scholarly journals CCR5 closes the temporal window for memory linking

2021 ◽  
Author(s):  
Yang Shen ◽  
Miou Zhou ◽  
Denise Cai ◽  
Daniel Almeida Filho ◽  
Giselle Fernandes ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Memory Allocation ◽  
Clinical Implications ◽  
Ccr5 Expression ◽  
Cellular Mechanisms ◽  
Temporal Window ◽  
Contextual Memory ◽  
Age Related ◽  
The Brain ◽  
Related Increase

Real world memories are formed in a particular context and are not acquired or recalled in isolation. Time is a key variable in the organization of memories, since events experienced close in time are more likely to be meaningfully associated, while those experienced with a longer interval are not. How does the brain segregate events that are temporally distinct? Here, we report that a delayed (12-24h) increase in the expression of the C-C chemokine receptor type 5 (CCR5), an immune receptor well known as a co-receptor for HIV infection, following the formation of a contextual memory, determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed CCR5 expression in mouse dorsal CA1 (dCA1) neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dCA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, thus closing the temporal window for memory linking. Remarkably, our findings also show that an age-related increase in CCL5/CCR5 expression leads to impairments in memory linking in aged mice, which could be reversed with a CCR5 knockout and an FDA approved drug that inhibits this receptor, a result with significant clinical implications. All together the findings reported here provide the first insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Neuronal Excitability in Memory Allocation: Mechanisms and Consequences

2020 ◽  
Author(s):  
Alexander D. Jacob ◽  
Andrew J. Mocle ◽  
Paul W. Frankland ◽  
Sheena A. Josselyn
Keyword(s):  
Neuronal Excitability ◽  
Memory System ◽  
Higher Order ◽  
Memory Allocation ◽  
System Function ◽  
Selection Mechanism ◽  
Cellular Mechanisms ◽  
Memory Circuit ◽  
Allocation Process ◽  
The Brain

Throughout the brain, sparse ensembles of neurons, termed “engrams,” are responsible for representing events. Engrams are composed of neurons active at the time of an event, and recent research has revealed how these active neurons compete to gain inclusion into a subsequently formed engram. This competitive selection mechanism, called “memory allocation,” is the process by which individual neurons become components of the engram. Memory allocation is crucially influenced by neuronal excitability, with more highly excitable neurons outcompeting their neighbors for inclusion into the engram. The dynamics of this excitability-dependent memory allocation process have important consequences for the function of the memory circuit, including effects on memory generalization and linking of events experienced closely in time. Memory allocation arises from cellular mechanisms of excitability, governs circuit-level dynamics of the engram, and has higher-order consequences for memory system function.

Memory Allocation: Mechanisms and Function

2018 ◽  
Vol 41 (1) ◽  
pp. 389-413 ◽  
Author(s):  
Sheena A. Josselyn ◽  
Paul W. Frankland
Keyword(s):  
Neuronal Excitability ◽  
Memory Allocation ◽  
Integration Process ◽  
Neuronal Ensembles ◽  
Memory Integration ◽  
And Function ◽  
The Brain

Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry.

scholarly journals Age-Related Increase in Caveolin-1 Expression Facilitates Cell-to-Cell Transmission of α-Synuclein in Neurons

2021 ◽  
Author(s):  
Tae-Young Ha ◽  
Yu Ree Choi ◽  
Hye Rin Noh ◽  
Seon-Heui Cha ◽  
Jae-Bong Kim ◽  
...  
Keyword(s):  
Risk Factor ◽  
Inclusion Bodies ◽  
Aging Process ◽  
Caveolin 1 ◽  
Age Related ◽  
Cell Transmission ◽  
Tyrosine 14 ◽  
The Relationship ◽  
The Brain ◽  
Related Increase

Abstract Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

scholarly journals Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Latarsha Porcher ◽  
Sophie Bruckmeier ◽  
Steven D. Burbano ◽  
Julie E. Finnell ◽  
Nicole Gorny ◽  
...  
Keyword(s):  
Statistical Tests ◽  
Ventral Hippocampus ◽  
Brain Regions ◽  
Cytokine Expression ◽  
Brown Norway ◽  
Mouse Strains ◽  
Gm Csf ◽  
Age Related ◽  
The Brain ◽  
Related Increase

Abstract Background Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound—particularly for interleukin 6 (IL-6)—possibly due to differences in sex, species/strain, and/or the brain regions studied. Methods As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. Results In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1β in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1β. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. Conclusions Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

scholarly journals A Walnut-Enriched Diet Modifies the Oxylipin Profile in Liver and Brain of Aged Mice — Impact on Inflammation Markers

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1203-1203
Author(s):  
Gunter Eckert ◽  
Gunter Esselun ◽  
Elisabeth Koch ◽  
Nils Schebb
Keyword(s):  
Physical Activity ◽  
Fatty Acids ◽  
Brain Aging ◽  
Inflammatory Marker ◽  
Inflammation Markers ◽  
Aged Mice ◽  
Funding Sources ◽  
Age Related ◽  
The Brain ◽  
Related Increase

Abstract Objectives Neuroinflammation contributes to brain-aging which may be mitigated by anti-inflammatory oxylipins. Based on our previous findings that a 6% walnut-enriched diet alone, and additional physical activity (PA), enhanced cognition in 18 months old NMRI, we now investigated the effects of this diet on oxylipin- and inflammatory marker levels in liver and brain. Methods 18 months and 3 months old female NMRI mice were fed with a 6% walnut-enriched diet. Oxylipins were determined in brain and liver sections using LC-MS. Expression of IL1β gene was determined by qRT-PCR. Results The walnut diet compensates for the age related increase in IL1β gene expression in the liver of mice, whereas expression in the brain was not affected. Basal levels of oxylipins in brain and liver samples isolated from young mice were generally lower compared to aged mice. The walnut diet further increased oxylipin levels of walnut specific fatty acids in liver and brain of aged mice. Enrichment of linoleic acid (LA) and α-linolenic acid (ALA) derived oxylipin levels were quantitatively higher in the liver compared to the brain (P < 0.0001). Hydroxy-oxylipins (HO) based on fatty acid LA were significantly increased in brain (P < 0.001) and liver (P < 0.0001) compared to control mice, while ALA based HO were only detected in the brains of walnut fed mice. The walnut diet in combination with physical activity (PA) reduced ARA based oxylipin levels (P < 0.05). Across all groups, concentrations of prostanoids were higher in the brain as compared to liver (P < 0.001). In the liver, walnuts tended to decrease PGD2 and TxB2 levels while increasing 6-keto PGF1α. The latter, as well as TxB2 tended to be decreased in the brain. Other ARA based prostanoids were unaffected. Effects of PA were contrary to each other, tending to increase ARA based prostanoids in the liver while decreasing them in the brain. PA further enhanced this effect in the brain, but tended to increase the inflammatory response in the liver. Conclusions A walnut diet differentially affects the oxylipin profile of liver and brain in aged mice. Production of oxylipins based on walnut fatty acids is generally increased. Attenuation of age-related, chronic inflammation in might be one of walnut's benefits and may contribute to a healthier aging of the brain. Funding Sources Research was supported by grants from California Walnut Commission.

scholarly journals Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Gabriel Berdugo-Vega ◽  
Gonzalo Arias-Gil ◽  
Adrian López-Fernández ◽  
Benedetta Artegiani ◽  
Joanna M. Wasielewska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Learning Strategies ◽  
Inhibitory Effect ◽  
Cell Cycle Regulators ◽  
Contextual Memory ◽  
Age Related ◽  
Hippocampal Activity ◽  
Navigational Learning ◽  
The Brain

AbstractFunctional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain’s endogenous reserve of neural stem cells.

scholarly journals Age-Related Compensatory Reconfiguration of PFC Connections during Episodic Memory Retrieval

2020 ◽  
Author(s):  
Lifu Deng ◽  
Mathew L Stanley ◽  
Zachary A Monge ◽  
Erik A Wing ◽  
Benjamin R Geib ◽  
...  
Keyword(s):  
Episodic Memory ◽  
Memory Retrieval ◽  
Medial Temporal Lobe ◽  
Memory Performance ◽  
Functional Integration ◽  
Brain Network ◽  
Age Related ◽  
Connectivity Patterns ◽  
The Brain ◽  
Related Increase

Abstract During demanding cognitive tasks, older adults (OAs) frequently show greater prefrontal cortex (PFC) activity than younger adults (YAs). This age-related increase in PFC activity is often associated with enhanced cognitive performance, suggesting functional compensation. However, the brain is a complex network of interconnected regions, and it is unclear how network connectivity of PFC regions differs for OAs versus YAs. To investigate this, we examined the age-related difference on the functional brain networks mediating episodic memory retrieval. YAs and OAs participants encoded and recalled visual scenes, and age-related differences in network topology during memory retrieval were investigated as a function of memory performance. We measured both changes in functional integration and reconfiguration in connectivity patterns. The study yielded three main findings. First, PFC regions were more functionally integrated with the rest of the brain network in OAs. Critically, this age-related increase in PFC integration was associated with better retrieval performance. Second, PFC regions showed stronger performance-related reconfiguration of connectivity patterns in OAs. Finally, the PFC reconfiguration increases in OAs tracked reconfiguration reductions in the medial temporal lobe (MTL)—a core episodic memory region, suggesting that PFC connectivity in OAs may be compensating for MTL deficits.

scholarly journals Age-related increase in caveolin-1 expression facilitates cell-to-cell transmission of α-synuclein in neurons

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Tae-Young Ha ◽  
Yu Ree Choi ◽  
Hye Rin Noh ◽  
Seon-Heui Cha ◽  
Jae-Bong Kim ◽  
...  
Keyword(s):  
Risk Factor ◽  
Inclusion Bodies ◽  
Aging Process ◽  
Caveolin 1 ◽  
Age Related ◽  
Cell Transmission ◽  
Tyrosine 14 ◽  
The Relationship ◽  
The Brain ◽  
Related Increase

AbstractParkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

scholarly journals Curcumin Ameliorates the Cd-Induced Anxiety-like Behavior in Mice by Regulating Oxidative Stress and Neuro-Inflammatory Proteins in the Prefrontal Cortex Region of the Brain

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1710
Author(s):  
Dhondup Namgyal ◽  
Sher Ali ◽  
Muhammad Delwar Hussain ◽  
Mohsin Kazi ◽  
Ajaz Ahmad ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Working Memory ◽  
Prefrontal Cortex ◽  
Neurodegenerative Diseases ◽  
Spatial Working Memory ◽  
Cellular Mechanisms ◽  
Behavioral Impairment ◽  
Age Related ◽  
The Brain ◽  
And Oxidative Stress

Age-related neurodegenerative diseases and vascular dementia are major challenges to the modern health care system. Most neurodegenerative diseases are associated with impaired spatial working memory and anxiety-like behavior. Thus, it is important to understand the underlying cellular mechanisms of neurodegenerative diseases in different regions of the brain to develop an effective therapeutic approach. In our previous research paper, we have reported the ameliorative effect of curcumin in Cd-induced hippocampal neurodegeneration. However, recently many researchers had reported the important role of the prefrontal cortex in higher cognitive functions. Therefore, to look into the cellular mechanism of curcumin protection against Cd-induced prefrontal cortex neurotoxicity, we investigated spatial working memory, anxiety-like behavior and analyzed prefrontal cortex inflammatory markers (IL-6, IL-10, and TNFα), antioxidant enzymes (SOD, GSH, and CAT), and pro-oxidant MDA level. Further, we conducted histological studies of the prefrontal cortex in Swiss albino mice exposed to cadmium (2.5 mg/kg). We observed that curcumin treatment improved the spatial working memory and anxiety-like behavior of mice through reduction of prefrontal cortex neuroinflammation and oxidative stress as well as increasing the number of viable prefrontal cortex neuronal cells. Our result suggests that environmental heavy metal cadmium can induce behavioral impairment in mice through prefrontal cortex cellular inflammation and oxidative stress. We found that curcumin has a potential therapeutic property to mitigate these behavioral and biochemical impairments induced by cadmium.

scholarly journals Aging is associated with changes in allopregnanolone concentrations in brain, endocrine glands and serum in male rats

1998 ◽  
pp. 316-321 ◽  
Author(s):  
F Bernardi ◽  
C Salvestroni ◽  
E Casarosa ◽  
RE Nappi ◽  
A Lanzone ◽  
...  
Keyword(s):  
Brain Cortex ◽  
Steroid Hormone ◽  
Serum Testosterone ◽  
Male Rats ◽  
Endocrine Glands ◽  
Brain Areas ◽  
Age Related ◽  
Specific Radioimmunoassay ◽  
The Brain ◽  
Related Increase

OBJECTIVE: Allopregnanolone is a potent neuroactive steroid hormone produced in the brain and in peripheral endocrine glands. The present study investigated possible age-related variations in allopregnanolone content in brain areas, endocrine glands and serum of male rats. DESIGN: Wistar male rats were categorized into 5 groups (6 rats in each) according to age: 6, 12, 16, 18 and 20 months respectively. METHODS: Allopregnanolone content in acidic homogenates of brain cortex, hypothalamus, pituitary, adrenals and gonads was measured by a specific radioimmunoassay. Serum allopregnanolone, corticosterone and testosterone were also assayed by radioimmunoassay. RESULTS: Brain cortex allopregnanolone content decreased significantly with age, while hypothalamic allopregnanolone content remained constant until 18 months and increased significantly at 20 months. Pituitary content showed a significant age-related reduction. Adrenal allopregnanolone content remained constant until 18 months, and was significantly higher at 20 months. Testis and serum allopregnanolone contents showed significant age-related increases. Serum testosterone levels showed an age-related decrease, while no age-related variation in serum corticosterone was found. CONCLUSIONS: The present study showed a significant impact of aging on allopregnanolone contents in brain, endocrine glands and serum, showing an age-related decrease in brain cortex and pituitary, and an age-related increase in testes, adrenals and serum.

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