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The anterior cingulate cortex (ACC) is a key cortical region that plays an important role in pain perception and emotional functions. Previous studies of the ACC projections have been collected primarily from monkeys, rabbits and rats. Due to technological advances, such as gene manipulation, recent progress has been made in our understanding of the molecular and cellular mechanisms of the ACC-related chronic pain and emotion is mainly obtained from adult mice. Few anatomic studies have examined the whole-brain projections of the ACC in adult mice. In the present study, we examined the continuous axonal outputs of the ACC in the whole brain of adult male mice. We used the virus anterograde tracing technique and an ultrahigh-speed imaging method of Volumetric Imaging with Synchronized on-the-fly-scan and Readout (VISoR). We created a three-dimensional (3D) reconstruction of mouse brains. We found that the ACC projected ipsilaterally primarily to the caudate putamen (CPu), ventral thalamic nucleus, zona incerta (ZI), periaqueductal gray (PAG), superior colliculus (SC), interpolar spinal trigeminal nucleus (Sp5I), and dorsal medullary reticular nucleus (MdD). The ACC also projected to contralateral brain regions, including the ACC, reuniens thalamic nucleus (Re), PAG, Sp5I, and MdD. Our results provide a whole-brain mapping of efferent projections from the ACC in adult male mice, and these findings are critical for future studies of the molecular and synaptic mechanisms of the ACC and its related network in mouse models of brain diseases.

Can mice recognize themselves in a mirror? The answer is unclear. Previous studies have reported that adult mice – when shown itch-like videos - demonstrated itch empathy. However, this was proven to be unreproducible in other studies. In the present study, we wanted to examine whether adult mice were able to recognize their mirror image. In our testing, we found that mice spent more time in the central area in an open field with mirrors surrounding the chamber than those in a normal open field. In a similar open field test with four mice placed in four directions, mice showed similar behavioral responses to those with mirrors. These results indicate that mice are able to recognize images in the mirror, however, they cannot distinguish their own mirror images from the mirror images of other mice. To repeat the experiments of itch empathy, we compared the itch responses of mice in the mirrored environment, to those without. No significant difference in itching responses was detected. Differently, in the case of chemical pain (formalin injection), animals’ nociceptive responses to formalin during Phase II were significantly enhanced in the mirrored open field. A new format of heat map was developed to help the analysis of the trace of mice in the open field. Our results suggest that mice do recognize the presence of mice in the mirror, and their nociceptive - but not itch - responses are enhanced.

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Chronic pain is experienced by the vast majority of patients living with Parkinson’s disease. The degeneration of dopaminergic neuron acts as the essential mechanism of Parkinson’s disease in the midbrain dopaminergic pathway. The impairment of dopaminergic neurons leads to dysfunctions of the nociceptive system. Key cortical areas, such as the anterior cingulate cortex (ACC) and insular cortex (IC) that receive the dopaminergic projections are involved in pain transmission. Dopamine changes synaptic transmission via several pathway, for example the D2-adenly cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway and D1-G protein-coupled receptor kinase 2 (GRK2)-fragile X mental retardation protein (FMRP) pathway. The management of Parkinson’s disease-related pain implicates maintenance of stable level of dopaminergic drugs and analgesics, however a more selective drug targeting at key molecules in Parkinson’s disease-related pain remains to be investigated.

Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.

Pain triggers emotional changes in humans and animals, including fear and anxiety. Conversely, fear and anxiety may enhance suffering of patients with pain. However, in animal models of acute pain, it has been reported that fear may inhibit pain by activating endogenous inhibitory systems. In this study, we wanted to examine if behavioral withdrawal responses may be affected during fear retrieval, a condition where fear-associated tone is applied. We found that thermal pain thresholds were significantly increased during fear retrieval. Our results indicate that animals are suffering fear like-events, while their behavioral responses are inhibited. These results indicate that it will be important to evaluate both emotional and behavioral withdrawal responses for future development of new pain medicine.

The anterior cingulate cortex (ACC) is a key brain region for the perception of pain and emotion. Cellular and molecular mechanisms of the ACC are usually investigated in rodents such as mice and rats. Studies of synaptic mechanisms in primates are limited. To facilitate the translation of basic results from rodents to humans, it is critical to use a primate-like animal model for the investigation of the ACC. The tree shrew presents a great opportunity for this as they have similar genome sequences to primates and are considered to have many similarities to primates. In the present study, by combining anatomy, immunostaining and micro-optical sectioning tomography methods, we examined the morphological properties of the ACC in the tree shrew and compared them with the mouse and rat. We found that the ACC in the tree shrew is significantly larger than those found in the mouse and rat. The sizes of cell bodies of ACC pyramidal cells in tree shrew are also larger than that found in the mouse or rat. Furthermore, there are significantly more apical/basal dendritic branches and apical dendritic spines of ACC pyramidal neurons in tree shrew. These results demonstrate that pyramidal cells of the ACC in tree shrews are more advanced than those found in rodents (mice and rats), indicating that the tree shrew can be used as a useful animal model for studying the cellular mechanism for ACC-related physiological and pathological changes in humans.

Background The 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. Conclusions Cytokines 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.