Healthy Rodents Research Articles

Chronic stability of single-channel neurophysiological correlates of gross and fine reaching movements in the rat.

While substantial task-related neural activity has been observed during motor tasks in rodent primary motor cortex and premotor cortex, the long-term stability of these responses in healthy rats is uncertain, limiting the interpretability of longitudinal changes in the specific patterns of neural activity associated with learning or motor recovery following injury. This study examined the stability of task-related neural activity associated with execution of two distinct reaching tasks in healthy rodents. A novel automated rodent behavioral apparatus was constructed and rats were trained to perform a reaching task combining a ‘gross’ lever press and a ‘fine’ pellet retrieval. In each animal, two chronic microelectrode arrays were implanted in motor cortex spanning the caudal forelimb area (rodent primary motor cortex) and the rostral forelimb area (rodent premotor cortex). We recorded multiunit spiking and local field potential activity from 10 days to 7–10 weeks post-implantation to characterize the patterns of neural activity observed during each task component and analyzed the consistency of channel-specific task-related neural activity. Task-related changes in neural activity were observed on the majority of channels. While the task-related changes in multi-unit spiking and local field potential spectral power were consistent over several weeks, spectral power changes were more stable, despite the trade-off of decreased spatial and temporal resolution. These results show that neural activity in rodent primary and premotor cortex is associated with specific phases of reaching movements with stable patterns of task-related activity across time, establishing the relevance of the rodent for future studies designed to examine changes in task-related neural activity during recovery from focal cortical lesions.

The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice.

Abnormalities in neural oscillations that occur in the gamma frequency range (30-80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130-180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.

Tumor Necrosis Factor-α-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model.

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1β (IL-1β), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1β levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1β antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.

Crypt- and Mucosa-Associated Core Microbiotas in Humans and Their Alteration in Colon Cancer Patients.

We have previously identified a crypt-specific core microbiota (CSCM) in the colons of healthy laboratory mice and related wild rodents. Here, we confirm that a CSCM also exists in the human colon and appears to be altered during colon cancer. The colonic microbiota is suggested to be involved in the development of colorectal cancer (CRC). Because the microbiota identified in fecal samples from CRC patients does not directly reflect the microbiota associated with tumor tissues themselves, we sought to characterize the bacterial communities from the crypts and associated adjacent mucosal surfaces of 58 patients (tumor and normal homologous tissue) and 9 controls with normal colonoscopy results. Here, we confirm that bacteria colonize human colonic crypts in both control and CRC tissues, and using laser-microdissected tissues and 16S rRNA gene sequencing, we further show that right and left crypt- and mucosa-associated bacterial communities are significantly different. In addition to Bacteroidetes and Firmicutes, and as with murine proximal colon crypts, environmental nonfermentative Proteobacteria are found in human colonic crypts. Fusobacterium and Bacteroides fragilis are more abundant in right-side tumors, whereas Parvimonas micra is more prevalent in left-side tumors. More precisely, Fusobacterium periodonticum is more abundant in crypts from cancerous samples in the right colon than in associated nontumoral samples from adjacent areas but not in left-side colonic samples. Future analysis of the interaction between these bacteria and the crypt epithelium, particularly intestinal stem cells, will allow deciphering of their possible oncogenic potential.IMPORTANCE Due to the huge number of bacteria constituting the human colon microbiota, alteration in the balance of its constitutive taxa (i.e., dysbiosis) is highly suspected of being involved in colorectal oncogenesis. Indeed, bacterial signatures in association with CRC have been described. These signatures may vary if bacteria are identified in feces or in association with tumor tissues. Here, we show that bacteria colonize human colonic crypts in tissues obtained from patients with CRC and with normal colonoscopy results. Aerobic nonfermentative Proteobacteria previously identified as constitutive of the crypt-specific core microbiota in murine colonic samples are similarly prevalent in human colonic crypts in combination with other anaerobic taxa. We also show that bacterial signatures characterizing the crypts of colonic tumors vary depending whether right-side or left-side tumors are analyzed.

Dysfunctional striatal dopamine signaling in Huntington's disease.

Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning. Alterations to dopamine transmission contribute to pathological features of many neurological diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disorder caused by a CAG repeat expansion in the Huntingtin gene. The striatum is preferentially degenerated in HD, and this region receives dopaminergic input from the substantia nigra. Studies of HD patients and genetic rodent models have shown changes to levels of dopamine and its receptors in the striatum, and alterations in dopamine receptor signaling and modulation of other neurotransmitters, notably glutamate. Throughout his career, Dr. Michael Levine's research has furthered our understanding of dopamine signaling in the striatum of healthy rodents and HD mouse models. This review will focus on the work of his group and others in elucidating alterations to striatal dopamine signaling that contribute to pathophysiology in HD mouse models, and how these findings relate to human HD studies. We will also discuss current and potential therapeutic interventions for HD that target the dopamine system, and future research directions for this field.

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood-brain barrier, and the blood-retinal/ocular barrier, and to effectively reach the site of action while minimizing the systemic impact. In recent years, piggybacking cell surface receptors have been considered a viable strategy for active drug delivery across the biological barriers. However, the ligands used to target drugs to plasma membrane receptors often have to compete against endogenous ligands, thereby limiting their binding to the cell surface and their transport across barriers. To address this problem, gambogic acid (GA) was identified as a noncompetitive ligand specific to the transferrin receptor (TfR), a receptor present on various barriers. However, the binding sites of the GA on TfR remain unknown, an essential step toward establishing structure-activity relationships. In silico binding site prediction tools, blind docking, and molecular docking simulation confirm that the GA binding site on the TfR is independent of the transferrin-bound iron binding sites. The GA-conjugated polyesters were processed into nanoparticles suitable for drug delivery applications that possess excellent storage stability under regulatory conditions. Traditionally, GA has been used as an anticancer compound that warrants safety assessment. The preliminary studies in healthy rodents on 10-repeated oral doses show no adverse effects. This work will generate paradigm shifting, new knowledge in the field of nanomedicines using unique noncompetitive nanosystems that do not compete with endogenous transferrin.

Frequency-specific effects of low-intensity rTMS can persist for up to 2 weeks post-stimulation: A longitudinal rs-fMRI/MRS study in rats

BackgroundEvidence suggests that repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, alters resting brain activity. Despite anecdotal evidence that rTMS effects wear off, there are no reports of longitudinal studies, even in humans, mapping the therapeutic duration of rTMS effects. ObjectiveHere, we investigated the longitudinal effects of repeated low-intensity rTMS (LI-rTMS) on healthy rodent resting-state networks (RSNs) using resting-state functional MRI (rs-fMRI) and on sensorimotor cortical neurometabolite levels using proton magnetic resonance spectroscopy (MRS). MethodsSprague-Dawley rats received 10 min LI-rTMS daily for 15 days (10 Hz or 1 Hz stimulation, n = 9 per group). MRI data were acquired at baseline, after seven days and after 14 days of daily stimulation and at two more timepoints up to three weeks post-cessation of daily stimulation. Results10 Hz stimulation increased RSN connectivity and GABA, glutamine, and glutamate levels. 1 Hz stimulation had opposite but subtler effects, resulting in decreased RSN connectivity and glutamine levels. The induced changes decreased to baseline levels within seven days following stimulation cessation in the 10 Hz group but were sustained for at least 14 days in the 1 Hz group. ConclusionOverall, our study provides evidence of long-term frequency-specific effects of LI-rTMS. Additionally, the transient connectivity changes following 10 Hz stimulation suggest that current treatment protocols involving this frequency may require ongoing “top-up” stimulation sessions to maintain therapeutic effects.

Study of the potential adverse effects caused by the dermal application of Dillenia indica L. fruit extract standardized to betulinic acid in rodents.

This study aimed to evaluate the potential adverse effects of the dermal administration of Dillenia indica Linnaeus (D. indica) fruit extract in healthy rodents; the extract was standardized to betulinic acid. In the initial phase, the acute effects were evaluated on the skin application site of a single extract dose. A skin irritation test was performed in male Wistar rats (n = 8/group) receiving the extract (50–150 mg/mL) with betulinic acid (0.5–1.5%, respectively). A photosensitivity test was performed in male BALB/c mice (n = 6/group) receiving the extract (150 mg/mL). Afterwards, other BALB/c mice (n = 20, male:female, 1:1) were used to assess the systemic alterations caused by 14 daily repeated doses (150 mg/mL) by monitoring the effects on mortality, body morphology, behavior, nutrition status, neuromotor reactions, organ morphology and weight, and blood tests. At this time, 0.5 mg/mL clobetasol was used as the positive control. The skin irritation index suggested that negligible skin irritation had occurred, even when the extract was applied to the rat skin at 150 mg/mL. However, the extract acted as a photosensitizer on mouse skin, showing a photosensitizing activity close to that of 10 mg/mL 5-methoxypsoralen. Repeated doses caused no mouse mortality, aggressiveness, piloerection, diarrhea, convulsions, neuromotor alterations or nutrition status changes. The mouse organ weights did not change, and the mice did not have alterations in their blood compositions. Clobetasol caused a reduction in the mononuclear leukocyte numbers. In general, the data suggest that the extract was safe in healthy rodents but indicate that caution should be taken with the photosensitizing activity; in addition, this activity should be further explored as it may be useful for phototherapeutic drug development.

Establishment of a model of sentinel lymph node metastasis using immunodeficient swine

Lymph node metastasis occurs via the migration of cancer cells through the lymphatic system. Sentinel lymph node (SLN) biopsy is a common diagnostic strategy. SLNs have been studied using healthy rodents and large animals without metastasis. Here we used immunodeficient swine to establish a model of lymph node metastasis. We used RAG2-knockout immunodeficient swine. A431 human epithelial carcinoma cells expressing green fluorescent protein were injected subcutaneously into the posterior sides of the auricle, forelimb and hindlimb of knockout swine. Indigo carmine dye was injected subcutaneously 8 weeks after tumour cell transplantation. SLNs were extracted, observed using a stereoscopic fluorescence microscope and analysed histologically using haematoxylin and eosin staining, and immunohistochemistry. Lymphoid follicles were found in wild-type swine, and a few aggregated lymphocytes and immature lymphoid follicles were observed in knockout swine. Fluorescence in the lymph nodes indicated metastasis of tumour cells to the lymph nodes. Tumour cells replaced lymph node architectures, showed high-grade nuclear atypia and formed irregular tumour nests. Our model may be useful for the preclinical validation of diagnostic methods and minimally invasive treatment of metastatic cancer.

Prolonged Cannabidiol Treatment Lacks on Detrimental Effects on Memory, Motor Performance and Anxiety in C57BL/6J Mice.

The Cannabis plant contains more than 100 currently known phytocannabinoids. Regarding the rising consumption of the non-psychotropic phytocannabinoid cannabidiol (CBD) in people’s everyday life (e.g., beauty products, food and beverages), the importance of studies on the influence of CBD on healthy humans and rodents is evident. Therefore, the behavioral profile of CBD was investigated with a battery of behavioral tests, including motor, anxiety, and memory tests after prolonged CBD treatment. Adult C57Bl/6J wildtype (WT) mice were daily intraperitoneally injected with 20 mg/kg CBD for 6 weeks starting at two different points of ages (3 months and 5 months) to compare the influence of prolonged CBD treatment with a washout period (former group) to the effects of long term CBD treatment (current group). Our results show that CBD treatment does not influence motor performance on an accelerating Rotarod test, while it also results in a lower locomotor activity in the open field (OF). No influence of CBD on spatial learning and long term memory in the Morris Water Maze (MWM) was observed. Memory in the Novel Object Recognition test (NORT) was unaffected by CBD treatment. Two different anxiety tests revealed that CBD does not affect anxiety behavior in the Dark-Light Box (DLB) and OF test. Although, anxiety is altered by current CBD treatment in the Elevated Plus Maze (EPM). Moreover, CBD-treated C57Bl/6J mice showed an unaltered acoustic startle response (ASR) compared to vehicle-treated mice. However, current CBD treatment impairs prepulse inhibition (PPI), a test to analyze sensorimotor gating. Furthermore, prolonged CBD treatment did not affect the hippocampal neuron number. Our results demonstrate that prolonged CBD treatment has no negative effect on the behavior of adult C57Bl/6J mice.

T69. The Effect of Dopamine Drugs on Reward Discounting: A Systematic Review and Meta-Analysis

Although numerous studies have suggested that pharmacological alteration of the dopamine system alters reward discounting, these studies have yielded inconsistent findings. Here, we conducted a pre-registered systematic review and meta-analysis to evaluate dopaminergic drug-mediated effects on reward discounting of time delays, probabilities, and physical effort requirements in studies of healthy humans, non-human primates, and rodents.

General Anesthesia Does Not Have Persistent Effects on Attention in Rodents.

Background: Studies in animals have shown that general anesthesia can cause persistent spatial memory impairment, but the influence of anesthetics on other cognitive functions is unclear. This study tested whether exposure to general anesthesia without surgery caused a persistent deficit in attention in rodents.Methods: To evaluate whether anesthesia has persistent effects on attention, rats were randomized to three groups. Group A was exposed for 2 h to isoflurane anesthesia, and tested the following seven days for attentional deficits. Group B was used as a control and received room air before attentional testing. Since there is some evidence that a subanesthetic dose of ketamine can improve cognition and reduce disorders of attention after surgery, rats in group C were exposed to isoflurane anesthesia in combination with a ketamine injection before cognitive assessment. Attention was measured in rats using the 5-Choice Serial Reaction Time Task, for which animals were trained to respond with a nose poke on a touchscreen to a brief, unpredictable visual stimulus in one of five possible grid locations to receive a food reward. Attention was analyzed as % accuracy, % omission, and premature responses.Results: Evaluating acute attention by comparing baseline values with data from the day after intervention did not reveal any differences in attentional measurements. No significant differences were seen in % accuracy, % omission, and premature responses for the three groups tested for 7 consecutive days.Conclusion: These data in healthy rodents suggest that general anesthesia without surgery has no persistent effect on attention and the addition of ketamine does not alter the outcome.

Brainstem pre‐sympathetic neurons contribute to irregular breathing patterns in volume overload heart failure

Chronic heart failure (CHF) is characterized by sympathoexcitation and a high prevalence of breathing disorders. It has been shown that rostral ventrolateral medulla catecholaminergic neurons (RVLM‐C1) contributes to sympathetic outflow regulation in CHF and that RVLM‐C1 neurons are hyperactivated in experimental CHF. Recently, it has been shown that acute activation of RVLM‐C1 neurons also stimulates breathing in healthy rodents. However, there is no evidence showing the contribution of RVLM‐C1 neurons, if any, on breathing disorders in CHF. Therefore, we aimed to determine the role of RVLM‐C1 neurons on disordered breathing in CHF. Sprague‐Dawley rats underwent volume overload to induce CHF. Stereotaxic bilateral injections of anti‐dopamine β‐hydroxylase‐saporin toxin (DβH–SAP: 5ng/150nl) were used to selectively eliminate RVLM‐C1 neurons. Whole‐body plethysmography, blood pressure radiotelemetry and pression‐volume conductance catheter were used to study breathing stability, chemoreflex function, cardiac autonomic control, respiratory‐cardiovascular coupling (RCC) and cardiac function. Depletion of RVLM‐C1 neurons (~70%) in CHF rats (CHF+Veh vs. CHF+DβH+SAP, respectively) restored regular breathing pattern (Breathing irregularity score: 25.5 ± 3.0 vs. 11.9 ± 1.2 %; p<0.05), decreased apnea/hypopnea incidence (11.0 ± 0.9 vs. 6.5 ± 0.8 events/hr; p<0.05) and improves cardiac autonomic control as evidenced by a decrease in the low/high frequency component of spectral analysis of heart rate variability (HRV) (LF/HFHRV 2.7 ± 0.3 vs. 1.5 ± 0.1; p<0.05). In addition, CHF rats displayed active expiration compared to Sham rats, evidenced by the increase in the early/late expiration ratio (E2/E1: 0.51 ± 0.02 vs. 1.07 ± 0.07 Sham+Veh vs. CHF+Veh, p<0.05) and DβH–SAP toxin treatment decrease active expiration in CHF rats (E2/E1: 1.07 ± 0.07 vs. 0.81 ± 0.01 ml, CHF+Veh vs. CHF+DβH‐SAP; p<0.05). Accordingly, DβH–SAP toxin treatment eliminate RCC in CHF rats (Coherencepeak: 0.74 ± 0.04 vs. 0.59 ± 0.05, CHF+Veh vs. HF+DβH–SAP; p<0.05). In addition, the deleterious effects of central chemoreflex activation on diastolic cardiac function and cardiac autonomic control were blunted after RVLM‐C1 neuron ablation (EDPVR: 0.023 ± 0.008 vs. 0.005 ± 0.001 mmHg/μl; LF/HFHRV 2.19 ± 0.15 vs. 1.09 ± 0.23; CHF+Veh+Hypercapnia vs. CHF+DβH‐SAP+ Hypercapnia; p<0.05). No changes in central chemoreflex drive and/or in the number of central chemoreceptor neurons (from the retrotrapezoid nucleus) were found in CHF+DβH‐SAP rats compared to CHF+Veh treated rats. Our results showed that RVLM‐C1 neurons play a critical role in the maintenance of altered breathing patterns in CHF rats and highlighted their contribution to the worsening of cardiac function during central chemoreflex activation.Support or Funding InformationFondecyt 1180172; The basal Center of Excellence in Aging and Regeneration (AFB 170005)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Isoflurane‐Induced Hypothermia Does Not Aggravate Memory Impairment in A Sporadic Alzheimer's Disease Rat Model Produced by Intracerebroventricular Streptozotocin

Several studies have shown that hypothermia and anesthesia are risk factors for Alzheimer's disease. Most of them were performed on healthy elderly rodents. However, the effect of anesthesia‐induced hypothermia in memory in a sporadic Alzheimer's disease animal model has never been studied. In this study, Wistar rats (3‐month‐old) were induced to anesthesia with 3% isoflurane and maintained with 1.5–2% isoflurane in 100% oxygen for 3 hours. In the first 30 min of anesthesia, rats were subjected to a single bilateral intracerebroventricular injection of streptozotocin (STZ, 1 mg/kg) to produce the sporadic Alzheimer's disease model, or its vehicle (0.05 mol/L citrate buffer, pH 4.5, 2 μL/ventricle). The rats were either subjected to hypothermia or not, induced by isoflurane (hypothermic and normothermic groups, respectively). In this sense, during anesthesia, normothermic rats were kept on a heating pad, and their rectal temperature was maintained at 37.5 ± 0.5°C. Hypothermic rats were kept without a heating pad. Spatial working memory was evaluated using Morris Water Maze from the 3rd to 28th‐day postsurgery, and by Y‐maze test on the 30th‐day postsurgery. Recognition memory was evaluated on the 31st‐day postsurgery using the Novel Object Recognition Test. All the procedures were approved by and are in accordance with the local ethics committee from St Joseph's Hospital and Medical Center (protocol n° 485). In the Morris water maze test, both hypothermic and normothermic STZ‐injected rats shown similar impairment in spatial working memory compared to their respective controls, i.e., hypothermic and normothermic vehicle‐injected rats, respectively. In the Y‐maze test, normothermic STZ‐injected rats shown a deficit in spatial working memory compared to normothermic vehicle‐injected rats (p = 0.028). However, this effect was missed in hypothermic groups with no difference between STZ‐ and vehicleinjected groups (p = 0.073). Similarly, in the Novel Object Recognition Test, recognition memory was impaired in normothermic STZ‐injected rats compared to normothermic vehicleinjected rats (p = 0.012) and no effect was observed between hypothermic STZ‐ and vehicleinject rats (p = 0.118). In conclusion, isoflurane‐induced hypothermia does not aggravate the STZ‐deleterious effect in recognition memory and spacial work memory in rats.Support or Funding InformationThis work was supported by the Brazilian National Council for Scientific and Technological Development (grant 449102/2014‐9 to D.C.C.) and the São Paulo Research Foundation (grants 2015/02991‐0 to M.C.A., 2015/23426‐9 to D.C.C., and 2016/01836‐3 to R.C.L.V.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tenophages: a novel macrophage-like tendon cell population expressing CX3CL1 and CX3CR1.

ABSTRACTTendon disorders frequently occur and recent evidence has clearly implicated the presence of immune cells and inflammatory events during early tendinopathy. However, the origin and properties of these cells remain poorly defined. Therefore, the aim of this study was to determine the presence of cells in healthy rodent and human tendon tissue fulfilling macrophage-like functions. Using various transgenic reporter mouse models, we demonstrate the presence of tendon-resident cells in the dense matrix of the tendon core expressing the fractalkine (Fkn) receptor CX3CR1 and its cognate ligand CX3CL1/Fkn. Pro-inflammatory stimulation of 3D tendon-like constructs in vitro resulted in a significant increase in the expression of IL-1β, IL-6, Mmp3, Mmp9, CX3CL1 and epiregulin, which has been reported to contribute to inflammation, wound healing and tissue repair. Furthermore, we demonstrate that inhibition of the Fkn receptor blocked tendon cell migration in vitro, and show the presence of CX3CL1/CX3CR1/EREG-expressing cells in healthy human tendons. Taken together, we demonstrate the presence of CX3CL1+/CX3CR1+ ‘tenophages’ within the healthy tendon proper, which potentially fulfill surveillance functions in tendons.This article has an associated First Person interview with the first author of the paper.

Specialized Pro-resolving Mediators Directs Cardiac Healing and Repair with Activation of Inflammation and Resolution Program in Heart Failure.

After myocardial infarction, splenic leukocytes direct biosynthesis of specialized pro-resolving mediators (SPMs) that are essential for the resolution of inflammation and tissue repair. In a laboratory environment, after coronary ligation of healthy risk free rodents (young adult mice) leukocytes biosynthesize SPMs with induced activity of lipoxygenases and cyclooxygenases, which facilitate cardiac repair. Activated monocytes/macrophages drive the biosynthesis of SPMs following experimental myocardial infarction in mice during the acute heart failure. In the presented review, we provided the recent updates on SPMs (resolvins, lipoxins and maresins) in cardiac repair that may serve as novel therapeutics for future heart failure therapy/management. We incorporated the underlying causesof non-resolving inflammation following cardiac injury if superimposed with obesity, hypertension, diabetes, disrupted circadianrhythm, co-medication (painkillers or oncological therapeutics), and/or aging that may delay or impair the biosynthesis of SPMs, intensifying pathological remodeling in heart failure.

A review: Biological activity of myrtenal and some myrtenal-containing medicinal plant essential oils

Introduction: Myrtenal, a component of many plants` essential oils, is a bicyclic monoterpenoid. Numerous effects of myrtenal in experimental animals have been found - bronchodilatory, anti-inflammatory, anti-aggregative and antihemolytic ( in vitro ), and antibacterial. Its other activities have been studied - antioxidant, antitumor, antihyperglycemic, vasodilating, heart rate reducing and hypotensive. Myrtenal is relatively little studied in the field of neuroscience. Aim : The aim of this article is to summarize the available information on the established biological activity of the monoterpenoid myrtenal. Materials and Methods : Scientific databases such as PubMed, ResearchGate, HMDB and others have been used to provide information on the published results of properties and activities of the test substance (myrtenal) over a period of 15 years (2003 - 2018). Results: Our research confirmed the available data for its central nervous system (CNS) activity - anxiolytic and potentiating the effects of the hypnotic drugs, as well as the antioxidant properties. We have evaluated the neuromodulatory activity of M in brain tissue manifested in elevated levels of major neurotransmitters in healthy rodents and those with neurodegenerative changes accompanied by improvement in the animals` memory. Conclusion : Significant protective effects of myrtenal on neurodegenerative processes were established. Probably they are related to its complex mechanisms, including neuromodulatory and antioxidant properties.

M3RNA Drives Targeted Gene Delivery in Acute Myocardial Infarction.

The M3RNA (microencapsulated modified messenger RNA) platform is an approach to deliver messenger RNA (mRNA) in vivo, achieving a nonintegrating and viral-free approach to gene therapy. This technology was, in this study, tested for its utility in the myocardium, providing a unique avenue for targeted gene delivery into the freshly infarcted myocardial tissue. This study provides the evidentiary basis for the use of M3RNA in the heart through depiction of its performance in cultured cells, healthy rodent myocardium, and acutely injured porcine hearts. By testing the technology in large animal models of infarction, compatibility of M3RNA with current coronary intervention procedures was verified.

Metabolic Activity of Sulfate-Reducing Bacteria from Rodents with Colitis.

Sulfate-reducing bacteria (SRB) are anaerobic microorganisms, which use sulfate as an electron acceptor in the process of dissimilatory sulfate reduction. The final metabolic product of these anaerobic microorganisms is hydrogen sulfide, which is known as toxic and can lead to damage to epithelial cells of the large intestine at high concentrations. Different genera of SRB are detected in the large intestine of healthy human and animals, and with diseases like Crohn's disease and ulcerative colitis. SRB isolated from rodents with ulcerative colitis have produced 1.14 (mice) and 1.03 (rats) times more sulfide ions than healthy rodents. The species of Desulfovibrio genus are the most widespread among all SRB in the intestine. The object of our research was to observe and compare the difference of production of sulfide and reduction of sulfate in intestinal SRB isolated from healthy rodents and rodents with ulcerative colitis.

Sympathetic neurotransmission in spleens from aging Brown-Norway rats subjected to reduced sympathetic tone

Senescence of innate and adaptive responses and low-grade inflammation (inflammaging) hallmarks normal aging, which increases vulnerability to infectious diseases, autoimmunity and cancer. In normal aging, sympathetic dysregulation contributes to the dysregulation of innate and adaptive immunity and inflammaging. Sympathetic innervation of immune cells in secondary immune organs regulates immune responses. Previously in Fischer 344 (F344) rats, we reported an age-related increase in sympathetic tone and sympathetic dysfunction in beta-adrenergic receptor (AR) signaling of splenic lymphocytes that contributes to immune senescence, although the responsible mechanisms remains unexplored. In this study, we extend our previous findings using the much longer-lived Brown-Norway (BN) rats, whose behavior and immune response profile differ strikingly from F344 rats. Here, we investigated whether increased sympathetic nerve activity (SNA) in the aging spleen contributes to age-related sympathetic neuropathy and altered neurotransmission in splenic lymphocytes in BN rats. Fifteen-month male BN rats received 0, 0.5 or 1.5 μg/kg/day rilmenidine intraperitoneally for 90 days to lower sympathetic tone. Untreated young and age-matched rats controlled for effects of age. We found that elevated SNA in the aging BN rat spleen does not contribute significantly to sympathetic neuropathy or the aging-induced impairment of canonical β-AR signal transduction. Despite the rilmenidine-induced increase in β-AR expression, splenocyte c-AMP production was comparable with age-matched controls, thus dampening nerve activity had no effect on receptor coupling to adenylate cyclase. Understanding how aging affects neuroimmune regulation in healthy aging rodent models may eventually lead to strategies that improve health in aging populations vulnerable to immunosenescence and low-grade systemic inflammation.