In a groundbreaking study that illuminates the complex molecular underpinnings of stress-related psychiatric disorders, researchers have identified a critical role for the bile acid receptor TGR5 in regulating the brain’s response to chronic social defeat stress. This discovery not only expands our understanding of the biochemical pathways implicated in stress resilience and vulnerability but also opens new therapeutic avenues for treating depression and anxiety. By elucidating the mechanistic involvement of the cAMP/PKA signaling cascade within the hippocampus, this research sheds light on how TGR5 dysfunction can disrupt neural plasticity and emotional regulation.
Chronic social defeat stress (CSDS) is a widely accepted animal model that mimics many aspects of human depression and anxiety disorders caused by persistent social adversity. Despite extensive research, the molecular players linking environmental stressors to neural circuit dysregulation remain poorly defined. The current study, spearheaded by Chen, Zhou, He, and colleagues, explores the role of the G protein-coupled bile acid receptor TGR5 (also known as GPBAR1) in mediating stress-induced hippocampal dysfunction. This receptor, traditionally associated with metabolic regulation in peripheral tissues, is now recognized as a crucial modulator of central nervous system processes including neuroinflammation and mood regulation.
Using a combination of behavioral experiments, molecular biology techniques, and electrophysiological analyses, the team demonstrated that mice subjected to chronic social defeat stress exhibited significant downregulation of TGR5 expression specifically in the hippocampus, a brain region integral to memory formation and emotional processing. This loss of TGR5 was closely correlated with heightened depressive- and anxiety-like behaviors, indicating that TGR5 activity might confer resilience or vulnerability to social stress. Intriguingly, restoring TGR5 function through pharmacological agonists effectively mitigated these behavioral deficits, underscoring the receptor’s therapeutic potential.
Delving deeper into intracellular signaling, the researchers uncovered that TGR5 dysfunction leads to impaired activation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway, a canonical intracellular cascade known to regulate synaptic plasticity and gene expression. Normally, TGR5 activation stimulates adenylyl cyclase to increase cAMP levels, which in turn activates PKA. In the hippocampus of stressed animals, reduced TGR5 expression caused a significant decrease in cAMP production and PKA activity, thereby disrupting downstream targets essential for neuronal survival and plasticity.
Electrophysiological recordings from hippocampal neurons revealed that TGR5-deficient mice displayed suppressed long-term potentiation (LTP), a cellular correlate of learning and memory. This synaptic impairment likely contributes to cognitive and mood disturbances observed after chronic stress exposure. By contrast, pharmacological activation of TGR5 restored robust LTP and normalized synaptic function, further validating the receptor’s critical regulatory role at the synapse during stress conditions.
The study also uncovered that TGR5-related cAMP/PKA signaling influences the phosphorylation state and activity of the transcription factor CREB (cAMP response element-binding protein), which orchestrates the expression of a battery of neuroprotective genes. In stressful contexts, diminished TGR5 signaling curtailed CREB phosphorylation, impeding the expression of neurotrophic factors such as BDNF (brain-derived neurotrophic factor), known for its pivotal function in maintaining neuronal health and plasticity. Enhancement of TGR5 activity, however, reinstated CREB activity and promoted BDNF expression, thereby reinforcing neural resilience mechanisms.
Remarkably, these findings link peripheral metabolic receptors such as TGR5 to central nervous system pathophysiology, suggesting a novel interface between metabolism, immune signaling, and mental health. This convergence highlights the potential influence of systemic metabolic states on brain function, a burgeoning area of neuropsychiatric research that may redefine treatment strategies. By targeting TGR5, it may be possible to modulate brain signaling pathways that traditionally have been considered inaccessible to metabolic interventions.
The translational implications of this research are profound. Depression and anxiety disorders represent leading causes of global disability, with existing pharmacotherapies often limited by delayed onset, side effects, and treatment resistance. The identification of TGR5 as a key molecular player offers a promising new target for rapid-acting and highly specific therapeutics. Moreover, because TGR5 agonists have already undergone clinical evaluation for metabolic diseases, drug repurposing could accelerate the development of novel antidepressant strategies.
This work builds upon emerging evidence implicating bile acid signaling in brain function, challenging the outdated view that these molecules and their receptors act solely in the liver and gastrointestinal tract. By adding a new dimension to neurochemical pathways influencing mood regulation, Chen and colleagues’ study paves the way for integrated approaches that consider the gut-brain axis and systemic physiology in psychiatric disorders.
Further research is needed to clarify how chronic social defeat stress triggers the downregulation of TGR5 and to determine whether similar mechanisms operate in human depression. Investigating whether genetic polymorphisms or epigenetic modifications affect TGR5 expression or function may reveal additional risk factors or biomarkers for mood disorders. Additionally, dissecting the interplay between TGR5 signaling and other neurotransmitter or neuroimmune systems will enrich our understanding of the multifactorial nature of stress pathology.
This seminal work exemplifies how interdisciplinary approaches that combine behavioral neuroscience, molecular biology, and pharmacology can unravel the complex biological tapestry underlying mental illness. It encourages scientists to probe the unexplored territory where peripheral metabolic regulation intersects with brain circuits governing affective behavior, potentially revolutionizing how psychiatric diseases are conceptualized and treated.
By demonstrating that TGR5 dysfunction disrupts hippocampal cAMP/PKA signaling and contributes to the behavioral manifestations of chronic social defeat stress, this study marks a significant advance in the field of stress neurobiology. It powerfully illustrates the potential for targeting nontraditional receptors to bolster stress resilience and offers a fresh perspective on therapeutic innovation. As the global burden of depression escalates, investigations like this provide hope for novel interventions capable of restoring mental health through previously uncharted molecular pathways.
In summary, the discovery of TGR5’s pivotal role in mediating hippocampal responses to chronic social stress unites diverse strands of neuroscience, metabolism, and psychiatry. It reveals that the molecular disturbances incited by prolonged psychosocial adversity extend beyond classical neurotransmitter dysregulation to encompass metabolic receptors once thought unrelated to brain function. This revolutionary insight challenges prevailing paradigms and lays the groundwork for safer, more effective treatments that harness the brain’s inherent capacity for plasticity and recovery.
As the field moves forward, integrating these findings into broader clinical and pharmacological frameworks holds the promise of enhancing diagnostic precision and personalizing therapeutic regimens. With TGR5 emerging as a novel molecular target, the frontier of stress-related disorder research may soon experience transformative breakthroughs, ultimately benefiting millions of individuals worldwide suffering from the devastating effects of persistent social stress and mood dysregulation.
Subject of Research: The role of the bile acid receptor TGR5 and cAMP/PKA signaling in the hippocampus in mediating chronic social defeat stress and its behavioral consequences.
Article Title: TGR5 dysfunction underlies chronic social defeat stress via cAMP/PKA signaling pathway in the hippocampus.
Article References:
Chen, X., Zhou, Q., He, Y. et al. TGR5 dysfunction underlies chronic social defeat stress via cAMP/PKA signaling pathway in the hippocampus. Transl Psychiatry 15, 366 (2025). https://doi.org/10.1038/s41398-025-03599-7
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