Cells In Anterior Cingulate Cortex Research Articles

Dopaminergic Inhibition of Pyramidal Cells in Anterior Cingulate Cortex is Defective in Chronic Neuropathic Pain

Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic pain conditions and their silencing abolishes hyperalgesia. We show here that dopamine, through D1-like receptor signaling, inhibits layer 2/3 pyramidal neurons of mouse ACC through modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Activation of Gs-coupled D1-like receptors by dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA in chronic neuropathic mice rescues HCN channel activity, normalizes pyramidal excitability in ACC, and has anti-allodynic effects on mechanical and thermal responses. Moreover, microinjection of a selective D1-like agonist in ACC induces relief of ongoing pain in neuropathic animals. We conclude that dopaminergic inhibition in ACC plays an analgesic role in physiological conditions and is defective in chronic pain.

Corrigendum: Chronic Inflammatory Pain Impairs mGluR5-Mediated Depolarization-Induced Suppression of Excitation in the Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC. DSE was mediated by endocannabinoid signaling and modulated by metabotropic glutamate receptor 5 (mGluR5). DSE was impaired by decreasing expression and dysfunction of mGluR5 in a mouse model of inflammatory pain induced by complete Freund's adjuvant. CDPPB, an mGluR5-positive allosteric modulator, could rescue hypersensitivity and anxiety-like behavior in this pain model. Our results demonstrated that mGluR5-mediated short-term plasticity in ACC may be a critical mechanism for chronic pain, and mGluR5 may potentially serve as a target of pain therapy, including treatments for hyperalgesia and anxiety.

Chronic Inflammatory Pain Impairs mGluR5-Mediated Depolarization-Induced Suppression of Excitation in the Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC. DSE was mediated by endocannabinoid signaling and modulated by metabotropic glutamate receptor 5 (mGluR5). DSE was impaired by decreasing expression and dysfunction of mGluR5 in a mouse model of inflammatory pain induced by complete Freund's adjuvant. CDPPB, an mGluR5-positive allosteric modulator, could rescue hypersensitivity and anxiety-like behavior in this pain model. Our results demonstrated that mGluR5-mediated short-term plasticity in ACC may be a critical mechanism for chronic pain, and mGluR5 may potentially serve as a target of pain therapy, including treatments for hyperalgesia and anxiety.

Strong Manual Acupuncture Stimulation of "Huantiao" (GB 30) Reduces Pain-Induced Anxiety and p-ERK in the Anterior Cingulate Cortex in a Rat Model of Neuropathic Pain.

Persistent neuropathic pain is associated with anxiety. The phosphorylation of extracellular signal-regulated kinase (p-ERK) in the anterior cingulate cortex (ACC) plays an important role in pain-induced anxiety. Acupuncture is widely used for pain and anxiety. However, little is known about which acupuncture technique is optimal on pain-induced anxiety and the relationship between acupuncture effect and p-ERK. The rat model was induced by L5 spinal nerve ligation (SNL). Male adult SD rats were randomly divided into control, SNL, strong manual acupuncture (sMA), mild manual acupuncture (mMA), and electroacupuncture (EA) group. Bilateral “Huantiao” (GB 30) were stimulated by sMA, mMA, and EA, respectively. The pain withdrawal thresholds (PWTs) and anxiety behavior were measured, and p-ERK protein expression and immunoreactivity cells in ACC were detected. PWTs increased significantly in both sMA and EA groups. Meanwhile, anxiety-like behavior was improved significantly in the sMA and mMA groups. Furthermore, the overexpression of p-ERK induced by SNL was downregulated by strong and mild manual acupuncture. Therefore, strong manual acupuncture on bilateral “Huantiao” (GB 30) could be a proper therapy relieving both pain and pain-induced anxiety. The effect of different acupuncture techniques on pain-induced anxiety may arise from the regulation of p-ERK in ACC.

Theta-activity in anterior cingulate cortex predicts task rules and their adjustments following errors

Accomplishing even simple tasks depend on neuronal circuits to configure how incoming sensory stimuli map onto responses. Controlling these stimulus-response (SR) mapping rules relies on a cognitive control network comprising the anterior cingulate cortex (ACC). Single neurons within the ACC convey information about currently relevant SR mapping rules and signal unexpected action outcomes, which can be used to optimize behavioral choices. However, its functional significance and the mechanistic means of interaction with other nodes of the cognitive control network remain elusive and poorly understood. Here, we report that core aspects of cognitive control are encoded by rhythmic theta-band activity within neuronal circuits in the ACC. Throughout task performance, theta-activity predicted which of two SR mapping rules will be established before processing visual target information. Task-selective theta-activity emerged particularly early during those trials, which required the adjustment of SR rules following an erroneous rule representation in the preceding trial. These findings demonstrate a functional correlation of cognitive control processes and oscillatory theta-band activity in macaque ACC. Moreover, we report that spike output of a subset of cells in ACC is synchronized to predictive theta-activity, suggesting that the theta-cycle could serve as a temporal reference for coordinating local task selective computations across a larger network of frontal areas and the hippocampus to optimize and adjust the processing routes of sensory and motor circuits to achieve efficient sensory-motor control.

The effects of chronic haloperidol administration on GABA‐immunoreactive. Axon terminals in rat medial prefrontal cortex

Several reports have suggested that chronic haloperidol (HAL) treatment induces ultrastructural changes in synapses of substantia nigra, corpus striatum, and medial prefrontal cortex (mPFC) of rat brain. The effects of HAL on specific cortical transmitter systems, however, are not well characterized. Recent studies have indicated that there may be a loss of gamma-aminobutyric acid (GABA)ergic cells in anterior cingulate cortex of schizophrenic subjects and this hypothesis has prompted interest in the question of whether dopamine receptor antagonists, such as HAL, may influence the activity of this transmitter system. This current report describes a quantitative light microscopic analysis of GABA-immunolabeled axosomatic terminals in mPFC of rats treated with HAL decanoate (0.5 mg/kg/day, i.m.) for a period of 4 months. GABA-containing terminals were visualized with an avidin-biotin immunoperoxidase method for localizing anti-GABA antibodies. Computer-assisted image processing was employed to determine the total number of pixels representing GABA-immunoreaction product in axon terminals that were in direct apposition to pyramidal cell bodies. Drug-treated animals showed a significant increase in the number of pixels representing GABA-immunoreaction product in axosomatic terminals of layers II, III, VI, and VI (93%, 63%, 31%, and 43%, respectively). These data are consistent with the idea that chronic HAL administration may be associated with a significant increase in the amount of GABA present in terminals surrounding pyramidal neurons of rat mPFC. The fact that GABA-containing terminals showed the greatest increase in layer II is not consistent with the known distribution of dopamine afferents to this region which is lowest in superficial laminae. Based on the laminar distribution of non-dopaminergic receptor types that have a high affinity for HAL, the effect of this drug on GABAergic transmission could potentially involve changes that are mediated through mechanisms in which 5-HT2 or sigma opiate receptors play a role.