Neuronal and Molecular Mechanisms Underlying Chronic Pain and Depression Comorbidity in the Paraventricular Thalamus.

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.

Multiple integrated social stress induces depressive-like behavioral and neural adaptations in female C57BL/6J mice.

Despite women representing most of those affected by major depression, preclinical studies have focused almost exclusively on male subjects, partially due to a lack of ideal animal paradigms. As the persistent need regarding the sex balance of neuroscience research and female-specific pathology of mental disorders surges, the establishment of natural etiology-based and systematically validated animal paradigms for depression with female subjects becomes an urgent scientific problem. This study aims to establish, characterize, and validate a "Multiple Integrated Social Stress (MISS)" model of depression in female C57BL/6J mice by manipulating and integrating daily social stressors that females are experiencing. Female C57BL/6J mice randomly experienced social competition failure in tube test, modified vicarious social defeat stress, unescapable overcrowding stress followed by social isolation on each day, for ten consecutive days. Compared with their controls, female MISS mice exhibited a relatively decreased preference for social interaction and sucrose, along with increased immobility in the tail suspension test, which could last for at least one month. These MISS mice also exhibited increased levels of blood serum corticosterone, interleukin-6 L and 1ß. In the pharmacological experiment, MISS-induced dysfunctions in social interaction, sucrose preference, and tail suspension tests were amended by systematically administrating a single dose of sub-anesthetic ketamine, a rapid-onset antidepressant. Compared with controls, MISS females exhibited decreased c-Fos activation in their anterior cingulate cortex, prefrontal cortex, nucleus accumbens and some other depression-related brain regions. Furthermore, 24 h after the last exposure to the paradigm, MISS mice demonstrated a decreased center zone time in the open field test and decreased open arm time in the elevated plus-maze test, indicating anxiety-like behavioral phenotypes. Interestingly, MISS mice developed an excessive nesting ability, suggesting a likely behavioral phenotype of obsessive-compulsive disorder. These data showed that the MISS paradigm was sufficient to generate pathological profiles in female mice to mimic core symptoms, serum biochemistry and neural adaptations of depression in clinical patients. The present study offers a multiple integrated natural etiology-based animal model tool for studying female stress susceptibility.

Noradrenergic modulation of stress resilience.

Resilience represents an active adaption process in the face of adversity, trauma, tragedy, threats, or significant sources of stress. Investigations of neurobiological mechanisms of resilience opens an innovative direction for preclinical research and drug development for various stress-related disorders. The locus coeruleus norepinephrine system has been implicated in mediating stress susceptibility versus resilience. It has attracted increasing attention over the past decades with the revolution of modern neuroscience technologies. In this review article, we first briefly go over resilience-related concepts and introduce rodent paradigms for segregation of susceptibility and resilience, then highlight recent literature that identifies the neuronal and molecular substrates of active resilience in the locus coeruleus, and discuss possible future directions for resilience investigations.

A DNAzyme-catalyzed label-free aptasensor based on multifunctional dendrimer-like DNA assembly for sensitive detection of carcinoembryonic antigen.

Carcinoembryonic antigen (CEA) is an important malign tumor marker. In this study, a simple, label-free and antibody-free aptasensor was fabricated based on a multifunctional dendrimer-like DNA nanoassembly. The DNA nanoassembly was embedded with multiple G-quadruplex DNAzyme motifs and a hanging CEA aptamer motif. It was prepared from short DNA sequences by autonomous-assembly. The aptasensor was prepared simply by self-assembly of a capture DNA (cpDNA) on a gold electrode, followed by hybridization with a CEA aptamer (AptGAC-P). CEA as a model target was detected through competitive binding of CEA with AptGAC-P, exposing cpDNA to bind with the DNA nanoassembly. The detection process only contains 2 incubation steps. The high load of G-quadruplex DNAzyme motifs and their catalytic activity resulted in an amplified and label-free differential pulse voltammetry (DPV) electrochemical signal. The peak current correlated linearly with the CEA concentration, with a linear range of 2-45 ng mL-1, and an LOD value of 0.24 ng mL-1. The aptasensor showed high specificity and reproducibility, and retained 96.5% of detection signal intensities after 31 days of storage. The recovery rates for spiked CEA in human serum were within 100 ± 5%, and the coincidence rates for clinical human serum samples with ELISA kits were 80.7-111%. Conceivably, possessing simplicity, sensitivity, reproducibility, storage stability, and accuracy, the aptasensor should be a very prominent and applicable tool for clinical CEA detection and cancer diagnosis, and is promisingly applicable as a platform for detecting other targets of interests.

Behaviors Related to Psychiatric Disorders and Pain Perception in C57BL/6J Mice During Different Phases of Estrous Cycle.

Robust sex difference among humans regarding psychiatry- and pain-related behaviors is being researched; however, the use of female mice in preclinical research is relatively rare due to an unchecked potential behavioral variation over the estrous cycle. In the present study, a battery of psychiatry- and pain-related behaviors are examined under physiological condition in female C57BL/6J mice over different estrous cycle phases: proestrus, estrous, metestrous, diestrous. Our behavioral results reveal that there is no significant difference over different phases of the estrous cycle in social interaction test, sucrose preference test, tail suspension test, open field test, marble burying test, novelty-suppressed feeding test, Hargreaves thermal pain test, and Von Frey mechanical pain test. These findings implicate those psychiatry- and pain-related behaviors in normal female C57BL/6J mice appear to be relatively consistent throughout the estrous cycle; the estrous cycle might not be a main contributor to female C57BL/6J mice's variability of behaviors.

An acetylcholinesterase biosensor based on doping Au nanorod@SiO2 nanoparticles into TiO2-chitosan hydrogel for detection of organophosphate pesticides.

A stable and sensitive electrochemical acetylcholinesterase (AChE) biosensor for detection of organophosphorus pesticides (OPs) was developed by doping Au nanorods (AuNRs)@mesoporous SiO2 (MS) core-shell nanoparticles into CS/TiO2-CS (CS denotes for chitosan) immobilization matrix. AuNRs@MS core-shell nanoparticles were synthesized and characterized. The doping and the biosensor fabrication process were probed and confirmed by scanning electron microscopy and electrochemistry techniques. The doping conditions were optimized. The matrix both before and after AChE immobilization had a mesoporous nanostructure. The nanoparticles dispersed homogeneously within the matrix. The doping significantly enhanced the electro-conductivity of the TiO2-CS hydrogel, and dramatically improved the bioelectrocatalytic activity and OPs detection sensitivity of the AChE immobilized matrix. The detection linear ranges for both dichlovos (DDVP) and fenthion were from 0.018 µM (4.0 ppb) to 13.6 µM, and the limit of detection (LOD) was 5.3 nM (1.2 ppb) and 1.3 nM (0.36 ppb), respectively. The biosensor exhibited high reproducibility and accuracy in detecting OPs spiked vegetable juice samples. In addition, it exhibited very high detection stability and storage stability. The developed AChE biosensor was provided to be a promisingly applicable tool for OPs detection with high reliability, simplicity, and rapidness.