-change responsive neurons (70%), but other neurons that were correlated with strategy-change, strategy value and reward-rate were not. However, hippocampal sharp wave-ripples modulated significantly higher proportions of rule-change, strategy-change and reward-rate responsive cells during post-session sleep but not pre-session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged.

Generalized Encoding of the Relative Subjective Value of Cognitive Effort in the Dorsal ACC.

Making choices about whether and when to engage cognitive effort are a common feature of everyday experience, with important consequences for academic, career, and health outcomes. Yet, despite their hypothesized importance, very little is understood about the underlying mechanisms that support this form of human cost-benefit decision-making. To investigate these mechanisms, we used the Cognitive Effort Discounting Paradigm (Cog-ED) during fMRI scanning to precisely quantify the neural encoding of varying cognitive effort demands relative to reward outcomes, within two distinct cognitive domains (working memory, speech comprehension). The findings provide strong evidence that the dorsal anterior cingulate cortex (dACC) plays a central and selective role in this decision-making process. Trial-by-trial modulations in dACC activation tracked the relative subjective value of the low-effort, low-reward option, with the strongest activity occurring when this was of greater value than the high-effort, high-reward option. In contrast, dACC activity was not modulated by decision difficulty, though such effects were found in other frontoparietal regions. Critically, dACC activity was also strongly correlated across the two decision-making task domains and further predicted subsequent choice behavior in both. Together, the results suggest that dACC activity modulation reflects a domain-general valuation comparison mechanism, which acts to bias participants away from decisions to engage in cognitive effort, when the perceived subjective costs of such engagement outweigh the reward-related benefits. These findings complement work in other cost domains and species by pointing to a clear role of the dACC in representing subjective value differences between choice options during cost-benefit decision-making.

The Projection-Specific Noradrenergic Modulation of Perseverative Spatial Behavior in Adult Male Rats.

Adaptive behavior relies on efficient cognitive control. The anterior cingulate cortex (ACC) is a key node within the executive prefrontal network. The reciprocal connectivity between the locus ceruleus (LC) and ACC is thought to support behavioral reorganization triggered by the detection of an unexpected change. We transduced LC neurons with either excitatory or inhibitory chemogenetic receptors in adult male rats and trained rats on a spatial task. Subsequently, we altered LC activity and confronted rats with an unexpected change of reward locations. In a new spatial context, rats with decreased noradrenaline (NA) in the ACC entered unbaited maze arms more persistently which was indicative of perseveration. In contrast, the suppression of the global NA transmission reduced perseveration. Neither chemogenetic manipulation nor inactivation of the ACC by muscimol affected the rate of learning, possibly due to partial virus transduction of the LC neurons and/or the compensatory engagement of other prefrontal regions. Importantly, we observed behavioral deficits in rats with LC damage caused by virus injection. The latter finding highlights the importance of careful histological assessment of virus-transduced brain tissue as inadvertent damage of the targeted cell population due to virus neurotoxicity or other factors might cause unwanted side effects. Although the specific role of ACC in the flexibility of spatial behavior has not been convincingly demonstrated, our results support the beneficial role of noradrenergic transmission for an optimal function of the ACC. Overall, our findings suggest the LC exerts the projection-specific modulation of neural circuits mediating the flexibility of spatial behavior.

Egocentric neural representation of geometric vertex in the retrosplenial cortex.

Egocentric neural representations of environmental features, such as edges and vertices, are important for constructing a geometrically detailed egocentric cognitive map for goal-directed navigation and episodic memory. While egocentric neural representations of edges like egocentric boundary/border cells exist, those that selectively represent vertices egocentrically are yet unknown. Here we report that granular retrosplenial cortex (RSC) neurons in male mice generate spatial receptive fields exclusively near the vertices of environmental geometries during free exploration, termed vertex cells. Their spatial receptive fields occurred at a specific orientation and distance relative to the heading direction of mice, indicating egocentric vector coding of vertex. Removing physical boundaries defining the environmental geometry abolished the egocentric vector coding of vertex, and goal-directed navigation strengthened the egocentric vector coding at the goal-located vertex. Our findings suggest that egocentric vector coding of vertex by granular RSC neurons helps construct an egocentric cognitive map that guides goal-directed navigation.

Neural populations in macaque anterior cingulate cortex encode social image identities.

The anterior cingulate cortex gyrus (ACCg) has been implicated in prosocial behaviors and reasoning about social cues. While this indicates that ACCg is involved in social behavior, it remains unclear whether ACCg neurons also encode social information during goal-directed actions without social consequences. To address this, we assessed how social information is processed by ACCg neurons in a reward localization task. Here we show that neurons in the ACCg of female rhesus monkeys differentiate the identities of conspecifics in task images, even when identity was task-irrelevant. This was in contrast to the prearcuate cortex (PAC), which has not been strongly linked to social behavior, where neurons differentiated identities in both social and nonsocial images. Many neurons in the ACCg also categorically distinguished social from nonsocial trials, but this encoding was only slightly more common in ACCg compared to the PAC. Together, our results suggest that ACCg neurons are uniquely sensitive to social information that differentiates individuals, which may underlie its role in complex social reasoning.

Anterior cingulate cortex lesions impair multiple facets of task engagement not mediated by dorsomedial striatum neuron firing.

The anterior cingulate cortex (ACC) has been implicated across multiple highly specialized cognitive functions-including task engagement, motivation, error detection, attention allocation, value processing, and action selection. Here, we ask if ACC lesions disrupt task performance and firing in dorsomedial striatum (DMS) during the performance of a reward-guided decision-making task that engages many of these cognitive functions. We found that ACC lesions impacted several facets of task performance-including decreasing the initiation and completion of trials, slowing reaction times, and resulting in suboptimal and inaccurate action selection. Reductions in movement times towards the end of behavioral sessions further suggested attenuations in motivation, which paralleled reductions in directional action selection signals in the DMS that were observed later in recording sessions. Surprisingly, however, beyond altered action signals late in sessions-neural correlates in the DMS were largely unaffected, even though behavior was disrupted at multiple levels. We conclude that ACC lesions result in overall deficits in task engagement that impact multiple facets of task performance during our reward-guided decision-making task, which-beyond impacting motivated action signals-arise from dysregulated attentional signals in the ACC and are mediated via downstream targets other than DMS.

Medial to lateral frontal functional connectivity mapping reveals the organization of cingulate cortex.

The functional organization of the frontal lobe is a source of debate, focusing on broad functional subdivisions, large-scale networks, or local refined specificities. Multiple neurocognitive models have tried to explain how functional interactions between cingulate and lateral frontal regions contribute to decision making and cognitive control, but their neuroanatomical bases remain unclear. We provide a detailed description of the functional connectivity between cingulate and lateral frontal regions using resting-state functional MRI in rhesus macaques. The analysis focuses on the functional connectivity of the rostral part of the cingulate sulcus with the lateral frontal cortex. Data-driven and seed-based analysis revealed three clusters within the cingulate sulcus organized along the rostro-caudal axis: the anterior, mid, and posterior clusters display increased functional connectivity with, respectively, the anterior lateral prefrontal regions, face-eye lateral frontal motor cortical areas, and hand lateral frontal motor cortex. The location of these clusters can be predicted in individual subjects based on morphological landmarks. These results suggest that the anterior cluster corresponds to the anterior cingulate cortex, whereas the posterior clusters correspond to the face-eye and hand cingulate motor areas within the anterior midcingulate cortex. These data provide a comprehensive framework to identify cingulate subregions based on functional connectivity and local organization.

Multiple faces of anxiety: a frontal lobe perspective.

Marked dysregulation of the human prefrontal cortex (PFC) and anterior cingulate cortex (ACC) characterises a variety of anxiety disorders, and its amelioration is a key feature of treatment success. Overall treatment response, however, is highly variable, and about a third of patients are resistant to treatment. In this review we hypothesise that a major contributor to this variation in treatment response are the multiple faces of anxiety induced by distinct forms of frontal cortex dysregulation. Comparison of findings from humans and non-human primates reveals marked similarity in the functional organisation of threat regulation across the frontal lobes. This organisation is discussed in relation to the 'predatory imminence continuum' model of threat and the differential engagement of executive functions at the core of both emotion generation and regulation strategies.

Prediction-error signals in anterior cingulate cortex drive task-switching.

Task-switching is a fundamental cognitive ability that allows animals to update their knowledge of current rules or contexts. Detecting discrepancies between predicted and observed events is essential for this process. However, little is known about how the brain computes cognitive prediction-errors and whether neural prediction-error signals are causally related to task-switching behaviours. Here we trained mice to use a prediction-error to switch, in a single trial, between responding to the same stimuli using two distinct rules. Optogenetic silencing and un-silencing, together with widefield and two-photon calcium imaging revealed that the anterior cingulate cortex (ACC) was specifically required for this rapid task-switching, but only when it exhibited neural prediction-error signals. These prediction-error signals were projection-target dependent and were larger preceding successful behavioural transitions. An all-optical approach revealed a disinhibitory interneuron circuit required for successful prediction-error computation. These results reveal a circuit mechanism for computing prediction-errors and transitioning between distinct cognitive states.

Differential stability of task variable representations in retrosplenial cortex.

Cortical neurons store information across different timescales, from seconds to years. Although information stability is variable across regions, it can vary within a region as well. Association areas are known to multiplex behaviorally relevant variables, but the stability of their representations is not well understood. Here, we longitudinally recorded the activity of neuronal populations in the mouse retrosplenial cortex (RSC) during the performance of a context-choice association task. We found that the activity of neurons exhibits different levels of stability across days. Using linear classifiers, we quantified the stability of three task-relevant variables. We find that RSC representations of context and trial outcome display higher stability than motor choice, both at the single cell and population levels. Together, our findings show an important characteristic of association areas, where diverse streams of information are stored with varying levels of stability, which may balance representational reliability and flexibility according to behavioral demands.