Neurons In Cingulate Cortex Research Articles

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.

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice.

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/β-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

Pain-like Facial Response Recruits and Requires Anterior Cingulate Cortex Neurons in Mice

Pain-like Facial Response Recruits and Requires Anterior Cingulate Cortex Neurons in Mice

Training-induced circuit-specific excitatory synaptogenesis in mice is required for effort control

Synaptogenesis is essential for circuit development; however, it is unknown whether it is critical for the establishment and performance of goal-directed voluntary behaviors. Here, we show that operant conditioning via lever-press for food reward training in mice induces excitatory synapse formation onto a subset of anterior cingulate cortex neurons projecting to the dorsomedial striatum (ACC→DMS). Training-induced synaptogenesis is controlled by the Gabapentin/Thrombospondin receptor α2δ−1, which is an essential neuronal protein for proper intracortical excitatory synaptogenesis. Using germline and conditional knockout mice, we found that deletion of α2δ−1 in the adult ACC→DMS circuit diminishes training-induced excitatory synaptogenesis. Surprisingly, this manipulation does not impact learning but results in a significant increase in effort exertion without affecting sensitivity to reward value or changing contingencies. Bidirectional optogenetic manipulation of ACC→DMS neurons rescues or phenocopies the behaviors of the α2δ−1 cKO mice, highlighting the importance of synaptogenesis within this cortico-striatal circuit in regulating effort exertion.

Gallic Acid Ameliorates Cognitive Impairment Caused by Sleep Deprivation through Antioxidant Effect.

Sleep deprivation (SD) has a profound impact on the central nervous system, resulting in an array of mood disorders, including depression and anxiety. Despite this, the dynamic alterations in neuronal activity during sleep deprivation have not been extensively investigated. While some researchers propose that sleep deprivation diminishes neuronal activity, thereby leading to depression. Others argue that short-term sleep deprivation enhances neuronal activity and dendritic spine density, potentially yielding antidepressant effects. In this study, a two-photon microscope was utilized to examine the calcium transients of anterior cingulate cortex (ACC) neurons in awake SD mice in vivo at 24-hour intervals. It was observed that SD reduced the frequency and amplitude of Ca2+ transients while increasing the proportions of inactive neurons. Following the cessation of sleep deprivation, neuronal calcium transients demonstrated a gradual recovery. Moreover, whole-cell patch-clamp recordings revealed a significant decrease in the frequency of spontaneous excitatory post-synaptic current (sEPSC) after SD. The investigation also assessed several oxidative stress parameters, finding that sleep deprivation substantially elevated the level of malondialdehyde (MDA), while simultaneously decreasing the expression of Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) and activities of Superoxide dismutase (SOD) in the ACC. Importantly, the administration of gallic acid (GA) notably mitigated the decline of calcium transients in ACC neurons. GA was also shown to alleviate oxidative stress in the brain and improve cognitive impairment caused by sleep deprivation. These findings indicate that the calcium transients of ACC neurons experience a continuous decline during sleep deprivation, a process that is reversible. GA may serve as a potential candidate agent for the prevention and treatment of cognitive impairment induced by sleep deprivation.

A neural substrate of sex-dependent modulation of motivation.

While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value more strongly in females than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) preferentially disrupts this relationship between value and motivation in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC-DMS neurons have stronger representations of negative outcomes and more neurons are active when the value of the chosen option is low. By contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value.

Selective engram coreactivation in idling brain inspires implicit learning

Passive priming of prior knowledge to assimilate ongoing experiences underlies advanced cognitive processing. However, the necessary neural dynamics of memory assimilation remains elusive. Uninstructed brain could also show boosted creativity, particularly after idling states, yet it remains unclear whether the idling brain can spontaneously spark relevant knowledge assimilations. We established a paradigm that links/separates context-dependent memories according to geometrical similarities. Mice exploring one of four contexts 1 d before undergoing contextual fear conditioning in a square context showed a gradual fear transfer to preexposed geometrically relevant contexts the next day, but not after 15 min. Anterior cingulate cortex neurons representing relevant, rather than distinct, memories were significantly coreactivated during postconditioning sleep only, before their selective integration the next day during testing. Disrupting sleep coreactivations prevented assimilation while preserving recent memory consolidation. Thus, assimilating pertinent memories during sleep through coreactivation of their respective engrams represents the neural underpinnings of sleep-triggered implicit cortical learning.

Altered pain sensitivity in 5×familial Alzheimer disease mice is associated with dendritic spine loss in anterior cingulate cortex pyramidal neurons.

Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer disease are a susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in patients with Alzheimer disease will affect pain processing. Here, we leverage animal behavior, neural activity recording, optogenetics, chemogenetics, and Alzheimer disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to pain response. The 5× familial Alzheimer disease mice show alleviated mechanical allodynia which can be regained by the genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation, as well as the dendritic spine reduction of ACC pyramidal neurons in 5×familial Alzheimer disease mice can be mimicked by Rac1 or actin polymerization inhibitor in wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.

Neuronal Activity in the Posterior Cingulate Cortex Signals Environmental Information and Predicts Behavioral Variability during Trapline Foraging.

Animals engage in routine behavior to efficiently navigate their environments. This routine behavior may be influenced by the state of the environment, such as the location and size of rewards. The neural circuits tracking environmental information and how that information impacts decisions to deviate from routines remain unexplored. To investigate the representation of environmental information during routine foraging, we recorded the activity of single neurons in posterior cingulate cortex (PCC) in 2 male monkeys searching through an array of targets in which the location of rewards was unknown. Outside the laboratory, people and animals solve such traveling salesman problems by following routine traplines that connect nearest-neighbor locations. In our task, monkeys also deployed traplining routines; but as the environment became better known, they deviate from them despite the reduction in foraging efficiency. While foraging, PCC neurons tracked environmental information but not reward and predicted variability in the pattern of choices. Together, these findings suggest that PCC may mediate the influence of information on variability in choice behavior.SIGNIFICANCE STATEMENT Many animals seek information to better guide their decisions and update behavioral routines. In our study, subjects visually searched through a set of targets on every trial to gather two rewards. Greater amounts of information about the distribution of rewards predicted less variability in choice patterns, whereas smaller amounts predicted greater variability. We recorded from the posterior cingulate cortex, an area implicated in the coding of reward and uncertainty, and discovered that these neurons signaled the expected information about the distribution of rewards instead of signaling expected rewards. The activity in these cells also predicted the amount of variability in choice behavior. These findings suggest that the posterior cingulate helps direct the search for information to augment routines.

The geometry of neuronal representations during rule learning reveals complementary roles of cingulate cortex and putamen

Learning new rules and adopting novel behavioral policies is a prominent adaptive behavior of primates. We studied the dynamics of single neurons in the dorsal anterior cingulate cortex and putamen of monkeys while they learned new classification tasks every few days over a fixed set of multi-cue patterns. Representing the rules and the neuronal selectivity as vectors in the space spanned by a set of stimulus features allowed us to characterize neuronal dynamics in geometrical terms. We found that neurons in the cingulate cortex mainly rotated toward the rule, implying a policy search, whereas neurons in the putamen showed a magnitude increase that followed the rotation of cortical neurons, implying strengthening of confidence for the newly acquired rule-based policy. Further, the neural representation at the end of a session predicted next-day behavior, reflecting overnight retention. The novel framework for characterization of neural dynamics suggests complementing roles for the putamen and the anterior cingulate cortex.

Abrupt, Asynchronous Changes in Action Representations by Anterior Cingulate Cortex Neurons during Trial and Error Learning.

The ability to act on knowledge about the value of stimuli or actions factors into simple foraging behaviors as well as complex forms of decision-making. In striatal regions, action representations are thought to acquire value through a gradual (reinforcement-learning based) process. It is unclear whether this is also true for anterior cingulate cortex (ACC) where neuronal representations tend to change abruptly. We recorded from ensembles of ACC neurons as rats deduced which of 3 levers was rewarded each day. The rat's lever preferences changed gradually throughout the sessions as they eventually came to focus on the rewarded lever. Most individual neurons changed their responses to both rewarded and nonrewarded lever presses abruptly (<2 trials). These transitions occurred asynchronously across the population but peaked near the point where the rats began to focus on the rewarded lever. Because the individual transitions were asynchronous, the overall change at the population level appeared gradual. Abrupt transitions in action representations of ACC neurons may be part of a mechanism that alters choice strategies as new information is acquired.

Group II metabotropic glutamate receptor expressing neurons in anterior cingulate cortex become sensitized after inflammatory and neuropathic pain.

The anterior cingulate cortex is a limbic region associated with the emotional processing of pain. How neuropathic and inflammatory pain models alter the neurophysiology of specific subsets of neurons in the anterior cingulate cortex remains incompletely understood. Here, we used a GRM2Cre:tdtomato reporter mouse line to identify a population of pyramidal neurons selectively localized to layer II/III of the murine anterior cingulate cortex. GRM2encodes the group II metabotropic glutamate receptor subtype 2 which possesses analgesic properties in mouse and human models, although its function in the anterior cingulate cortex is not known. The majority of GRM2-tdtomato anterior cingulate cortex neurons expressed GRM2gene product in situ but did not overlap with cortical markers of local inhibitory interneurons, parvalbumin or somatostatin. Physiological properties of GRM2-tdtomato anterior cingulate cortex neurons were investigated using whole-cell patch clamp techniques in slice from animals with neuropathic or inflammatory pain, and controls. After hind-paw injection of Complete Freund’s Adjuvant or chronic constriction injury, GRM2-tdtomato anterior cingulate cortex neurons exhibited enhanced excitability as measured by an increase in the number of evoked action potentials and a decreased rheobase. This hyperexcitability was reversed pharmacologically by bath application of the metabotropic glutamate receptor subtype 2 agonist (2R, 4R)-4-Aminopyrrolidine-2,4-dicarboxylate APDC (1 µM) in both inflammatory and neuropathic models. We conclude that layer II/III pyramidal GRM2-tdtomato anterior cingulate cortex neurons express functional group II metabotropic glutamate receptors and undergo changes to membrane biophysical properties under conditions of inflammatory and neuropathic pain.

Neonatal 6-OHDA lesion model in mouse induces Attention-Deficit/ Hyperactivity Disorder (ADHD)-like behaviour

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impaired attention, impulsivity and hyperactivity. The “neonatal 6-hydroxydopamine” (6-OHDA) lesion is a commonly used model of ADHD in rat. However, a comprehensive assessment of ADHD‐like symptoms is still missing, and data in mouse remain largely unavailable. Our aim was to analyse symptoms of ADHD in the mouse neonatal 6‐OHDA model. 6‐OHDA mice exhibited the major ADHD‐like symptoms, i.e. hyperactivity (open field), attention deficit and impulsivity (five‐choice serial reaction time task). Further, the model revealed discrete co‐existing symptoms, i.e. anxiety‐like (elevated plus maze test) and antisocial (social interaction) behaviours and decreased cognitive functioning (novel object recognition). The efficacy of methylphenidate, a classical psychostimulant used in the treatment of ADHD, was also evaluated. A histological analysis further supports the model validity by indicating dopamine depletion, changes in cortical thickness and abnormalities in anterior cingulate cortex neurons. A principal component analysis of the behaviour profile confirms that the 6‐OHDA mouse model displayed good face and predictive validity. We conclude that neonatal dopamine depletion results in behavioural and morphological changes similar to those seen in patients and therefore could be used as a model for studying ADHD pathophysiological mechanisms and identifying therapeutic targets.

Persistent Valence Representations by Ensembles of Anterior Cingulate Cortex Neurons.

The anterior cingulate cortex (ACC) responds to outcomes of a positive or negative valence, but past studies typically focus on one valence or the other, making it difficult to know how opposing valences are disambiguated. We recorded from ACC neurons as rats received tones followed by aversive, appetitive or null outcomes. The responses to the different tones/outcomes were highly inter-mixed at the single neuron level but combined to produce robust valence-specific representations at the ensemble level. The valence-specific patterns far outlasted the tones and outcomes, persisting throughout the long inter-trial intervals (ITIs) and even throughout trial blocks. When the trials were interleaved, the valence-specific patterns abruptly shifted at the start of each new trial. Overall the aversive trials had the greatest impact on the neurons. Thus within the ACC, valence-specificity is largely an emergent property of ensembles and valence-specific representations can appear quickly and persist long after the initiating event.

Ethanol facilitates socially evoked memory recall in mice by recruiting pain-sensitive anterior cingulate cortical neurons

Alcohol is a traditional social-bonding reinforcer; however, the neural mechanism underlying ethanol-driven social behaviors remains elusive. Here, we report that ethanol facilitates observational fear response. Observer mice exhibited stronger defensive immobility while observing cagemates that received repetitive foot shocks if the observer mice had experienced a brief priming foot shock. This enhancement was associated with an observation-induced recruitment of subsets of anterior cingulate cortex (ACC) neurons in the observer mouse that were responsive to its own pain. The vicariously activated ACC neurons projected their axons preferentially to the basolateral amygdala. Ethanol shifted the ACC neuronal balance toward inhibition, facilitated the preferential ACC neuronal recruitment during observation, and enhanced observational fear response, independent of an oxytocin signaling pathway. Furthermore, ethanol enhanced socially evoked fear response in autism model mice.

Dendritic spine density and EphrinB2 levels of hippocampal and anterior cingulate cortex neurons increase sequentially during formation of recent and remote fear memory in the mouse

Memory consolidation is a dynamic process that involves a sequential remodeling of hippocampal–cortical circuits. Although synaptic events underlying memory consolidation are well assessed, fine molecular events controlling this process deserve further characterization.To this aim, we challenged male C57BL/6N mice in a contextual fear conditioning (CFC) paradigm and tested their memory 24 h, 7 days or 36 days later. Mice displayed a strong fear response at all time points with an increase in dendritic spine density and protein levels of the cell adhesion factor EphrinB2 in CA1 hippocampal neurons 24 h and 7 days post conditioning (p.c.), and in anterior cingulate cortex (ACC) neurons 36 days p.c. We then investigated whether the formation of remote memory and neuronal modifications in the ACC would depend on p.c. protein synthesis in hippocampal neurons. Bilateral intrahippocampal infusions with the protein synthesis inhibitor anisomycin administered immediately p.c. decreased fear response, neuronal spine growth and EphrinB2 protein levels of hippocampal and ACC neurons 24 h and 36 days p.c., respectively. Anisomycin infusion 24 h p.c. had no effects on fear response, increase in spine density and in EphrinB2 protein levels in ACC neurons 36 days p.c. Our results thus confirm that early but not late p.c. hippocampal protein synthesis is necessary for the formation of remote memory and provide the first evidence of a possible involvement of EphrinB2 in neuronal plasticity in the ACC.

No requirement of interlukine-1 for long-term potentiation in the anterior cingulate cortex of adult mice.

BackgroundThe enhanced expression of cytokines in the pathological states suggests that they have important roles in the initiation or maintenance of disease states.Findings: To determine the involvement of cytokines in chronic neuropathic pain, the expression of cytokines in the anterior cingulate cortex neurons in the ligation of the common peroneal nerve mice was investigated. We utilized a cytokine enzyme-linked immunosorbent assay plate array to detect 23 cytokines in total eight mice including a female, and no significant differences were found in those cytokines between the common peroneal nerve model and sham surgery mice. Quantification of TNF-α at protein level revealed the unvaried expression in the anterior cingulate cortex in both neuropathic pain and visceral pain, but enhanced expression in the insular cortex in the visceral pain. Furthermore, we found that the IL-Ira, a kind of IL-1 receptor antagonist, had no effect on the theta burst stimulation-induced long-term potentiation in the anterior cingulate cortex.ConclusionsCytokines are not involved in chronic neuropathic pain induced by nerve injury in the anterior cingulate cortex. Our findings suggested that cytokines may not be a viable drug target to treat chronic neuropathic pain in the anterior cingulate cortex.

Posterior Cingulate Neurons Dynamically Signal Decisions to Disengage during Foraging

Foraging for resources is a fundamental behavior balancing systematic search and strategic disengagement. The foraging behavior of primates is especially complex and requires long-term memory, value comparison, strategic planning, and decision-making. Here we provide evidence from two different foraging tasks that neurons in primate posterior cingulate cortex (PCC) signal decision salience during foraging to motivate disengagement from the current strategy. In our foraging tasks, salience refers to the difference between decision thresholds and the net harvested reward. Salience signals were stronger in poor foraging contexts than rich ones, suggesting low harvest rates recruit mechanisms in PCC that regulate strategic disengagement and exploration during foraging.

Calcium-binding proteins expression in the septum and cingulate cortex of the adult guinea pig

For the first time this study demonstrates the distribution pattern and expression of three neuroanatomical markers: calbindin D28k (CB), calretinin (CR) and parvalbumin (PV) in topographically connected brain regions — the septum (SE) and the cingulate cortex (CC). The co-existence among calcium-binding proteins (CaBPs) was also examined. The study was conducted on the adult guinea pig with the use of immunohistochemical and molecular biological techniques. Among the studied CaBPs, which occurred in both examined brain regions at transcript and protein levels, CB was the most expressed in the SE, while CR in the CC. CR, unlike CB and PV, showed higher immunoreactivity in the superficial layers (II–III) of the CC than in the deep ones (V–VI). Most of CB and PV-positive perikarya were detected in the deep layers of the CC. Some CC neurons contained both CB and PV, suggesting cooperation between these CaBPs in the CC. Co-localization between CB and CR in the CC was not observed.

Prefrontal and anterior cingulate cortex neurons encode attentional targets even when they do not apparently bias behavior.

Neurons in anterior cingulate and prefrontal cortex (ACC/PFC) carry information about behaviorally relevant target stimuli. This information is believed to affect behavior by exerting a top-down attentional bias on stimulus selection. However, attention information may not necessarily be a biasing signal but could be a corollary signal that is not directly related to ongoing behavioral success, or it could reflect the monitoring of targets similar to an eligibility trace useful for later attentional adjustment. To test this suggestion we quantified how attention information relates to behavioral success in neurons recorded in multiple subfields in macaque ACC/PFC during a cued attention task. We found that attention cues activated three separable neuronal groups that encoded spatial attention information but were differently linked to behavioral success. A first group encoded attention targets on correct and error trials. This group spread across ACC/PFC and represented targets transiently after cue onset, irrespective of behavior. A second group encoded attention targets on correct trials only, closely predicting behavior. These neurons were not only prevalent in lateral prefrontal but also in anterior cingulate cortex. A third group encoded target locations only on error trials. This group was evident in ACC and PFC and was activated in error trials "as if" attention was shifted to the target location but without evidence for such behavior. These results show that only a portion of neuronaly available information about attention targets biases behavior. We speculate that additionally a unique neural subnetwork encodes counterfactual attention information.