Behavioral and Brain Functions最新文献

Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation in Alzheimer's disease (AD). However, the specific mechanism of NLRP1 inflammasome in the pathogenesis of AD is still unclear. It has been reported that autophagy dysfunction can aggravate the pathological symptoms of AD and plays an important role in regulating Aβ generation and clearance. We hypothesized that NLRP1 inflammasome activation may induce autophagy dysfunction contributing to the progression of AD. In the present study, we observed the relationship between Aβ generation and NLRP1 inflammasome activation, as well as AMPK/mTOR mediated-autophagy dysfunction in WT 9-month-old (M) mice, APP/PS1 6 M and APP/PS1 9 M mice. Additionally, we further studied the effect of NLRP1 knockdown on cognitive function, Aβ generation, neuroinflammation and AMPK/mTOR mediated autophagy in APP/PS1 9 M mice. Our results indicated that NLRP1 inflammasome activation and AMPK/mTOR mediated-autophagy dysfunction are closely implicated in Aβ generation and deposition in APP/PS1 9 M mice, but not in APP/PS1 6 M mice. Meanwhile, we found that knockdown of NLRP1 significantly improved learning and memory impairments, decreased the expressions of NLRP1, ASC, caspase-1, p-NF-κB, IL-1β, APP, CTF-β, BACE1 and Aβ_1-42, and decreased the level of p-AMPK, Beclin 1 and LC3 II, and increased the level of p-mTOR and P62 in APP/PS1 9 M mice. Our study suggested that inhibition of NLRP1 inflammasome activation improves AMPK/mTOR mediated-autophagy dysfunction, resulting in the decrease of Aβ generation, and NLRP1 and autophagy might be important targets to delay the progression of AD.

Background: Theoretical models posit abnormalities in cortico-striatal pathways in two of the most common neurodevelopmental disorders (Developmental dyslexia, DD, and Attention deficit hyperactive disorder, ADHD), but it is still unclear what distinct cortico-striatal dysfunction might distinguish language disorders from others that exhibit very different symptomatology. Although impairments in tasks that depend on the cortico-striatal network, including reinforcement learning (RL), have been implicated in both disorders, there has been little attempt to dissociate between different types of RL or to compare learning processes in these two types of disorders. The present study builds upon prior research indicating the existence of two learning manifestations of RL and evaluates whether these processes can be differentiated in language and attention deficit disorders. We used a two-step RL task shown to dissociate model-based from model-free learning in human learners.

Results: Our results show that, relative to neurotypicals, DD individuals showed an impairment in model-free but not in model-based learning, whereas in ADHD the ability to use both model-free and model-based learning strategies was significantly compromised.

Conclusions: Thus, learning impairments in DD may be linked to a selective deficit in the ability to form action-outcome associations based on previous history, whereas in ADHD some learning deficits may be related to an incapacity to pursue rewards based on the tasks' structure. Our results indicate how different patterns of learning deficits may underlie different disorders, and how computation-minded experimental approaches can differentiate between them.

Background: Alzheimer's disease (AD) is the core cause of dementia in elderly populations. One of the main hallmarks of AD is extracellular amyloid beta (Aβ) accumulation (APP-pathology) associated with glial-mediated neuroinflammation. Whole-Body Vibration (WBV) is a passive form of exercise, but its effects on AD pathology are still unknown.

Methods: Five months old male J20 mice (n = 26) and their wild type (WT) littermates (n = 24) were used to investigate the effect of WBV on amyloid pathology and the healthy brain. Both J20 and WT mice underwent WBV on a vibration platform or pseudo vibration treatment. The vibration intervention consisted of 2 WBV sessions of 10 min per day, five days per week for five consecutive weeks. After five weeks of WBV, the balance beam test was used to assess motor performance. Brain tissue was collected to quantify Aβ deposition and immunomarkers of astrocytes and microglia.

Results: J20 mice have a limited number of plaques at this relatively young age. Amyloid plaque load was not affected by WBV. Microglia activation based on IBA1-immunostaining was significantly increased in the J20 animals compared to the WT littermates, whereas CD68 expression was not significantly altered. WBV treatment was effective to ameliorate microglia activation based on morphology in both J20 and WT animals in the Dentate Gyrus, but not so in the other subregions. Furthermore, GFAP expression based on coverage was reduced in J20 pseudo-treated mice compared to the WT littermates and it was significantly reserved in the J20 WBV vs. pseudo-treated animals. Further, only for the WT animals a tendency of improved motor performance was observed in the WBV group compared to the pseudo vibration group.

Conclusion: In accordance with the literature, we detected an early plaque load, reduced GFAP expression and increased microglia activity in J20 mice at the age of ~ 6 months. Our findings indicate that WBV has beneficial effects on the early progression of brain pathology. WBV restored, above all, the morphology of GFAP positive astrocytes to the WT level that could be considered the non-pathological and hence "healthy" level. Next experiments need to be performed to determine whether WBV is also affective in J20 mice of older age or other AD mouse models.

Background: ADHD is a disorder where a common symptom is impulsive behaviour, a broad term associated with making sub-optimal choices. One frequently used method to investigate impulsive behaviour is delay discounting, which involves choosing between a small, immediate reinforcer and a delayed, larger one. Choosing the small immediate reinforcer is by itself, however, not sufficient for terming the choice impulsive, as all organisms eventually switch to choosing the small, immediate reinforcer when the delay to the larger reinforcer becomes long. This switch can be termed impulsive only when it occurs more frequently, or at shorter LL delays, than typically observed in normal controls. A poorly understood aspect is how choice is influenced by previous experience with delays. Using an animal model of Attention-Deficit/Hyperactivity Disorder, the Spontaneously Hypertensive Rat, we manipulated the order of exposure to delays in a delay discounting task. Following a preference test, the Ascending group experienced gradually increasing delays between choice and reinforcer while the Descending group were exposed to these delays in reverse order.

Results: The results showed that the Descending group chose the small, immediate reinforcer over the larger delayed to a much larger extent than the Ascending group, and continued to do so even when the delay component was ultimately removed. Strain effects were found in the Ascending group, with SHRs switching to the small, immediate reinforcer earlier than controls as the delay to the larger reinforcer increased.

Conclusion: The data suggests that delay discounting is affected by history of exposure to delayed consequences. When reinforcement contingencies are incrementally changed from having no response-reinforcer delay to a long delay, discounting of delayed consequences is gradual. However, a sudden change from no delay to a long delay, without intermediate training, results in a rapid switch to the small, immediate reinforcer option, and this behaviour is somewhat resilient to the shortening and eventual removal of the large reinforcer delay. The implication is that attempting to reduce already existing impulsive behaviour in children with ADHD will require gradual habituation and not sudden changes in reinforcement contingencies.

Background: The pristane-induced lupus (PIL) model is a useful tool for studying environmental-related systemic lupus erythematosus (SLE). However, neuropsychiatric manifestations in this model have not been investigated in detail. Because neuropsychiatric lupus (NPSLE) is an important complication of SLE, we investigated the neuropsychiatric symptoms in the PIL mouse model to evaluate its suitability for NPSLE studies.

Results: PIL mice showed olfactory dysfunction accompanied by an anxiety- and depression-like phenotype at month 2 or 4 after pristane injection. The levels of cytokines (IL-1β, IFN-α, IFN-β, IL-10, IFN-γ, IL-6, TNF-α and IL-17A) and chemokines (CCL2 and CXCL10) in the brain and blood-brain barrier (BBB) permeability increased significantly from week 2 or month 1, and persisted throughout the observed course of the disease. Notably, IgG deposition in the choroid plexus and lateral ventricle wall were observed at month 1 and both astrocytes and microglia were activated. Persistent activation of astrocytes was detected throughout the observed course of the disease, while microglial activation diminished dramatically at month 4. Lipofuscin deposition, a sign of neuronal damage, was detected in cortical and hippocampal neurons from month 4 to 8.

Conclusion: PIL mice exhibit a series of characteristic behavioral deficits and pathological changes in the brain, and therefore might be suitable for investigating disease pathogenesis and for evaluating potential therapeutic targets for environmental-related NPSLE.

Background: Novel flavors elicit a cautious neophobic response which is attenuated as the flavor becomes familiar and safe. The attenuation of neophobia reveals the formation of a safe memory. Previous lesion studies in rats have reported that basolateral amygdala integrity is required for taste neophobia, but not neophobia to flavor, i.e., taste linked to an odorous component. Accordingly, immunohistochemical analyses show that novel tastes induced higher basolateral amygdala activity when compared to familiar ones. However, a different role of basolateral amygdala in flavor attenuation of neophobia is suggested by lesion studies using a vinegar solution. Studies assessing basolateral amygdala activity during flavor attenuation of neophobia are lacking. Thus, we quantified cytochrome oxidase as an index of basolateral amygdala activity along the first and second vinegar exposures in order to assess flavor neophobia and attenuation of neophobia.

Methods: We exposed adult male Wistar rats either once or twice to a 3% cider vinegar solution or water, and compared the basolateral amygdala, piriform cortex and caudate putamen brain metabolic activity using cytochrome c-oxidase histochemistry.

Results: We found increased flavor intake and cytochrome c-oxidase histochemistry activity during the second exposure in basolateral amygdala, but not in the piriform cortex and caudate/putamen.

Conclusions: The main finding of the study is that BLA metabolic activity was higher in the group exposed to a familiar vinegar solution than in the groups exposed to either water or a novel vinegar solution.

Despite significant differences between men and women in the symptoms of PTSD and the response to therapeutic interventions, most PTSD studies have been done on male subjects. Continuing our previous study in male rats, this study aimed at better understanding the effect of a combination therapy of exercise with fluoxetine on female PTSD rats. The results were then compared with our past findings in male animals. Female adult Wistar rats subjected to PTSD were treated with moderate treadmill exercise or fluoxetine, or a combination of both. PTSD was induced by the single prolonged stress (SPS) model. Elevated plus-maze (EPM), serum and prefrontal BDNF, and fear extinctions were evaluated. The results showed that exercise plus fluoxetine decreased anxiety-like behavior, improved fear extinction, and increased BDNF changes in female rats. The effects of exercise alone were comparable with those of combination therapy except that combination therapy was more effective on OAT (open arm entry). The majority of results in female rats, except for those of prefrontal BDNF, 4th extinction, and OAT, were similar to those of male rats as shown in our previous study. According to our findings, exercise as a safe and cost-effective intervention can be considered as a complementary efficient option for PTSD treatment in both sexes. To achieve better treatment outcomes in PTSD patient, considering sex differences is recommended.

Background: Reporting the second of the two targets is impaired when it occurs 200-500 ms after the first, the phenomenon in the study of consciousness is the attentional blink (AB). In the AB task, both the emotional salience and the expectation of the second target increase the likelihood of that target being consciously reported. Yet, little is known about how expectations modulate the prioritized processing of affective stimuli. We examined the role of expecting fearful expression when processing fear in an AB task. Participants were presented with an AB task where the 2nd target (T2) is either a fearful face or a neutral face, and had to report the target's gender. The frequency of fearful to neutral faces on a given block was manipulated, such that participants could either expect more or less fearful faces.

Results: In the Experiment 1, we found that fearful faces were more likely to be recognized than neutral faces during the blink period (lag3) when participants were not expecting a fearful face (low fear-expectation); however, high fear-expectation increased the discrimination of fearful T2 than neutral T2 outside the blink period (lag8). In the Experiment 2, we assessed ERP brain activity in response to perceived T2 during the blink period. The results revealed that fearful faces elicited larger P300 amplitudes compared to neutral faces, but only in the low fear-expectation condition, suggesting that expecting a fearful expression can suppress the processing of task-irrelevant facial expression and unexpected fearful expression can break through this suppression. Fearful T2 elicited larger vertex positive potential (VPP) amplitudes than neutral T2, and this affective effect was independent of fear-expectation. Since no effect of expectation was found on the VPP amplitude while P300 exhibited significant interaction between expectation and expression, this suggests that expectations modulate emotional processing at a later stage, after the fearful face has been differentially processed.

Conclusions: These results provided clear evidence for the contribution of the expectation to the prioritized processing of second affective stimuli in the AB.

Previous research has demonstrated behavioral and neural differences associated with experiencing adversity. However, adversity is unlikely to be a monolithic construct, and we expect that examining effects of more specific components such as exposure to violence in the home community will yield more concretely interpretable results. Here we account for effects of low socioeconomic status (SES) to examine the specific effects of exposure to violence on functional connectivity between brain areas known to be related to emotion regulation and working memory. Decreased resting state functional connectivity for individuals exposed to high compared to low levels of violence during childhood was predicted for two sets of areas: (1) bilateral amygdala with anterior medial regions involved in cognitive control of emotion, and (2) the right dorsolateral prefrontal cortex (dlPFC) with frontal and parietal regions implicated in working memory. Consistent with our predictions, increasing exposure to violence was related to decreased resting state functional connectivity between the right amygdala and anterior cingulate cortex, even after accounting for SES. Also after accounting for SES, exposure to violence was related to reductions in connectivity between the right dlPFC and frontal regions, but not with parietal regions typically associated with working memory. Overall, this pattern suggests increased exposure to violence in childhood is associated with reduced connectivity among key areas of the circuitry involved in emotion regulation and cognitive control, but not working memory. These results offer insight into the neural underpinnings of behavioral outcomes associated with exposure to violence, laying the foundation for ultimately designing interventions to address the effects of such exposure.

Background: The P3a response is thought to reflect involuntary orienting to an unexpected stimulus and has been connected with set-shifting and inhibition in some studies. In our exploratory study, we investigated if the amplitude and the latency of the P3a response were associated with the performance in a modified flanker task measuring inhibition and set-shifting in 10-year-old children (N = 42). Children participated in electroencephalography (EEG) measurement with an auditory multifeature paradigm including standard, deviating, and novel sounds. In addition, they performed a separate flanker task requiring inhibition and set-shifting skills.

Results: The P3a latencies for deviant sounds were associated with the reaction time reflecting inhibition: the shorter the response latencies were, the faster the reaction time was. The P3a latencies for novel sounds were not linked to the reaction times reflecting either inhibition or set-shifting. In addition, the magnitude of the P3a response was not associated with the performance in the flanker task.

Conclusions: Our results suggest that P3a response latency and reaction speed reflecting inhibitory skills are based on shared neural mechanism. Thus, the present study brings new insight to the field investigating the associations between behavior and its neural indices.