An insular cortical circuit required for itch sensation and aversion.

Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC → dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC â†’ dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.

Sexually dimorphic control of affective state processing and empathic behaviors.

Recognizing the affective states of social counterparts and responding appropriately fosters successful social interactions. However, little is known about how the affective states are expressed and perceived and how they influence social decisions. Here, we show that male and female mice emit distinct olfactory cues after experiencing distress. These cues activate distinct neural circuits in the piriform cortex (PiC) and evoke sexually dimorphic empathic behaviors in observers. Specifically, the PiC → PrL pathway is activated in female observers, inducing a social preference for the distressed counterpart. Conversely, the PiC → MeA pathway is activated in male observers, evoking excessive self-grooming behaviors. These pathways originate from non-overlapping PiC neuron populations with distinct gene expression signatures regulated by transcription factors and sex hormones. Our study unveils how internal states of social counterparts are processed through sexually dimorphic mechanisms at the molecular, cellular, and circuit levels and offers insights into the neural mechanisms underpinning sex differences in higher brain functions.

Differences in the neural basis and transcriptomic patterns in acute and persistent pain-related anxiety-like behaviors.

Background: Both acute and persistent pain is associated with anxiety in clinical observations, but whether the underlying neural mechanisms differ is poorly understood. Methods: We used formalin or complete Freund's adjuvant (CFA) to induce acute or persistent pain. Behavioral performance was assessed by the paw withdrawal threshold (PWT), open field (OF), and elevated plus maze (EPM) tests. C-Fos staining was used to identify the activated brain regions. Chemogenetic inhibition was further performed to examine the necessity of brain regions in behaviors. RNA sequencing (RNA-seq) was used to identify the transcriptomic changes. Results: Both acute and persistent pain could lead to anxiety-like behavior in mice. The c-Fos expression indicates that the bed nucleus of the stria terminalis (BNST) is activated only in acute pain, whereas the medial prefrontal cortex (mPFC) is activated only in persistent pain. Chemogenetic manipulation reveals that the activation of the BNST excitatory neurons is required for acute pain-induced anxiety-like behaviors. In contrast, the activation of the prelimbic mPFC excitatory neurons is essential for persistent pain-induced anxiety-like behaviors. RNA-seq reveals that acute and persistent pain induces differential gene expression changes and protein-protein interaction networks in the BNST and prelimbic mPFC. The genes relevant to neuronal functions might underline the differential activation of the BNST and prelimbic mPFC in different pain models, and be involved in acute and persistent pain-related anxiety-like behaviors. Conclusion: Distinct brain regions and gene expression patterns are involved in acute and persistent pain-related anxiety-like behaviors.

Enriched Environment Prevents Surgery-Induced Persistent Neural Inhibition and Cognitive Dysfunction.

Perioperative neurocognitive disorders (PND) encompass short-term delirium and long-term cognitive dysfunction. Aging increases the susceptibility to PND, yet the neural mechanism is not known. In this study, we monitored the dynamic changes of neuronal activity in the prelimbic cortex before and after surgery. We found that anesthesia combined with surgery, but not anesthesia alone, induced a prolonged decrease in neuronal activity during the post-operation period in the aged mice, but not in the adult mice. The prolonged decrease in neuronal activity was accompanied by surgery-induced microglial activation and proinflammatory cytokines expression. Importantly, we found that the enriched environment (EE) completely prevented both the prolonged neural inhibition and neuroinflammation, and improved cognitive function in the aged mice. These results indicate that the prolonged neural inhibition correlated to PND and that EE before the surgery could effectively alleviate the surgery- induced cognitive dysfunction.

Reduced Dendritic Spines in the Visual Cortex Contralateral to the Optic Nerve Crush Eye in Adult Mice.

Purpose: To determine alteration of dendritic spines and associated changes in the primary visual cortex (V1 region) related to unilateral optic nerve crush (ONC) in adult mice. Methods: Adult unilateral ONC mice were established. Retinal nerve fiber layer (RNFL) thickness was measured by spectral-domain optical coherence tomography. Visual function was estimated by flash visual evoked potentials (FVEPs). Dendritic spines were observed in the V1 region contralateral to the ONC eye by two-photon imaging in vivo. The neurons, reactive astrocytes, oligodendrocytes, and activated microglia were assessed by NeuN, glial fibrillary acidic protein, CNPase, and CD68 in immunohistochemistry, respectively. Tropomyosin receptor kinase B (TrkB) and the markers in TrkB trafficking were estimated using western blotting and co-immunoprecipitation. Transmission electron microscopy and western blotting were used to evaluate autophagy. Results: The amplitude and latency of FVEPs were decreased and delayed at 3 days, 1 week, 2 weeks, and 4 weeks after ONC, and RNFL thickness was decreased at 2 and 4 weeks after ONC. Dendritic spines were reduced in the V1 region contralateral to the ONC eye at 2, 3, and 4 weeks after ONC, with an unchanged number of neurons. Reactive astrocyte staining was increased at 2 and 4 weeks after ONC, but oligodendrocyte and activated microglia staining remained unchanged. TrkB was reduced with changes in the major trafficking proteins, and enhanced autophagy was observed in the V1 region contralateral to the ONC eye. Conclusions: Dendritic spines were reduced in the V1 region contralateral to the ONC eye in adult mice. Reactive astrocytes and decreased TrkB may be associated with the reduced dendritic spines.

Apoptosis-inducing factor (AIF) nuclear translocation mediated caspase-independent mechanism involves in X-ray-induced MCF-7 cell death.

PURPOSE: Breast cancer is the most common cancer among women and radiotherapy is a conventional therapy following surgery. Previous studies have demonstrated that except the caspase-dependent pathway, caspase-independent pathway is also involved in the cell death responding to irradiation, despite the unclear mechanism. The purpose of the present study was to observe the role of apoptosis-inducing factor (AIF), the first identified caspase-independent molecule, in X-ray-induced breast cancer cell (MCF-7) cell death. MATERIALS AND METHODS: In this study, WST-1 assay, DAPI nuclear staining and clonogenic survival assay were used to test the cell response to different treatments; Western blot was used to detect the protein expression; RT-PCR and plasmid transfection were used to observe the role of AIF. RESULTS: X-ray-induced AIF transferred from the mitochondrion to the nucleus. Inhibition of AIF expression reduced X-ray-induced MCF-7 cell death. Further, AIF nuclear translocation is in a caspase-independent manner in this process, but not caspase-dependent manner. CONCLUSIONS: The present study revealed that AIF nuclear translocation proceeded in X-ray-induced MCF-7 cell death in a caspase-independent manner.

Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy.