Aug 2026· Genes, Brain and Behavior· Vol 25· 0 citations· 31 references
Medicine
TL;DR
Findings reveal a profound impairment with female GPR158 knockout mice in hippocampal‐dependent cognition and highlight the importance of low‐stress, ethologically testing environments.
Abstract
GPR158 is a G protein coupled receptor (GPCR) that is abundantly expressed in the brain and has been shown to organize synaptic architecture and regulate synaptic function. Previous studies have demonstrated a role for GPR158 in hippocampal‐dependent learning and stress‐related affective behaviors yet its contribution to cognitive function under naturalistic, low‐stress conditions remains unclear. Here, we investigated the role of GPR158 in spatial learning, cognitive flexibility, and working memory using both traditional and automated home‐cage paradigms. The use of automated, socially enriched testing paradigms minimizes stress‐related confounds and allows us to discover the naturalistic roles of GPR158 in cognition and behavior. Using the IntelliCage to test spatial learning and working memory in a social enriched environment, we found that female GPR158 knockout mice exhibited deficits in spatial learning but showed intact working memory. Consistent with these findings, spatial impairments were also observed in the Barnes Maze, where female GPR158 KO mice showed pronounced deficits in spatial strategy acquisition, increased latency, reduced time spent in the reward area, and impaired performance during the probe trial. Male GPR158 knockout mice showed no significant difference in either spatial learning or working memory compared to their wild‐type littermates in the IntelliCage, whereas in the Barnes Maze knockout mice showed mild impairment in spatial strategy acquisition. These findings reveal a profound impairment with female GPR158 knockout mice in hippocampal‐dependent cognition and highlight the importance of low‐stress, ethologically testing environments.
These findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Huanqing Yang, V. Kovářová, Alena O. Godunova et al.· Neurobiology of Stress· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
Free-living animals encounter a wide range of ecological and environmental stressors throughout their lifetime, which can shape both cognitive performance and neural function. While cognitive abilities, particularly learning and memory, are critical for responding effectively to these stressors, evidence suggests that stress exposure – in particular glucocorticoid hormones – can, in turn, affect cognition. However, the neurobiological mechanisms underlying these bidirectional interactions remain poorly understood, especially in wild systems. Thus, in this dissertation, I investigated how chronic predation risk and glucocorticoid hormones influence cognition in wild white-footed mice (Peromyscus leucopus). I further examined the effects of predation risk on the relationship between neuronal activation patterns and cognitive performance. In Chapter 2, I show that chronic predation risk did not impair learning but had a small effect on memory, and affected exploratory behaviour, suggesting that exploration strategies might help animals maintain learning performance under chronic predation risk conditions. In Chapter 3, I show that glucocorticoids had no effect on associative learning and memory, but did affect spatial learning and memory, and the opposite pattern was true for long-term memory. Finally, in Chapter 4, I show how predation risk reduced neuronal activation patterns in the hippocampus and alters the relationship between neuronal activation patterns and cognitive performance. Overall, this work provides novel insight into how predation risk and stress hormones shape cognition and brain function in wild animals. These findings highlight the importance of studying neurobiological mechanisms in ecologically relevant contexts to better understand how animals maintain adaptive function under chronic environmental stress.
Fear conditioning is widely used to assess associative memory in mice, yet percent freezing conflates memory with baseline locomotor and anxiety-related traits. A systematic survey of recent studies (2020–2025) found that fewer than 1% statistically integrate locomotor activity into freezing analyses. Here, we address this gap using a large-scale dataset of >10,000 mice across >160 comparisons, including genetic mutations, pharmacological interventions and aging, tested in 15 standardized behavioral paradigms. Conventional freezing scores covaried strongly with general locomotor activity, obscuring memory-related phenotypes. Multiple factor analysis identified two principal behavioral dimensions, locomotor activity and learning/memory: conventional freezing aligned with the locomotor dimension, whereas freezing subtraction and the activity suppression ratio mapped onto the memory dimension and improved detection of synaptic plasticity phenotypes. These analyses show that baseline locomotor normalization is essential for interpreting fear conditioning as a memory assay and provide an open framework for selecting and reporting locomotor-normalized metrics.
Daiki X. Sato, M. M. Chatzigiannis, Hirotaka Shoji et al.· bioRxiv· 0 citations
Social isolation is a pervasive stressor that disrupts social cognition, yet its neural mechanisms in adulthood remain unclear. Here, we showed that four weeks of social isolation in adult male mice selectively impaired social novelty memory without affecting general sociability, object recognition, working memory, or anxiety- and depression-like behaviors. This deficit was sex-specific, as female mice remained unaffected. Mechanistically, c-Fos mapping and in vivo calcium imaging revealed that social isolation induced a maladaptive shift in prefrontal excitatory-inhibitory (E/I) balance, characterized by both exaggerated activation of medial prefrontal cortex (mPFC) glutamatergic neurons and attenuated recruitment of local GABAergic interneurons specifically during novel social exploration. Causal manipulations showed that chemogenetic or optogenetic activation of mPFC glutamatergic neurons in group-housed males was sufficient to recapitulate the social novelty memory impairment, whereas inhibition of these neurons in isolated mice rescued the deficit. At the cellular level, electrophysiological recordings demonstrated that SI enhanced the intrinsic excitability of mPFC pyramidal neurons and induced a synaptic E/I imbalance, characterized by increased excitatory and decreased inhibitory drive. Together, our findings establish that adult social isolation disrupts social novelty memory processing by shifting the mPFC excitatory-inhibitory balance toward a net hyperexcitable state, revealing a reversible, circuit-specific mechanism for isolation-induced social cognitive deficits.
Quan Yuan, Bingyu Ren, Laijian Wang et al.· Translational Psychiatry· 0 citations
BACKGROUND
Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive decline. G protein-coupled receptor 55 (GPR55) has been linked to cognitive regulation, yet its precise role in AD pathogenesis remains unclear.
OBJECTIVES
Here, we investigated the role of GPR55 in AD and its molecular mechanism.
METHODS
This study utilized APP/PS1 and GPR55 knockout (GPR55KO) mice to investigate the role and possible mechanism of GPR55 in AD.
RESULTS
We observed progressive reduction of GPR55 levels in the hippocampus of aging APP/PS1 mice. Conversely, hippocampal GPR55 overexpression rescued cognitive deficits, neuroinflammation, and impairment of synaptic plasticity in APP/PS1 mice. Moreover, GPR55 activation reduced neuronal death and memory impairments in APP/PS1 mice. In addition, aged GPR55KO mice showed cognitive deficits, but hippocampal GPR55 reexpression improved cognition. We also demonstrated that GPR55 activation mitigates Aβ1-42-induced synaptic damage and apoptosis in HT22 cells. Further studies revealed that in both animal and cell models, the activation levels of P-AKT/AKT and P-GSK3β/GSK3β were significantly decreased, and the activation level of P-ERK/ERK was markedly increased, while upregulation of GPR55 reversed this trend.
CONCLUSIONS
These results indicate that hippocampal GPR55 may improve cognitive dysfunction by regulating the AKT/GSK3β and ERK signaling pathways, highlighting its crucial role in AD.
Yusheng Liang, T. Zhi, Bing Fan et al.· Neuropharmacology· 0 citations