Neural Circuits for Emotion.

Emotions are fundamental to our experience and behavior, affecting and motivating all aspects of our lives. Scientists of various disciplines have been fascinated by emotions for centuries, yet even today vigorous debates abound about how to define emotions and how to best study their neural underpinnings. Defining emotions from an evolutionary perspective and acknowledging their important functional roles in supporting survival allows the study of emotion states in diverse species. This approach enables taking advantage of modern tools in behavioral, systems, and circuit neurosciences, allowing the precise dissection of neural mechanisms and behavior underlying emotion processes in model organisms. Here we review findings about the neural circuit mechanisms underlying emotion processing across species and try to identify points of convergence as well as important next steps in the pursuit of understanding how emotions emerge from neural activity.

The Theory and Neuroscience of Cerebellar Cognition.

Cerebellar neuroscience has undergone a paradigm shift. The theories of the universal cerebellar transform and dysmetria of thought and the principles of organization of cerebral cortical connections, together with neuroanatomical, brain imaging, and clinical observations, have recontextualized the cerebellum as a critical node in the distributed neural circuits subserving behavior. The framework for cerebellar cognition stems from the identification of three cognitive representations in the posterior lobe, which are interconnected with cerebral association areas and distinct from the primary and secondary cerebellar sensorimotor representations linked with the spinal cord and cerebral motor areas. Lesions of the anterior lobe primary sensorimotor representations produce dysmetria of movement, the cerebellar motor syndrome. Lesions of the posterior lobe cognitive-emotional cerebellum produce dysmetria of thought and emotion, the cerebellar cognitive affective/Schmahmann syndrome. The notion that the cerebellum modulates thought and emotion in the same way that it modulates motor control advances the understanding of the mechanisms of cognition and opens new therapeutic opportunities in behavioral neurology and neuropsychiatry.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age.

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

Brain representations of affective valence and intensity in sustained pleasure and pain.

Pleasure and pain are two fundamental, intertwined aspects of human emotions. Pleasurable sensations can reduce subjective feelings of pain and vice versa, and we often perceive the termination of pain as pleasant and the absence of pleasure as unpleasant. This implies the existence of brain systems that integrate them into modality-general representations of affective experiences. Here, we examined representations of affective valence and intensity in an functional MRI (fMRI) study (n = 58) of sustained pleasure and pain. We found that the distinct subpopulations of voxels within the ventromedial and lateral prefrontal cortices, the orbitofrontal cortex, the anterior insula, and the amygdala were involved in decoding affective valence versus intensity. Affective valence and intensity predictive models showed significant decoding performance in an independent test dataset (n = 62). These models were differentially connected to distinct large-scale brain networks-the intensity model to the ventral attention network and the valence model to the limbic and default mode networks. Overall, this study identified the brain representations of affective valence and intensity across pleasure and pain, promoting a systems-level understanding of human affective experiences.

Brain decoding of spontaneous thought: Predictive modeling of self-relevance and valence using personal narratives.

The contents and dynamics of spontaneous thought are important factors for personality traits and mental health. However, assessing spontaneous thoughts is challenging due to their unconstrained nature, and directing participants' attention to report their thoughts may fundamentally alter them. Here, we aimed to decode two key content dimensions of spontaneous thought-self-relevance and valence-directly from brain activity. To train functional MRI-based predictive models, we used individually generated personal stories as stimuli in a story-reading task to mimic narrative-like spontaneous thoughts (n = 49). We then tested these models on multiple test datasets (total n = 199). The default mode, ventral attention, and frontoparietal networks played key roles in the predictions, with the anterior insula and midcingulate cortex contributing to self-relevance prediction and the left temporoparietal junction and dorsomedial prefrontal cortex contributing to valence prediction. Overall, this study presents brain models of internal thoughts and emotions, highlighting the potential for the brain decoding of spontaneous thought.

Memory decline, anxiety and depression in the mouse model of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant hereditary disorder, caused by an expansion of polyglutamine in the ataxin-3 protein. SCA3 symptoms include progressive motor decline caused by an atrophy of the cerebellum and brainstem. However, it was recently reported that SCA3 patients also suffer from the cerebellar cognitive affective syndrome. The majority of SCA3 patients exhibit cognitive decline and approximately half of them suffer from depression and anxiety. The necessity to find a combined therapy for both motor and cognitive deficits in a SCA3 mouse model is required for the development of SCA3 treatment. Here, we demonstrated that the SCA3-84Q transgenic mice exhibited anxiety over the novel brightly illuminated environment in the open field, novelty suppressed feeding, and light-dark place preference tests. Moreover, SCA3-84Q mice also suffered from a decline in recognition memory during the novel object recognition test. SCA3-84Q mice also demonstrated floating behavior during the Morris water maze that can be interpreted as a sign of low mood and aversion to activity, i.e. depressive-like state. SCA3-84Q mice also spent more time immobile during the forced swimming and tail suspension tests which is also evidence for depressive-like behavior. Therefore, the SCA3-84Q mouse model may be used as a model system to test the possible treatments for both ataxia and non-motor symptoms including depression, anxiety, and memory loss.

A combination of chlorzoxazone and folic acid improves recognition memory, anxiety and depression in SCA3-84Q mice.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS). We previously observed signs of CCAS in mouse model of SCA3. Particularly, SCA3-84Q mice suffer from anxiety, recognition memory decline, and also exhibit signs of low mood and aversion to activity. Here we studied the effect of long-term injections of SK channels activator chlorzoxazone (CHZ) together and separately with the folic acid (FA) on the cerebellar Purkinje cell (PC) firing and histology, and also on the motor and cognitive functions as well as mood alterations in SCA3-84Q hemizygous transgenic mice. We realized that both CHZ and CHZ-FA combination had similar positive effect on pure cerebellum impairments including PC firing precision, PC histology, and motor performance in SCA3-84Q mice. However, only the CHZ-FA combination, but not CHZ, had significantly ameliorated the signs of anxiety and depression, and also noticeably improved recognition memory in SCA3-84Q mice. Our results suggest that the combination therapy for both ataxia and non-motor symptoms is required for the complex treatment of ADCA.

The competition dynamics of approach and avoidance motivations following interpersonal transgression.

Two behavioral motivations coexist in transgressors following an interpersonal transgression-approaching and compensating the victim and avoiding the victim. Little is known about how these motivations arise, compete, and drive transgressors' decisions. The present study adopted a social interaction task to manipulate participants' (i.e., the transgressor) responsibility for another's (i.e., the victim) monetary loss and measure the participants' tradeoff between compensating the victim and avoiding face-to-face interactions with the victim. Following each transgression, participants used a computer mouse to choose between two options differing in the amount of compensation to the victim and the probability of face-to-face contact with the victim. Results showed that as participants' responsibility increased, 1) the decision weights on contact avoidance relative to compensation increased, and 2) the onset of the contact-avoidance attribute was expedited and that of the compensation attribute was delayed. These results demonstrate how competing social motivations following transgression evolve and determine social decision-making and shed light on how social-affective state modulates the dynamics of decision-making in general.

Neuronal and Molecular Mechanisms Underlying Chronic Pain and Depression Comorbidity in the Paraventricular Thalamus.

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.

Neural patterns associated with mixed valence feelings differ in consistency and predictability throughout the brain.

Mixed feelings, the simultaneous presence of feelings with positive and negative valence, remain an understudied topic. They pose a specific set of challenges due to individual variation, and their investigation requires analtyic approaches focusing on individually self-reported states. We used functional magnetic resonance imaging (fMRI) to scan 27 subjects watching an animated short film chosen to induce bittersweet mixed feelings. The same subjects labeled when they had experienced positive, negative, and mixed feelings. Using hidden-Markov models, we found that various brain regions could predict the onsets of new feeling states as determined by self-report. The ability of the models to identify these transitions suggests that these states may exhibit unique and consistent neural signatures. We next used the subjects' self-reports to evaluate the spatiotemporal consistency of neural patterns for positive, negative, and mixed states. The insula had unique and consistent neural signatures for univalent states, but not for mixed valence states. The anterior cingulate and ventral medial prefrontal cortex had consistent neural signatures for both univalent and mixed states. This study is the first to demonstrate that subjectively reported changes in feelings induced by naturalistic stimuli can be predicted from fMRI and the first to show direct evidence for a neurally consistent representation of mixed feelings.

Boosting interpersonal emotion regulation through facial imitation: functional neuroimaging foundations.

Empathic function, which is primarily manifested by facial imitation, is believed to play a pivotal role in interpersonal emotion regulation for mood reinstatement. To explore this association and its neural substrates, we performed a questionnaire survey (study l) to identify the relationship between empathy and interpersonal emotion regulation; and a task-mode fMRI study (study 2) to explore how facial imitation, as a fundamental component of empathic processes, promotes the interpersonal emotion regulation effect. Study 1 showed that affective empathy was positively correlated with interpersonal emotion regulation. Study 2 showed smaller negative emotions in facial imitation interpersonal emotion regulation (subjects imitated experimenter's smile while followed the interpersonal emotion regulation guidance) than in normal interpersonal emotion regulation (subjects followed the interpersonal emotion regulation guidance) and Watch conditions. Mirror neural system (e.g. inferior frontal gyrus and inferior parietal lobe) and empathy network exhibited greater activations in facial imitation interpersonal emotion regulation compared with normal interpersonal emotion regulation condition. Moreover, facial imitation interpersonal emotion regulation compared with normal interpersonal emotion regulation exhibited increased functional coupling from mirror neural system to empathic and affective networks during interpersonal emotion regulation. Furthermore, the connectivity of the right orbital inferior frontal gyrus-rolandic operculum lobe mediated the association between the accuracy of facial imitation and the interpersonal emotion regulation effect. These results show that the interpersonal emotion regulation effect can be enhanced by the target's facial imitation through increased functional coupling from mirror neural system to empathic and affective neural networks.

Identifying suicide attempter in major depressive disorder through machine learning: the importance of pain avoidance, event-related potential features of affective processing.

How to achieve a high-precision suicide attempt classifier based on the three-dimensional psychological pain model is a valuable issue in suicide research. The aim of the present study is to explore the importance of pain avoidance and its related neural features in suicide attempt classification models among patients with major depressive disorder. By recursive feature elimination with cross-validation and support-vector-machine algorithms, scores from the measurements and the task-based EEG signals were chosen to achieve a suicide attempt classification model. In the multimodal suicide attempt classifier with an accuracy of 83.91% and an area under the curve of 0.90, pain avoidance ranked as the top one in the optimal feature set. Theta (reward positive feedback minus neutral positive feedback) was the shared neural representation ranking as the top one of event-related potential features in pain avoidance and suicide attempt classifiers. In conclusion, the suicide attempt classifier based on pain avoidance and its related affective processing neural features has excellent accuracy among patients with major depressive disorder. Pain avoidance is a stable and strong indicator for identifying suicide risks in both traditional analyses and machine-learning approaches. A novel methodology is needed to clarify the relationship between cognitive and affective processing evoked by punishment stimuli and pain avoidance.

Caresses, whispers and affective faces: A theoretical framework for a multimodal interoceptive mechanism underlying ASMR and affective touch: An evolutionary and developmental perspective for understanding ASMR and affective touch as complementary processes within affiliative interactions.

Autonomous sensory meridian response (ASMR) and affective touch (AT) are two phenomena that have been independently investigated from separate lines of research. In this article, I provide a unified theoretical framework for understanding and studying them as complementary processes. I highlight their shared biological basis and positive effects on emotional and psychophysiological regulation. Drawing from evolutionary and developmental theories, I propose that ASMR results from the development of biological mechanisms associated with early affiliative behaviour and self-regulation, similar to AT. I also propose a multimodal interoceptive mechanism underlying both phenomena, suggesting that different sensory systems could specifically respond to affective stimulation (caresses, whispers and affective faces), where the integration of those inputs occurs in the brain's interoceptive hubs, allowing physiological regulation. The implications of this proposal are discussed with a view to future research that jointly examines ASMR and AT, and their potential impact on improving emotional well-being and mental health.

Current research overstates American support for political violence.

SignificanceRecent political events show that members of extreme political groups support partisan violence, and survey evidence supposedly shows widespread public support. We show, however, that, after accounting for survey-based measurement error, support for partisan violence is far more limited. Prior estimates overstate support for political violence because of random responding by disengaged respondents and because of a reliance on hypothetical questions about violence in general instead of questions on specific acts of political violence. These same issues also cause the magnitude of the relationship between previously identified correlates and partisan violence to be overstated. As policy makers consider interventions designed to dampen support for violence, our results provide critical information about the magnitude of the problem.

Politicians polarize and experts depolarize public support for COVID-19 management policies across countries.

Political polarization impeded public support for policies to reduce the spread of COVID-19, much as polarization hinders responses to other contemporary challenges. Unlike previous theory and research that focused on the United States, the present research examined the effects of political elite cues and affective polarization on support for policies to manage the COVID-19 pandemic in seven countries (n = 12,955): Brazil, Israel, Italy, South Korea, Sweden, the United Kingdom, and the United States. Across countries, cues from political elites polarized public attitudes toward COVID-19 policies. Liberal and conservative respondents supported policies proposed by ingroup politicians and parties more than the same policies from outgroup politicians and parties. Respondents disliked, distrusted, and felt cold toward outgroup political elites, whereas they liked, trusted, and felt warm toward both ingroup political elites and nonpartisan experts. This affective polarization was correlated with policy support. These findings imply that policies from bipartisan coalitions and nonpartisan experts would be less polarizing, enjoying broader public support. Indeed, across countries, policies from bipartisan coalitions and experts were more widely supported. A follow-up experiment replicated these findings among US respondents considering international vaccine distribution policies. The polarizing effects of partisan elites and affective polarization emerged across nations that vary in cultures, ideologies, and political systems. Contrary to some propositions, the United States was not exceptionally polarized. Rather, these results suggest that polarizing processes emerged simply from categorizing people into political ingroups and outgroups. Political elites drive polarization globally, but nonpartisan experts can help resolve the conflicts that arise from it.

Dynamic threat-reward neural processing under semi-naturalistic ecologically relevant scenarios.

Studies of affective neuroscience have typically employed highly controlled, static experimental paradigms to investigate the neural underpinnings of threat and reward processing in the brain. Yet our knowledge of affective processing in more naturalistic settings remains limited. Specifically, affective studies generally examine threat and reward features separately and under brief time periods, despite the fact that in nature organisms are often exposed to the simultaneous presence of threat and reward features for extended periods. To study the neural mechanisms of threat and reward processing under distinct temporal profiles, we created a modified version of the PACMAN game that included these environmental features. We also conducted two automated meta-analyses to compare the findings from our semi-naturalistic paradigm to those from more constrained experiments. Overall, our results revealed a distributed system of regions sensitive to threat imminence and a less distributed system related to reward imminence, both of which exhibited overlap yet neither of which involved the amygdala. Additionally, these systems broadly overlapped with corresponding meta-analyses, with the notable absence of the amygdala in our findings. Together, these findings suggest a shared system for salience processing that reveals a heightened sensitivity toward environmental threats compared to rewards when both are simultaneously present in an environment. The broad correspondence of our findings to meta-analyses, consisting of more tightly controlled paradigms, illustrates how semi-naturalistic studies can corroborate previous findings in the literature while also potentially uncovering novel mechanisms resulting from the nuances and contexts that manifest in such dynamic environments.

Amygdala structural and functional reorganization as an indicator of affective dysfunction in patients with tinnitus.

The aim of this study was to systematically investigate structural and functional alterations in amygdala subregions using multimodal magnetic resonance imaging (MRI) in patients with tinnitus with or without affective dysfunction. Sixty patients with persistent tinnitus and 40 healthy controls (HCs) were recruited. Based on a questionnaire assessment, 26 and 34 patients were categorized into the tinnitus patients with affective dysfunction (TPAD) and tinnitus patients without affective dysfunction (TPWAD) groups, respectively. MRI-based measurements of gray matter volume, fractional anisotropy (FA), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), degree centrality (DC), and functional connectivity (FC) were conducted within 14 amygdala subregions for intergroup comparisons. Associations between the MRI properties and clinical characteristics were estimated via partial correlation analyses. Compared with that of the HCs, the TPAD and TPWAD groups exhibited significant structural and functional changes, including white matter integrity (WMI), fALFF, ReHo, DC, and FC alterations, with more pronounced WMI changes in the TPAD group, predominantly within the left auxiliary basal or basomedial nucleus (AB/BM), right central nucleus, right lateral nuclei (dorsal portion), and left lateral nuclei (ventral portion containing basolateral portions). Moreover, the TPAD group exhibited decreased FC between the left AB/BM and left middle occipital gyrus and right superior frontal gyrus (SFG), left basal nucleus and right SFG, and right lateral nuclei (intermediate portion) and right SFG. In combination, these amygdalar alterations exhibited a sensitivity of 65.4% and specificity of 96.9% in predicting affective dysfunction in patients with tinnitus. Although similar structural and functional amygdala remodeling were observed in the TPAD and TPWAD groups, the changes were more pronounced in the TPAD group. These changes mainly involved alterations in functionality and white matter microstructure in various amygdala subregions; in combination, these changes could serve as an imaging-based predictor of emotional disorders in patients with tinnitus.

Neural substrates of affective temperaments: An intersubject representational similarity analysis to resting-state functional magnetic resonance imaging in nonclinical subjects.

Previous research has suggested that certain types of the affective temperament, including depressive, cyclothymic, hyperthymic, irritable, and anxious, are subclinical manifestations and precursors of mental disorders. However, the neural mechanisms that underlie these temperaments are not fully understood. The aim of this study was to identify the brain regions associated with different affective temperaments. We collected the resting-state functional magnetic resonance imaging (fMRI) data from 211 healthy adults and evaluated their affective temperaments using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire. We used intersubject representational similarity analysis to identify brain regions associated with each affective temperament. Brain regions associated with each affective temperament were detected. These regions included the prefrontal cortex, anterior cingulate cortex (ACC), precuneus, amygdala, thalami, hippocampus, and visual areas. The ACC, lingual gyri, and precuneus showed similar activity across several affective temperaments. The similarity in related brain regions was high among the cyclothymic, irritable, and anxious temperaments, and low between hyperthymic and the other affective temperaments. These findings may advance our understanding of the neural mechanisms underlying affective temperaments and their potential relationship to mental disorders and may have potential implications for personalized treatment strategies for mood disorders.

Effect of minocycline on changes in affective behaviors, cognitive function, and inflammation in breast cancer survivors undergoing chemotherapy: a pilot randomized controlled trial.

PURPOSE: Minocycline suppresses chemotherapy-induced neuroinflammation in preclinical models, but its effects in cancer survivors are unknown. This study evaluated the longitudinal effects of minocycline on affective behaviors, cognitive functions, and inflammation in women with breast cancer (BC) undergoing chemotherapy. METHODS: This is a pilot, double-blind, randomized controlled trial of oral minocycline (100 mg BID) versus placebo for chemotherapy-induced affective disorders in women initiating chemotherapy for stage I-III BC. Participants received minocycline or placebo up to one week before chemotherapy, continuing through cycle 4 (C4). Epidemiologic Studies Depression Scale (CES-D) and State-Trait Anxiety Inventory (STAI) were assessed at baseline, each cycle of chemotherapy (C1-C4), 2-3-week post-chemotherapy (end of chemotherapy), and 6-month post-chemotherapy (6 M) as the primary outcomes. Sub-group analysis of CES-D and STAI based on the severity of symptoms was also performed. Changes in self-reported cognition and serum inflammatory markers were also evaluated. RESULTS: Fifty-seven women enrolled and 55 completed the study. Except for Interleukin-8 (p ≤ 0.03), changes in inflammatory markers, cognitive function, CES-D, and STAI were not significantly different between groups from baseline to any cycle or post-chemotherapy time point (all p > 0.05), adjusting for baseline scores. Increases in serum Interleukin-8 from baseline to C4 and 6 M were ameliorated by minocycline (p < 0.05). The sub-group symptomatic for depression (CES-D > = 16 at baseline) treated with minocycline had a greater reduction in CES-D score compared to placebo from baseline to 6 M (p = 0.01). CONCLUSION: Despite attenuation of IL-8, minocycline did not alter self-reported affective symptoms or cognition in this cohort of BC survivors undergoing chemotherapy. The effect of minocycline on BC survivors symptomatic for depression before chemotherapy warrants further investigation.

Rodent tests of depression and anxiety: Construct validity and translational relevance.

Behavioral testing constitutes the primary method to measure the emotional states of nonhuman animals in preclinical research. Emerging as the characteristic tool of the behaviorist school of psychology, behavioral testing of animals, particularly rodents, is employed to understand the complex cognitive and affective symptoms of neuropsychiatric disorders. Following the symptom-based diagnosis model of the DSM, rodent models and tests of depression and anxiety focus on behavioral patterns that resemble the superficial symptoms of these disorders. While these practices provided researchers with a platform to screen novel antidepressant and anxiolytic drug candidates, their construct validity-involving relevant underlying mechanisms-has been questioned. In this review, we present the laboratory procedures used to assess depressive- and anxiety-like behaviors in rats and mice. These include constructs that rely on stress-triggered responses, such as behavioral despair, and those that emerge with nonaversive training, such as cognitive bias. We describe the specific behavioral tests that are used to assess these constructs and discuss the criticisms on their theoretical background. We review specific concerns about the construct validity and translational relevance of individual behavioral tests, outline the limitations of the traditional, symptom-based interpretation, and introduce novel, ethologically relevant frameworks that emphasize simple behavioral patterns. Finally, we explore behavioral monitoring and morphological analysis methods that can be integrated into behavioral testing and discuss how they can enhance the construct validity of these tests.