A shared neural ensemble links distinct contextual memories encoded close in time.

Evaluation of Systemic Follistatin as an Adjuvant to Stimulate Muscle Repair and Improve Motor Function in Pompe Mice

Disruption of ClC-2 expression is associated with progressive neurodegeneration in aging mice

Sjögren’s Syndrome-Like Ocular Surface Disease in Thrombospondin-1 Deficient Mice

Previous studies in mice have reported a decrease in epidermal Langerhans cell (LC) density in aged skin, however, the impact of this reduction on LC function and cutaneous immune responses is unclear. In the present series of experiments, the frequency of major histocompatibility complex class II+ LC in the epidermis of older (6-month-old) mice was found to be reduced significantly compared with that observed for young (6-8-week-old) mice. LC mobilization and the subsequent accumulation of dendritic cells (DC) in regional lymph nodes in response to topical challenge with a chemical allergen were found to be less vigorous in older mice. Flow cytometric analyses of DC derived from the draining lymph nodes of fluorescein isothiocyanate (FITC)-sensitized mice revealed that the frequency of FITC+-DC arriving in draining lymph nodes was also reduced in older mice but that the fluorescence intensity was comparable. Control and allergen-treated-older mice also displayed decreased total lymph node cellularity. Contact hypersensitivity responses were found not to be compromised in older mice. However, the cytokine regulation of LC migration in the two age groups of mice did differ. LC migration provoked by intradermal injection of tumour necrosis factor-alpha (TNF-alpha) was reduced in older animals, whereas, the percentage of LC that migrated in response to exogenous interleukin-1beta (IL-1beta) was comparable for both young and aged mice. Since both allergen- and TNF-alpha-induced LC responses are known to require receipt by LC of a signal from IL-1beta for effective migration, the suggestion is that impaired LC migration in older mice may be due to a reduced availability of epidermal IL-1beta.

The central nucleus of the amygdala (CeA) is a key brain region involved in emotional and stressor responses due to its many projections to autonomic regulatory centers. It is also a primary site of action from ethanol consumption. However, the influence of active metabolites of ethanol such as acetate on the CeA neural circuitry has yet to be elucidated. Here, we investigated the effect of acetate on CeA neurons with the axon projecting to the rostral ventrolateral medulla (CeA-RVLM), as well as quantified cytosolic calcium responses in primary neuronal cultures. Whole-cell patch-clamp recordings in brain slices containing autonomic CeA-RVLM neurons revealed a dose-dependent increase in neuronal excitability in response to acetate. N-Methyl-d-aspartate receptor (NMDAR) antagonists suppressed the acetate-induced increase in CeA-RVLM neuronal excitability and memantine suppressed the direct activation of NMDAR-dependent inward currents by acetate in brain slices. We observed that acetate increased cytosolic Ca2+ in a time-dependent manner in primary neuronal cell cultures. The acetate enhancement of calcium signaling was abolished by memantine. Computational modeling of acetic acid at NMDAR/NR1 glutamatergic and glycinergic sites suggests potential active site interactions. These findings suggest that within the CeA, acetate is excitatory at least partially through activation of NMDAR, which may underlie the impact of ethanol consumption on autonomic circuitry.

In long-lived organisms, cells in many tissues are replaced from a population of stem or progenitor cells that retain the capacity to proliferate. The ability of these cells to proliferate decreases with age, which may be linked to a reduced capacity to repair or regenerate tissue. Three studies, focused on three different tissues, investigated the role of the cyclin-dependent kinase inhibitor p16 INK4a , the abundance of which increases in some cell types with age, in this loss of proliferative and regenerative capacity. Janzen et al . found that p16 INK4a mRNA expression increased in the bone marrow-derived hematopoietic stem cells (HSCs) of older mice. Older mice that lacked p16 INK4a had more HSCs than did older wild-type mice, and the ability of HSCs from older mice lacking p16 INK4a to reconstitute the immune system through bone marrow transplants was superior to that of HSCs from older wild-type mice. Expression of the Notch effector Hes1, which has been implicated in regulating HSC cycling and preserving their function, was enhanced in HSCs from mice lacking p16 INK4a and decreased in HSCs from mice overexpressing p16 INK4a . Molofsky et al . investigated the role of p16 INK4a in neural progenitor cell proliferation in the subventricular zone (SVZ) and olfactory bulb neurogenesis in aging mice. They found an increase in SVZ p16 INK4a mRNA expression with aging and observed an age-related decrease in SVZ proliferation, in the number of SVZ cells that could form multipotent colonies in culture, and in olfactory bulb neurogenesis. In older mice lacking p16 INK4a , the decreases in SVZ proliferation and olfactory bulb neurogenesis were attenuated and the decline in colony-forming cells was abolished (suggesting an effect on stem cells rather than downstream progenitor cells). However, p16 INK4a did not appear to affect progenitor cell function or neurogenesis in the dentate gyrus or in the enteric nervous system. Krishnamurthy et al . showed that p16 INK4a mRNA expression increased with age in mouse pancreatic islet cells. Transgenic mice with an additional copy of the p16 INK4a gene (in which young mice expressed p16 INK4a to an extent comparable to that of old wild-type mice) showed a reduction in islet proliferation, whereas an age-related decrease in proliferation seen in wild-type mice was profoundly attenuated in mice lacking p16 INK4a . Islet regeneration and the ability of mice to survive treatment with streptozotocin, a β cell toxin, decreased with age; both islet proliferation after streptozotocin treatment and survival were enhanced in older mice lacking p16 INK4a . Thus, in at least some tissues, p16 INK4a appears to play a role in aging-related loss of progenitor cell proliferation and regenerative capacity. Beausejour and Campisi discuss the research in the context of the role of stem cell proliferation in both regeneration and susceptibility to cancer, noting that p16 INK4a is a tumor suppressor and that mice lacking it are prone to tumor formation. V. Janzen, R. Forkert, H. E. Fleming, Y. Saito, M. T. Waring, D. M. Dombkowski, T. Cheng, R. A. DePinho, N. E. Sharpless, D. T. Scadden, Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 INK4a . Nature 443 , 421-426 (2006). [PubMed] J. Krishnamurthy, M. R. Ramsey, K. L. Ligon, C. Torrice, A. Koh, S. Bonner-Weir, N. E. Sharpless, p16 INK4a induces an age-dependent decline in islet regenerative potential. Nature 443 , 453-457 (2006). [PubMed] A. V. Molofsky, S. G. Slutsky , N. M. Joseph, S. He, R. Pardal, J. Krishnamurthy, N. E. Sharpless, S. J. Morrison, Increasing p16 INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443 , 448-452 (2006). [PubMed] C. M. Beausejour, J. Campisi, Balancing regeneration and cancer. Nature 443 , 404-405 (2006). [PubMed]

Background Increasing age was shown to decrease the requirements for propfol. However, the mechanisms of ageinginduced potentiation of anesthetic actions have not been clearly explored. The aim of this study is to compare the effects of propofol on the field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices of young and aging mice. Methods Brain slices were prepared from C57BL6 male young (2 months) and aging (>12 months) mice. The dendritic field excitatory postsynaptic potential was recorded from the CA1 stratum radiatum using patch clamp electrophysiological methods. A bipolar concentric stimulating electrode was placed along the Schaffer collateral for othodromic stimulation. The effects of clinically-relevant concentrations of propofol were studied in the young and ageing mouse tissues. Results Propofol application increased the orthodromically evoked fEPSP produced in slices taken from young and older animals. A striking feature in the I/O relationship was the decreased enhancement of the fEPSPs by propofol in slices from older mice. A clinically relevant concentration of propofol, 10 μmol/L, showed more significant enhancement in amplitude and area under the curve (AUC) of fEPSP in young compared to tissues from older mice (amplitude: young (24.9±3.4)%, old (4.6±1.6)%; AUC young (30.6±5.4)%, old (2.1±1.7)%). There was no statistically significant difference between the paired-pulse facilitation (PPF) ratios calculated for the responses obtained in tissues from young mice. In slices from older mice, in the presence of 10 μmol/L propofol, PPF was decreased and returned to baseline after washout (baseline 1.21±0.01, propofol: 1.16±0.01). Bicuculline (15 μmol/L) blocked the enhancement of propofol on fEPSP in tissues from young and old mice. Conclusion The fEPSP of slices from aging mice demonstrates diminished sensitivity to the enhancing actions of propofol.

We tested the hypothesis that daily melatonin treatment protects endothelial lineage and functional integrity against the aging process, oxidative stress/endothelial denudation (ED), and toxic environment and restored blood flow in murine critical limb ischemia (CLI). In vitro study using HUVECs, in vivo models (ie, CLI through left femoral artery ligation and ED through carotid artery wire injury), and model of lipopolysaccharide-induced aortic injury in young (3months old) and aged (8months old) mice were used to elucidate effects of melatonin treatment on vascular endothelial integrity. In vitro study showed that menadione-induced oxidative stress (NOX-1/NOX-2), inflammation (TNF-α/NF-kB), apoptosis (cleaved caspase-3/PARP), and mitochondrial damage (cytosolic cytochrome c) in HUVECs were suppressed by melatonin but reversed by SIRT3-siRNA (all P<.001). In vivo, reduced numbers of circulating endothelial progenitor cells (EPCs) (C-kit/CD31+/Sca-1/KDR+/CXCR4/CD34+), and angiogenesis (Matrigel assay of bone marrow-derived EPC and ex vivo aortic ring cultures) in older (compared with younger) mice were significantly reversed through daily melatonin administration (20mg/kg/d, ip) (all P<.001). Aortic vasorelaxation and nitric oxide release were impaired in older mice and reversed in age-match mice receiving melatonin (all P<.01). ED-induced intimal/medial hyperplasia, reduced blood flow to ischemic limb, and angiogenesis (reduced CD31+/vWF+ cells/small vessel number) were improved after daily melatonin treatment (all P<.0001). Lipopolysaccharide-induced aortic endothelial cell detachment, which was more severe in aged mice, was also alleviated after daily melatonin treatment (P<.0001). Daily melatonin treatment protected both structural and functional integrity of vascular endothelium against aging-, oxidative stress-, lipopolysaccharide-, and ischemia-induced damage probably through upregulating the SIRT signaling pathway.

Pulmonary effects of inhaled diesel exhaust in aged mice

Susceptibility of DNA to oxidative stressors in young and aging mice

In the brain, groups of neurons that are activated together – also known as neuronal ensembles – are the basic units that underpin perception and behavior. Yet, exactly how these coactive circuits are established remains under investigation. In 1949, Canadian psychologist Donald Hebb proposed that, when brains learn something new, the neurons which are activated together connect to form ensembles, and their connections become stronger each time this specific piece of knowledge is recalled. This idea that ‘neurons that fire together, wire together’ can explain how memories are acquired and recalled, by strengthening their wiring. However, recent studies have questioned whether strengthening connections is the only mechanism by which neural ensembles can be created. Changes in the excitability of neurons (how easily they are to fire and become activated) may also play a role. In other words, ensembles could emerge because certain neurons become more excitable and fire more readily. To solve this conundrum, Alejandre-García et al. examined both hypotheses in the same system. Neurons in slices of the mouse visual cortex were stimulated electrically or optically, via a technique that controls neural activity with light. The activity of individual neurons and their connections was then measured with electrodes. Spontaneous activity among connected neurons increased after stimulation, indicative of the formation of neuronal ensembles. Connected neurons also showed small changes in the strength of their connections, which first decreased and then rebounded after an initial recovery period. Intriguingly, cells also showed unexpected strong and persistent increases in neuronal excitability after stimulation, such that neurons fired more readily to the same stimulus. In other words, neurons maintained a cellular memory of having been stimulated. The authors conclude that ensembles form because connected neurons become more excitable, which in turn, may strengthen connections of the circuit at a later stage. These results provide fresh insights about the neural circuits underpinning learning and memory. In time, the findings could also help to understand disorders such as Alzheimer’s disease and schizophrenia, which are characterised by memory impairments and disordered thinking.

In the brain, groups of neurons that are activated together – also known as neuronal ensembles – are the basic units that underpin perception and behavior. Yet, exactly how these coactive circuits are established remains under investigation. In 1949, Canadian psychologist Donald Hebb proposed that, when brains learn something new, the neurons which are activated together connect to form ensembles, and their connections become stronger each time this specific piece of knowledge is recalled. This idea that ‘neurons that fire together, wire together’ can explain how memories are acquired and recalled, by strengthening their wiring. However, recent studies have questioned whether strengthening connections is the only mechanism by which neural ensembles can be created. Changes in the excitability of neurons (how easily they are to fire and become activated) may also play a role. In other words, ensembles could emerge because certain neurons become more excitable and fire more readily. To solve this conundrum, Alejandre-García et al. examined both hypotheses in the same system. Neurons in slices of the mouse visual cortex were stimulated electrically or optically, via a technique that controls neural activity with light. The activity of individual neurons and their connections was then measured with electrodes. Spontaneous activity among connected neurons increased after stimulation, indicative of the formation of neuronal ensembles. Connected neurons also showed small changes in the strength of their connections, which first decreased and then rebounded after an initial recovery period. Intriguingly, cells also showed unexpected strong and persistent increases in neuronal excitability after stimulation, such that neurons fired more readily to the same stimulus. In other words, neurons maintained a cellular memory of having been stimulated. The authors conclude that ensembles form because connected neurons become more excitable, which in turn, may strengthen connections of the circuit at a later stage. These results provide fresh insights about the neural circuits underpinning learning and memory. In time, the findings could also help to understand disorders such as Alzheimer’s disease and schizophrenia, which are characterised by memory impairments and disordered thinking.

Epilepsy is a significant long-term consequence of traumatic brain injury (TBI) and is likely to result from multiple mechanisms. One feature that is common to many forms of TBI is denervation. We asked whether chronic partial denervation in vivo would lead to a homeostatic increase in the excitability of a denervated cell population. To answer this question, we took advantage of the unique anatomy of the hippocampus where the input to the CA1 neurons, the Schaffer collaterals, could be transected in vivo with preservation of their outputs and only minor cell death. We observed a delayed increase in neuronal excitability, as apparent in extracellular recordings from hippocampal brain slices prepared 14 days (but not 3 days) post lesion. Although population spikes in slices from control and lesioned animals were comparable under resting conditions, application of solutions that were mildly proconvulsive (high K(+) , low Mg(2+) , low concentrations of bicuculline) produced increases in the number of population spikes in slices from lesioned rats, but not in slices from unlesioned sham controls. Denervation did not produce changes in several markers of γ-aminobutyric acid (GABA)ergic synaptic inhibition, including the number of GABAergic neurons, α1 GABA(A) receptor subunits, the vesicular GABA transporter, or miniature inhibitory postsynaptic currents. We conclude that chronic partial denervation does lead to a delayed homeostatic increase in neuronal excitability, and may, therefore, contribute to the long-term neurologic consequences of TBI.

3-methylcholanthrene induces differential inhibition of humoral and cell mediated immune responses in mice of different ages

Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-beta (Abeta) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Abeta pathology. We describe improved cognitive function following a reduction in both soluble Abeta and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Abeta alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Abeta immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice.