Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice

Abstract Background: Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. Methods: In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. Results: The plasma levels and hypothalamic mRNA levels of IL-1b and TNF-a were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the NAc and insula. Moreover, microglial activation in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice.Conclusions: Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.

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Intermittent peripheral exposure to lipopolysaccharide induces exploratory behavior in mice and regulates brain glial activity in obese mice

10.21203/rs.2.22927/v1 ◽

2020 ◽

Author(s):

Hui-Ting Huang ◽

Po-See Chen ◽

Yu-Ming Kuo ◽

Shun-Fen Tzeng

Keyword(s):

Exploratory Behavior ◽

Microglial Activation ◽

Basolateral Amygdala ◽

Brain Regions ◽

Anterior Cingulate ◽

Mrna Levels ◽

Morphological Examination ◽

Intermittent Exposure ◽

Immune Challenges ◽

Hypothalamic Tissue

Abstract Background Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. Methods In this study, we administered 1 mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8 weeks of a regular diet (show) or HFD. The level of interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) expression in the plasma and hypothalamic tissue was analyzed 24 h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5 months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. Results The plasma levels and hypothalamic mRNA levels of IL-1b and TNF-a were significantly upregulated 24 h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5 months after feeding. However, this LPS-induced exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5 months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the NAc and insula. Moreover, microglial activation in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice. Conclusions Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced exploratory behavior. Our findings suggest that intermittent acute peripheral immune challenges and chronic HFD intake can cause microglia to modify the microenvironment and further modify animal behaviors.

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Moderate maternal separation mitigates the altered synaptic transmission and neuronal activation in amygdala by chronic stress in adult mice

Molecular Brain ◽

10.1186/s13041-019-0534-4 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 5

Author(s):

Xia Qin ◽

Ye He ◽

Na Wang ◽

Jia-Xin Zou ◽

Yong-Mei Zhang ◽

...

Keyword(s):

Life Stress ◽

Basolateral Amygdala ◽

Neuronal Excitability ◽

Maternal Separation ◽

Glutamate Release ◽

Later Life ◽

Brain Regions ◽

Stressful Events ◽

Stress Inoculation ◽

Glutamatergic Transmission

AbstractExposure to moderate level of stress during the perinatal period helps the organisms to cope well with stressful events in their later life, an effect known as stress inoculation. Amygdala is one of the kernel brain regions mediating stress-coping in the brain. However, little is known about whether early life stress may affect amygdala to have its inoculative effect. Here, we observed that moderate maternal separation (MS) from postnatal day 3 to day 21 (D3–21, 1 h per day) significantly alleviated the increased anxiety-like behavior induced by chronic social defeat stress (CSDS) in adulthood, suggesting an obvious inoculative effect of moderate MS. Further studies revealed that MS prevented CSDS-evoked augmentation of glutamatergic transmission onto principal neurons (PNs) in the basolateral amygdala (BLA) by inhibiting presynaptic glutamate release. By contrast, it did not affect GABAergic transmission in BLA PNs, as indicated by unaltered frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Moreover, the CSDS-induced increase of neuronal excitability was also mitigated by MS in BLA PNs. In conclusion, our results suggest that MS may have its inoculative effect through alleviating the influences of later life stress on the glutamatergic transmission and neuronal activity in amygdala neurons.

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Specialized medial prefrontal-amygdala coordination in other-regarding decision preference

10.1101/640292 ◽

2019 ◽

Author(s):

Olga Dal Monte ◽

Cheng-Chi J. Chu ◽

Nicholas A. Fagan ◽

Steve W. C. Chang

Keyword(s):

Cognitive Processes ◽

Basolateral Amygdala ◽

Brain Regions ◽

Brain Network ◽

Anterior Cingulate ◽

Social Brain ◽

Social Decisions ◽

The Social ◽

Oscillatory Coupling ◽

Other Regarding

AbstractSocial behaviors recruit multiple cognitive processes requiring coordinated interactions among brain regions. Oscillatory coupling provides one mechanism for cortical and subcortical neurons to synchronize their activity. However, it remains unknown how neurons from different nodes in the social brain network interact when making social decisions. We investigated neuronal coupling between the rostral anterior cingulate gyrus of the medial prefrontal cortex and the basolateral amygdala while monkeys expressed context-dependent positive other-regarding preference (ORP) or negative ORP impacting the reward of another monkey. We found an enhanced synchronization between the two nodes for positive ORP, but a suppressed synchronization for negative ORP. These interactions occurred in dedicated frequency channels depending on the area contributing spikes, exhibited a specific directionality of information flow associated with expressing positive ORP, and could be used to decode social decisions. These findings support that specialized coordination in the medial prefrontal-amygdala network underlies social decision preference.

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Inflammational Animal Models for Schizophrenia

Zeitschrift für Psychologie ◽

10.1027/2151-2604/a000216 ◽

2015 ◽

Vol 223 (3) ◽

pp. 157-164 ◽

Cited By ~ 1

Author(s):

Georg Juckel

Keyword(s):

Animal Model ◽

Animal Models ◽

Immune Activation ◽

Microglial Activation ◽

Treatment Options ◽

Early Adulthood ◽

Brain Regions ◽

Synaptic Connections ◽

Preventive Interventions ◽

Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

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Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model

Molecular Pain ◽

10.1177/1744806921990934 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199093

Author(s):

Dan-jie Su ◽

Long-fei Li ◽

Sai-ying Wang ◽

Qi Yang ◽

Yu-jing Wu ◽

...

Keyword(s):

Chronic Pain ◽

Mouse Model ◽

Anterior Cingulate Cortex ◽

Analgesic Effect ◽

Microglial Activation ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1β, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

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Very Early Exercise Rehabilitation After Intracerebral Hemorrhage Promotes Inflammation in the Brain

Neurorehabilitation and Neural Repair ◽

10.1177/15459683211006337 ◽

2021 ◽

pp. 154596832110063

Author(s):

Keigo Tamakoshi ◽

Madoka Maeda ◽

Shinnosuke Nakamura ◽

Nae Murohashi

Keyword(s):

Intracerebral Hemorrhage ◽

Protein Expression ◽

Brain Regions ◽

Motor Dysfunction ◽

Inflammatory Factors ◽

Mrna Levels ◽

Exercise Rehabilitation ◽

Early Exercise ◽

Polymerase Chain ◽

To Receive

Background Very early exercise has been reported to exacerbate motor dysfunction; however, its mechanism is largely unknown. Objective This study examined the effect of very early exercise on motor recovery and associated brain damage following intracerebral hemorrhage (ICH) in rats. Methods Collagenase solution was injected into the left striatum to induce ICH. Rats were randomly assigned to receive placebo surgery without exercise (SHAM) or ICH without (ICH) or with very early exercise within 24 hours of surgery (ICH+VET). We observed sensorimotor behaviors before surgery, and after surgery preexercise and postexercise. Postexercise brain tissue was collected 27 hours after surgery to investigate the hematoma area, brain edema, and Il1b, Tgfb1, and Igf1 mRNA levels in the striatum and sensorimotor cortex using real-time reverse transcription polymerase chain reaction. NeuN, PSD95, and GFAP protein expression was analyzed by Western blotting. Results We observed significantly increased skillful sensorimotor impairment in the horizontal ladder test and significantly higher Il1b mRNA levels in the striatum of the ICH+VET group compared with the ICH group. NeuN protein expression was significantly reduced in both brain regions of the ICH+VET group compared with the SHAM group. Conclusion Our results suggest that very early exercise may be associated with an exacerbation of motor dysfunction because of increased neuronal death and region-specific changes in inflammatory factors. These results indicate that implementing exercise within 24 hours after ICH should be performed with caution.

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Peripheral arterial stiffness during electrocutaneous stimulation is positively correlated with pain-related brain activity and subjective pain intensity: an fMRI study

Scientific Reports ◽

10.1038/s41598-021-83833-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Toshio Tsuji ◽

Fumiya Arikuni ◽

Takafumi Sasaoka ◽

Shin Suyama ◽

Takashi Akiyoshi ◽

...

Keyword(s):

Arterial Stiffness ◽

Pain Intensity ◽

Brain Activity ◽

Brain Regions ◽

Anterior Cingulate ◽

Electrocutaneous Stimulation ◽

Pain Matrix ◽

Fmri Study ◽

Subjective Pain ◽

Peripheral Arterial

AbstractBrain activity associated with pain perception has been revealed by numerous PET and fMRI studies over the past few decades. These findings helped to establish the concept of the pain matrix, which is the distributed brain networks that demonstrate pain-specific cortical activities. We previously found that peripheral arterial stiffness $${\beta }_{\text{art}}$$ β art responds to pain intensity, which is estimated from electrocardiography, continuous sphygmomanometer, and photo-plethysmography. However, it remains unclear whether and to what extent $${\beta }_{\text{art}}$$ β art aligns with pain matrix brain activity. In this fMRI study, 22 participants received different intensities of pain stimuli. We identified brain regions in which the blood oxygen level-dependent signal covaried with $${\beta }_{\text{art}}$$ β art using parametric modulation analysis. Among the identified brain regions, the lateral and medial prefrontal cortex and ventral and dorsal anterior cingulate cortex were consistent with the pain matrix. We found moderate correlations between the average activities in these regions and $${\beta }_{\text{art}}$$ β art (r = 0.47, p < 0.001). $${\beta }_{\text{art}}$$ β art was also significantly correlated with self-reported pain intensity (r = 0.44, p < 0.001) and applied pain intensity (r = 0.43, p < 0.001). Our results indicate that $${\beta }_{\text{art}}$$ β art is positively correlated with pain-related brain activity and subjective pain intensity. This study may thus represent a basis for adopting peripheral arterial stiffness as an objective pain evaluation metric.

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Cannabinoids, reward processing, and psychosis

Psychopharmacology ◽

10.1007/s00213-021-05801-2 ◽

2021 ◽

Author(s):

Brandon Gunasekera ◽

Kelly Diederen ◽

Sagnik Bhattacharyya

Keyword(s):

Psychotic Disorders ◽

Neural Substrates ◽

Brain Regions ◽

Reward Processing ◽

Anterior Cingulate ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Future Research ◽

Drug Challenge ◽

Psychotomimetic Effects

Abstract Background Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. Aims We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. Methods This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis Results There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. Conclusions There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.

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