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Background and Purpose: Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice., Experimental Approach: The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry., Key Results: At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L-lactate was increased in diabetic mice and injection of L-lactate into non-diabetic mice increased freezing at 0.45 mA. In addition, L-lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L-lactate was inhibited by acadesine. Dorsomorphin-induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX., Conclusions and Interpretation: In diabetic mice, L-lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function., (© 2024 British Pharmacological Society.)

Type 1 diabetes mellitus (T1D) is associated with cognitive impairments in humans. A well-established animal model of T1D is induced through the administration of streptozotocin (STZ), a glucose analog that induces pancreatic β-cell death, resulting in hyperglycemia and cognitive impairment linked to neuroinflammation and oxidative stress. Tumor necrosis factor (TNF)-α, a key inflammatory mediator, is elevated in the central nervous system (CNS) of diabetic animals. In this study, we utilized TNFR1 knockout mice to investigate the role of TNFR1 signaling in short-term T1D-related cognitive impairment. Our findings showed that diabetic animals did not develop cognitive damage within the first 2 weeks of T1D but exhibited reduced exploration in all behavioral tests. Our findings suggest that this reduction in exploration was attributable to motor impairment, as there was no reduction in motivated novelty-seeking behavior. Additionally, deletion of TNFR1 signaling attenuated gait speed impairment in diabetic mice, but did not affect other motor-related or exploratory behaviors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

The effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes were evaluated in streptozotocin-induced diabetic rats. Male diabetic rats were orally treated with 1 ml of saline, nano-niosome, tyrosol, and nano-tyrosol (20 mg/dl) for 30 days. Anxiety-like behavior and memory process were evaluated by an elevated plus-maze (EPM) test-retest paradigm. The results showed that a single intraperitoneal (i.p.) administration of streptozotocin (50 mg/kg) raised blood glucose. While daily intragastric administration of tyrosol and nano-tyrosol reduced blood glucose. Induction of type II diabetes produced a distorted cellular arrangement whereas treatment with tyrosol and nano-tyrosol showed a typical cellular arrangement in the liver. Furthermore, induction of type II diabetes decreased %OAT (%open-arm time) but daily intragastric application of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) enhanced %OAT and %OAE (%open-arm entry) in the EPM when compared to the saline groups, showing anxiogenic- and anxiolytic-like effects, respectively. Also, induction of type II diabetes increased %OAT while daily intragastric administration of tyrosol (20 mg/dl) and nano-tyrosol (20 mg/dl) decreased %OAT and %OAE in the EPM in comparison to the saline groups, displaying impairment and improvement of emotional memory, respectively. Interestingly, nano-tyrosol exhibited the highest significant effect rather than tyrosol. Upon these results, we proposed the beneficial effects of tyrosol and nano-tyrosol on the modulation of anxiety-like behavior and memory processes in streptozotocin-induced diabetic rats., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Depression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia., Methods: To this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21)., Results: Our results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior., Conclusion: We interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationale: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain., Objectives: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota., Methods: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation., Results: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum., Conclusions: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses., Methods: After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index., Results: A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT., Conclusion: CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.

The relationship between diabetes mellitus type 2 (DM2) and sexual desire in women has not been systematically studied, therefore, animal models have been used for this purpose. When streptozotocin (STZ) is administered in the neonatal stage, the rat shows moderate chronic hyperglycemia and glucose intolerance in adulthood, resembling a DM2 model. These females show less alterations of sexual behavior (a slight decreased proceptivity and loss of paced mating) than their counterpart with severe hyperglycemia. However, the motivational components of copulation in female rats in this DM2 model have not been examined. The aim of this study was to evaluate female sexual motivation in a model of DM2 in three behavioral paradigms: the partner preference (PP), the sexual incentive motivation (SIM) and the odor preference test (OPT) tests. Neonatal females (3-4 days) were administered with streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed, females with blood glucose levels ≥ 250 mg/dl 60 min after a sucrose load (2 g/kg) were considered for the study. Behavioral tests were conducted at week 12, when the females were in natural proestrus. For PP we registered the time in each compartment and the sexual behavior, while in the SIM test, we calculated the time the females remained in each incentive zone. In these tests a castrated male and a sexually experienced male were used as stimuli. In OPT we evaluated the time the females spent sniffing the sawdust coming from cages housing these stimuli. In the PP and OPT hyperglycemic females behave similarly than controls, i.e., they retain a preference for sexually active males. In the SIM test there was a decrease in the time the hyperglycemic females remain in the vicinity of the sexually expert male. Data are discussed on the bases of the accessibility of the females to the stimuli., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 μl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM., Competing Interests: Declaration of competing interest The authors declare no conflicting interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes., Methods: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of V Max , 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aβ) and Tau were also assessed using Western blot., Results: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM., Conclusions: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau., (© 2024. The Author(s).)

Introduction: Type 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear., Objectives: The purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics., Methods: We developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice., Results: The results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus., Conclusion: Our results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

Background and Purpose: Post-stroke cognitive impairment (PSCI) has become a major public health issue, as a leading cause of dementia. The inflammation that develops soon after cerebral artery occlusion and may persist for weeks or months after stroke is a key component of PSCI. Our aim was to take advantage of the immunomodulatory properties of peripheral blood mononuclear cells (PB-MNC) stimulated with ephrin-B2/fc (PB-MNC + ) for preventing PSCI., Methods: Cortical infarct was induced by thermocoagulation of the middle cerebral artery in male diabetic mice (streptozotocin IP). PB-MNC were isolated from diabetic human donors, washed with recombinant ephrin-B2/Fc and injected into the mice intravenously on the following day. Infarct volume, sensorimotor deficit, cell death and immune cell densities were assessed on day 3. Six weeks later, cognitive assessment was performed using the Barnes maze., Results: PB-MNC + transplanted in post-stroke diabetic mice reduced the neurological deficit, infarct volume and apoptosis at D3, without modification of microglial cells, astrocytes and T-lymphocytes densities in the brain. Barnes maze assessment of memory showed that the learning, retention and reversal phases were not significantly modified by cell therapy., Conclusions: Intravenous PB-MNC + administration the day after stroke induction in diabetic mice improved sensorimotor deficit and reduced infarct volume at the short term, but was unable to prevent long-term memory loss. To what extent diabetes impacts on cell therapy efficacy will have to be specifically investigated in the future. Including vascular risk factors systematically in preclinical studies of cell therapy will provide a comprehensive understanding of the mechanisms potentially limiting cell efficacy and also to identify good and bad responders, particularly in the long term., (Copyright © 2021 Elsevier Inc. All rights reserved.)