Greater Anxiety-like Behavior Research Articles

Dissecting Genetic Mechanisms of Differential Locomotion, Depression, and Allodynia after Spinal Cord Injury in Three Mouse Strains.

Strain differences have been reported for motor behaviors, and only a subset of spinal cord injury (SCI) patients develop neuropathic pain, implicating genetic or genomic contribution to this condition. Here, we evaluated neuropsychiatric behaviors in A/J, BALB/c, and C57BL/6 male mice and tested genetic or genomic alterations following SCI. A/J and BALB/c naive mice showed significantly less locomotor activity and greater anxiety-like behavior than C57BL/6 mice. Although SCI elicited locomotor dysfunction, C57BL/6 and A/J mice showed the best and the worst post-traumatic recovery, respectively. Mild (m)-SCI mice showed deficits in gait dynamics. All moderate/severe SCI mice exhibited similar degrees of anxiety/depression. mSCI in BALB/c and A/J mice resulted in depression, whereas C57BL/6 mice did not exhibit depression. mSCI mice had significantly lower mechanical thresholds than their controls, indicating high cutaneous hypersensitivity. C57BL/6, but not A/J and BLAB/c mice, showed significantly lower heat thresholds than their controls. C57BL/6 mice exhibited spontaneous pain. RNAseq showed that genes in immune responses and wound healing were upregulated, although A/J mice showed the largest increase. The cell cycle and the truncated isoform of trkB genes were robustly elevated in SCI mice. Thus, different genomics are associated with post-traumatic recovery, underscoring the likely importance of genetic factors in SCI.

Effects of tooth loss on anxiety‐like behaviors in Heterocephalus glaber

Tooth loss is an ailment affecting a large percentage of the population, particularly individuals of lower socioeconomic status and the elderly. Extensive tooth loss is known to result in anatomical changes in the face, including atrophy of masticatory muscles and decreases in mandibular and maxillary bone density, as well as volumetric changes within the brain. Human studies have reported strong correlations between tooth loss and levels of both anxiety and depression. However, little has been reported to date regarding the effect of dental health on emotional states, with only sparse information available from animal models regarding the psychiatric effects of tooth loss.Our study investigated the short‐term effects of tooth loss on anxiety‐like behaviors using Heterocephalus glaber, an animal with extensive sensory dedication to and behavioral reliance on its incisors. Adult naked mole‐rats underwent either tooth extraction or sham surgeries, followed by testing in both an open field maze and elevated plus maze in the weeks following. As there are no known studies to date that have utilized this animal model in behavioral tests of anxiety, our study provides critical information about the methodologies and modifications necessary to ascertain these important translational behavioral states so that future researchers can apply similar tests in other fields such as neurodegeneration, aging, and oncology.We hypothesized that tooth extraction will result in greater anxiety‐like behaviors, manifesting in various ways: greater defecation in the mazes, more time spent in the outer regions of the open field maze, and less time in the open arms of the elevated plus maze. The study demonstrated a trend towards tooth extraction increasing anxiety‐like behaviors in naked mole‐rats when investigated using the open field maze paradigm. There is evidence that, with an increase in sample sizes, this research will make evident the causal relationship of tooth loss and anxiety. Future research will investigate the long‐term behavioral changes associated with extensive tooth loss and the neurocircuitry associated with these behavioral alterations. Uncovering these details will provide potential therapeutic targets for negating the mental health difficulties associated with deficits in dental health.

Caffeine Functions by Inhibiting Dorsal and Ventral Hippocampal Adenosine 2A Receptors to Modulate Memory and Anxiety, Respectively.

As a nonspecific antagonist of the adenosine A2A receptor (A2AR), caffeine enhances learning and improves memory impairment. Simultaneously, the consumption of caffeine correlates with a feeling of anxiety. The hippocampus is functionally differentiated along its dorsal/ventral axis and plays a crucial role both in memory and anxiety. Whether caffeine exerts its regulation by inhibiting A2ARs in different subregions of the hippocampus is still unknown. In the present study, we found that after chronic intake of drinking water containing caffeine (1 g/L, 3 weeks), mice exhibited aggravated anxiety-like behavior and enhanced memory function. Tissue-specific, functional disruption of dorsal hippocampal A2ARs by the CRE-LoxP system prevented the memory-enhancing effect of caffeine, while selective disruption of ventral hippocampal A2ARs blocked the impact of caffeine on anxiety. These results, together with the enhanced memory of dorsal hippocampus A2AR knockout mice and greater anxiety-like behavior of ventral hippocampus A2AR knockout mice without caffeine, indicates a dissociation between the roles of ventral and dorsal hippocampal A2A receptors in caffeine’s effects on anxiety-like and memory-related behavioral measures, respectively. Furthermore, optogenetic activation of dorsal or ventral hippocampal A2ARs reversed the behavioral alterations caused by drinking caffeine, leading to impaired memory or decreased anxiety-like behaviors, respectively. Taken together, our findings suggest that the memory- and anxiety-enhancing effects of caffeine are related to the differential effects of inhibiting A2ARs in the dorsal and ventral hippocampus, respectively.

Changes Depression- and Anxiety- like Behaviors following Selective Breeding for Cocaine Reinforcement

The LS and HS are rat lines selectively bred for altered cocaine self-administration. Given the importance of mental health in substance use, these lines were evaluated for putative depression- and anxiety- like behaviors through forced swimming and exploration of a plus maze. We found increases of struggling in LS males, climbing in LS females, and swimming in HS males; with biphasic effects on immobility in the HS strain. HS rats had fewer entries into and less time spent in open arms of the plus maze, consistent with greater anxiety-like behavior, which may contribute to enhanced drug taking.

Avoidant Coping Style to High Imminence Threat Is Linked to Higher Anxiety-Like Behavior.

Human studies with self-reported measures have suggested a link between an avoidant coping style and high anxiety. Here, using the common marmoset as a model, we characterize the latent factors underlying behavioral responses of these monkeys towards low and high imminence threat and investigate if a predominantly avoidant behavioral response to high imminence threat is associated with greater anxiety-like behavior in a context of low imminence threat. Exploratory factor analysis (EFA) of the human intruder test of low imminence threat revealed a single factor in which a combination of active vigilance and avoidance responses underpinned anxiety-like behavior. In contrast, two negatively-associated factors were revealed in the model snake test reflecting active and avoidant coping to high imminence threat. Subsequent analysis showed that animals with a predominantly avoidant coping style on the model snake test displayed higher anxiety-like behavior on the human intruder test, findings consistent with those described in humans. Together they illustrate the richness of the behavioral repertoire displayed by marmosets in low and high imminence threatening contexts and the additional insight that factor analysis can provide by identifying the latent factors underlying these complex behavioral datasets. They also highlight the translational value of this approach when studying the neural circuits underlying complex anxiety-like states in this primate model.

Premature aging in behavior and immune functions in tyrosine hydroxylase haploinsufficient female mice. A longitudinal study

Aging is accompanied by impairment in the nervous, immune, and endocrine systems as well as in neuroimmunoendocrine communication. In this context, there is an age-related alteration of the physiological response to acute stress, which is modulated by catecholamine (CA), final products of the sympathetic-adreno-medullary axis. The involvement of CA in essential functions of the nervous system is consistent with the neuropsychological deficits found in mice with haploinsufficiency (hemizygous; HZ) of tyrosine hydroxylase (TH) enzyme (TH-HZ). However, other possible alterations in regulatory systems have not been studied in these animals. The aim of the present work was to analyze whether adult TH-HZ female mice presented the impairment of behavioral traits and immunological responses that occurs with aging and whether they had affected their mean lifespan. ICR-CD1 female TH-HZ and wild type (WT) mice were used in a longitudinal study. Behavioral tests were performed on adult and old mice in order to evaluate their sensorimotor abilities and exploratory capacity, as well as anxiety-like behaviors. At the ages of 2 ± 1, 4 ± 1, 9 ± 1, 13 ± 1 and 20 ± 1 months, peritoneal leukocytes were extracted and several immune functions were assessed (phagocytic capacity, Natural Killer (NK) cytotoxicity, and lymphoproliferative response to lipopolysaccharide (LPS) and concanavalin A (ConA)). In addition, several oxidative stress parameters (catalase, glutathione reductase and glutathione peroxidase activities, and reduced glutathione (GSH) concentrations as antioxidant compounds as well as xanthine oxidase activity, oxidized glutathione (GSSG) concentrations, and GSSG/GSH ratio as oxidants) were analyzed. As inflammatory stress parameters TNF-alpha and IL-10 concentrations, and TNF-alpha/IL-10 ratios as inflammatory/anti-inflammatory markers, were measured. Animals were maintained in standard conditions until their natural death. The results indicate that adult TH-HZ mice presented worse sensorimotor abilities and exploratory capacity than their WT littermates as well as greater anxiety-like behaviors. With regards to the immune system, adult TH-HZ animals exhibited lower values of phagocytic capacity, NK cytotoxicity, and lymphoproliferative response to LPS and ConA than WT mice. Moreover, immune cells of TH-HZ mice showed higher oxidative and inflammatory stress than those of WT animals. Although these differences between TH-HZ and WT, in general, decreased with aging, this premature immunosenescence and impairment of behavior of TH-HZ mice was accompanied by a shorter mean lifespan in comparison to WT counterparts. In conclusion, haploinsufficiency of th gene in female mice appears to provoke premature aging of the regulatory systems affecting mean lifespan.

Control diet in a high-fat diet study in mice: Regular chow and purified low-fat diet have similar effects on phenotypic, metabolic, and behavioral outcomes

Background: Differences in the composition of control diets may confound outcomes in studies investigating dietary effects.Objective: We compared the effects of two control diets commonly used in mice studies, chow (SD) and a purified low-fat diet (LFD), in relation to a chronic high-fat diet (HFD). We hypothesized that SD and LFD will have similar effects on phenotypic, metabolic, and behavioral outcomes.Methods: Fifty-four 5-week-old male C57BL/6J mice were randomly assigned to one of the three dietary interventions (SD, LFD, or HFD) for 18 weeks. At week 16, mice were tested for behavioral changes. Glucose tolerance testing was conducted at week 17 and terminal blood collection at week 18.Results: SD and LFD mice exhibited no differences in cognitive performance on the Y-maze test and comparable anxiety-like behavior in the open-field and elevated zero maze tests. Significant declines in cognitive function and greater anxiety-like behavior were observed in the HFD group compared to both SD and LFD. Areas under the glucose tolerance curve were similar for SD and LFD, as were levels of high-density lipoprotein, triglycerides, cytokines, and adipocytokines. Only total cholesterol was significantly higher in LFD mice compared to SD mice. All measures were significantly higher in the HFD group.Discussion: Our data demonstrate that young mice develop similar phenotypic, metabolic, and behavioral profiles when fed SD vs. LFD. The two diets may thus be equally appropriate as controls for an HFD, although some studies may want to consider differences in effects on cholesterol levels.

Behavioral changes in male mice fed a high-fat diet are associated with IL-1β expression in specific brain regions

High-fat diet (HFD)-induced obesity is associated with not only increased risk of metabolic and cardiovascular diseases, but cognitive deficit, depression and anxiety disorders. Obesity also leads to low-grade peripheral inflammation, which plays a major role in the development of metabolic alterations. Previous studies suggest that obesity-associated central inflammation may underlie the development of neuropsychiatric deficits, but further research is needed to clarify this relationship. We used 48 male C57BL/6J mice to investigate whether chronic consumption of a high-fat diet leads to increased expression of interleukin-1β (IL-1β) in the hippocampus, amygdala and frontal cortex. We also determined whether IL-1β expression in those brain regions correlates with changes in the Y-maze, open field, elevated zero maze and forced swim tests.After 16weeks on dietary treatments, HFD mice showed cognitive impairment on the Y-maze test, greater anxiety-like behavior during the open field and elevated zero maze tests, and increased depressive-like behavior in the forced swim test. Hippocampal and amygdalar expression of IL-1β were significantly higher in HFD mice than in control mice fed a standard diet (SD). Additionally, hippocampal GFAP and Iba1 immunoreactivity were increased in HFD mice when compared to SD controls. Cognitive performance negatively correlated with level of IL-1β in the hippocampus and amygdala whereas an observed increase in anxiety-like behavior was positively correlated with higher expression of IL-1β in the amygdala. However, we observed no association between depressive-like behavior and IL-1β expression in any of the brain regions investigated.Together our data provide evidence that mice fed a HFD exhibit cognitive deficits, anxiety and depressive-like behaviors. Our results also suggest that increased expression of IL-1β in the hippocampus and amygdala may be associated with the development of cognitive deficits and anxiety-like behavior, respectively.

Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats.

Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

Greater Physiological and Behavioral Effects of Interrupted Stress Pattern Compared to Daily Restraint Stress in Rats

Repeated stress can trigger a range of psychiatric disorders, including anxiety. The propensity to develop abnormal behaviors after repeated stress is related to the severity, frequency and number of stressors. However, the pattern of stress exposure may contribute to the impact of stress. In addition, the anxiogenic nature of repeated stress exposure can be moderated by the degree of coping that occurs, and can be reflected in homotypic habituation to the repeated stress. However, expectations are not clear when a pattern of stress presentation is utilized that diminishes habituation. The purpose of these experiments is to test whether interrupted stress exposure decreases homotypic habituation and leads to greater effects on anxiety-like behavior in adult male rats. We found that repeated interrupted restraint stress resulted in less overall homotypic habituation compared to repeated daily restraint stress. This was demonstrated by greater production of fecal boli and greater corticosterone response to restraint. Furthermore, interrupted restraint stress resulted in a lower body weight and greater adrenal gland weight than daily restraint stress, and greater anxiety-like behavior in the elevated plus maze. Control experiments demonstrated that these effects of the interrupted pattern could not be explained by differences in the total number of stress exposures, differences in the total number of days that the stress periods encompased, nor could it be explained as a result of only the stress exposures after an interruption from stress. These experiments demonstrate that the pattern of stress exposure is a significant determinant of the effects of repeated stress, and that interrupted stress exposure that decreases habituation can have larger effects than a greater number of daily stress exposures. Differences in the pattern of stress exposure are therefore an important factor to consider when predicting the severity of the effects of repeated stress on psychiatric disorders.

Increasing maternal or post-weaning folic acid alters gene expression and moderately changes behavior in the offspring.

BackgroundStudies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice.MethodsDams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring.ResultsResults from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns’ cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.

Anxiety- and depression-like behavior are correlated with leptin and leptin receptor expression in prefrontal cortex of streptozotocin-induced diabetic rats

Anxiety and depression are common in diabetics. Diabetes also may cause reduced leptin levels in the blood. We investigated the relation between diabetes induced anxiety- and depression-like behavior, and leptin and leptin receptor expression levels in diabetic rats. The anxiety- and depression-like behaviors of rats were assessed 4 weeks after intraperitoneal injection of streptozotocin. Diabetic rats exhibited greater anxiety-like behavior; they spent more time in closed branches of the elevated plus maze test and less time in the center cells of the open field arena. Increased depression-like behavior was observed in diabetic rats using the Porsolt swim test. Prefrontal cortex (PFC), blood leptin levels and PFC neuron numbers were decreased, and leptin receptor expression and apoptosis were increased in diabetic rats. Blood corticosterone levels also were increased in diabetic rats. These results indicate that reduction of leptin up-regulates leptin receptor expression and may affect PFC neurons, which eventually triggers anxiety- and depression-like behaviors in diabetic rats.

Maternal bisphenol A (BPA) decreases attractiveness of male offspring

Are you having little luck in the search for your soulmate? When you finally meet a woman does she seem disinterested? What could it be? Your breath? Your clothes? Findings from a new study (1) suggest it may be your mother's dietary exposure to bisphenol A (BPA). In the study published in PNAS, Jasarevic′ et al. (1) find that maternal BPA exposure impairs spatial ability, decreases exploratory behavior, and reduces attractiveness of male deer mice progeny. These traits are sexually dimorphic and are subjected to sexual selection because they are essential characteristics needed to find mates and reproduce in male deer mice (and other polygynous species) (2). Male deer mice, much like male meadow voles, traverse large territories during the breeding season to gain access to dispersed females (3). Female meadow voles prefer male meadow voles with better spatial ability, and male meadow voles with better spatial ability visit more female nest boxes (4, 5). Thus, home range size and spatial ability favor males in most polygynous species. Intriguingly, these sexually dimorphic traits also manifest in the hippocampus, an area important for spatial memory. Males have a larger hippocampus and greater levels of adult hippocampal neurogenesis than females during the breeding season (6, 7). The expression of sexually dimorphic spatial ability depends on both early (pre- or perinatal) and adult levels of sex hormones in rodents (3). The report by Jasarevic′ et al. (1) shows that these sexually dimorphic traits, spatial ability and exploratory behavior, in addition to attractiveness, are affected by maternal dietary exposure to the environmental endocrine disrupter BPA. Specifically, the authors show that maternal consumption of low levels of dietary BPA renders male offspring at a disadvantage for mating, not only because of poorer spatial navigation and greater anxiety-like behavior but also because they are less attractive to female conspecifics. These findings are significant as coupled with other studies, it seems that maternal dietary consumption of low levels of BPA may affect the fecundity of adult offspring through a number of mediating factors.

Cortical kindling induces elevated levels of AMPA and GABA receptor subunit mRNA within the amygdala/piriform region and is associated with behavioral changes in the rat

Cortical kindling causes alterations within the motor cortex and results in long-standing motor deficits. Less attention has been directed to other regions that also participate in the epileptiform activity. We examined if cortical kindling could induce changes in excitatory and inhibitory receptor subunit mRNA in the amygdala/piriform regions and if such changes are associated with behavioral deficits. After cortical kindling, amygdala/piriform regions were dissected to analyze mRNA levels of NMDA, AMPA, and GABA receptor subunits using reverse transcription polymerase chain reaction, or rats were subjected to a series of behavioral tests. Kindled rats had significantly greater amounts of GluR1 and GluR2 AMPA receptor mRNA, and α1 and α2 GABA receptor subunit mRNA, compared with sham controls, which was associated with greater anxiety-like behaviors in the elevated plus maze and reduced freezing behaviors in the fear conditioning task. In summary, cortical kindling produces dynamic receptor subunit changes in regions in addition to the seizure focus.