Behavior In Animal Models Research Articles

EthoWatcher OS: improving the reproducibility and quality of categorical and morphologic/kinematic data from behavioral recordings in laboratory animals.

Behavioral recordings annotated by human observers (HOs) from video recordings are a fundamental component of preclinical animal behavioral models of neurobiological diseases. These models are often criticized for their vulnerability to reproducibility issues. Here, we present the EthoWatcher-Open Source (EW-OS), with tools and procedures for the use of blind-to-condition categorical transcriptions that are simultaneous with tracking, for the assessment of HOs intra- and interobserver reliability during training and data collection, for producing video clips of samples of behavioral categories that are useful for observer training. The use of these tools can inform and optimize the performance of observers, thus favoring the reproducibility of the data obtained. Categorical and machine vision-derived outputs are presented in an open data format for increased interoperability with other applications, where behavioral categories are associated frame-by-frame with tracking, morphological and kinematic attributes of an animal's image. The center of mass (X and Y pixel coordinates), the animal's area in square millimeters, the length and width in millimeters, and the angle in degrees were recorded. It also assesses the variation in each morphological descriptor to produce kinematic descriptors. While the initial measurements are in pixels, they are later converted to millimeters using the scale calibrated by the user via the graphical user interfaces. This process enables the creation of databases suitable for machine learning processing and behavioral pharmacology studies. EW-OS is constructed for continued collaborative development, available through an open-source platform, to support initiatives toward the adoption of good scientific practices in behavioral analysis, including tools for evaluating the quality of the data that can alleviate problems associated with low reproducibility in the behavioral sciences.

Animal Models of Autistic-like Behavior in Rodents: A Scoping Review and Call for a Comprehensive Scoring System

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models.

How life events may confer vulnerability to addiction: the role of epigenetics.

Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap.

Adaptive closed-loop modulation of cortical theta oscillations: Insights into the neural dynamics of navigational decision-making

Navigational decision-making tasks, such as spatial working memory (SWM), rely highly on information integration from several cortical and sub-cortical regions. Performance in SWM tasks is associated with theta rhythm, including low-frequency oscillations related to movement and memory. The interaction of the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC), reflected in theta synchrony, is essential in various steps of information processing during SWM. We used a closed-loop neurofeedback (CLNF) system to upregulate theta power in the mPFC and investigate its effects on circuit dynamics and behavior in animal models. Specifically, we hypothesized that enhancing the power of the theta rhythm in the mPFC might improve SWM performance. Animals were divided into three groups: closed-loop (CL), random-loop (RL), and OFF (without stimulation). We recorded local field potential (LFP) in the mPFC while electrical reward stimulation contingent on cortical theta activity was delivered to the lateral hypothalamus (LH), which is considered one of the central reward-associated regions. We also recorded LFP in the vHPC to evaluate the related subcortical neural changes. Results revealed a sustained increase in the theta power in both mPFC and vHPC for the CL group. Our analysis also revealed an increase in mPFC-vHPC synchronization in the theta range over the stimulation sessions in the CL group, as measured by coherence and cross-correlation in the theta frequency band. The reinforcement of this circuit improved spatial decision-making performance in the subsequent behavioral results. Our findings provide direct evidence of the relationship between specific theta upregulation and SWM performance and suggest that theta oscillations are integral to cognitive processes. Overall, this study highlights the potential of adaptive CLNF systems in investigating neural dynamics in various brain circuits.

Behavioral Animal Models and Neural-Circuit Framework of Depressive Disorder.

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.

Ghrelin, Neuroinflammation, Oxidative Stress, and Mood Disorders: What Are the Connections?

Ghrelin is a gut peptide hormone associated with feeding behavior and energy homeostasis. Acylated ghrelin binds to the growth hormone secretagogue receptor 1a subtype (GHS-R1a) in the hippocampus, leading to GH release from the anterior pituitary. However, in recent years, ghrelin and its receptor have also been implicated in other processes, including the regulation of cardiomyocyte function, muscle trophism, and bone metabolism. Moreover, GHS-R1a is distributed throughout the brain and is expressed in brain areas that regulate the stress response and emotional behavior. Consistently, a growing body of evidence supports the role of ghrelin in regulating stress response and mood. Stress has consistently been shown to increase ghrelin levels, and despite some inconsistencies, both human and rodent studies suggested antidepressant effects of ghrelin. Nevertheless, the precise mechanism by which ghrelin influences stress response and mood remains largely unknown. Intriguingly, ghrelin and GHS-R1a were consistently reported to exert anti-inflammatory, antioxidant, and neurotrophic effects both in vivo and in vitro, although this has never been directly assessed in relation to psychopathology. In the present review we will discuss available literature linking ghrelin with the stress response and depressive-like behavior in animal models as well as evidence describing the interplay between ghrelin and neuroinflammation/oxidative stress. Although further studies are required to understand the mechanisms involved in the action of ghrelin on mood, we hypothesize that the antiinflammatory and anti-oxidative properties of ghrelin may give a key contribution.

The Effectiveness of the Single Object Burying Test in Assessing Hypervigilance-like Behavior in the Single Prolonged Stress Model of Post-Traumatic Stress Disorder (PTSD) in Male Sprague Dawley Rats

Abstract Introduction Post-traumatic stress disorder (PTSD) is recognized nowadays as a major public health issue. It arises as a long-term reaction to severe stressors considered to be life-threatening. It’s characterized by intrusive symptoms, avoidance, and hypervigilance. Although its prevalence is rather high, the mechanisms behind this serious condition are little understood, and its treatment is currently challenging. To get insights into this disorder, a variety of PTSD models were developed in the last 15 years as well as several tests have been proposed to assess the PTSD-like behaviors in these animal models. The single object burying test (OBT) was used to examine the hypervigilant behavior in electric shock animal model of PTSD. To the best of our knowledge, no prior studies have utilized the OBT to assess hypervigilance in the traditional single prolonged stress (SPS) animal model of PTSD. Our study aims to compare the behavioral response of the SPS-exposed and SPS-unexposed rats in the OBT. Methods This study employed the single prolonged stress (SPS) model to induce PTSD in male Sprague-Dawley rats (n = 12 rats, divided as control group = 6 rats, and SPS group = 6 rats) to investigate whether the single object burying test can detect the hypervigilance like behavior in the SPS rats as compared to control group. Parameters used are the percentage of time spent manipulating the object and the percentage of time spent burying the object. Results SPS rats demonstrated decrease in the percentage of time spent manipulating the object and increase in the percentage of time spent burying the object as compared to control group in the OBT. These responses are interpreted as hypervigilance like behavior. Conclusion The OBT can be considered a successful test in assessing hypervigilance of the rats exposed to the SPS animal model of PTSD

A Novel Animal Behavioral Model For Assessing Arousal and Anxiety States: Implications for Post-Traumatic Stress Disorder

Background: Post-traumatic stress disorder (PTSD) is a highly prevalent disorder with widespread impact on health co-morbidities, including cardiovascular disease (CVD). There is a pressing need to understand its underlying mechanisms. This study builds upon our previous published clinical and pre-clinical findings assessing cardiovascular and autonomic responses to stress. Using a recently developed behavioral model and lab-developed software for integrated behavioral and cardio-autonomic analysis, we sought to assess the impact of chronic unpredictable threat reminders on arousal and anxiety behavior as well as cardiovascular and autonomic function in pair-housed mice. Methods: Male and female C57bl/6J mice underwent Pavlovian auditory fear conditioning (n=10-16/group) and were returned to the home cage, equipped with speaker and top-down camera with infrared capabilities. Using a customized software to remotely deliver the conditioned stimulus (CS), pair-housed mice received 6 tones (30sec. 6kHz) throughout the light-dark (LD) cycle over a 24hr period (3 light, 3 dark), repeated for 14 days. The first CS during each LD cycle was recorded and freezing behavior was manually scored. Videos were used to train DeepLabCutTM (DLC) for automated behavioral analysis. On day 15, to evaluate whether evoked freezing is context-dependent, mice were placed into a novel context and CS-dependent freezing was measured. Mice then underwent elevated plus maze (EPM), uncued startle reactivity testing, and fear-potentiated startle (FPS) to assess locomotor, anxiety, and hyperarousal and heightened vigilant behaviors. Results: Following 14 days of chronic unpredictable conditioned threat reminders, fear-conditioned male and female mice exhibited strong CS-evoked freezing in the home cage. Circadian evaluation revealed enhanced freezing in the light versus the dark phase ( males, p<0.01; females, p<0.01). DLC analysis successfully and accurately quantified freezing of group-housed mice. Over 14 days, CS-dependent freezing declined, though this was context-dependent as freezing was significantly higher in a novel context on day 15 ( males, p<0.01; females, p=0.02). While chronic threat reminders did not affect behavior in the EPM, males, but not females, displayed hyperarousal in both uncued (startle to 120dB, males, p<0.01, females, p=0.62) and cued (FPS, males, p=0.04, females, p=0.60) startle testing, though neither males nor females had increased background anxiety during FPS ( males, p=0.77, females, p=0.77). Conclusions: Here we demonstrate, using lab-developed software, environment- and circadian-dependent conditioned freezing in the home cage of group-housed mice. These results further demonstrate that the delivery of chronic intermittent unpredictable conditioned threat reminders leads to an enhanced startle phenotype, that may be sex-dependent. Future studies are needed to assess direct measures of autonomic function in this model, which could provide novel insights into and potentially revealing new therapeutic and preventive strategies for mitigating PTSD-related autonomic dysfunction. (CDMRP) PR210574. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Navigating the complex terrain of motivated behavior: a bibliometric and neuroscientific perspective.

Over several decades, motivated behavior has emerged as a crucial study area within neuroscience. Understanding the neural substrates and mechanisms driving behaviors related to reward, addiction, and other motivation forms is pivotal for novel therapeutic interventions. This review provides a bibliometric analysis of the literature, highlighting the main trends, influential authors, and the potential future direction of the field. Utilizing a dataset comprised by 3,150 publications from the Web of Science and Scopus databases ("motivated behavior as query), we delve into key metrics like publication trends, keyword prevalence, author collaborations, citation impacts, and employed an unsupervised natural language processing technique - Latent Dirichlet Allocation - for topic modeling. From early investigations focusing on basic neural mechanism and behaviors in animal models to more recent studies exploring the complex interplay of neurobiological, psychological, and social factors in humans, the field had undergone a remarkable transformation. The last century has seen a proliferation of research dedicated to uncovering the intricacies of motivation, significantly enriching our understanding of its myriad implications for human behavior and mental health. This bibliometric analysis aims to offer comprehensive insights into this dynamic research area, highlighting the field's key contributions and potential future directions, thereby serving as a valuable resource for researchers, and hopefully give a more thorough understanding of the research area.

Differential effects of voluntary exercise and housing density on anxiety-like behavior in C57Bl/6 mice

The interaction of voluntary exercise and housing density on a) anxiety-like behavior and b) the stimulant effects of methamphetamine in C57Bl/6 mice were evaluated. Upon arrival, mice were housed singly or in pairs, and permitted access to home-cage running wheels or not for 4 weeks. Testing for anxiety-like behavior occurred over the next 3 weeks, one test per week [Elevated-Plus Maze (EPM) → Hyponeophagia (HNP) task → Open-Field (OF) task]. The final, OF task involved an 8-hour session in which mice were permitted to explore the chamber (drug free) during Hours 1–3; given an injection (s.c.) of methamphetamine (1.0 mg/kg) after Hour 3; followed by continued behavioral sampling during Hours 4–8. Several tasks (HNP and OF, but not EPM) consistently showed voluntary exercise induced anxiety-like behavior. In addition, two measures (time in center and time resting in the perimeter) in the OF task revealed that exercise mice compared to controls were more responsive to the anxiogenic effects of methamphetamine. Although pair housing was anxiolytic, it did not ameliorate the anxiogenic effects of voluntary exercise. Taken together, these results, when viewed in tandem with previous studies that utilized a less anxious mouse strain (Swiss Webster), may suggest that voluntary exercise is anxiogenic in an anxiety-prone mouse strain such as C57Bl/6 and highlight the importance of considering mouse strain when evaluating the impact of environmental manipulations on anxiety-like behavior in animal models.

The Physics of Animal Behavior: Form, Function, and Interactions

Understanding the physics of behavior in animals is a challenging and fascinating area of research that has gained increasing attention in recent years. In this review, we delve into the intricate temporal and spatial scales of animal behavior for both individuals and collectives. We explore the experimental and theoretical approaches used to study behavior, highlighting the importance of feedback loops, emergent behavior, and environmental factors in shaping the actions of creatures great and small. The emergence of novel technologies, such as high-speed imaging and tracking, has provided unparalleled insight into the captivating nuances of animal behavior, and we review how these insights have been used to validate physics-based models of animal behavior. We also consider the potential applications of this research in robotics and artificial intelligence, identify new areas for exploration, and envision the possibility of further breakthroughs that will illuminate the complex dynamics of animal behavior.

Behavioral evidence of the modulation filterbank in an avian animal model of complex-sound perception

Behavioral detection of amplitude modulation (AM) can be adversely affected by competing AM “noise” present in the acoustic environment. Called AM masking, human studies suggest the existence of a modulation filterbank that separates sounds (signal from noise) based on differences in AM frequency. The modulation filterbank is an important theoretical advancement in hearing science because in addition to explaining AM masking, the model successfully predicts differences in speech perception across noisy listening environments with different AM statistics. Currently, there are no behavioral animal models of the modulation filterbank, presenting a serious impediment to understanding neural underpinnings. We trained budgerigars, a parakeet species, to detect AM frequencies from 64 to 400 Hz in the presence of narrowband AM maskers applied to a 2.8-kHz carrier signal. AM masker center frequencies spanned a >2 octave range centered on the target AM frequency. Behavioral AM sensitivity was evaluated with operant conditioning, a single-interval two-alternative discrimination task, and two-down one-up adaptive threshold tracking procedures. Budgerigar AM masking functions had a band-pass characteristic, consistent with the modulation filterbank and with human AM masking results for the same stimuli. To our knowledge, these are the first behaviorally estimated modulation filter shapes in a nonhuman species. [Funding: NIDCD R01-DC017519.]

The Anxiolytic Potential of Citrus Aurantium Essential Oil: A focused critical review

Anxiety disorders rank among the most common mental health issues globally, prompting extensive research into both traditional and alternative treatments. In this context, Citrus aurantium essential oil (bitter orange) has attracted scientific interest due to its anxiolytic properties. This essential oil's pharmacological effects are attributed to its active components, which interact with key neurotransmitter systems, including the serotoninergic and GABAergic, to exert anxiolytic, antidepressant, and sedative effects. Recent studies have explored these properties in various models, demonstrating Citrus aurantium's ability to alleviate anxiety-like behaviors in animal models and manage preoperative anxiety in humans. Despite promising preliminary findings, research on Citrus aurantium essential oil's efficacy and safety in anxiety treatment presents considerable variability in study design, methodologies, and outcomes. This review aims to synthesize current evidence on the anxiolytic effects of Citrus aurantium essential oil, highlighting its potential therapeutic applications and the need for further research to clarify its efficacy and safety in clinical settings. By critically evaluating existing literature, this paper contributes to a deeper understanding of Citrus aurantium essential oil as a potential non-pharmacological intervention for anxiety disorders, underscoring the importance of continued investigation in this promising area of complementary and alternative medicine.

Social Behavior in Animal Models of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and stereotyped, repetitive patterns of behaviors, limited interests, and cognitive impairment. Especially, social deficit has been considered a core feature of ASD. Because of the limitations of the experimental approach in humans, valid animal models are essential in an effort to identify novel therapeutics for social deficits in ASD. The genetic and environmental factors are clinically relevant to the pathophysiology of ASD. Epidemiological studies demonstrate environmental interventions such as prenatal exposure to valproic acid (VPA). Prenatal exposure to VPA represents a robust model of ASD exhibiting face, construct, and predictive validity. Here, we introduce protocols of the social interaction test and the three-chamber test for evaluating social deficits in mice prenatally exposed to VPA.

Fustin alleviates lipopolysaccharide-induced anxiety-depression-like performances by modulation of oxidative stress/neuroinflammatory markers/ NF-κB/caspase-3/BDNF expression in rodents.

Anxiety and depression are common psychiatric disorders that affect millions of people worldwide. Lipopolysaccharide (LPS) is a bacterial endotoxin that has been demonstrated to cause depression and anxiety-like behaviors in animal models. Fustin is a flavonoid found in various plant species that have been reported to have neuroprotective effects. The study proposed the evaluation of fustin's impact on anxiety and depression in LPS-injected rats. The efficacy of fustin in higher and lower doses was studied by administering a single dose of LPS-injected anxiety/depression in rodents. Behavioral models like the elevated plus maze test, open field test, marble burying test, force swimming test, tail suspension test, and hyperemotionality behavior were performed to evaluate anxiety/depression in rodents. The neuroinflammatory markers such as interleukin-6 (IL-6), interleukin-1β (IL-1β), nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), apoptosis marker caspase-3, and brain-derived neurotrophic factor (BDNF) were also measured as a part of the study. Additionally, biochemical markers of oxidative stress, such as malonaldehyde (MDA) and antioxidants, including superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and nitric oxide (NO), were also evaluated. LPS administration resulted in significant (p<0.001) changes in behavior tests and biochemical markers including IL-1β, IL-6, NF-κB, TNF-α, NO, caspase-3, BDNF, MDA, CAT, SOD, and GSH. In contrast, treating the rats with fustin significantly improved the behavior tests and restored the changes in biochemical markers. The current work established the efficacy of fustin with its therapeutic impact on depression and anxiety-like behaviors in rodent experimental models through its modulation of apoptosis markers, oxidative stress, and neuroinflammation.

The Influence and Mechanism of the Nervous System and Other Factors Inducing Anxiety-like Behavior in Animal Models

Researches on the actions that trigger anxiety is being undertaken gradually, which has shown that anxiety is a common occurrence. In order to gain a comprehensive understanding of the influences and mechanisms of the nervous system and other factors inducing anxiety-like behaviors, this paper employs an animal model as its research topic in order to better understand how the nervous system and other elements impact anxiety and its mechanism. Using optogenetic activation, chemical genetics, electrophysiology, total internal reflection fluorescence (TIRF) imaging, immunoelectron microscopy, viral tracer, and other techniques, this study examines the interaction between the immune and neurological systems in a simulated animal model. The development of the NAc-VTA circuit, the nucleus accumbens, the ventromedial prefrontal cortexs action mechanism, and three other elements, show that the nervous system and related components may induce anxiety-like behavior in a mouse-based animal model and that these factors can also create or obstruct the regulatory pathway for anxiety-like behavior. Human anxiety can be controlled using this knowledge.

The physicochemical characteristics and antidepressant-like effects of a polysaccharide-rich fraction from Schisandra chinensis (Turcz.) Baill in behavioral despair mice and olfactory bulbectomy-induced depression-like mice

Ethnopharmacological relevanceThe dried fruit of Schisandra chinensis (Turcz.) Baill (S. chinensis) is widely used in treating central nervous system disorders. Increasing evidence has suggested that alcohol-soluble extracts and lignans from S. chinensis could significantly ameliorate depression-like behaviors in animal models, while there was little research on the potential of alcohol-insoluble polysaccharides as a candidate in the treatment of depression. Aim of the studyOur research was designed to explore both the physicochemical characteristics and antidepressant-like effects of an alcohol-insoluble polysaccharide-rich fraction named SCP from S. chinensis. Simultaneously, the underlying mechanisms were elucidated in the study. Materials and methodsThe physicochemical characteristics were accomplished by colorimetric assays, CE, HPGPC, and FT-IR. Behavioral despair testing accompanied by LAT were processed to promptly assess the antidepressant-like effects of SCP in mice. Then OBX-induced mice were established to explore the impacts of chronic co-treatments with SCP. Furthermore, effects of SCP on the HPA axis, oxidant/antioxidant system, neurotrophic and synaptic factors, and gut microbiota in OBX-induced mice were detected through ELISA and 16S rDNA (V3 + V4 regions) gene sequencing. ResultsSCP is a polysaccharide-rich fraction mainly comprised of xylose, glucose, rhamnose, galactose, mannose, and galacturonic acid in ratios of 0.27, 5.09, 0.24, 1.00, 0.63, and 2.86, of which the MW distribution ranges from 681 to 3232 Da. Acute pre-treatment with SCP (200 mg/kg, i.g.) remarkably reduced mice’s immobility in the FST without motor stimulation. Prolonged pre-treatments effectively enhanced the effects of SCP on the behavioral despair testing in mice. Chronic co-treatments with SCP (50, 200, and 800 mg/kg, i.g.) could ameliorate the slow increase of body weight and behavioral abnormality of OBX-induced mice in systemic behavioral testing. SCP (200 mg/kg) also successfully restored hyperactivity of the HPA axis, oxidative damage in the liver, neurotrophic disturbance and abnormal synaptic plasticity in the hippocampus, and dysregulation of gut microbiota in OBX-induced mice. ConclusionSCP exerts noteworthy antidepressant-like impacts on behavioral despair mice and OBX-induced mice via multiple targets, indicating a potential therapeutic candidate in depression therapy.

Neuroprotective evaluation of diospyrin against drug-induced Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease linked to memory impairment. A current investigation was performed to assess the neuroprotective effect of Diospyrin, a novel therapeutic agent, for the curing of Alzheimer's disease. For this purpose, in-vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory assays and antioxidant studies were conducted, whereas in-vivo studies involved different behavioral animal models tests such as elevated plus maze (EPM), morris water maze (MWM) and paddling Y-maze test. Results of the in-vitro analysis showed IC50 values of 95 μg/mL for AChE and 110 μg/mL for BChE as compared to the standard drug donepezil (IC50: 95 & 85 μg/mL, respectively). DPPH antioxidant assay showed a maximum of 72.85% inhibition (IC50: 139.74 μg/mL) of DPPH-free radicals at the highest concentration of 1000 μg/mL as compared to the ascorbic acid (IC50: 13.72 μg/mL). Moreover, the in-vivo analysis revealed that diospyrin treatment demonstrated gradual betterment in memory and enhanced motor functionality. On the other hand, the computational analysis also showed that the diospyrin had exceptional binding affinities for both AChE and BChE enzymes. In the net shell, it may be deduced that our compound diospyrin could be a valuable drug candidate in managing neurodegenerative disorders like AD.

Biodistribution of Agmatine to Brain and Spinal Cord after Systemic Delivery.

Agmatine, an endogenous polyamine, has been shown to reduce chronic pain behaviors in animal models and in patients. This reduction is due to inhibition of the GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAR) in the central nervous system (CNS). The mechanism of action requires central activity, but the extent to which agmatine crosses biologic barriers such as the blood-brain barrier (BBB) and intestinal epithelium is incompletely understood. Determination of agmatine distribution is limited by analytical protocols with low sensitivity and/or inefficient preparation. This study validated a novel bioanalytical protocol using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for quantification of agmatine in rat biologic matrices. These protocols were then used to determine the plasma pharmacokinetics of agmatine and the extent of distribution to the CNS. Precision and accuracy of the protocol met US Food and Drug Administration (FDA) standards in surrogate matrix as well as in corrected concentrations in appropriate matrices. The protocol also adequately withstood stability and dilution conditions. Upon application of this protocol to pharmacokinetic study, intravenous agmatine showed a half-life in plasma ranging between 18.9 and 14.9 minutes. Oral administration led to a prolonged plasma half-life (74.4-117 minutes), suggesting flip-flop kinetics, with bioavailability determined to be 29%-35%. Intravenous administration led to a rapid increase in agmatine concentration in brain but a delayed distribution and lower concentrations in spinal cord. However, half-life of agmatine in both tissues is substantially longer than in plasma. These data suggest that agmatine adequately crosses biologic barriers in rat and that brain and spinal cord pharmacokinetics can be functionally distinct. SIGNIFICANCE STATEMENT: Agmatine has been shown to be an effective nonopioid therapy for chronic pain, a significantly unmet medical necessity. Here, using a novel bioanalytical protocol for quantification of agmatine, we present the plasma pharmacokinetics and the first report of agmatine oral bioavailability as well as variable pharmacokinetics across different central nervous system tissues. These data provide a distributional rationale for the pharmacological effects of agmatine as well as new evidence for kinetic differences between brain and spinal cord.

Sounds of danger and post-traumatic stress responses in wild rodents: ecological validity of a translational model of post-traumatic stress disorder

In the wild, animals face a highly variable world full of predators. Most predator attacks are unsuccessful, and the prey survives. According to the conventional perspective, the fear responses elicited by predators are acute and transient in nature. However, the long-term, non-lethal effects of predator exposure on prey behavioral stress sequelae, such as anxiety and post-traumatic symptoms, remain poorly understood. Most experiments on animal models of anxiety-related behavior or post-traumatic stress disorder have been carried out using commercial strains of rats and mice. A fundamental question is whether laboratory rodents appropriately express the behavioral responses of wild species in their natural environment; in other words, whether behavioral responses to stress observed in the laboratory can be generalized to natural behavior. To further elucidate the relative contributions of the natural selection pressures influences, this study investigated the bio-behavioral and morphological effects of auditory predator cues (owl territorial calls) in males and females of three wild rodent species in a laboratory set-up: Acomys cahirinus; Gerbillus henleyi; and Gerbillus gerbillus. Our results indicate that owl territorial calls elicited not only “fight or flight” behavioral responses but caused PTSD-like behavioral responses in wild rodents that have never encountered owls in nature and could cause, in some individuals, enduring physiological and morphological responses that parallel those seen in laboratory rodents or traumatized people. In all rodent species, the PTSD phenotype was characterized by a blunting of fecal cortisol metabolite response early after exposure and by a lower hypothalamic orexin-A level and lower total dendritic length and number in the dentate gyrus granule cells eight days after predator exposure. Phenotypically, this refers to a significant functional impairment that could affect reproduction and survival and thus fitness and population dynamics.