Use Of Rodent Models Research Articles

Consumption of oxycodone prevents oxytocin from attenuating alcohol intake in rats

Alcohol and opioid polysubstance use (PSU) is common and often accompanied by higher trait anxiety. Oxytocin decreases anxiety, alcohol- and opioid-seeking and -taking but has not been assessed in the context of PSU. Here we developed a rat model of sequential oxycodone and alcohol PSU to examine the relationship between anxiety, alcohol and oxycodone intake, and the efficacy of systemic oxytocin to attenuate alcohol intake. Male and female Sprague-Dawley rats were assessed for baseline anxiety-like behavior using acoustic startle and the elevated plus maze (EPM). Rats were then given 2-bottle choice access to oxycodone and/or water for 6-hr/day for 7 days, followed by 2-bottle choice access to alcohol (20% v/v) and/or water for five 24-hr sessions across 10 days. Next, monosubstance (oxycodone- or alcohol-alone) rats continued to have access to only one substance/day while PSU rats had access to oxycodone and water for 3-hr, followed by alcohol and water for 6-hr. After 12 days, rats were tested in the EPM 20 hours after alcohol access to examine withdrawal-related anxiety. Next, oxytocin (0, 0.3 or 1.0 mg/kg IP) was administered following the oxycodone/water session, 30 minutes prior to alcohol access. Rats received intragastric oxycodone (2 mg/kg) or water followed by intragastric alcohol (2 g/kg) and blood was collected to determine blood alcohol levels. Elevated baseline anxiety-like behavior was accompanied by reduced alcohol intake. Consumption of oxycodone did not alter alcohol intake but resulted in less anxiety-like behavior during withdrawal and prevented oxytocin from attenuating alcohol intake. Oxytocin (1 mg/kg) reduced alcohol intake in the alcohol-only condition, an effect that persisted for days after a single oxytocin administration. Rats that received oxycodone prior to non-contingent alcohol displayed higher blood alcohol levels than those that did not. These results support the necessity for the testing of medications for substance use in rodent models of PSU.

Induction of Diabetes Mellitus Using Alloxan in Sprague Dawley Rats.

The use of rodent models for diabetes, particularly with pancreatic islet transplantation, has been prevalent in various preclinical trials. The purpose of this study is to establish a diabetes mellitus (DM) model in Sprague Dawley (SD) rats using alloxan evaluated by assessing alloxan dosage, the induction rate of diabetes, and glucose stability through insulin treatment. Over the course of 13 experimental rounds, diabetes was induced in 86 SD rats using alloxan at concentrations of 200 mg/kg (16 rats) or 150 mg/kg (70 rats). Various parameters, including diabetes induction rates, average insulin doses, extent of weight loss, and adverse effects such as diabetic ketoacidosis (DKA), were measured. The administration of 200 mg/kg of alloxan in rats resulted in severe diabetes induction, leading to DKA in three individuals, despite daily insulin glargine administration, DKA prevention was unsuccessful. The stability of alloxan decreases over time, especially when refrigeration is compromised during weighing. In the group treated with 150 mg/kg of alloxan, the diabetes induction rate was 83%. The average insulin dose was 2.21 units/kg/day. In contrast, the group treated with 200 mg/kg of alloxan exhibited a diabetes induction rate of 81% with a statistically significant higher average insulin requirement at 7.58 units/kg/day compared to 150 mg/kg of alloxan. Inducing diabetes in rats with 150 mg/kg of alloxan is considered more suitable for creating a diabetes model for xenogeneic islet transplantation compared to using 200 mg/kg of alloxan. This is due to fewer complications related to DKA or hyperglycemia and reduced need for exogenous insulin treatment.

Most utilized rodent models for Alzheimer’s and Parkinson’s disease: A critical review of the past 5 years

The past few years have witnessed extensive research on the two most common neurodegenerative diseases, Alzheimer’s disease (AD), and Parkinson’s disease (PD). With an urgent need for new treatments, drug targets, and a better understanding of the pathophysiological mechanisms underlying these conditions, researchers have turned to animal models, especially rodents, to address these issues. However, the abundance of reported models poses a challenge when choosing the most suitable model for a specific study. In this critical review, we systematically scrutinized studies using rodent models of AD or PD over the past 5 years. A comprehensive literature search was conducted on PubMed, followed by the meticulous screening of the identified studies. Among the retrieved publications, 1,222 studies reported the use of rodent models of PD, with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, α-synuclein, and 6-hydroxydopamine emerging as the most frequently used models. Similarly, 2,961 studies reported the use of rodent models of AD, with APP/PS1, 5×FAD, APP-based models, and 3×Tg being the most prevalent. In this review, we summarize and highlight the main characteristics of these models. By providing a comprehensive overview of their features and applications, this review guides future studies in the AD and PD field, eventually aiding in the selection of the most appropriate animal model tailored to the specific research question under scrutiny.

Implantation and Decidualization in PCOS: Unraveling the Complexities of Pregnancy.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, affecting 5-15% globally with a large proportion undiagnosed. This review explores the multifaceted nature of PCOS and its impact on pregnancy, including challenges in fertility due to hormonal imbalances and insulin resistance. Despite restoring ovulation pharmacologically, women with PCOS face lower pregnancy rates and higher risks of implantation failure and miscarriage. Our review focuses on the complexities of hormonal and metabolic imbalances that impair endometrial receptivity and decidualization in PCOS. Disrupted estrogen signaling, reduced integrity of endometrial epithelial tight junctions, and insulin resistance impair the window of endometrial receptivity. Furthermore, progesterone resistance adversely affects decidualization. Our review also examines the roles of various immune cells and inflammatory processes in the endometrium, contributing to the condition's reproductive challenges. Lastly, we discuss the use of rodent models in understanding PCOS, particularly those induced by hormonal interventions, offering insights into the syndrome's impact on pregnancy and potential treatments. This comprehensive review underscores the need for advanced understanding and treatment strategies to address the reproductive complications associated with PCOS, emphasizing its intricate interplay of hormonal, metabolic, and immune factors.

Comparative Antihyperglycemic and Antihyperlipidemic Effects of Lawsone Methyl Ether and Lawsone in Nicotinamide-Streptozotocin-Induced Diabetic Rats.

Our previous study uncovered potent inhibitory effects of two naphthoquinones from Impatiens balsamina, namely lawsone methyl ether (2-methoxy-1,4-naphthoquinone, LME) and lawsone (2-hydroxy-1,4-naphthoquinone), against α-glucosidase. This gave us the insight to compare the hypoglycemic and hypolipidemic effects of LME and lawsone in high-fat/high-fructose-diet- and nicotinamide-streptozotocin-induced diabetic rats for 28 days. LME and lawsone at the doses of 15, 30, and 45 mg/kg, respectively, produced a substantial and dose-dependent reduction in the levels of fasting blood glucose (FBG), HbA1c, and food/water intake while boosting the insulin levels and body weights of diabetic rats. Additionally, the levels of total cholesterol (TC), triglycerides (TGs), high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), aspartate transaminase (AST), alanine transaminase (ALT), creatinine, and blood urea nitrogen (BUN) in diabetic rats were significantly normalized by LME and lawsone, without affecting the normal rats. LME at a dose of 45 mg/kg exhibited the most potent antihyperglycemic and antihyperlipidemic effects, which were significantly comparable to glibenclamide but higher than those of lawsone. Furthermore, the toxicity evaluation indicated that both naphthoquinones were entirely safe for use in rodent models at doses ≤ 50 mg/kg. Therefore, the remarkable antihyperglycemic and antihyperlipidemic potentials of LME make it a promising option for future drug development.

Behavioral Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain-(-Related) Phenotypes in Rats with Bone Cancer.

Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. The use of rodent models is the most common approach to uncovering the mechanisms underlying CIBP; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative of relevant pain in patients. To improve the accuracy and strength of the preclinical, experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a home-cage monitoring assay (HCM). Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of the CIBP-phenotype, including evoked and non-evoked based assays and HCM. Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and differently) in males. Additionally, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex. This multimodal battery allows for an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalizability of results and provide information for targeted drug development in the future.

Behavioral tests for evaluating the characteristics of brain diseases in rodent models: Optimal choices for improved outcomes (Review).

Behavioral assessment is the dominant approach for evaluating whether animal models of brain diseases can successfully mimic the clinical characteristics of diseases. At present, most research regarding brain diseases involves the use of rodent models. While studies have reported numerous methods of behavioral assessments in rodent models of brain diseases, each with different principles, procedures, and assessment criteria, only few reviews have focused on characterizing and differentiating these methods based on applications for which they are most appropriate. Therefore, in the present review, the representative behavioral tests in rodent models of brain diseases were compared and differentiated, aiming to provide convenience for researchers in selecting the optimal methods for their studies.

The use of rodent models to better characterize the relationship among epilepsy, sleep, and memory.

Epilepsy, a neurological disorder characterized by recurrent seizures, is known to be associated with impaired sleep and memory. Although the specific mechanisms underlying these impairments are uncertain, the known role of sleep in memory consolidation suggests a potential relationship may exist between seizure activity, disrupted sleep, and memory impairment. A possible mediator in this relationship is the sleep spindle, the characteristic electroencephalographic (EEG) feature of non-rapid-eye-movement (NREM) sleep in humans and other mammals. Growing evidence supports the idea that sleep spindles, having thalamic origin, may mediate the process of long-term memory storage and plasticity by generating neuronal conditions that favor these processes. To study this potential relationship, a single model in which memory, sleep, and epilepsy can be simultaneously observed is of necessity. Rodent models of epilepsy appear to fulfill this requirement. Not only do rodents express both sleep spindles and seizure-induced sleep disruptions, but they also allow researchers to invasively study neurobiological processes both pre- and post- epileptic onset via the artificial induction of epilepsy (a practice that cannot be carried out in human subjects). However, the degree to which sleep architecture differs between rodents and humans makes direct comparisons between the two challenging. This review addresses these challenges and concludes that rodent sleep studies are useful in observing the functional roles of sleep and how they are affected by epilepsy.

GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment

The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.

Catheterization of Ventral Caudal Artery in Rats: A Modified Technique for Repeatable Angiography and Intervention

Background The use of digital silhouette angiography (DSA) has been restricted due to lack of a technique that allows for repeated intra-arterial inspections over a prolonged period. Current studies are focused on the arteries that can be cannulated multiple times. We intended to develop and test a technique that would enable repeated performance of various catheterizations and transcatheter operations for a prolonged period, at the same site, with fewer postsurgical complications. Methods Thirty rats were randomly divided into five groups. Ventral caudal artery cannulation was performed via the transtail approach after grouping for subsequent experiments. Histological staining and scanning electron microscopy were used to assess endothelial injuries. Results The rats survived post catheterization of ventral caudal artery and establishment of animal models. The average time of ventral caudal artery cannulation was significantly shorter than that of the femoral (p < 0.01) and common carotid arteries (p < 0.01). In rats, the transtail artery technique effectively allowed selective arterial catheterization and angiography. Histological staining and scanning electron microscopy of the abdominal aorta revealed disruption of the intima and denuded wavy endothelial surface. Conclusions We describe a novel method for artery sheath catheterization through the ventral caudal artery in rats; it may be possible to perform serial DSA studies and interventional operations with a single sheath channel in rats over a prolonged period. We believe that this approach will improve the utility of rats as models of human diseases and enable the broader use of rodent models for endovascular therapy research.

Cognitive behavioral markers of neurodevelopmental trajectories in rodents

Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a ‘U-shaped’ developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts.

Autism spectrum disorders (ASDs) are a highly variable and complex set of neurological disorders that alter neurodevelopment and cognitive function, which usually presents with social and learning impairments accompanied with other comorbid symptoms like hypersensitivity or hyposensitivity, or repetitive behaviors. Autism can be caused by genetic and/or environmental factors and unraveling the etiology of ASD has proven challenging, especially given that different genetic mutations can cause both similar and different phenotypes that all fall within the autism spectrum. Furthermore, the list of ASD risk genes is ever increasing making it difficult to synthesize a common theme. The use of rodent models to enhance ASD research is invaluable and is beginning to unravel the underlying molecular mechanisms of this disease. Recently, zebrafish have been recognized as a useful model of neurodevelopmental disorders with regards to genetics, pharmacology and behavior and one of the main foundations supporting autism research (SFARI) recently identified 12 ASD risk genes with validated zebrafish mutant models. Here, we describe what is known about those 12 ASD risk genes in human, mice and zebrafish to better facilitate this research. We also describe several non-genetic models including pharmacological and gnotobiotic models that are used in zebrafish to study ASD.

Myristoylation of LMCD1 leads to its species‐specific derepression of E2F1 and NFATc1 in the modulation of CDC6 and IL‐33 expression during development of vascular lesions

Majority of translational research is focused on the use of rodent models to understand the pathophysiology of human disease. However, many experimental findings of rodent models fail to translate to human. In this regard, our previous studies show that LIM and cysteine‐rich domains 1 (LMCD1) plays a role in thrombin‐induced vascular smooth muscle cell (VSMC) proliferation and migration only in human but not rodents. Based on these findings, we asked the question whether LMCD1 exhibits any species‐specific role in the development of vascular lesions. A combination of genetic, molecular, cellular and disease models were used to test species‐specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species‐specific regulation of LMCD1 expression in mediating VSMC proliferation and migration during vascular wall remodeling in human versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells (HASMCs) but not mouse aortic smooth muscle cells (MASMCs). We found association of ‘rapid promoter evolution’ in this expression divergence of LMCD1 in human versus mice. In exploring the mechanism, we found that Par1‐Gαq/11‐PLCβ3‐NFATc1 signaling axis mediates thrombin‐induced LMCD1 expression in HASMCs. Furthermore, although LMCD1 mediates thrombin‐induced proliferation and migration of both HASMCs and MASMCs via influencing CDC6 and IL‐33 expression, respectively, in humans it acts as an activator and in mice it acts as a repressor of their promoters. Interestingly, its repressor activity was revoked by its myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to non‐stenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to non‐injured arteries. Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in human and mice, respectively, in the induction of CDC6 and IL‐33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.Support or Funding InformationThis work was supported by a grant HL069908 from NIH to Dr. Gadiparthi N. Rao

Interhemispheric modulations of motor outputs by the rostral and caudal forelimb areas in rats.

In rats, forelimb movements are evoked from two cortical regions, the caudal and rostral forelimb areas (CFA and RFA, respectively). These areas are densely interconnected and RFA induces complex and powerful modulations of CFA outputs. CFA and RFA also have interhemispheric connections, and these areas from both hemispheres send projections to common targets along the motor axis, providing multiple potential sites of interactions for movement production. Our objective was to characterize how CFA and RFA in one hemisphere can modulate motor outputs of the opposite hemisphere. To do so, we used paired-pulse protocols with intracortical microstimulation techniques (ICMS), while recording electromyographic (EMG) activity of forelimb muscles in sedated rats. A subthreshold conditioning stimulation was applied in either CFA or RFA in one hemisphere simultaneously or before a suprathreshold test stimulation in either CFA or RFA in the opposite hemisphere. Both CFA and RFA tended to facilitate motor outputs with short (0–2.5 ms) or long (20–35 ms) delays between the conditioning and test stimuli. In contrast, they tended to inhibit motor outputs with intermediate delays, in particular 10 ms. When comparing the two areas, we found that facilitatory effects from RFA were more frequent and powerful than the ones from CFA. In contrast, inhibitory effects from CFA on its homolog were more frequent and powerful than the ones from RFA. Our results demonstrate that interhemispheric modulations from CFA and RFA share some similarities but also have clear differences that could sustain specific functions these cortical areas carry for the generation of forelimb movements.NEW & NOTEWORTHY We show that caudal and rostral forelimb areas (CFA and RFA) have distinct effects on motor outputs from the opposite hemisphere, supporting that they are distinct nodes in the motor network of rats. However, the pattern of interhemispheric modulations from RFA has no clear equivalent among premotor areas in nonhuman primates, suggesting they contribute differently to the generation of ipsilateral hand movements. Understanding these interspecies differences is important given the common use of rodent models in motor control and recovery studies.

Investigating TBI Using Animal Models

In the USA, there are 2.8 million emergency room visits for traumatic brain injury (TBI) each year and about 1.2 million people are living with brain function problems due to TBI. Although much information has been gained from experimental and clinical studies showing how injuries happen, no effective treatments are currently available for TBI. To understand the effects of TBI on the brain and spinal cord, scientists use animal models as a cost-effective research method. Larger animal models, such as pigs or sheep, are closer in bodily functions to humans. However, the use of rodent models is preferred because they are easy to work with in the lab. Importantly, this also fits with the national recommendations to use the lowest mammalian species that can provide the answer to the scientific question. Using rodents, scientists can control specific details, such as the type of brain injury and the severity of the injury. There are ethical concerns about injuring in animals in scientific experiments, but scientists make substantial efforts to ensure the most humane treatment of these animals. Recently, animal models have been used to discover certain proteins, called biomarkers that are present in the brains of people with TBI and could lead to the development of new therapies to prevent or reduce disability that can result from TBI.

Immunobiology of Cervix Ripening.

The cervix is the essential gatekeeper for birth. Incomplete cervix remodeling contributes to problems with delivery at or post-term while preterm birth is a major factor in perinatal morbidity and mortality in newborns. Lack of cervix biopsies from women during the period preceding term or preterm birth have led to use of rodent models to advanced understanding of the mechanism for prepartum cervix remodeling. The critical transition from a soft cervix to a compliant prepartum lower uterine segment has only recently been recognized to occur in various mammalian species when progesterone in circulation is at or near the peak of pregnancy in preparation for birth. In rodents, characterization of ripening resembles an inflammatory process with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages in the cervix. Although a role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process. The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth. Moreover, use of endpoints to determine the effectiveness of various therapeutic approaches to forestall remodeling and reduce risks for preterm birth, or facilitate ripening to promote parturition will improve the postpartum well-being of mothers and newborns.

Cannabis use and the sperm epigenome: a budding concern?

The United States is swiftly moving toward increased legalization of medical and recreational cannabis. Currently considered the most commonly used illicit psychoactive drug, recreational cannabis is legal in 11 states and Washington, DC, and male use is an important and understudied concern. Questions remain, however, about the potential long-term consequences of this exposure and how cannabis might impact the epigenetic integrity of sperm in such a way that could influence the health and development of offspring. This review summarizes cannabis use and potency in the USA, provides a brief overview of DNA methylation as an epigenetic mechanism that is vulnerable in sperm to environmental exposures including cannabis, and summarizes studies that have examined the effects of parental exposure to cannabis or delta-9 tetrahydrocannabinol (THC, the main psychoactive component of cannabis) on the epigenetic profile of the gametes and behavior of offspring. These studies have demonstrated significant changes to the sperm DNA methylome following cannabis use in humans, and THC exposure in rats. Furthermore, the use of rodent models has shown methylation and behavioral changes in rats born to fathers exposed to THC or synthetic cannabinoids, or to parents who were both exposed to THC. These data substantiate an urgent need for additional studies assessing the effects of cannabis exposure on childhood health and development. This is especially true given the current growing state of cannabis use in the USA.

Targeting Gap Junctions: New Insights into the Treatment of Major Depressive Disorder.

Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and associated with excess mortality. Treatments for this disease are not effective in all patients showing the need to find new therapeutic targets. This review aims to update our knowledge on the involvement of astroglial gap junctions and hemichannels in MDD and to show how they have become potential targets for the treatment of this pathology. The method applied in this review includes a systematic compilation of the relevant literature. The use of rodent models of depression, gene analysis of hippocampal tissues of MDD patients and post-mortem studies on the brains from MDD patients suggest that astrocytic gap junction dysfunction may be a part of MDD etiologies. Chronic antidepressant treatments of rats, rat cultured cortical astrocytes and human astrocytoma cell lines support the hypothesis that the up-regulation of gap junctional coupling between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants. However, two recent functional studies suggest that connexin43 hemichannel activity is a part of several antidepressants' mode of action and that astrocyte gap junctional intercellular communication and hemichannels exert different effects on antidepressant drug response. Even if they emerge as new therapeutic targets for new and more active treatments, further studies are needed to decipher the sophisticated and respective role of astrocytic gap junctions and hemichannels in MDD.

Whisker-Mediated Touch System in Rodents: From Neuron to Behavior.

A key question in systems neuroscience is to identify how sensory stimuli are represented in neuronal activity, and how the activity of sensory neurons in turn is “read out” by downstream neurons and give rise to behavior. The choice of a proper model system to address these questions, is therefore a crucial step. Over the past decade, the increasingly powerful array of experimental approaches that has become available in non-primate models (e.g., optogenetics and two-photon imaging) has spurred a renewed interest for the use of rodent models in systems neuroscience research. Here, I introduce the rodent whisker-mediated touch system as a structurally well-established and well-organized model system which, despite its simplicity, gives rise to complex behaviors. This system serves as a behaviorally efficient model system; known as nocturnal animals, along with their olfaction, rodents rely on their whisker-mediated touch system to collect information about their surrounding environment. Moreover, this system represents a well-studied circuitry with a somatotopic organization. At every stage of processing, one can identify anatomical and functional topographic maps of whiskers; “barrelettes” in the brainstem nuclei, “barreloids” in the sensory thalamus, and “barrels” in the cortex. This article provides a brief review on the basic anatomy and function of the whisker system in rodents.

Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry.

Exercise stimulates cellular and physiological adaptations that are associated with widespread health benefits. To uncover conserved protein phosphorylation events underlying this adaptive response, we performed mass spectrometry-based phosphoproteomic analyses of skeletal muscle from two widely used rodent models: treadmill running in mice and insitu muscle contraction in rats. We overlaid these phosphoproteomic signatures with cycling in humans to identify common cross-species phosphosite responses, as well as unique model-specific regulation. We identified >22,000 phosphosites, revealing orthologous protein phosphorylation and overlapping signaling pathways regulated by exercise. This included two conserved phosphosites on stromal interaction molecule 1 (STIM1), which we validate as AMPK substrates. Furthermore, we demonstrate that AMPK-mediated phosphorylation of STIM1 negatively regulates store-operated calcium entry, and this is beneficial for exercise in Drosophila. This integrated cross-species resource of exercise-regulated signaling in human, mouse, and rat skeletal muscle has uncovered conserved networks and unraveled crosstalk between AMPK and intracellular calcium flux.