Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways.

Threat and extinction memories are crucial for organisms' survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

Intranasal administration of white tea alleviates the olfactory function deficit induced by chronic unpredictable mild stress.

CONTEXT: White tea [Camellia sinensis (L) O.Ktze. (Theaceae)] is popular in Asia, but its benefits on olfactory injury are unknown. OBJECTIVE: The present study explores the effects of white tea on the olfactory injury caused by chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: C57BL/6J mice (WT) were exposed to CUMS. CUMS mice (CU) were intranasally treated with white tea extract [low tea (LT), 20 mg/kg; high tea (HT), 40 mg/kg] and fluoxetine (CF, 20 mg/kg) for 7 days. Several behavioural tests were conducted to assess depression and olfactory function. The transmission electron microscope (TEM) and semi-quantitative reverse transcription PCR were performed separately to observe the changes of related structures and genes transcription level. RESULTS: The depressive behaviours of the LT and HT mice were reversed. The latency time of the buried food pellet test decreased from 280 s (CU) to 130 s (HT), while the olfactory sensitivity and olfactory avoidance test showed that the olfactory behaviours disorder of LT and HT mice were alleviated. The white tea increased the A490 nm values of the cortisol treated cells from 0.15 to 1.4. Reduced mitochondrial and synaptic damage in the olfactory bulb (OB), enhanced expression of the brain-derived neurotrophic factor (BDNF) and olfactory marker protein (OMP) were observed in the LT and HT mice. CONCLUSIONS AND DISCUSSION: White tea has the potential in curing the olfactory deficiency related to chronic stress. It lays the foundation for the development of new and reliable drug to improve olfactory.

Age-specific effects of P2X7 receptors on olfactory function in mice.

This study aimed to explore the age-specific effects of P2X7 receptor (P2X7R) knockout on olfactory function in mice. In this study, we analyzed olfactory functions of 2-month-old, 10-month-old and 18-month-old female P2X7R KO mice and age-matched female C57BL/6 wildtype mice (WT mice) by buried food seeking test and olfactory avoidance test. The structure of mitochondria and synapses in olfactory bulb were observed by electron microscopy. The content of interleukin-1 (IL-1ß) in olfactory bulb and transforming growth factor beta 1 (TGF-ß1) in olfactory epithelium were analyzed by ELISA. The results indicated that middle and old-aged P2X7R KO mice showed better olfactory function than middle and old-aged WT mice. Mitochondrial structures were complete and more spine synapses were observed in middle and old-aged P2X7R KO mice. Compared with middle and old-aged WT mice, IL-1ß content in olfactory bulb was decreased in middle and old-aged P2X7R KO mice, and there was no significant difference in TGF-ß1 content in olfactory epithelium. However, worse olfactory function was observed in young-aged P2X7R KO mice compared with young-aged WT mice. Abnormal mitochondrial structure and less synapses in olfactory bulb were observed. TGF-ß1 content in olfactory epithelium was significantly higher in P2X7R KO mice compared with young-aged WT mice. There was no significant difference in IL-1ß content in olfactory bulb of young-aged mice. In conclusion, P2X7R knockout can improve the olfactory function of middle and old-aged mice, while it may cause damage to young-aged mice, suggesting that P2X7R plays age-specific role on olfactory functions in mice.

The effects of P2X7 receptor knockout on emotional conditions over the lifespan of mice.

Neuroinflammation is one of the key factors contributing to depression. Recent studies have identified P2X7 receptor (P2X7r) as a major inflammatory regulator. However, the effects of P2X7r knockout (KO) on emotional conditions over the lifespan of mice are unknown. In this study, the effects of P2X7r deletion on emotional conditions over the lifespan of mice were investigated in young-aged (2 month old), middle-aged (10 month old), and old-aged (18 month old) female P2X7r KO mice and age-matched female C57BL/6 mice. Behavioral tasks were conducted by open field test, forced swimming test and sucrose preference test. Mitochondrial structures and spine synapses in hippocampus were examined by electron microscopy. Enzyme-linked immunosorbent assay was used to analyze the expression of interleukin-1ß and tumor necrosis factor-α. Western blot analysis was used to assess the expression of nuclear factor-kappa B (NF-κB) pathway-related proteins. The results indicated that middle-aged P2X7r KO mice displayed better emotional conditions than middle-aged WT mice. However, worse emotional conditions were observed in young-aged P2X7r KO mice. Moreover, abnormal mitochondrial structures and less spine synapses were observed in young-aged P2X7r KO mice. Mitochondrial structures were recovered and more spine synapses occurred in middle-aged P2X7r KO mice. In addition, expressions of interleukin-1ß, tumor necrosis factor-α, p-IKKα, p-IKKß, p-IκBα, and p-NF-κBp65 were decreased in middle-aged P2X7r KO mice, but increased in young-aged P2X7r KO mice. In conclusion, P2X7r KO improves the emotional conditions at later stages of the lifespan of mice, but not in all ages, suggesting time-specific roles of immune response in nervous system through NF-κB signaling pathway. Video abstract: http://links.lww.com/WNR/A494.

Hypolipidemic effect of Fragarianilgerrensis Schlecht. medicine compound on hyperlipidemic rats.

BACKGROUND: Fragarianilgerrensis Schlecht. medicine compound (FN-MC) is a kind of Chinese herbs' compound consisted of Fragarianilgerrensis Schlecht. and Centella asiatica (L.) Urban. The study was to investigate the hypolipidemia effect of FN-MC in a hypolipidemic rat model. METHODS: Male SD rats were randomly divided into five groups: normal-fat diet (NFD) group, high-fat diet (HFD) group, FN-MC (2 g/Kg) group, FN-MC (4 g/Kg) group and simvastatin (PDC) group. After FN-MC treatment, body weight, food intake, serum and hepatic biochemistry parameters of rats were measured and the pathological changes of liver and its cells were observed by optical microscope and transmission electron microscopy. RESULTS: The results showed that FN-MC significantly decreased the levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), apolipoprotein B (ApoB) and hepatic malondialdehyde (MDA), while increased serum high-density lipoprotein (HDL-C), apolipoprotein A1 (ApoA1) and hepatic Superoxide Dismutase (SOD). FN-MC also improved the structure of liver and decreased the lipid drops in the cytoplasm significantly. In addition, FN-MC significantly decreased the weight gain and had no significant effects on food intake. CONCLUSIONS: The study suggested that FN-MC exhibited strong ability to improve the dyslipidemia and prevent hepatic fatty deposition in rats fed with high-fat diet. Meanwhile, FN-MC exerted anti-obesity and antioxidant properties. HIGHLIGHTS: Fragarianilgerrensis Schlecht. medicine compound possesses a hypolipidemic effect on hyperlipidemic rat model Fragarianilgerrensis Schlecht. medicine compound administration improves the antioxidant capacity of rats Fragarianilgerrensis Schlecht. medicine compound prevents hepatic fatty deposition.

Antidiabetic and Neuroprotective Effect of the N-Butanol Extract of Fragaria nilgerrensis Schlecht. in STZ-Induced Diabetic Mice.

Diabetes has been associated with neurodegenerative disorders that are accompanied by memory loss and cognitive impairments, but there is no effective treatment for it at present. Fragaria nilgerrensis Schlecht. (FNS), a well-known Chinese materia medica, has been traditionally used for the folkloric treatment of diabetes and other diseases. However, its effects are poorly documented. Here, we investigated the antidiabetic and neuroprotective effect of FNS in diabetic mice. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) evaluations of N-butanol extract of Fragaria nilgerrensis Schlecht. (N-FNS) showed the presence of flavonoid and its structure is similar to scutellarin. For the first time, we show the potential neuroprotective and antidiabetic effects of FNS. After 4 weeks of FNS intervention, a significant decrease in blood glucose, increase in body weight, and amelioration in glucose tolerance were observed in FNS treated diabetic mice. In the acute study, FNS enhanced motor activity in the open field task and significantly prevented spatial-learning deficits in Morris water maze tests. Besides, synapse ultrastructure of the hippocampus showed that the mitochondrial morphology was basically restored and all the synaptic structural parameters were gradually normalized after treatment with FNS. Importantly, we found that the activities of SOD and CAT in liver and hippocampus of diabetic mice significantly increased after FNS administration. In vitro, FNS and scutellarin showed high DPPH radical scavenging activity. The study suggests that FNS exerted significant antidiabetic and neuroprotective effects which may be attributed to its antioxidant property.