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1.
Am J Pathol ; 193(10): 1568-1586, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37356575

RESUMO

High-fat diet (HFD) consumption may contribute to the high prevalence of cognitive-emotional issues in modern society. Mice fed a HFD for a prolonged period develop more severe neurobehavioral disturbances when first exposed to a HFD in the juvenile period than in adulthood, suggesting an initial age-related difference in the detrimental effects of long-term HFD feeding. However, the mechanism underlying this difference remains unclear. Here, male C57BL/6J mice initially aged 4 (IA4W) or 8 (IA8W) weeks were fed a control diet (CD) or HFD for 6 months and then subjected to metabolic, neurobehavioral, and histomorphological examinations. Although the detrimental effects of long-term HFD feeding on metabolism and neurobehavior were observed in mice of both ages, IA4W-HFD mice showed significant cognitive inflexibility accompanied by significantly greater levels of anxiety-like behavior than age-matched controls. Hippocampal neuroplasticity and microglial phenotype were altered by HFD feeding, whereas significant morphological alterations were more frequently observed in IA4W-HFD mice than in IA8W-HFD mice. Additionally, significantly increased hippocampal microglial engulfment of postsynaptic proteins and elevated phospho-insulin-receptor levels were observed in IA4W-HFD, but not in IA8W-HFD, mice. These findings suggest that aberrant microglia-related histomorphological changes in the hippocampus underlie the exacerbated detrimental neurobehavioral effects of prolonged early HFD exposure and indicate that enhanced insulin signaling might drive microglial dysfunction after prolonged early HFD exposure.


Assuntos
Dieta Hiperlipídica , Insulina , Camundongos , Masculino , Animais , Dieta Hiperlipídica/efeitos adversos , Microglia , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Hipocampo/metabolismo
2.
Brain Behav Immun ; 119: 236-250, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38604269

RESUMO

Mounting evidence suggests that high-fat diet (HFD) consumption increases the risk for depression, but the neurophysiological mechanisms involved remain to be elucidated. Here, we demonstrated that HFD feeding of C57BL/6J mice during the adolescent period (from 4 to 8 weeks of age) resulted in increased depression- and anxiety-like behaviors concurrent with changes in neuronal and myelin structure in the hippocampus. Additionally, we showed that hippocampal microglia in HFD-fed mice assumed a hyperactive state concomitant with increased PSD95-positive and myelin basic protein (MBP)-positive inclusions, implicating microglia in hippocampal structural alterations induced by HFD consumption. Along with increased levels of serum free fatty acids (FFAs), abnormal deposition of lipid droplets and increased levels of HIF-1α protein (a transcription factor that has been reported to facilitate cellular lipid accumulation) within hippocampal microglia were observed in HFD-fed mice. The use of minocycline, a pharmacological suppressor of microglial overactivation, effectively attenuated neurobehavioral abnormalities and hippocampal structural alterations but barely altered lipid droplet accumulation in the hippocampal microglia of HFD-fed mice. Coadministration of triacsin C abolished the increases in lipid droplet formation, phagocytic activity, and ROS levels in primary microglia treated with serum from HFD-fed mice. In conclusion, our studies demonstrate that the adverse influence of early-life HFD consumption on behavior and hippocampal structure is attributed at least in part to microglial overactivation that is accompanied by an elevated serum FFA concentration and microglial aberrations represent a potential preventive and therapeutic target for HFD-related emotional disorders.


Assuntos
Ansiedade , Dieta Hiperlipídica , Ácidos Graxos não Esterificados , Hipocampo , Camundongos Endogâmicos C57BL , Microglia , Animais , Hipocampo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microglia/metabolismo , Camundongos , Masculino , Ansiedade/metabolismo , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Depressão/metabolismo , Comportamento Animal , Minociclina/farmacologia
3.
Brain Behav Immun ; 114: 325-348, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37683962

RESUMO

Acquired peripheral hearing loss (APHL) in midlife has been identified as the greatest modifiable risk factor for dementia; however, the pathophysiological neural mechanisms linking APHL with an increased risk of dementia remain to be elucidated. Here, in an adult male mouse model of noise-induced hearing loss (NIHL), one of the most common forms of APHL, we demonstrated accelerated age-related cognitive decline and hippocampal neurodegeneration during a 6-month follow-up period, accompanied by progressive hippocampal microglial aberrations preceded by immediate-onset transient elevation in serum glucocorticoids and delayed-onset sustained myelin disruption in the hippocampus. Pretreatment with the glucocorticoid receptor antagonist RU486 before stressful noise exposure partially mitigated the early activation of hippocampal microglia, which were present at 7 days post noise exposure (7DPN), but had no impact on later microglial aberrations, hippocampal neurodegeneration, or cognitive decline exhibited at 1 month post noise exposure (1MPN). One month of voluntary wheel exercise following noise exposure barely affected either the hearing threshold shift or hippocampal myelin changes but effectively countered cognitive impairment and the decline in hippocampal neurogenesis in NIHL mice at 1MPN, paralleled by the normalization of microglial morphology, which coincided with a reduction in microglial myelin inclusions and a restoration of microglial hypoxia-inducible factor-1α (HIF1α) expression. Our results indicated that accelerated cognitive deterioration and hippocampal neuroplastic decline following NIHL are most likely driven by the maladaptive response of hippocampal microglia to myelin damage secondary to hearing loss, and we also demonstrated the potential of voluntary physical exercise as a promising and cost-effective strategy to alleviate the detrimental impact of APHL on cognitive function and thus curtail the high and continuously increasing global burden of dementia. Furthermore, the findings of the present study highlight the contribution of myelin debris overload to microglial malfunction and identify the microglial HIF1α-related pathway as an attractive candidate for future comprehensive investigation to obtain a more definitive picture of the underlying mechanisms linking APHL and dementia.

4.
J Integr Neurosci ; 22(1): 16, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36722241

RESUMO

BACKGROUND: The overconsumption of a high-fat diet (HFD) has been repeatedly blamed as being a possible contributor to the global prevalence of emotional problems in modern society. Our group recently demonstrated the deleterious effect of a chronic HFD throughout adulthood on both emotional behavior and neuroplasticity markers in mice. As a heightened preference for palatable HFDs from the time of the juvenile period (when the brain is particularly vulnerable to environmental insults) is universal among populations around the world, a comparison of the consequences of chronic HFDs starting from juveniles or adults will assist in obtaining better knowledge of the impact that chronic HFDs have on mental health, thus potentially leading to the discovery of more effective strategies for reducing the incidence of psychiatric disorders. METHODS: In the present study, male C57BL/6J mice with an initial age of 4 weeks (IA-4 W) or 8 weeks (IA-8 W) were separately assigned to two subgroups and fed either a control diet (CD, 10 kJ% from fat) or HFD (60 kJ% from fat) for 9 months followed by an analysis focused on metabolic, emotional behavioral, and neuroplastic profiles. RESULTS: The results illustrated that, in addition to abnormal glucolipid metabolism and insulin sensitivity, mice on a chronic HFD exhibited increased levels of anxiety and depression-like behaviors and aberrant hippocampal neuroplasticity. When compared with IA-8 W mice, several changes indicating systemic metabolic disturbance and neurobehavioral disorder after chronic HFD consumption were aggravated in IA-4 W mice, accompanied by exaggerated impairments in hippocampal insulin sensitivity and neurogenesis. CONCLUSIONS: These results not only provide in vivo evidence that the juvenile stage is a critical period of vulnerability to detrimental effects of HFD consumption on metabolic and neuronal function but also suggest dampened hippocampal insulin signaling as a potential link between prolonged HFD consumption and negative neurobehavioral outcomes. Considering the substantial burden posed by psychiatric disorders and the high prevalence of HFD among youth, these observations are meaningful for raising awareness of the harmful effects of excessive dietary fat intake and developing strategy for preventing mental disorders.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Hipocampo
5.
Int J Mol Sci ; 24(11)2023 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-37298345

RESUMO

The association between a high-fat diet (HFD) consumption and emotional/cognitive disorders is widely documented. One distinctive feature of the prefrontal cortex (PFC), a kernel emotion- and cognition-related brain region, is its protracted adolescent maturation, which makes it highly vulnerable to the detrimental effects of environmental factors during adolescence. Disruption of the PFC structure and function is linked to emotional/cognitive disorders, especially those that emerge in late adolescence. A HFD consumption is common among adolescents, yet its potential effects on PFC-related neurobehavior in late adolescence and any related underlying mechanisms are yet to be established. In the present study, adolescent (postnatal days 28-56) male C57BL/6J mice were fed a control diet (CD) or a HFD and underwent behavioral tests in addition to Golgi staining and immunofluorescence targeting of the medial PFC (mPFC). The HFD-fed adolescent mice exhibited anxiety- and depression-like behavior and abnormal mPFC pyramidal neuronal morphology accompanied by alterations in microglial morphology indicative of a heightened state of activation and increased microglial PSD95+ inclusions signifying excessive phagocytosis of the synaptic material in the mPFC. These findings offer novel insights into the neurobehavioral effects due to adolescent HFD consumption and suggest a contributing role in microglial dysfunction and prefrontal neuroplasticity deficits for HFD-associated mood disorders in adolescents.


Assuntos
Dieta Hiperlipídica , Microglia , Camundongos , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Neurônios , Córtex Pré-Frontal/fisiologia
6.
Brain Behav Immun ; 100: 155-171, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34848340

RESUMO

High-fat diet (HFD) consumption is generally associated with an increased risk of cognitive and emotional dysfunctions that constitute a sizeable worldwide health burden with profound social and economic consequences. Middle age is a critical time period that affects one's health later in life; pertinently, the prevalence of HFD consumption is increasing among mature adults. Given the growing health-related economic burden imposed globally by increasing rates of noncommunicable diseases in rapidly aging populations, along with the pervasive but insidious health impairments associated with HFD consumption, it is critically important to understand the effects of long-term HFD consumption on brain function and to gain insights into their potential underlying mechanisms. In the present study, adult male C57BL/6J mice were randomly assigned a control diet (CD, 10 kJ% from fat) or an HFD (60 kJ% from fat) for 6 months (6 M) or 9 months (9 M) followed by behavioral tests, serum biochemical analysis, and histological examinations of both the dorsal and ventral regions of the hippocampus. In both the 6 M and 9 M cohorts, mice that consumed an HFD exhibited poorer memory performance in the Morris water maze test (MWM) and greater depression- and anxiety-like behavior during the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST) than control mice. Compared with age-matched mice in the CD group, mice in the HFD group showed abnormal hippocampal neuronal morphology, which was particularly evident in the ventral hippocampus. Hippocampal microglia in mice in the HFD group generally had a more activated phenotype evidenced by a smaller microglial territory area and increased cluster of differentiation 68 (CD68, a marker of phagocytic activity) immunoreactivity, while the microglial density in the dentate gyrus (DG) was decreased, indicating microglial decline. The engulfment of postsynaptic density 95 (PSD95, a general postsynaptic marker) puncta by microglia was increased in the HFD groups. Histological analysis of neutral lipids using a fluorescent probe (BODIPY) revealed that the total neutral lipid content in regions of interests (ROIs) and the lipid load in microglia were increased in the HFD group relative to the age-matched CD group. In summary, our results demonstrated that chronic HFD consumption from young adulthood to middle age induced anxiety- and depression-like behavior as well as memory impairment. The negative influence of chronic HFD consumption on behavioral and hippocampal neuroplasticity appears to be linked to a change in microglial phenotype that is accompanied by a remarkable increase in cellular lipid accumulation. These observations highlighting the potential to target lipid metabolism deficits to reduce the risk of HFD-associated emotional dysfunctions.


Assuntos
Dieta Hiperlipídica , Microglia , Animais , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Plasticidade Neuronal
7.
Int J Mol Sci ; 23(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35955450

RESUMO

Adolescence is a developmental epoch characterized by massive neural circuit remodeling; thus, the brain is particularly vulnerable to environmental influences during this period. Excessive high-fat diet (HFD) consumption, which is very common among adolescents, has long been recognized as a potent risk factor for multiple mood disorders, including depression and anxiety. However, the precise mechanisms underlying the influences of HFD consumption in adolescence on emotional health are far from clear. In the present study, C57BL/6 mice were fed a control diet (CD) or HFD for about 4 weeks from postnatal day (P) 28 to P60, spanning most of the adolescence period, and then subjected to behavioral assessments and histological examinations. HFD mice exhibited elevated levels of depression and anxiety, decreased hippocampal neurogenesis, and excessive microglial activation in the ventral hippocampus. Furthermore, in HFD-fed mice, microglia showed increased DCX+ inclusions, suggesting aberrant microglial engulfment of newborn neurons in HFD-fed adolescents. To our knowledge, this is the first observation suggesting that the negative effects of HFD consumption in adolescence on emotion and neuroplasticity may be attributed at least in part to aberrant microglial engulfment of nascent neurons, extending our understanding of the mechanism underlying HFD-related affective disorders in young people.


Assuntos
Dieta Hiperlipídica , Microglia , Animais , Dieta Hiperlipídica/efeitos adversos , Emoções , Hipocampo/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Neurogênese/fisiologia
8.
Metab Brain Dis ; 30(5): 1295-308, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26141074

RESUMO

The aim of this study was to evaluate the structural integrity of the thalamic connectivity of specific fiber tracts in different stages of Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Thirty-five patients with AD and 22 normal control (NC) subjects were recruited. Based on Mini Mental State Examination score, the AD patients were divided into three subgroups for comparison with the NC group: mild (mi-AD, n = 14), moderate (mo-AD, n = 12), and severe (se-AD, n = 9) AD. The fornix (FX), anterior thalamic radiation (ATR), and posterior thalamic radiation (PTR) were selected to represent the thalamic connectivity with other brain regions. The fornix was divided into the column and body of the fornix (FX-1) and the bilateral fornix (crus)/stria terminalis (FX-2/ST) based on the atlas. Through the atlas-based analysis and fiber tracking method, we measured fractional anisotropy (FA), mean diffusivity (MD), and tract volume to reflect the microstructural and macrostructural changes of these fibers during AD progression. There were significant differences in the FA and MD of all fibers, except the right PTR, between the AD and NC subjects. Further subgroup analyses revealed that the mi-AD subgroup had decreased FA only in the FX-1 and increased MD in the FX-1 and bilateral ATR, the mo-AD subgroup showed declined FA and increased MD in the FX-1, bilateral FX-2/ST and ATR; the se-AD subgroup exhibited lower FA and higher MD values in all fibers except the right PTR. We also found reduced tract volume values in the FX and left ATR in the AD patients. Further subgroup analyses revealed that these differences only existed in the se-AD patients. Our DTI analyses indicate that the integrity of thalamic connectivity is progressively disrupted following cognitive decline in AD and that DTI parameters in the column and body of the fornix show promise as potential markers for the early diagnosis of AD and for monitoring disease progression.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Imagem de Tensor de Difusão , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Idoso , Idoso de 80 Anos ou mais , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Front Neurosci ; 15: 749925, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34955715

RESUMO

Noise-induced hearing loss (NIHL) is one of the most prevalent forms of acquired hearing loss, and it is associated with aberrant microglial status and reduced hippocampal neurogenesis; however, the nature of these associations is far from being elucidated. Beyond its direct effects on the auditory system, exposure to intense noise has previously been shown to acutely activate the stress response, which has increasingly been linked to both microglial activity and adult hippocampal neurogenesis in recent years. Given the pervasiveness of noise pollution in modern society and the important implications of either microglial activity or hippocampal neurogenesis for cognitive and emotional function, this study was designed to investigate how microglial status and hippocampal neurogenesis change over time following acoustic exposure and to analyze the possible roles of the noise exposure-induced stress response and hearing loss in these changes. To accomplish this, adult male C57BL/6J mice were randomly assigned to either a control or noise exposure (NE) group. Auditory function was assessed by measuring ABR thresholds at 20 days post noise exposure. The time-course profile of serum corticosterone levels, microglial status, and hippocampal neurogenesis during the 28 days following noise exposure were quantified by ELISA or immunofluorescence staining. Our results illustrated a permanent moderate-to-severe degree of hearing loss, an early but transient increase in serum corticosterone levels, and time-dependent dynamic alterations in microglial activation status and hippocampal neurogenesis, which both present an early but transient change and a late but enduring change. These findings provide evidence that both the stress response and hearing loss contribute to the dynamic alterations of microglia and hippocampal neurogenesis following noise exposure; moreover, noise-induced permanent hearing loss rather than noise-induced transient stress is more likely to be responsible for perpetuating the neurodegenerative process associated with many neurological diseases.

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