Nest building is an instinctive behavior toward protection from predators, body temperature regulation, and courtship. Previously, we discovered that acute and chronic social defeat stress suppresses the onset of nest-building behavior in male mice (C57BL/6J). Here, we analyzed nest building and other behavioral deficits induced by acute social defeat stress (ASDS). We utilized a customized cage and specifically developed observational programs for nest building, social avoidance, and other behaviors using an infrared depth camera to acquire three-dimensional (3D) data of animal behavior (Negura system). We determined the volume of nesting materials from these 3D depth images. Mice exposed to ASDS showed increased spontaneous activities, decreased rearing, and delayed nest building; however, nest-building activity was gradually recovered during the dark period of the 24 hr observation interval. At the endpoint following 24 hr, the ASDS and control groups showed no differences in nest volumes. Furthermore, we observed the time courses of both nest building and social avoidance behaviors and their relationship using the Negura system. Our data demonstrated a weak positive correlation between nest-building delay and social avoidance in ASDS mice. The Negura system can observe various behaviors that reflect the effects of social defeat stress.
Abstract Lactate is known to have diverse roles in the brain at the molecular and behavioral levels under both physiological and pathophysiological conditions, such as learning and memory and regulation of mood. Recently, a novel post-translational modification called lysine lactylation has been found in histone H3 of mouse macrophages, and the lactylation levels paralleled the intracellular lactate levels 1 . However, it is unknown whether lysine lactylation occurs in brain cells, and if it does, whether lactylation is induced by the stimuli that accompany changes in lactate levels. Herein, we reveal that lysine lactylation in brain cells is regulated by systemic changes in lactate levels, neural excitation, and behaviorally relevant stimuli. Lysine lactylation levels were increased by lactate treatment and by high-potassium-induced depolarization in cultured primary neurons; these increases were attenuated by pharmacological inhibition of monocarboxylate transporter 2 and lactate dehydrogenase, respectively, suggesting that both cell-autonomous and non-cell-autonomous neuronal mechanisms are involved in overall lysine lactylation. In vivo , electroconvulsive stimulation increased lysine lactylation levels in the prefrontal cortices of mice, and its levels were positively correlated with the expression levels of the neuronal activity marker c-Fos on an individual cell basis. In the social defeat stress model of depression in which brain lactate levels increase, lactylation levels were increased in the prefrontal cortices of the defeated mice, which was accompanied by increased c-Fos expression, decreased social behaviors, and increased anxiety-like behaviors, suggesting that stress-induced neuronal excitation may induce lysine lactylation, thereby affecting mood-related behaviors. Further, we identified 63 candidate lysine-lactylated proteins in the mouse cortex and found that lactylation levels in histone H1 increased in response to defeat stress. This study may open up an avenue for exploration of a novel role of neuronal activity-induced lactate mediated by protein lactylation in the brain.
Stress contributes to mental disorders as well as functional gastrointestinal disorders. In functional gastrointestinal disorders, gastrointestinal motility is thought to play a role. Therefore, we evaluated the effects of chronic social defeat stress on gastrointestinal motility in C57BL/6J mice, by measuring gastric emptying, fecal pellet output, and gastrointestinal transit. In mice subjected to 10 days of social defeat stress, serum corticosterone concentrations were significantly higher, relative tissue weights of spleen and adrenal gland tissues were significantly heavier, and thymus sizes were smaller than in the control mice. Stressed mice exhibited social avoidance behavior in a social interaction test and anxiety-like behavior and lower locomotor activity in an elevated plus maze test. In gastric emptying test, stressed mice displayed increased gastric emptying rate with significant suppression of short-time (30 min.) test diet intake. Fecal pellet output and gastrointestinal transit were not different in control and stressed mice. These results suggest that chronic social defeat stress influences gastric motility. Thus, the social defeat stress model may be useful for studying psychiatric disease and functional gastrointestinal disorders simultaneously.
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
Probiotics and prebiotics have become viable alternatives of growth-promoting antimicrobials in animal production. Here, we tested partially hydrolyzed guar gum (PHGG) as a possible prebiotic for piglets in the commercial farm. Five hundred and ninety-four piglets were used for the experiments, with 293 given a normal pig feed (control), while the rest the feed plus 0.06% (w/w) of PHGG (PHGG). One and three months post-PHGG supplementation, fecal samples were collected from randomly selected 20 piglets in each group and analyzed for microbiota and organic acid concentrations. Notably, the abundance of Streptococcus, and unclassified Ruminococcaceae were lower (p < 0.05) in PHGG than in control, one-month post-supplementation. Lactobacillus and Prevotella were higher (p < 0.05), while Streptococcus was lower (p < 0.05), in PHGG than in control, three months post-supplementation. The concentrations of acetate, propionate, and butyrate were greater in PHGG than in control, three months post-supplementation. Finally, PHGG grew faster and had fewer deaths until slaughter time (p < 0.05), than control. We concluded that PHGG not only was an effective prebiotic to alter gut microbiota of weanling piglets but also can possibly promote body weight accretion and health.
Early child maltreatment, such as child abuse and neglect, is well known to affect the development of social skills. However, the mechanisms by which such an adverse environment interrupts the development of social skills remain unelucidated. Identifying the period and brain regions that are susceptible to adverse environments can lead to appropriate developmental care later in life. We recently reported an excitatory/inhibitory imbalance and low activity during social behavior in the medial prefrontal cortex (mPFC) of the maternal separation (MS) animal model of early life neglect after maturation. Based on these results, in the present study, we investigated how MS disturbs factors related to excitatory and inhibitory neurons in the mPFC until the critical period of mPFC development. Additionally, we evaluated whether the effects of MS could be recovered in an enriched environment after MS exposure. Rat pups were separated from their dams on postnatal days (PDs) 2–20 (twice daily, 3 h each) and compared with the mother-reared control (MRC) group. Gene expression analysis revealed that various factors related to excitatory and inhibitory neurons were transiently disturbed in the mPFC during MS. A similar tendency was found in the sensory cortex; however, decreased parvalbumin (PV) expression persisted until PD 35 only in the mPFC. Moreover, the number of PV + interneurons decreased in the ventromedial prefrontal cortex (vmPFC) on PD 35 in the MS group. Additionally, perineural net formation surrounding PV + interneurons, which is an indicator of maturity and critical period closure, was unchanged, indicating that the decreased PV + interneurons were not simply attributable to developmental delay. This reduction of PV + interneurons improved to the level observed in the MRC group by the enriched environment from PD 21 after the MS period. These results suggest that an early adverse environment disturbs the development of the mPFC but that these abnormalities allow room for recovery depending on the subsequent environment. Considering that PV + interneurons in the mPFC play an important role in social skills such as empathy, an early rearing environment is likely a very important factor in the subsequent acquisition of social skills.
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
