Behaviors In Mouse Model Research Articles

Characterization of Apathy-Like Behaviors in Mouse Models of Down Syndrome.

Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer's disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging.

Cognitive behavioral phenotyping of DSCAM heterozygosity as a model for autism spectrum disorder.

It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss-of-function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM, as in the DSCAM2J+/-, that is, DSCAM heterozygous mice, displayed hyperactivity, increased anxiety-like behavior, and motor coordination deficits. Additionally, hippocampal-dependent learning and memory was affected, including impairments in working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic-like behaviors that are similar to those observed in human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM2J+/- as a suitable model for ASD research.

Low-intensity transcranial focused ultrasound suppresses pain by modulating pain-processing brain circuits

AbstractThere is an urgent and unmet clinical need to develop nonpharmacological interventions for chronic pain management because of the critical side effects of opioids. Low-intensity transcranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly focused 128-element ultrasound transducer to specifically target small mouse brains using dynamic focus steering. We demonstrate that tFUS stimulation at pain-processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (eg, insula) and multisession focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitivity-related and chronic hyperalgesia–associated neural signals after focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting interexperiment intervals, and investigating effects on age, sex, and genotype in a head-fixed awake model. Importantly, tFUS was found to be safe, causing no adverse effects on motor function or the brain’s neuropathology. In conclusion, the validated proof-of-principle experimental evidence demonstrates the translational potential of novel focused ultrasound neuromodulation for next-generation pain treatment without adverse effects.

Peripherally restricted cannabinoid and mu-opioid receptor agonists synergistically attenuate neuropathic mechanical hypersensitivity in mice.

Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors (Cnr1 and Oprm1) is coexpressed across different neuron clusters. Myc-CB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain.

Gut-brain barrier dysfunction bridge autistic-like behavior in mouse model of maternal separation stress: A behavioral, histopathological, and molecular study.

Autism spectrum disorder (ASD) is a fast-growing neurodevelopmental disorder throughout the world. Experiencing early life stresses (ELS) like maternal separation (MS) is associated with autistic-like behaviors. It has been proposed that disturbance in the gut-brain axis-mediated psychiatric disorders following MS. The role of disruption in the integrity of gut-brain barrier in ASD remains unclear. Addressing this knowledge gap, in this study we aimed to investigate role of the gut-brain barrier integrity in mediating autistic-like behaviors in mouse models of MS stress. To do this, mice neonates are separated daily from their mothers from postnatal day (PND) 2 to PND 14 for 3hours. During PND58-60, behavioral tests related to autistic-like behaviors including three-chamber sociability, shuttle box, and resident-intruder tests were performed. Then, prefrontal cortex (PFC), hippocampus, and colon samples were dissected out for histopathological and molecular evaluations. Results showed that MS is associated with impaired sociability and social preference indexes, aggressive behaviors, and impaired passive avoidance memory. The gene expression of CLDN1 decreased in the colon, and the gene expression of CLDN5, CLDN12, and MMP9 increased in the PFC of the MS mice. MS is associated with decrease in the diameter of CA1 and CA3 areas of the hippocampus. In addition, MS led to histopathological changes in the colon. We concluded that, probably, disturbance in the gut-brain barrier integrities mediated the autistic-like behavior in MS stress in mice.

Reviving: restoring depression-like behaviour through glial cell-derived neurotrophic factor treatment in the medial prefrontal cortex.

Depression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease. We used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC. We included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models. A subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design. Our findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease.

The developmental timing of spinal touch processing alterations predicts behavioral changes in genetic mouse models of autism spectrum disorders

Altered somatosensory reactivity is frequently observed among individuals with autism spectrum disorders (ASDs). Here, we report that although multiple mouse models of ASD exhibit aberrant somatosensory behaviors in adulthood, some models exhibit altered tactile reactivity as early as embryonic development, whereas in others, altered reactivity emerges later in life. Additionally, tactile overreactivity during neonatal development is associated with anxiety-like behaviors and social behavior deficits in adulthood, whereas tactile overreactivity that emerges later in life is not. The locus of circuit disruption dictates the timing of aberrant tactile behaviors, as altered feedback or presynaptic inhibition of peripheral mechanosensory neurons leads to abnormal tactile reactivity during neonatal development, whereas disruptions in feedforward inhibition in the spinal cord lead to touch reactivity alterations that manifest later in life. Thus, the developmental timing of aberrant touch processing can predict the manifestation of ASD-associated behaviors in mouse models, and differential timing of sensory disturbance onset may contribute to phenotypic diversity across individuals with ASD.

Umbelliprenin via increase in the MECP2 and attenuation of oxidative stress mitigates the autistic-like behaviors in mouse model of maternal separation stress.

Introduction: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition. Maternal separation (MS) stress is an early-life stress factor associated with behaviors resembling Autism. Both MECP2 and oxidative stress are implicated in the pathophysiology of Autism. Umbelliprenin (UMB) is a coumarin compound with various pharmacological properties. Our study aimed to investigate the potential effects of UMB in mitigating autistic-like behaviors in a mouse model subjected to MS stress, focusing on probable alterations in MECP2 gene expression in the hippocampus. Methods: MS paradigm was performed, and mice were treated with saline or UMB. Behavioral tests consisting of the three-chamber test (evaluating social interaction), shuttle box (assessing passive avoidance memory), elevated plus-maze (measuring anxiety-like behaviors), and marble-burying test (evaluating repetitive behaviors) were conducted. Gene expression of MECP2 and measurements of total antioxidant capacity (TAC), nitrite level, and malondialdehyde (MDA) level were assessed in the hippocampus. Results: The findings demonstrated that MS-induced behaviors resembling Autism, accompanied by decreased MECP2 gene expression, elevated nitrite, MDA levels, and reduced TAC in the hippocampus. UMB mitigated these autistic-like behaviors induced by MS and attenuated the adverse effects of MS on oxidative stress and MECP2 gene expression in the hippocampus. Conclusion: In conclusion, UMB likely attenuated autistic-like behaviors caused by MS stress, probably, through the reduction of oxidative stress and an increase in MECP2 gene expression.

Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen

Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior.

Fosphenytoin alleviates subacute herpetic neuralgia and postherpetic neuralgia in mice

Abstract Objective This study aimed to explore the analgesic effects of fosphenytoin (fPHT) on pain-related behaviours in mouse models of subacute herpetic neuralgia (subAHN) and postherpetic neuralgia (PHN). SubAHN refers to pain experienced immediately after the disappearance of a skin rash, while PHN is characterized by persistent pain long after skin rash resolution. Methods Our experimental approach involved the induction of acute herpes zoster-like skin lesions and pain-related responses (mechanical allodynia and hyperalgesia) in the hind paws of mice through cutaneous inoculation with herpes simplex virus type 1 (HSV-1). Subsequently, subAHN and PHN developed in the mice. Key findings Intravenous administration of fPHT (30 mg/kg) effectively mitigated HSV-1-induced subAHN and PHN. The suppressive effect of fPHT on subAHN was comparable to that of pregabalin (3 mg/kg, oral), a commonly used positive control. However, fPHT exhibited a slightly more potent effect than pregabalin in alleviating PHN. Conclusions These findings suggest that intravenous fPHT could serve as a promising alternative for pain relief in both subAHN and PHN.

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models.

Autism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology. The GABA B receptor agonist R-Baclofen and the selective agonist for the 5HT7 serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD. To evaluate the efficacy of these compounds in more details, we treated BTBR T+ Itpr3 tf /J and B6.129P2-Fmr1 tm1Cgr /J mice acutely with R-Baclofen or LP-211 and evaluated the behavior of animals in a series of tests. BTBR mice showed motor deficits, elevated anxiety, and highly repetitive behavior of self-grooming. Fmr1-KO mice exhibited decreased anxiety and hyperactivity. Additionally, Fmr1-KO mice's ultrasonic vocalizations were impaired suggesting a reduced social interest and communication of this strain. Acute LP-211 administration did not affect the behavioral abnormalities observed in BTBR mice but improved repetitive behavior in Fmr1-KO mice and showed a trend to change anxiety of this strain. Acute R-Baclofen treatment improved repetitive behavior only in Fmr1-KO mice. Our results add value to the current available data on these mouse models and the respective compounds. Yet, additional studies are needed to further test R-Baclofen and LP-211 as potential treatments for ASD therapy.

Decreased β-hydroxybutyrate and ketogenic amino acid levels in depressed human adults.

β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analysed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the prefrontal cortex at 6 h. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly decreased in the liver and PFC after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.

Real-Time Void Spot Assay.

Normal voiding behavior is the result of the coordinated function of the bladder, the urethra, and the urethral sphincters under the proper control of the nervous system. To study voluntary voiding behavior in mouse models, researchers have developed the void spot assay (VSA), a method that measures the number and area of urine spots deposited on a filter paper lining the floor of an animal's cage. Although technically simple and inexpensive, this assay has limitations when used as an end-point assay, including a lack of temporal resolution of voiding events and difficulties quantifying overlapping urine spots. To overcome these limitations, we developed a video-monitored VSA, which we call real-time VSA (RT-VSA), and which allows us to determine voiding frequency, assess voided volume and voiding patterns, and make measurements over 6 h time windows during both the dark and light phases of the day. The method described in this report can be applied to a wide variety of mouse-based studies that explore the physiological and neurobehavioral aspects of voluntary micturition in health and disease states.

Combination of curcumin and piperine synergistically improves pain-like behaviors in mouse models of pain with no potential CNS side effects

BackgroundCurcumin and piperine are major bioactive compounds of Curcuma longa and Piper nigrum, widely consumed as spices and flock medicine. The combinational use of these plants is a common practice in Southeast Asia. Synergism between curcumin and piperine has been found in several animal models but not in periodontal disease and diabetes, and the antinociceptive interaction is still unknown. Hence, the present study aimed to assess the interaction between curcumin and piperine in pain and its potential CNS side effect profile.MethodsFormalin test and in vitro LPS-stimulated RAW 264.7 macrophage cells were used to assess the synergistic interaction of curcumin and piperine in a mouse model of inflammatory pain. Tail-flick and cold plate tests were applied to determine the antinociceptive synergism between piperine and curcumin. The interaction was determined by applying isobolographic analysis. The potential CNS-side effects of the curcumin and piperine combination were also assessed using LABORAS automated home-cage behavioral analysis.ResultsCurcumin alone dose-dependently improved pain-like behaviors in the formalin, tail-flick, and cold plate tests with the ED50 of 71.4, 34.4, and 31.9 mg/kg, respectively. Additionally, piperine exhibited efficacy in the formalin, tail-flick, and cold plate tests with the ED50 of 18.4, 8.1, and 28.1 mg/kg, respectively. The combination of curcumin and piperine (1:1 ED50 ratio) produced synergistic interaction in the formalin, tail-flick, and cold plate tests as assessed significantly lower experimental ED50 values (5.9, 5.2, and 5.5 mg/kg) compared to theoretical ED50 values (44.9, 21.3, and 30.0 mg/kg), isobologram analysis, and interaction index values of 0.13, 0.24 and 0.18, respectively. The synergistic interaction of curcumin and piperine was further confirmed by the efficacy of the combination in LPS-stimulated RAW 264.7 macrophage cells. Curcumin and piperine interacted synergistically, reducing proinflammatory mediators. The combination also demonstrated better compatibility profiles with neuronal cells. Furthermore, the curcumin-piperine combination had no effects on mouse spontaneous locomotor behaviors in LABORAS automated home cage monitoring.ConclusionOverall, the present study demonstrates strong antinociceptive synergism between curcumin and piperine in mouse models with no potential CNS side effects, suggesting its possible use in clinical trials.

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

BackgroundMajor depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation.MethodsWe established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence.ResultsDrd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression.ConclusionsDrd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

An open-source, low-cost voluntary running activity tracking tool for in vivo rodent studies

In vivo rodent behavioral and physiological studies often benefit from measurement of general activity. However, many existing instruments necessary to track such activity are high in cost and invasive within home cages, some even requiring extensive separate cage systems, limiting their widespread use to collect data. We present here a low-cost open-source alternative that measures voluntary wheel running activity and allows for modulation and customization, along with a reproducible and easy to set-up code pipeline for setup and analysis in Arduino IDE and R. Our robust, non-invasive scalable voluntary running activity tracker utilizes readily accessible magnets, Hall effect sensors, and an Arduino microcontroller. Importantly, it can interface with existing rodent home cages and wheel equipment, thus eliminating the need to transfer the mice to an unfamiliar environment. The system was validated both for accuracy by a rotating motor used to simulate mouse behavior, and in vivo. Our recorded data is consistent with results found in the literature showing that the mice run between 3 to 16 kilometers per night, and accurately captures speed and distance traveled continuously on the wheel. Such data are critical for analysis of highly variable behavior in mouse models and allow for characterization of behavioral metrics such as general activity. This system provides a flexible, low-cost methodology, and minimizes the cost, infrastructure, and personnel required for tracking voluntary wheel activity.

Depression-like behaviors in mouse model of Sjögren's syndrome: A role of gut–microbiota–brain axis

Depression is a common psychiatric symptom in patients with Sjögren's syndrome (SS). Prevalence of depression in SS patients is significantly higher than that in the general population. Increasing evidence suggests a crucial role of gut–microbiota–brain axis in depression. In this study, we investigated whether non-obese diabetic (NOD) mice, a widely used animal model of SS, exhibit depression-like phenotypes and abnormal composition of gut microbiota. Eleven-week-old NOD mice spontaneously exhibited SS-related symptoms without pancreatic destruction. NOD mice displayed depression-like behaviors, decreased expression of synaptic proteins in the prefrontal cortex (PFC), and abnormal composition of gut microbiota. Interestingly, SS-related proinflammatory factors in the submandibular gland (SMG) and autoantibodies (anti-SSA and anti-SSB) in the plasma were correlated with the expression of synaptic proteins in the PFC or depression-like behaviors. In addition, there were correlations between the relative abundance of microbiota and SS-related symptoms (or depression-related phenotypes). These data suggest that SS-related symptoms and abnormal composition of gut microbiota may play a role in depression-like phenotypes in NOD mice through gut–microbiota–brain axis.

The Role of AlphαSynuclein in Mouse Models of Acute, Inflammatory and Neuropathic Pain.

(1) AlphαSynuclein (αSyn) is a synaptic protein which is expressed in the nervous system and has been linked to neurodegenerative diseases, in particular Parkinson’s disease (PD). Symptoms of PD are mainly due to overexpression and aggregation of αSyn and include pain. However, the interconnection of αSyn and pain has not been clarified so far. (2) We investigated the potential effects of a αSyn knock-out on the nociceptive behaviour in mouse models of acute, inflammatory and neuropathic pain. Furthermore, we assessed the impact of αSyn deletion on pain-related cellular and molecular mechanisms in the spinal cord in these models. (3) Our results showed a reduction of acute cold nociception in αSyn knock-out mice while responses to acute heat and mechanical noxious stimulation were similar in wild type and knock-out mice. Inflammatory nociception was not affected by αSyn knock-out which is also mirrored by unaltered inflammatory gene expression. In contrast, in the SNI model of neuropathic pain, αSyn knock-out mice showed decreased mechanical allodynia as compared to wild type mice. This effect was associated with reduced proinflammatory mechanisms and suppressed activation of MAP kinase signalling in the spinal cord while endogenous antinociceptive mechanisms are not inhibited. (4) Our data indicate that αSyn plays a role in neuropathy and its inhibition might be useful to ameliorate pain symptoms after nerve injury.

Batatasin III, a Constituent of Dendrobium scabrilingue, Improves Murine Pain-like Behaviors with a Favorable CNS Safety Profile.

Batatasin III is a stilbenoid compound present in a wide variety of Dendrobium species. Although the pharmacological efficacy of batatasin III has been reported in several disease models, its antinociceptive efficacy and central nervous system (CNS) side effects remain unknown. Thus, this study examined the effects of batatasin III on pain-like behaviors in mouse models of formalin- and lipopolysaccharide (LPS)-induced inflammatory pain. The results revealed a significant antinociceptive effect of batatasin III in both models, as 50 mg/kg batatasin III elicited comparable antinociception as 10 mg/kg indomethacin. Further, the anti-inflammatory effect of batatasin III was assessed in LPS-induced RAW 264.7 macrophages and BV-2 microglial cells. The compound significantly reduced the levels of inflammatory mediators (nitric oxide, TNF-α, and IL-6) in LPS-stimulated cells in a concentration-dependent manner. Following efficacy evaluations, the potential CNS side effects of batatasin III were evaluated using the rotarod test and the Laboratory Animal Behavior Observation, Registration, and Analysis System. Batatasin III-treated mice exhibited comparable forced, spontaneous, and general locomotive behaviors to vehicle-treated mice, indicating no potential CNS side effects. Overall, this study demonstrated the preclinical antinociceptive efficacy and CNS safety of batatasin III, suggesting its potential role in the development of new analgesics.

Assessing negative affect in mice during abstinence from alcohol drinking: Limitations and future challenges.

Alcohol use disorder (AUD) is frequently comorbid with mood disorders, and these co-occurring neuropsychiatric disorders contribute to the development and maintenance of alcohol dependence and relapse. In preclinical models, mice chronically exposed to alcohol display anxiety-like and depressive-like behaviors during acute withdrawal and protracted abstinence. However, in total, results from studies using voluntary alcohol-drinking paradigms show variable behavioral outcomes in assays measuring negative affective behaviors. Thus, the main objective of this review is to summarize the literature on the variability of negative affective behaviors in mice after chronic alcohol exposure. We compare the behavioral phenotypes that emerge during abstinence across different exposure models, including models of alcohol and stress interactions. The complicated outcomes from these studies highlight the difficulties of assessing negative affective behaviors in mouse models designed for the study of AUD. We discuss new behavioral assays, comprehensive platforms, and unbiased machine-learning algorithms as promising approaches to better understand the interaction between alcohol and negative affect in mice. New data-driven approaches in the understanding of mouse behavior hold promise for improving the identification of mechanisms, cell subtypes, and neurocircuits that mediate negative affect. In turn, improving our understanding of the neurobehavioral basis of alcohol-associated negative affect will provide a platform to test hypotheses in mouse models that aim to improve the development of more effective strategies for treating individuals with AUD and co-occurring mood disorders.