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How The Triune brain and The Affective Neuroscience Scale corresponds to the RDoC system. According to the RDoC system, behavioural endophenotypes attribute 5 main behavioural domains. They are not only distinct but describe personality as an interacting and dynamic individual trait. The domains are objectively different, determined by particular neuronal networks. Separation of the networks is due to a distinction in the functions they serve (The Affective Neuroscience Scale, Panksepp, 1998). This distinction corresponds well with the concept of a gradual evolution of the brain (the triune brain model of MacLean, 1970).
Source publication
The recently proposed Research Domain Criteria (RDoC) system defines psychopathologies as phenomena of multilevel neurobiological existence and assigns them to 5 behavioural domains characterizing a brain in action. We performed an analysis on this contemporary concept of psychopathologies in respect to a brain phylogeny and biological substrates o...
Citations
... However, species nuances may limit extrapolation of these findings to humans and the degree Gqefficacy thresholds align in humans and rodents is unclear. Finally, we chose not to use the forced swim test or tail suspension to assess antidepressant-like effects with 5-HT 2A R β-arrestin-biased agonists, because animal behavioral despair models lack translational validity [79][80][81] . Utilizing an RDoC-like approach 82 to investigate potential clinical applications will best serve to illuminate the therapeutic potential of biased or partial 5-HT 2A R agonists. ...
Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that β-arrestin-biased 5-HT2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
... RDoC's positive valence behaviour domain relates to the endophenotype which includes responsiveness to reward, reward learning, habits, approach, and motivation. Since mesolimbic circuitry anatomy is conserved throughout mammalian evolution, and reward-related behaviours can be translationally assessed [21], rodent models are valid tools to investigate the link between chronic stress, inflammation and effort related decision making deficits. ...
Aims
To investigate the role of peripheral metabolic change and chronic low-grade inflammation on striatal dopamine dynamics and anhedonia-like behaviour induced by hypothalamic–pituitary–adrenal (HPA) axis disruption.
Methods
Wistar rats were trained in a progressive-ratio/concurrent effort-related choice paradigm to assess effort-related decision making. After reaching a stable baseline, animals received daily injections of adrenocorticotrophic hormone (ACTH) or saline for 24 days. On the 23 rd and 24 th day, animals received a bupropion challenge (10mg/kg and 20mg/kg respectively) 30 minutes prior to the behavioural testing session. On the 25 th day, animals received a single injection of bupropion (20mg/kg) 30 minutes prior to euthanasia. Peripheral and central inflammatory markers were assessed through ELISA and In-Cell Western assay; glucose transport activity was assessed in peripheral blood mononuclear cells though a commercial assay kit; brain levels of dopaminergic and inflammatory markers were assessed in the nucleus accumbens (NAc) and prefrontal cortex (PFC) through immunohistochemistry; and serum central carbon metabolism metabolites were assessed through a metabolomics approach.
Results
ACTH induced an anhedonia-like phenotype, decreased tyrosine hydroxylase (TH) levels in the NAc, increased peripheral IL-6 levels, and decreased glucose transport activity and glucose metabolites when compared to control group. Bupropion treatment was not able to reverse the anhedonic phenotype. Glucose uptake was positively correlated to behaviour; TH levels were correlated to microglia volume; metabolites were correlated to TH levels; and IL6 was correlated to TH levels and metabolites.
Conclusion
Chronic ACTH treatment can induce treatment-resistant anhedonia in rats, and the interaction between peripheral immunometabolic state and central dopamine synthesis is a potential mechanism underlying this phenotype.
... The chronic corticosterone treatment approach used here has been found to recapitulate most of the endophenotypes related to depression based on the current Research Domain Criteria (RDoC) system [133], that is, avoidance of negative valence behaviors [33,55], detachment of positive valence behaviors [30,55] and impaired social and cognitive abilities [134][135][136][137], revealing it as a suitable experimental protocol to study behavioral consequences of chronic stress-related diseases. Different chronic stress protocols are also commonly used to study anxiety and depressive phenotypes in animal research, including unpredictable chronic mild stress protocol and social defeat [27,28]. ...
Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca²⁺ signaling in MDD are poorly understood. Here, we found that corticosterone-treated juvenile mice (Cort-mice) showed altered astrocytic Ca²⁺ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca²⁺ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca²⁺ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca²⁺ signaling with Gq-DREADDS restored to the control levels mood and cognitive abilities in Cort-mice. This study highlights the important role of astrocyte Ca²⁺ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states.
... Since the RDoC domains are mainly constructed by basic neuroscience work including animal models, the animal model studies will have a much better opportunity to be aligned well with the RDoC frame. This can potentially lead to addressing fundamental questions on establishing neurobiological models for mental health disorders (Anderzhanova et al., 2017). In this regard, future studies of microbiota-gut-brain axis using animal models may seriously consider implementing the RDoC approach, by focusing on dimensional psychopathologies and underlying neurobiological mechanisms, avoiding focusing on categorical psychiatric diagnoses. ...
There are previous epidemiological studies reporting associations between antibiotic use and psychiatric symptoms. Antibiotic-induced gut dysbiosis and alteration of microbiota-gut-brain axis communication has been proposed to play a role in this association. In this systematic review and meta-analysis, we reviewed published articles that have presented results on changes in cognition, emotion, and behavior in rodents (rats and mice) after antibiotic-induced gut dysbiosis. We searched three databases—PubMed, Web of Science, and SCOPUS to identify such articles using dedicated search strings and extracted data from 48 articles. Increase in anxiety and depression-like behavior was reported in 32.7 and 40.7 percent of the study-populations, respectively. Decrease in sociability, social novelty preference, recognition memory and spatial cognition was found in 18.1, 35.3, 26.1, and 62.5 percent of the study-populations, respectively. Only one bacterial taxon (increase in gut Proteobacteria) showed statistically significant association with behavioral changes (increase in anxiety). There were no consistent findings with statistical significance for the potential biomarkers [Brain-derived neurotrophic factor (BDNF) expression in the hippocampus, serum corticosterone and circulating IL-6 and IL-1β levels]. Results of the meta-analysis revealed a significant association between symptoms of negative valence system (including anxiety and depression) and cognitive system (decreased spatial cognition) with antibiotic intake (p < 0.05). However, between-study heterogeneity and publication bias were statistically significant (p < 0.05). Risk of bias was evaluated to be high in the majority of the studies. We identified and discussed several reasons that could contribute to the heterogeneity between the results of the studies examined. The results of the meta-analysis provide promising evidence that there is indeed an association between antibiotic-induced gut dysbiosis and psychopathologies. However, inconsistencies in the implemented methodologies make generalizing these results difficult. Gut microbiota depletion using antibiotics may be a useful strategy to evaluate if and how gut microbes influence cognition, emotion, and behavior, but the heterogeneity in methodologies used precludes any definitive interpretations for a translational impact on clinical practice.
... Therefore, the reduction of GABAergic transmission mediated by miR-34a in the DRN could represent a step in the successful adaptation to a severe aversive experience. The conceptual framework of the Research Domain Criteria (RDoC) guidelines (43)(44)(45) provides another appealing interpretation. According to the RDoC, behavioral responses to real/acute and to potential threats are considered two different constructs of human behavior within the negative valence domain and therefore could be driven by different neural circuits. ...
The brain employs distinct circuitries to encode positive and negative valence stimuli, and dysfunctions of these neuronal circuits have a key role in the etiopathogenesis of many psychiatric disorders. The Dorsal Raphè Nucleus (DRN) is involved in various behaviors and drives the emotional response to rewarding and aversive experiences. Whether specific subpopulations of neurons within the DRN encode these behaviors with different valence is still unknown. Notably, microRNA expression in the mammalian brain is characterized by tissue and neuronal specificity, suggesting that it might play a role in cell and circuit functionality. However, this specificity has not been fully exploited. Here, we demonstrate that microRNA-34a (miR-34a) is selectively expressed in a subpopulation of GABAergic neurons of the ventrolateral DRN. Moreover, we report that acute exposure to both aversive (restraint stress) and rewarding (chocolate) stimuli reduces GABA release in the DRN, an effect prevented by the inactivation of DRN miR-34a or its genetic deletion in GABAergic neurons in aversive but not rewarding conditions. Finally, miR-34a inhibition selectively reduced passive coping with severe stressors. These data support a role of miR-34a in regulating GABAergic neurotransmitter activity and behavior in a context-dependent manner and suggest that microRNAs could represent a functional signature of specific neuronal subpopulations with valence-specific activity in the brain.
... Drug toxicity studies on non-human animals became legislated as a requirement for new drug development under food and drug regulatory frameworks in the late 1930s, and the requirement of animal research before human trials was written into both the Nuremberg code (1946) (Leenaars et al., 2019), bias towards anthropomorphism (Anderzhanova et al., 2017) and methodological concerns such as lack of replicability and inter-species variability (Herzog et al., 2018) as well as the limitations implicit in generalizing results from the adolescent-aged, in-bred rodent strains standard to animal investigations (Duque et al., 2021). Living in controlled experimental conditions results in chronic stress on study animals with resultant effects on neuromodulatory and self-regulatory systems (Alexander et al., 1981). ...
... By its focus on smaller units of analysis, RDoC proposes an interdisciplinary science of psychopathologies, identifying basic mechanisms which cut across diagnostic boundaries (Zoellner & Foa, 2016). The domains of analysis within RDoC serve as a matrix for model validation; homologies between human and experimental non-human animals in the domains justifies the validity, reliably and translatability of animal models appearing as endophenotypes of negative and positive affect, social interaction and general arousal/modulatory systems, while the complexity of the RDoC cognitive behavioural domain requires ongoing clarification (Anderzhanova et al., 2017). ...
... Allogrooming aids individual rodents in thermoregulation and provides markers such as scent for social recognition (identification as part of a social set). The broad value of studying self-grooming in animals is as a model of complex, repetitive and self-directed, sequentially patterned behaviours (Kalueff et al., 2016), an example of a coordinated activity and not so much a pathological endophenotype (Anderzhanova et al., 2017). Ten studies identified in this scoping review investigate the effect of Psi on grooming behaviour. ...
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Abstract
Psilocybin is a psychedelic compound of interest to clinicians, researchers and the general public for its unique effects on perception, cognition and emotion. Fifteen years of clinical trials, reviewed here using the scoping review method of knowledge synthesis , provide evidence for the safety and therapeutic efficacy of psilocybin when combined with psychological supports. A similar review of more than 50 years of research on non-human animals shows the safety of psilocybin and demonstrates persisting positive effects of psilocybin on self-regulation. To provide context to these scoping reviews, I conducted a detailed literature review and a separate narrative review on the neuroscience of psilocybin, with a marked interest in the dynamics of neuroplasticity and how habits of self-regulation are formed, revised and updated. While my working hypothesis considered mystical states as the mechanism of therapeutic action underlying psilocybin’s apparent benefits, the evidence was stronger to support a revised hypothesis: that psilocybin improves self-regulation. It does so by disrupting habit, potentiating new learning and promoting improvements to health behaviours. I offer here a novel contribution to the literature: a time-based Transition State Model of Psychedelic Effect which views psilocybin as a catalyst to improved flexibility of thought and behaviour. Psilocybin appears to attenuate or loosen the effects of past conditioning which appear as habits and which have become hard-wired into brain networks. This learning model heavily weights the activities undertaken in the days and weeks following psilocybin administration, providing a basis for psilocybin-assisted therapies to leverage this critical period for improvements to health behaviours.
... Among these areas, "Cognitive Control" is a system that modulates cognitive and emotional systems to bring out a goal-oriented behaviour and is, as a mechanism, activated in the process of selecting appropriate responses among alternatives (Insel et al. 2010). Disruptions in cognitive control may contribute to the occurrence or maintenance of various disorders by way of their impact on emotional or cerebral processes (Anderzhanova et al. 2017). Given the fact that compulsion stems from a disruption in the ability to employ goal-oriented strategies to control behaviour (Voon 2015, Gillan et al. 2017, Fineberg 2018, cognitive control is a construct of influence in OCD. ...
The categorical approach of traditional psychiatric nosology has been a forceful approach for a very long time for explaining psychological disorders which are defined by symptom based diagnostic categories. However, in recent years, the importance of the "transdiagnostic" approach which is a new classification system is increasing. The transdiagnostic approach aims to examine dimensionally the common cognitive, behavioral, interpersonal and biological processes underlying many psychopathologies away from the categorical approach that classifies psychopathologies according to observable symptoms. This approach intends to treat the disorders through the common underlying processes and risk factors, thus heterogeneous and comorbid symptoms are better addressed and diagnostic categories that may change during treatment are avoided. In this review study, the current problems in diagnosing based on classification and gaps in the field were examined, and the approach itself was proposed as a solution. RDoC (Research Domain Criteria) which is a new classification system for psychiatric disorders within the scope of the approach, has created a new structure using modern research approaches in genetics, neuroscience and behavioral sciences. In the present study, the definition and emergence of the transdiagnostic approach, obsessive compulsive disorder and RDoC in the context of transdiagnostic approach and transdiagnostic treatment are explained. This review is intended to be a resource for both basic psychopathology research and the development of treatment methods within the framework of a transdiagnostic approach.
... Environmental stressors and genetic factors appear to initiate a plethora of morphologic and functional changes which eventually manifest themselves as depression (Jesulola et al., 2018). A battery of preferentially rodent tests have been used to model the symptoms of depression without exception based on the understanding that chronic stress is the most common risk factor of depression (Anderzhanova et al., 2017;Pryce and Fuchs, 2017. Although chronic stress models are considered to be more reliable to induce so called depressive-like behavior in rats/mice, acute stressful stimulation is easier to handle and is therefore frequently used (e.g. ...
We used low and high molecular weight fluorescence tracers to investigate the entry of foreign solutes into the brain parenchyma and their exit from it by the glymphatic system, during experimentally induced depressive-like behavior in rats. The tail suspension test (TST), as an acute stressor, is known to induce such a type of behavior, considered to model the human major depressive disorder (MDD). Electroacupuncture (EAP) relieves both depressive-like behavior in rodents and the symptoms of MDD in humans. Here we report that 180 min after the intracisternal injection of the low molecular weight tracer Fluorescein-5-Isothiocianate Conjugated Dextran (FITC-d3), a 15-min duration TST tended to increase the control fluorescence in the brain of rats. Both EAP and sham EAP decreased the fluorescence of FITC-d3 in comparison with the TST, but not the control value. In addition, EAP and sham EAP counteracted the effects of TST. The high molecular weight tracer Ovalbumin Alexa Fluor 555 Conjugate (OA-45) failed to enter the brain parenchyma and accumulated at more superficial sites; however, EAP or sham EAP modified the distribution of fluorescence under TST application in a similar manner as that observed during the use of FITC-d3. It is concluded that EAP is possibly a valid treatment to slow down the entry of foreign solutes into the brain; in view of the comparable effects of EAP on FITC-d3 and OA-45 distribution, EAP seems to act before FITC-d3 passes the astroglial aquaporin-4 water channels, which are a critical constituent of the glymphatic system.
... In an attempt to overcome the above issues, the Research Domain Criteria (RDoC) proposal was launched to create a framework for research stemming mainly from neuroscience and genomic research, with the aim of providing an improved scientifically-grounded basis for future classification of psychiatric symptoms/disorders and treatments [181,182]. It attempts to describe the complete range of variation of each dimension, to gain further understanding of the normalto-pathological continuum regarding neurobehavioral features for each dimension. ...
Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia- relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO- SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.
... Each domain contains several constructs that can be considered as endophenotypes. For instance, fear is an endophenotype in the negative valence domain [30]. Each endophenotype can be studied at different biological levels (e.g., genes, molecules, cells, circuits, behavior, and self-report) within a defined developmental and environmental context. ...
... Acknowledging the limitations of short reductive behavioral tests RDoC is a promising framework for experimenting with humans as well as with animal models. For instance, a matrix designed for depression in humans can further serve as a reference for hypothesis testing of various mechanisms and endophenotypes underlying depression in animal models [30,31]. However, since behavior is the final output of the nervous system, even within the RDoC framework, the quality of the behavioral measures is of cardinal importance. ...
Mental disorders are a significant cause of disability worldwide. They profoundly affect individuals’ well-being and impose a substantial financial burden on societies and governments. However, despite decades of extensive research, the effectiveness of current therapeutics for mental disorders is often not satisfactory or well tolerated by the patient. Moreover, most novel therapeutic candidates fail in clinical testing during the most expensive phases (II and III), which results in the withdrawal of pharma companies from investing in the field. It also brings into question the effectiveness of using animal models in preclinical studies to discover new therapeutic agents and predict their potential for treating mental illnesses in humans. Here, we focus on rodents as animal models and propose that they are essential for preclinical investigations of candidate therapeutic agents’ mechanisms of action and for testing their safety and efficiency. Nevertheless, we argue that there is a need for a paradigm shift in the methodologies used to measure animal behavior in laboratory settings. Specifically, behavioral readouts obtained from short, highly controlled tests in impoverished environments and social contexts as proxies for complex human behavioral disorders might be of limited face validity. Conversely, animal models that are monitored in more naturalistic environments over long periods display complex and ethologically relevant behaviors that reflect evolutionarily conserved endophenotypes of translational value. We present how semi-natural setups in which groups of mice are individually tagged, and video recorded continuously can be attainable and affordable. Moreover, novel open-source machine-learning techniques for pose estimation enable continuous and automatic tracking of individual body parts in groups of rodents over long periods. The trajectories of each individual animal can further be subjected to supervised machine learning algorithms for automatic detection of specific behaviors (e.g., chasing, biting, or fleeing) or unsupervised automatic detection of behavioral motifs (e.g., stereotypical movements that might be harder to name or label manually). Compared to studies of animals in the wild, semi-natural environments are more compatible with neural and genetic manipulation techniques. As such, they can be used to study the neurobiological mechanisms underlying naturalistic behavior. Hence, we suggest that such a paradigm possesses the best out of classical ethology and the reductive behaviorist approach and may provide a breakthrough in discovering new efficient therapies for mental illnesses.
