97 research outputs found
Neural Circuits Underlying Context-Dependent Fear Memory Retrieval
Exposure therapy for stress- and anxiety-related disorders is very effective, but fear
return after treatment is not uncommon. During extinction, repeated exposure to a
conditioned stimulus (CS) gradually decreases the probability and magnitude of the
conditioned fear response (CR). However, extinction does not eliminate the fear
memory; rather, it generates a new extinction memory that competes with the fear
memory for control of behavior. Importantly, the extinction memory is highly contextdependent
insofar as it is only expressed in the extinction context. That is, if the CS is
encountered outside of the extinction context, the conditioned fear response returns or
āārenewsāā. The renewal of extinguished fear is a considerable challenge for maintaining
long-lasting fear suppression after exposure therapy. The hippocampus, the medial
prefrontal cortex (mPFC) and the amygdala are thought to play essential roles for
context-dependent memory retrieval after extinction, but the circuit mechanism is not
clear. To explore the neural circuits underlying contextual regulation of fear memory
retrieval, we first used functional tracing approach to examine the activity of prelimbic
prefrontal cortex (PL)- and basal amygdala (BA)-projecting neurons in the ventral
hippocampus (vHPC) during extinction retrieval and fear renewal. We then used circuitspecific
chemogenetic approach to examine the role of infralimbic prefrontal cortex (IL)-
projecting vHPC neurons in contextual retrieval. Finally, we used pharmacological and
chemogenetic approaches to test the role of the nucleus reuniens (RE) in contextdependent
fear memory retrieval. The results showed that vHPC inputs to both the PL and BA are activated during fear renewal, with PL- and BA-dual projecting neurons
showing the greatest level of activation. Moreover, we showed that IL-projecting vHPC
neurons are required for fear renewal by inducing feedforward inhibition within the IL.
Lastly, we demonstrated that the RE is required for extinction retrieval, and the
prefrontal modulation on the RE activity is essential in this process. Together, these
results provided circuit mechanisms underlying context-dependent fear memory
retrieval
Fear renewal preferentially activates ventral hippocampal neurons projecting to both amygdala and prefrontal cortex in rats
Anxiety, trauma and stress-related disorders are often characterized by a loss of context-appropriate emotional responding. The contextual retrieval of emotional memory involves hippocampal projections to the medial prefrontal cortex and amygdala; however the relative contribution of these projections is unclear. To address this question, we characterized retrieval-induced Fos expression in ventral hippocampal (VH) neurons projecting to the prelimbic cortex (PL) and basal amygdala (BA) after the extinction of conditioned fear in rats. After extinction, freezing behavior (an index of learned fear) to the auditory conditioned stimulus was suppressed in the extinction context, but was ārenewedā in another context. Hippocampal neurons projecting to either PL or BA exhibited similar degrees of context-dependent Fos expression; there were more Fos-positive neurons in each area after the renewal, as opposed, to suppression of fear. Importantly, however, VH neurons projecting to both PL and BA were more likely to express Fos during fear renewal than neurons projecting to either PL or BA alone. These data suggest that although projections from the hippocampus to PL and BA are similarly involved in the contextual retrieval of emotional memories, VH neurons with collaterals to both areas may be particularly important for synchronizing prefrontal-amygdala circuits during fear renewal
Neural Circuits Underlying Context-Dependent Fear Memory Retrieval
Exposure therapy for stress- and anxiety-related disorders is very effective, but fear
return after treatment is not uncommon. During extinction, repeated exposure to a
conditioned stimulus (CS) gradually decreases the probability and magnitude of the
conditioned fear response (CR). However, extinction does not eliminate the fear
memory; rather, it generates a new extinction memory that competes with the fear
memory for control of behavior. Importantly, the extinction memory is highly contextdependent
insofar as it is only expressed in the extinction context. That is, if the CS is
encountered outside of the extinction context, the conditioned fear response returns or
āārenewsāā. The renewal of extinguished fear is a considerable challenge for maintaining
long-lasting fear suppression after exposure therapy. The hippocampus, the medial
prefrontal cortex (mPFC) and the amygdala are thought to play essential roles for
context-dependent memory retrieval after extinction, but the circuit mechanism is not
clear. To explore the neural circuits underlying contextual regulation of fear memory
retrieval, we first used functional tracing approach to examine the activity of prelimbic
prefrontal cortex (PL)- and basal amygdala (BA)-projecting neurons in the ventral
hippocampus (vHPC) during extinction retrieval and fear renewal. We then used circuitspecific
chemogenetic approach to examine the role of infralimbic prefrontal cortex (IL)-
projecting vHPC neurons in contextual retrieval. Finally, we used pharmacological and
chemogenetic approaches to test the role of the nucleus reuniens (RE) in contextdependent
fear memory retrieval. The results showed that vHPC inputs to both the PL and BA are activated during fear renewal, with PL- and BA-dual projecting neurons
showing the greatest level of activation. Moreover, we showed that IL-projecting vHPC
neurons are required for fear renewal by inducing feedforward inhibition within the IL.
Lastly, we demonstrated that the RE is required for extinction retrieval, and the
prefrontal modulation on the RE activity is essential in this process. Together, these
results provided circuit mechanisms underlying context-dependent fear memory
retrieval
TLR4 Mutation Reduces Microglial Activation, Increases AĪ² Deposits and Exacerbates Cognitive Deficits in a Mouse Model of Alzheimer\u27s Disease
BACKGROUND: Amyloid plaques, a pathological hallmark of Alzheimer\u27s disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing AĪ² deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in AĪ² deposits and buffer-soluble AĪ² in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of AĪ² deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when AĪ² deposits start.
METHODS: Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble AĪ² were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and AĪ²-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze.
RESULTS: While no difference was found in cerebral AĪ² load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased AĪ² deposition and soluble AĪ²42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1Ī², CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished AĪ²-induced IL-1Ī², CCL3, and CCL4 expression in monocytes.
CONCLUSION: This is the first demonstration of TLR4-dependent activation of microglia at the early stage of Ī²-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of AĪ² deposition and that, as AĪ² deposits start, microglia are activated via TLR4 signaling to reduce AĪ² deposits and preserve cognitive functions from AĪ²-mediated neurotoxicity
Simvastatin Enhances Immune Responses to AĪ² Vaccination and Attenuates Vaccination-Induced Behavioral Alterations
Statins are widely used to lower cholesterol levels by inhibiting cholesterol biosynthesis. Some evidence has indicated that statins might have therapeutic and preventive benefits for Alzheimer\u27s disease (AD). We and others also have shown the beneficial effect of statin treatment in reversing learning and memory deficits in animal models of AD. However, data from clinical trials are inconclusive. We previously documented that the adenovirus vector encoding 11 tandem repeats of AĪ²1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A, AdPEDI-(AĪ²1-6)(11), is effective in inducing an immune response against amyloid-Ī² protein (AĪ²) and reducing brain AĪ² load in Alzheimer\u27s mouse models. In the present study, we examined whether the administration of simvastatin can modulate immune and behavioral responses of C57BL/6 mice to vaccination. Simvastatin was given to the animals as a diet admixture for four weeks, followed by nasal vaccination with AdPEDI-(AĪ²1-6)(11) once per week for four weeks. The cholesterol-lowering action of simvastatin was monitored by measuring the cholesterol levels in plasma. Simvastatin significantly increased the number of the mice responding to vaccination compared with the mice receiving only AdPEDI-(AĪ²1-6)(11). Immunoglobulin isotyping revealed that the vaccination predominantly induced Th2 immune responses. Simvastatin treatment prevented AĪ²-induced production of IFN-Ī³ in splenocytes. The adenovirus vaccination altered mouse behavior in T- and elevated plus-maze tests and simvastatin counteracted such behavioral changes. Our results indicate that simvastatin clearly enhances the immune responses of C57BL/6 mice to the nasal vaccination with AdPEDI-(AĪ²1-6)(11). Simvastatin may be effective in preventing behavioral changes associated with vaccination
Identification of Mammalian Mediator Subunits with Similarities to Yeast Mediator Subunits Srb5, Srb6, Med11, and Rox3
The Mediator is a multiprotein coactivator required for activation of RNA polymerase II transcription by DNA binding transactivators. We recently identified a mammalian homologue of yeast Mediator subunit Med8 and partially purified a Med8-containing Mediator complex from rat liver nuclei (Brower, C. S., Sato, S., Tomomori-Sato, C., Kamura, T., Pause, A., Stearman, R., Klausner, R. D., Malik, S., Lane, W. S., Sorokina, I., Roeder, R. G., Conaway, J. W., and Conaway, R. C. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 10353-10358). Analysis of proteins present in the most highly purified Med8-containing fractions by tandem mass spectrometry led to the identification of many known mammalian Mediator subunits, as well as four potential Mediator subunits exhibiting sequence similarity to yeast Mediator subunits Srb5, Srb6, Med11, and Rox3. Here we present direct biochemical evidence that these four proteins are bona fide mammalian Mediator subunits. In addition, we identify direct pairwise binding partners of these proteins among the known mammalian Mediator subunits. Taken together, our findings identify a collection of novel mammalian Mediator subunits and shed new light on the underlying architecture of the mammalian Mediator complex
Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD)
Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD). HIV promotion of an M1 antigen presenting cell (APC) - like microglial phenotype, through the promotion of CD40 activity, may impair endogenous mechanisms important for amyloid- beta (AĪ²) protein clearance. Further, a chronic pro-inflammatory cycle is established in this manner. CD45 is a protein tyrosine phosphatase receptor which negatively regulates CD40L-CD40-induced microglial M1 activation; an effect leading to the promotion of an M2 phenotype better suited to phagocytose and clear AĪ². Moreover, this CD45 mediated activation state appears to dampen harmful cytokine production. As such, this property of microglial CD45 as a regulatory "off switch" for a CD40-promoted M1, APC-type microglia activation phenotype may represent a critical therapeutic target for the prevention and treatment of neurodegeneration, as well as microglial dysfunction, found in patients with HAD
Antiretroviral medications disrupt microglial phagocytosis of Ī²-amyloid and increase its production by neurons: Implications for HIV-associated neurocognitive disorders
Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of AĪ² plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced AĪ² elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) AĪ²1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-AĪ²1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 Ī¼M) generally increase AĪ² generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-AĪ²1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated AĪ² found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND)
TLR4 mutation reduces microglial activation, increases AĪ² deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease
<p>Abstract</p> <p>Background</p> <p>Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing AĪ² deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in AĪ² deposits and buffer-soluble AĪ² in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of AĪ² deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when AĪ² deposits start.</p> <p>Methods</p> <p>Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble AĪ² were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and AĪ²-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze.</p> <p>Results</p> <p>While no difference was found in cerebral AĪ² load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased AĪ² deposition and soluble AĪ²42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1Ī², CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished AĪ²-induced IL-1Ī², CCL3, and CCL4 expression in monocytes.</p> <p>Conclusion</p> <p>This is the first demonstration of TLR4-dependent activation of microglia at the early stage of Ī²-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of AĪ² deposition and that, as AĪ² deposits start, microglia are activated via TLR4 signaling to reduce AĪ² deposits and preserve cognitive functions from AĪ²-mediated neurotoxicity.</p
Potential coordination role between O-GlcNAcylation and epigenetics
Abstract Dynamic changes of the post-translational O-GlcNAc modification (O-GlcNAcylation) are controlled by O-linked Ī²-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the glycoside hydrolase O-GlcNAcase (OGA) in cells. O-GlcNAcylation often occurs on serine (Ser) and threonine (Thr) residues of the specific substrate proteins via the addition of O-GlcNAc group by OGT. It has been known that O-GlcNAcylation is not only involved in many fundamental cellular processes, but also plays an important role in cancer development through various mechanisms. Recently, accumulating data reveal that O-GlcNAcylation at histones or non-histone proteins can lead to the start of the subsequent biological processes, suggesting that O-GlcNAcylation as āprotein codeā or āhistone codeā may provide recognition platforms or executive instructions for subsequent recruitment of proteins to carry out the specific functions. In this review, we summarize the interaction of O-GlcNAcylation and epigenetic changes, introduce recent research findings that link crosstalk between O-GlcNAcylation and epigenetic changes, and speculate on the potential coordination role of O-GlcNAcylation with epigenetic changes in intracellular biological processes
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