倉橋 仁美

Animal models are essential for studying aversive states such as fear and pain. Facial expressions may provide non-invasive readouts of aversive states in animals. This study investigated whether changes in facial expressions, which are potentially consistent between humans and mice, can serve as objective indicators of fear responses and distinguish fear from pain. We analyzed changes in the facial expressions of mice associated with conditioned fear stress (CFS) using convolutional neural networks (CNNs). Photographs of CFS and control mice were analyzed using four advanced CNN models: VGG16, ResNet50, DenseNet121, and InceptionV3. The CNNs identified CFS mice from facial images under contrasts: control/non-freezing vs CFS/freezing and control/non-freezing vs CFS/non-freezing, with consistently high performance (Control/non-freezing vs CFS/freezing: sensitivity 0.942, specificity 0.929, accuracy 0.935, precision 0.929, AUC 0.966; Control/non-freezing vs CFS/non-freezing: sensitivity 0.912, specificity 0.900, accuracy 0.906, precision 0.902, AUC 0.950). The ability to detect CFS without freezing decreased as stress intensity weakened, from an AUC of 0.950 to 0.701, suggesting that CNNs can detect facial changes depending on the degree of stress exposure. Facial changes were particularly pronounced in freezing mice, further supporting their association with CFS-related emotional responses. During testing, mice were returned to the conditioning chamber without shock; therefore, this facial expression could reflect fear response rather than pain response. These findings demonstrate the potential of CNNs to serve as non-invasive tools for detecting stress-induced affective changes in mice.

High salt (HS) intake is a major risk factor of hypertension and has been implicated in emotional and cognitive decline. On the other hand, dietary supplementation may represent a potential preventive strategy against health risks induced by HS intake. Soybean lecithin is widely used as a phospholipid supplement. Here, we investigated the effects of lysolecithin enriched in lysophosphatidylcholine (>70% of total phospholipids; LPC70) on hypertension and behavioral impairments under high-salt diet (HSD) conditions in mice. To further characterize these effects, we examined changes in prostaglandin (PG)-related pathways by integrating gene expression and lipidomic analyses. Mice were fed an HSD (chow containing 8% NaCl) with or without LPC70 for 10 weeks. HSD elevated systolic blood pressure and impaired social behavior and object recognition memory in mice. Quantitative gene expression analyses revealed that HSD increased renal expression of cyclooxygenase-2 (COX-2) and EP3 (PGE2 receptor), and reduced expression of DP1 (PGD2 receptor) in the prefrontal cortex. LPC70 attenuated these changes in behavior, blood pressure, and PG-related gene expression. Furthermore, lipidomic analyses revealed that HSD reduced circulating arachidonic acid (AA) levels, whereas LPC70 increased AA-derived PG, such as PGE2 and PGD2, in HSD-fed mice. These findings demonstrate that LPC70 may protect against hypertension and behavioral impairments under HSD conditions in mice, potentially in association with modulation of PG signaling. LPC70 may serve as a functional dietary component that reshapes lipid mediator signaling under HSD conditions.

Abstract Background and Purpose Lifestyle is closely related to major depressive disorder (MDD). Given the growing focus on the impact of diet on mental health, this study examined how dietary habits affect the pathophysiology of MDD. Experimental Approach Health check‐up data were analysed. Mice received sucrose under chronic unpredictable mild stress (CUMS) and were evaluated by behavioural, neurochemical and metabolic analysis. Key Results Health check‐up data showed increased sucrose intake in MDD patients. When mice received sucrose under CUMS, hyperactivity and aggression were attenuated, although social deficits or behavioural despair induced by CUMS persisted, and recognition memory was impaired. The behavioural changes were associated with dysfunction of the locus coeruleus‐prefrontal cortex circuit, caused by impaired noradrenaline release due to presynaptic α ₂ ‐adrenoceptor upregulation, and postsynaptic α ₁ ‐adrenoceptor and β ₁ ‐adrenoceptor downregulation. α ₂ ‐Adrenoceptor antagonism by atipamezole rescued behavioural changes induced by sucrose intake under CUMS, whereas α ₂ ‐adrenoceptor agonism by guanfacine in CUMS mice mimicked these behavioural changes. Among the antidepressants, mirtazapine effectively increased noradrenaline release and rescued behavioural changes induced by sucrose intake under CUMS. Sucrose intake under CUMS induced peripheral hyperglycaemia and dysregulation of central glucose metabolism. Glucose transporter inhibition by phloretin rescued behavioural changes induced by sucrose intake under CUMS. Intracerebroventricular and systemic streptozotocin administration reproduced these behavioural changes and α ₂ ‐adrenoceptor upregulation. Conclusions and Implications Our findings suggest that the observed behavioural changes are associated with dysfunction of the noradrenergic α ₂ ‐adrenoceptor system induced by impaired glucose metabolism. These insights targeting the noradrenergic‐metabolic axis might be a new strategy for sugar‐induced depression subtypes.

Background and Purpose Alterations in tryptophan‐kynurenine (TRP‐KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3‐monooxygenase (KMO) induces depression‐like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP‐KYN pathway in stress‐induced behavioural changes and the regulation of the HPA axis. Experimental Approach Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP‐KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS‐induced behavioural changes and an increase in serum corticosterone (CORT) concentration. Key Results CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo^+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short‐term CUMS. Nicotine attenuated CUMS‐induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin‐releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine. Conclusions and Implications CUMS‐induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.