Current rodent models for anxiety and depression assessment face methodological challenges compromising both scientific rigor and animal welfare.

Mice have been shown to learn from each other through social interactions. However, the extent and strategies of social learning in mice remain largely unknown, beyond spatially and temporally limited tests of social memory retention. Here, we present a method that integrates (1) the IntelliCage, a commercially available tool for automated behavioral testing, and (2) the Live Mouse Tracker (LMT), an open-source solution for 24/7 live animal tracking. This approach allows for the investigation of learning behavior in semi-naturalistic group settings while minimizing experimenter interference. In this study, we report on the development of the method, evaluate its accuracy, and identify current limitations. While automated presentation of spatial learning tasks and behavior annotation were effective, identifying individual animals proved unreliable in a highly enriched environment. In response, we provide a rationale for identifying the reliable portion of tracking data, to which we confine the exemplary behavioral analysis. We acknowledge imperfect animal identification as a clear limitation of the method in its current configuration. However, we outline a path to mitigate this and are confident in presenting a promising tool that, after straightforward optimization, may prove useful for various research questions, including the investigation of social learning behavior in mice. The proof-of-principle experiment in this study did not indicate that place learning is facilitated by co-learning over individual learning, and we could not establish a clear association between social interactions and learning performance. While we observed some sporadic differences in interaction rates between co-learning and individually learning animals, we emphasize that these results do not support any conclusions about the mechanisms of social learning in mice. Rather, we present a tool for simultaneously studying learning and tracking behavior with minimal experimenter interference, which, after refinement, may aid future studies of social learning in mice alongside other research questions.

Social behavior involves sociability-the drive to interact-and social preference-the choice of partners. Using FlySocialer, an automated system for tracking group interactions, we analyzed male Drosophila melanogaster and found highly individualized, non-random social behaviors. Compared to randomized controls, flies showed stable individual differences in sociability and distinct partner preferences. Sociability exhibited a sensory-specific lateralized asymmetry: visual inputs via the left eye modulated interaction number, while olfactory inputs via the left antenna influenced interaction duration. Conversely, neither sensory manipulation exerted a significant effect on social preference. These results reveal distinct mechanisms for sociability and selectivity, highlighting lateralized sensory drive versus bilateral integration as core principles of social behavior in Drosophila.

Spontaneous recovery is regarded as an experimental analogue of relapse following successful treatment of anxiety and traumatic disorders using exposure therapy. This systematic review examines the evidence for spontaneous recovery within human fear conditioning, highlighting its broad application in research and implications of findings for potential clinical implications. PubMed, Medline, and PsycINFO were searched from inception to 09/04/2026. In total, the search yielded 4,655 articles, of which 242 were included in the review. A meta-analysis was not conducted and the review was not preregistered. Evidence suggests differences in spontaneous recovery exist between clinical populations and healthy control groups, particularly for posttraumatic stress disorder, with mixed evidence observed in anxious versus healthy individuals. Our review reveals that paradigms involving a ~ 24-h delay between extinction and spontaneous recovery test (typically conducted across two consecutive days) are most frequently used and might produce the strongest effects. Importantly, we identify converging patterns between experimental findings and clinical outcomes between spontaneous recovery and the real-world efficacy of pharmacological interventions, providing preliminary support for the translational relevance of the paradigm. However, we note the slow uptake of non-pharmacological interventions in clinical trials despite promising experimental data and discuss findings from neurotransmitter and sleep studies that offer insights for optimizing exposure therapy. These findings suggest future research directions, including evaluating the correlation between experimental and clinical outcomes, exploring optimal conditions for the observation of spontaneous recovery, and understanding the effects of brain stimulation on fear conditioning.

Decades of literature point to a critical role for prefrontal-hippocampal interactions in emotion and memory. Recent studies in both rodents and humans have revealed that these interactions are coordinated by the midline thalamic nucleus reuniens (RE), a brain region that mediates bidirectional communication between the hippocampus (HPC) and medial prefrontal cortex (mPFC). Here, we aimed to review studies that implicate the RE in memory, emotion, and executive function across a range of behavioral tasks. We also discuss the role the RE may play in the maladaptive cognitive and emotional processes associated with neuropsychiatric and neurological disorders. We conclude that the RE plays a critical role in coordinating oscillations in the mPFC-HPC network to support the flexible and context-dependent expression of memory and emotion.

The endocannabinoid system is a neuromodulatory network regulating synaptic plasticity, neuronal activity, and neuroinflammatory responses in both the central and peripheral nervous systems. The endocannabinoid system comprises endogenous ligands, termed endocannabinoids, and two principal receptors, cannabinoid receptor type 1 and type 2 (CB1R and CB2R). While CB1R is predominantly associated with the central nervous system and mediates the psychotropic effects of cannabis-derived compounds, CB2R was initially considered mainly peripheral. However, growing evidence over the last decades has highlighted a pivotal role for CB2R in central nervous system homeostasis and pathology. Importantly, the lack of psychotropic effects associated with CB2R signaling has positioned this receptor as a promising therapeutic target for several brain-related disorders, including neuroinflammatory, neurodegenerative, neuropsychiatric, and neurovascular conditions. Here, we provide a structured review of experimental studies published over the last 3 years investigating CB2R modulation in the central nervous system, with a particular focus on disease mechanisms and emerging therapeutic strategies.

Fear-related disorders-including post-traumatic stress disorder (PTSD), specific phobias, and generalized anxiety disorder-are among the most prevalent and treatment-resistant psychiatric conditions. Despite decades of molecular and cellular advances, systemic pharmacological interventions and approaches targeting isolated brain regions have had limited therapeutic capacity, particularly in refractory patients. This mini-review argues that the translational impasse stems from a reductionist framework that treats mental disorders in general, and fear-related disorders in particular, as a localized phenomenon rather than a distributed network property. We synthesize recent evidence from engram research, oscillatory dynamics, and systems consolidation demonstrating that fear memories are encoded, maintained, and retrieved through brain-wide networks. We outline how emerging technologies such as high-density electrophysiology, calcium imaging, and functional neuroimaging combined with graph-theoretical analysis can map memory networks at scale, enabling precision interventions such as closed-loop neuromodulation and connectivity-based treatment prediction. Adopting a transdiagnostic perspective aligned with the Research Domain Criteria (RDoC), we position persistent aversive memory as a dimensional mechanism that crosses diagnostic boundaries, a perspective we propose as necessary for the development of more effective clinical interventions.

Rett syndrome (RTT) stands at the forefront of the genetic therapy revolution. This severe X-linked neurodevelopmental disorder, primarily caused by mutations in the MECP2 gene, was historically considered a static condition but is now recognized as a potentially reversible neurodevelopmental disorder. This review synthesizes recent breakthroughs in our understanding of MeCP2's role in chromatin architecture, including its involvement in liquid-liquid phase separation (LLPS). We critically examine the transition from conventional symptom management to precision epigenetic therapeutics. Key advances discussed include next-generation gene replacement strategies with autoregulatory control to prevent toxicity, programmable epigenetic editing (e.g., CRISPR-off/on) to correct MECP2 expression endogenously, and novel approaches for X-chromosome reactivation (XCI). Furthermore, we propose a stratified therapeutic framework (genotype-guided therapies) based on specific mutation types. Finally, we analyze data from ongoing clinical trials and highlight the remaining hurdles-such as delivery efficiency, immunogenicity, and the urgent need for objective biomarkers-that must be overcome to translate these epigenetic innovations into a cure.