Masaya Hasegawa

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 α2-adrenoceptor upregulation, and postsynaptic α1-adrenoceptor and β1-adrenoceptor downregulation. α2-Adrenoceptor antagonism by atipamezole rescued behavioural changes induced by sucrose intake under CUMS, whereas α2-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 α2-adrenoceptor upregulation. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that the observed behavioural changes are associated with dysfunction of the noradrenergic α2-adrenoceptor system induced by impaired glucose metabolism. These insights targeting the noradrenergic-metabolic axis might be a new strategy for sugar-induced depression subtypes.

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.

Multiple sclerosis (MS) is a common autoimmune demyelinating disease of the central nervous system (CNS). Although activation of the kynurenine (KYN) pathway has been observed in patients with MS, its pathological significance remains unclear. In this study, we investigated the role of the KYN pathway in MS using an experimental autoimmune encephalomyelitis (EAE) mouse model, a widely recognized animal model of MS. We found an increase in the expression of kynureninase (KYNU), a key enzyme in the KYN pathway that is specifically localized within monocytes in the spinal cord of EAE mice. This was accompanied by a significant accumulation of quinolinic acid (QUIN) in the spinal cord. Importantly, similar increases in KYNU expression and QUIN levels were observed in the spinal cord of proteolipid protein overexpressing mice (PLP-tg mice), another model of demyelination. Notably, KYNU knockout (KO) reduced EAE severity and monocyte recruitment to the spinal cord of EAE model mice. These findings suggest that the increase in KYNU expression and the subsequent accumulation of QUIN may contribute to the exacerbation of MS. Taken together, our results indicate that KYNU could be a novel therapeutic target for MS.

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia (CHN) may induce neurological manifestations, including psychological symptoms. However, the specific psychological symptoms induced by CHN, the mechanisms underlying these symptoms, and their potential reversibility remain unclear. Therefore, this study aimed to determine whether monoaminergic neurotransmission is associated with innate anxiety-like behaviors potentiated by CHN in a mouse model of CHN secondary to the syndrome of inappropriate antidiuresis. In the present study, using a mouse model of the syndrome of inappropriate antidiuresis presenting with CHN, we showed that the sustained reduction of serum sodium ion concentrations potentiated innate anxiety-like behaviors in the light/dark transition and open field tests. We also found that serotonin and dopamine levels in the amygdala were significantly lower in mice with CHN than in controls. Additionally, phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala was significantly reduced in mice with CHN. Notably, after correcting for CHN, the increased innate anxiety-like behaviors, decreased serotonin and dopamine levels, and reduced phosphorylation of ERK in the amygdala were normalized. These findings further underscore the importance of treating CHN and highlight potential therapeutic strategies for alleviating anxiety in patients with CHN, which will improve their quality of life.

Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.