Egr1 Expression Is Correlated With Synaptic Activity but Not Intrinsic Membrane Properties in Mouse Adult-Born Dentate Granule Cells.

The discovery of adult-born granule cells (aDGCs) in the dentate gyrus of the hippocampus has raised questions regarding how they develop, incorporate into the hippocampal circuitry, and contribute to learning and memory. Here, we used patch-clamp electrophysiology to investigate the intrinsic and synaptic excitability of mouse aDGCs as they matured, enabled by using a tamoxifen-induced genetic label to birth date the aDGCs at different animal ages. Importantly, we also undertook immunofluorescence studies of the expression of the immediate early gene Egr1 and compared these findings with the electrophysiology data in the same animals. We examined two groups of animals, with aDGC birthdating when the mice were 2 months and at 7-9 months of age. In both groups, cells 4 weeks old had lower thresholds for current-evoked action potentials than older cells but fired fewer spikes during long current pulses and responded more poorly to synaptic activation. aDGCs born in both 2 and 7-9-month-old mice matured in their intrinsic excitability and synaptic properties from 4-12 weeks postgenesis, but this occurred more slowly for the older age animals. Interestingly, this pattern of intrinsic excitability changes did not correlate with the pattern of Egr1 expression. Instead, the development of Egr1 expression was correlated with the frequency of spontaneous excitatory postsynaptic currents. These results suggest that in order for aDGCs to fully participate in hippocampal circuitry, as indicated by Egr1 expression, they must have developed enough synaptic input, in spite of the greater input resistance and reduced firing threshold that characterizes young aDGCs.

Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Fasting for 20 h does not affect exercise-induced increases in circulating BDNF in humans.

Intermittent fasting and exercise provide neuroprotection from age-related cognitive decline. A link between these two seemingly distinct stressors is their capability to steer the brain away from exclusively glucose metabolism. This cerebral substrate switch has been implicated in upregulating brain-derived neurotrophic factor (BDNF), a protein involved in neuroplasticity, learning and memory, and may underlie some of these neuroprotective effects. We examined the isolated and interactive effects of (1) 20-h fasting, (2) 90-min light exercise, and (3) high-intensity exercise on peripheral venous BDNF in 12 human volunteers. A follow-up study isolated the influence of cerebrovascular shear stress on circulating BDNF. Fasting for 20 h decreased glucose and increased ketones (P ≤ 0.0157) but had no effect on BDNF (P ≥ 0.4637). Light cycling at 25% of peak oxygen uptake ( V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ ) increased serum BDNF by 6 ± 8% (independent of being fed or fasted) and was mediated by a 7 ± 6% increase in platelets (P < 0.0001). Plasma BDNF was increased from 336 pg l-1 [46,626] to 390 pg l-1 [127,653] by 90-min of light cycling (P = 0.0128). Six 40-s intervals at 100% of V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ increased plasma and serum BDNF, as well as the BDNF-per-platelet ratio 4- to 5-fold more than light exercise did (P ≤ 0.0044). Plasma BDNF was correlated with circulating lactate during the high-intensity intervals (r = 0.47, P = 0.0057), but not during light exercise (P = 0.7407). Changes in cerebral shear stress - whether occurring naturally during exercise or induced experimentally with inspired CO2 - did not correspond with changes in BDNF (P ≥ 0.2730). BDNF responses to low-intensity exercise are mediated by increased circulating platelets, and increasing either exercise duration or particularly intensity is required to liberate free BDNF. KEY POINTS: Intermittent fasting and exercise both have potent neuroprotective effects and an acute upregulation of brain-derived neurotrophic factor (BDNF) appears to be a common mechanistic link. Switching the brain's fuel source from glucose to either ketone bodies or lactate, i.e. a cerebral substrate switch, has been shown to promote BDNF production in the rodent brain. Fasting for 20 h caused a 9-fold increase in ketone body delivery to the brain but had no effect on any metric of BDNF in peripheral circulation at rest. Prolonged (90 min) light cycling exercise increased plasma- and serum-derived BDNF irrespective of being fed or fasted and seemed to be independent of changes in cerebral shear stress. Six minutes of high-intensity cycling intervals increased every metric of circulating BDNF by 4 to 5 times more than prolonged low-intensity cycling; the increase in plasma-derived BDNF was correlated with a 6-fold increase in circulating lactate irrespective of feeding or fasting. Compared to 1 day of fasting with or without prolonged light exercise, high-intensity exercise is a much more efficient means to increase BDNF in circulation.

Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1ΔE9 Mouse Model of Alzheimer's Disease.

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer's disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aß). APPswe/PSdE1 (APP/PS1) mice display age-related Aß accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS+/- mice by crossing complete eNOS deficient (eNOS-/-) mice and APP/PS1 mice. APP/PS1/eNOS+/- mice at 8 months of age displayed a more severe spatial working memory deficit relative to age-matched APP/PS1 mice. Moreover, immunohistochemistry and immunoblotting revealed significantly increased Aß plaque load in the brains of APP/PS1/eNOS+/- mice, concomitant with upregulated BACE-1 (hence increased Aß production), downregulated insulin-degrading enzyme (hence reduced Aß clearance) and increased immunoreactivity and expression of microglia. The present study, for the first time, demonstrated that partial eNOS deficiency exacerbated behavioral dysfunction, Aß brain deposition, and microglial pathology in APP/PS1 mice, further implicating endothelial dysfunction in the pathogenesis of AD. The present findings also provide the scientific basis for developing preventive and/or therapeutic strategies by targeting endothelial dysfunction.

Postsynaptic cell firing triggers bidirectional metaplasticity depending on the LTP induction protocol.

Cell firing has been reported to variably upregulate or downregulate subsequently induced long-term potentiation (LTP). The aim of this study was to elucidate the parameters critical to driving each direction of the metaplasticity effect. The main focus was on the commonly used θ-burst stimulation (TBS) and high-frequency stimulation (HFS) protocols that are known to trigger distinct intracellular signaling cascades. To study action potential (AP)-induced metaplasticity, we used intracellular recordings from CA1 pyramidal cells of rat hippocampal slices. Somatic current injections were used to induce θ-burst firing (TBF) or high-frequency firing (HFF) for priming purposes, whereas LTP was induced 15 min later via TBS of Schaffer collaterals in stratum radiatum. TBS-LTP was inhibited by both priming protocols. Conversely, HFS-LTP was facilitated by HFF priming but not affected by TBF priming. Interestingly, both priming protocols reduced AP firing during TBS-LTP induction, and this effect correlated with the reduction of TBS-LTP. However, LTP was not rescued by restoring AP firing with somatic current injections during the TBS. Analysis of intrinsic properties revealed few changes, apart from a priming-induced increase in the medium afterhyperpolarization (HFF priming) and a decrease in the EPSP amplitude/slope ratio (TBF priming), which could in principle contribute to the inhibition of TBS-LTP by reducing depolarization and associated Ca2+ influx following synaptic activity or AP backpropagation. Overall, these data indicate that the more physiological TBS protocol for inducing LTP is particularly susceptible to homeostatic feedback inhibition by prior bouts of postsynaptic cell firing.NEW & NOTEWORTHY The induction of LTP in the hippocampus was bidirectionally regulated by prior postsynaptic cell firing, with θ-burst stimulation-induced LTP being consistently impaired by prior spiking, whereas high-frequency stimulation-induced LTP was either not changed or facilitated. Reductions in cell firing during LTP induction did not explain the LTP impairment. Overall, different patterns of postsynaptic firing induce distinct intracellular changes that can increase or decrease LTP depending on the induction protocol.

Bilateral histone deacetylase 1 and 2 activity and enrichment at unique genes following induction of long-term potentiation in vivo.

Long-term potentiation (LTP) is a synaptic plasticity mechanism critical to long-term memory. LTP induced in vivo is characterized by altered transcriptional activity, including a period of upregulation of gene expression which is followed by a later dominant downregulation. This temporal shift to downregulated gene expression is predicted to be partly mediated by epigenetic inhibitors of gene expression, such as histone deacetylases (HDACs). Further, pharmacological inhibitors of HDAC activity have previously been shown to enhance LTP persistence in vitro. To explore the contribution of HDACs to the persistence of LTP in vivo, we examined HDAC1 and HDAC2 activity over a 24 hr period following unilateral LTP induction in the dentate gyrus of freely moving rats. Surprisingly, we found significant changes in HDAC1 and HDAC2 activity in both the stimulated as well as the unstimulated hemispheres, with the largest increase in activity occurring bilaterally, 20 min after LTP stimulation. During this time point of heightened activity, chromatin immunoprecipitation assays showed that both HDAC1 and HDAC2 were enriched at distinct sets of genes within each hemispheres. Further, the HDAC inhibitor Trichostatin A enhanced an intermediate phase of LTP lasting days, which has not previously been associated with altered transcription. The inhibitor had no effect on the persistence of LTP lasting weeks. Together, these data suggest that HDAC activity early after the induction of LTP may negatively regulate plasticity-related gene expression that is involved in the initial stabilization of LTP, but not its long-term maintenance.

Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

Tumor Necrosis Factor-α-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model.

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1ß (IL-1ß), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1ß levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1ß antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.

Glutamate Receptor Trafficking and Protein Synthesis Mediate the Facilitation of LTP by Secreted Amyloid Precursor Protein-Alpha.

Secreted amyloid precursor protein-alpha (sAPPα) has growth factor-like properties and can modulate long-term potentiation (LTP) and memory. Here, we demonstrate that exposure to sAPPα converts short-lasting LTP into protein-synthesis-dependent late LTP in hippocampal slices from male rats. sAPPß had no discernable effect. We hypothesized that sAPPα facilitated LTP via regulated glutamate receptor trafficking and de novo protein synthesis. We found using a linear mixed model that sAPPα stimulated trafficking of GluA2-lacking AMPARs, as well as NMDARs to the extrasynaptic cell surface, in a calcium/calmodulin-dependent kinase II and protein kinase G-dependent manner. Both cell surface receptor accumulation and LTP facilitation were present even after sAPPα washout and inhibition of receptor trafficking or protein synthesis prevented all these effects. Direct visualization of newly synthesized proteins (FUNCAT-PLA) confirmed the ability of sAPPα to stimulate de novo protein synthesis and revealed GluA1 as one of the upregulated proteins. Therefore, sAPPα generates a coordinated synthesis and trafficking of glutamate receptors to the cell surface that facilitate LTP.SIGNIFICANCE STATEMENT Secreted amyloid precursor protein-alpha (sAPPα) is a neurotrophic and neuroprotective protein that can promote synaptic plasticity and memory, yet the molecular mechanisms underlying these effects are still not well understood. Here, we show that sAPPα facilitates long-term potentiation (LTP) in a concentration-dependent fashion through cellular processes involving de novo protein synthesis and trafficking of both GluA2-lacking AMPARs and NMDARs to the extrasynaptic cell surface. sAPPα also enhances GluA1, but not GluA2, synthesis. The trafficking effects, along with the LTP facilitation, persist after sAPPα washout, revealing a metaplastic capability of exogenous sAPPα administration. sAPPα thus facilitates LTP through coordinated activation of protein synthesis and trafficking of glutamate receptors to the cell surface, where they are positioned for priming LTP.

Association of Childhood Lead Exposure With MRI Measurements of Structural Brain Integrity in Midlife.

Importance: Childhood lead exposure has been linked to disrupted brain development, but long-term consequences for structural brain integrity are unknown. Objective: To test the hypothesis that childhood lead exposure is associated with magnetic resonance imaging (MRI) measurements of lower structural integrity of the brain in midlife. Design, Setting, and Participants: The Dunedin Study followed a population-representative 1972-1973 birth cohort in New Zealand (N = 564 analytic sample) to age 45 years (until April 2019). Exposures: Childhood blood lead levels measured at age 11 years. Main Outcomes and Measures: Structural brain integrity at age 45 years assessed via MRI (primary outcomes): gray matter (cortical thickness, surface area, hippocampal volume), white matter (white matter hyperintensities, fractional anisotropy [theoretical range, 0 {diffusion is perfectly isotropic} to 100 {diffusion is perfectly anisotropic}]), and the Brain Age Gap Estimation (BrainAGE), a composite index of the gap between chronological age and a machine learning algorithm-estimated brain age (0 indicates a brain age equivalent to chronological age; positive and negative values represent an older and younger brain age, respectively). Cognitive function at age 45 years was assessed objectively via the Wechsler Adult Intelligence Scale IV (IQ range, 40-160, standardized to a mean of 100 [SD, 15]) and subjectively via informant and self-reports (z-score units; scale mean, 0 [SD, 1]). Results: Of 1037 original participants, 997 were alive at age 45 years, of whom 564 (57%) had received lead testing at age 11 years (302 [54%] male) (median follow-up, 34 [interquartile range, 33.7-34.7] years). Mean blood lead level at age 11 years was 10.99 (SD, 4.63) µg/dL. After adjusting for covariates, each 5-µg/dL higher childhood blood lead level was significantly associated with 1.19-cm2 smaller cortical surface area (95% CI, -2.35 to -0.02 cm2; P = .05), 0.10-cm3 smaller hippocampal volume (95% CI, -0.17 to -0.03 cm3; P = .006), lower global fractional anisotropy (b = -0.12; 95% CI, -0.24 to -0.01; P = .04), and a BrainAGE index 0.77 years older (95% CI, 0.02-1.51 years; P = .05) at age 45 years. There were no statistically significant associations between blood lead level and log-transformed white matter hyperintensity volume (b = 0.05 log mm3; 95% CI, -0.02 to 0.13 log mm3; P = .17) or mean cortical thickness (b = -0.004 mm; 95% CI, -0.012 to 0.004 mm; P = .39). Each 5-µg/dL higher childhood blood lead level was significantly associated with a 2.07-point lower IQ score at age 45 years (95% CI, -3.39 to -0.74; P = .002) and a 0.12-point higher score on informant-rated cognitive problems (95% CI, 0.01-0.23; P = .03). There was no statistically significant association between childhood blood lead levels and self-reported cognitive problems (b = -0.02 points; 95% CI, -0.10 to 0.07; P = .68). Conclusions and Relevance: In this longitudinal cohort study with a median 34-year follow-up, higher childhood blood lead level was associated with differences in some MRI measures of brain structure that suggested lower structural brain integrity in midlife. Because of the large number of statistical comparisons, some findings may represent type I error.

Environmental enrichment increases prefrontal EEG power and synchrony with the hippocampus in rats with anterior thalamus lesions.

The anterior thalamic nuclei (ATN) are a major interface between the hippocampus and prefrontal cortex within an extended Papez circuit. Rat models suggest that the deficits caused by ATN damage, which is associated with "diencephalic amnesia", can be ameliorated by environmental enrichment (EE) through unknown mechanisms. We examined whether changes in theta rhythmicity within and between the hippocampus and prefrontal cortex are influenced by EE in rats with ATN lesions. Here, we show that ATN lesions and EE produced essentially opposed functional effects in terms of changes in rhythmicity between two consecutive trials when rats forage for chocolate hail. On the second trial, standard-housed rats with ATN lesions showed: (a) a clear reduction in prefrontal cortex experience-dependent power change in the theta band and in two adjacent bands; (b) little change in the theta band in hippocampal area CA1; and (c) only a modest overall reduction in experience-dependent power change at lower theta frequencies in the dentate gyrus. EE exposure prevented the decrease in prefrontal theta power in rats with ATN lesions, and in fact caused a clear increase in prefrontal cortex power across all bands. While ATN lesions did not reliably affect prefrontal-CA1 or prefrontal-dentate theta coherence, EE increased the coherence between prefrontal cortex and area CA1 in both the sham and ATN groups. Thus, EE increases functional connectivity between prefrontal cortex and hippocampus via pathways that bypass the ATN, and increases behaviorally dependent prefrontal rhythmicity. These EEG effects may contribute to improved learning and memory in the ATN-lesion model of diencephalic amnesia.

Exposure to complex environments results in more sparse representations of space in the hippocampus.

The neural circuitry mediating sensory and motor representations is adaptively tuned by an animal's interaction with its environment. Similarly, higher order representations such as spatial memories can be modified by exposure to a complex environment (CE), but in this case the changes in brain circuitry that mediate the effect are less well understood. Here, we show that prolonged CE exposure was associated with increased selectivity of CA1 "place cells" to a particular recording arena compared to a social control (SC) group. Furthermore, fewer CA1 and DG neurons in the CE group expressed high levels of Arc protein, a marker of recent activation, following brief exposure to a completely novel environment. The reduced Arc expression was not attributable to overall changes in cell density or number. These data indicate that one effect of CE exposure is to modify high-level spatial representations in the brain by increasing the sparsity of population coding within networks of neurons. Greater sparsity could result in a more efficient and compact coding system that might alter behavioural performance on spatial tasks. The results from a behavioural experiment were consistent with this hypothesis, as CE-treated animals habituated more rapidly to a novel environment despite showing equivalent initial responding.

Waitlist Outcomes of Liver Transplant Candidates Who Were Reprioritized Under Share 35.

Under Share 35, deceased donor (DD) livers are offered regionally to candidates with Model for End-Stage Liver Disease (MELD) scores ≥35 before being offered locally to candidates with MELD scores <35. Using Scientific Registry of Transplant Recipients data from June 2013 to June 2015, we identified 1768 DD livers exported to regional candidates with MELD scores ≥35 who were transplanted at a median MELD score of 39 (interquartile range [IQR] 37-40) with 30-day posttransplant survival of 96%. In total, 1764 (99.8%) exports had an ABO-compatible candidate in the recovering organ procurement organization (OPO), representing 1219 unique reprioritized candidates who would have had priority over the regional candidate under pre-Share 35 allocation. Reprioritized candidates had a median waitlist MELD score of 31 (IQR 27-34) when the liver was exported. Overall, 291 (24%) reprioritized candidates had a comparable MELD score (within 3 points of the regional recipient), and 209 (72%) were eventually transplanted in 11 days (IQR 3-38 days) using a local (50%), regional (50%) or national (<1%) liver; 60 (21%) died, 13 (4.5%) remained on the waitlist and nine (3.1%) were removed for other reasons. Of those eventually transplanted, MELD score did not increase in 57%; it increased by 1-3 points in 37% and by ≥4 points in 5.7% after the export. In three cases, OPOs exchanged regional exports within a 24-h window. The majority of comparable reprioritized candidates were not disadvantaged; however, 21% died after an export.

Secreted amyloid precursor protein-alpha can restore novel object location memory and hippocampal LTP in aged rats.

Secreted amyloid precursor protein-α (sAPPα) is a neurotrophic and neuroprotective molecule which can enhance learning and synaptic plasticity. Aging is associated with memory decline and impaired long-term potentiation (LTP). SAPPα therefore has potential as a nootropic agent which could be used to offset age-related cognitive decline. In this study we investigated the effects of sAPPα on spatial memory tasks and LTP in aged and young Long-Evans rats. Two hippocampus-dependent tasks were employed to measure spatial memory that is susceptible to impairments during aging. Aged rats showed a mild deficit in the novel object location task, but memory was significantly enhanced by bilateral intrahippocampal injections of sAPPα. There was no effect on the performance of young animals. In the watermaze task, however, sAPPα did not alleviate age-related decline in spatial memory. In subsequent electrophysiological experiments, LTP was impaired in slices from aged animals, but plasticity was rescued in a concentration-dependent manner by exogenous sAPPα administration. In contrast, LTP was impaired in young animals by sAPPα. Overall, these data support the hypothesis that sAPPα has therapeutic potential as a treatment for age-related cognitive decline.

Astrocytes and synaptic plasticity in health and disease.

Activity-dependent synaptic plasticity phenomena such as long-term potentiation and long-term depression are candidate mechanisms for storing information in the brain. Regulation of synaptic plasticity is critical for healthy cognition and learning and this is provided in part by metaplasticity, which can act to maintain synaptic transmission within a dynamic range and potentially prevent excitotoxicity. Metaplasticity mechanisms also allow neurons to integrate plasticity-associated signals over time. Interestingly, astrocytes appear to be critical for certain forms of synaptic plasticity and metaplasticity mechanisms. Synaptic dysfunction is increasingly viewed as an early feature of AD that is correlated with the severity of cognitive decline, and the development of these pathologies is correlated with a rise in reactive astrocytes. This review focuses on the contributions of astrocytes to synaptic plasticity and metaplasticity in normal tissue, and addresses whether astroglial pathology may lead to aberrant engagement of these mechanisms in neurological diseases such as Alzheimer's disease.

The persistence of long-term potentiation in the projection from ventral hippocampus to medial prefrontal cortex in awake rats.

A potentially vital pathway in the processing of spatial memory is the pathway from ventral hippocampus to medial prefrontal cortex (vHPC-mPFC). To assess long-term potentiation (LTP) induction and maintenance across days in this pathway, the effects of several induction paradigms were compared in awake, freely moving rats. Two different high-frequency stimulation (HFS) protocols generated LTP lasting no longer than 1 week. However, after delivering HFS on three consecutive days, LTP lasted an average of 20 days, due mainly to the greater initial induction. Thus the pathway does not require extensive multi-day stimulation to induce LTP, as for other intra-neocortical pathways, but also it does not exhibit the extremely long-lasting and stable LTP previously observed in area CA1 and the dentate gyrus. By using bilaterally placed stimulating and recording electrodes, we found that HFS in one vHPC generated responses and LTP in the contralateral mPFC, even when the ipsilateral mPFC was inactivated by CNQX. We attribute this crossed response to a polysynaptic pathway from the vHPC to the contralateral mPFC. Finally, we found that repeated overnight exposure to an enriched environment also potentiated the vHPC-mPFC response, but this too was a transient effect lasting < 9 days, declining to baseline even before the enriched environment treatment was completed. Overall, these findings are consistent with the view that potentiation of vHPC-mPFC pathway may play a key role in promoting the hippocampus-mPFC interplay that, over days, leads to long-term storage in the frontal cortex of memories that are independent of the hippocampus.

The Impact of Redistricting Proposals on Health Care Expenditures for Liver Transplant Candidates and Recipients.

Redistricting, which means sharing organs in novel districts developed through mathematical optimization, has been proposed to reduce pervasive geographic disparities in access to liver transplantation. The economic impact of redistricting was evaluated with two distinct data sources, Medicare claims and the University HealthSystem Consortium (UHC). We estimated total Medicare payments under (i) the current allocation system (Share 35), (ii) full regional sharing, (iii) an eight-district plan, and (iv) a four-district plan for a simulated population of patients listed for liver transplant over 5 years, using the liver simulated allocation model. The model predicted 5-year transplant volumes (Share 35, 29,267; regional sharing, 29,005; eight districts, 29,034; four districts, 28,265) and a reduction in overall mortality, including listed and posttransplant patients, of up to 676 lives. Compared with current allocation, the eight-district plan was estimated to reduce payments for pretransplant care ($1638 million to $1506 million, p < 0.001), transplant episode ($5607 million to $5569 million, p < 0.03) and posttransplant care ($479 million to $488 million, p < 0.001). The eight-district plan was estimated to increase per-patient transportation costs for organs ($8988 to $11,874 per patient, p < 0.001) and UHC estimated hospital costs ($4699 per case). In summary, redistricting appears to be potentially cost saving for the health care system but will increase the cost of performing liver transplants for some transplant centers.

Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation.

The updated Banff classification allows for the diagnosis of antibody-mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d-negative AMR (n = 51) compared with C4d-positive AMR patients (n = 156) and matched control subjects without AMR. All first-year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor-specific antibody (DSA). C4d-negative AMR patients were not different from C4d-positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ABO-incompatibility). C4d-positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8-32] days vs. 46 [interquartile range 20-191], p < 0.001) and were three times more common (7.8% vs 2.5%). One- and 2-year post-AMR-defining biopsy graft survival in C4d-negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d-positive AMR patients, respectively (p = 0.4). C4d-negative AMR was associated with a 2.56-fold (95% confidence interval, 1.08-6.05, p = 0.033) increased risk of graft loss compared with AMR-free matched controls. No clinical characteristics were identified that reliably distinguished C4d-negative from C4d-positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.

A Voltage-Based STDP Rule Combined with Fast BCM-Like Metaplasticity Accounts for LTP and Concurrent "Heterosynaptic" LTD in the Dentate Gyrus In Vivo.

Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.

Early changes in liver distribution following implementation of Share 35.

In June 2013, a change to the liver waitlist priority algorithm was implemented. Under Share 35, regional candidates with MELD ≥ 35 receive higher priority than local candidates with MELD < 35. We compared liver distribution and mortality in the first 12 months of Share 35 to an equivalent time period before. Under Share 35, new listings with MELD ≥ 35 increased slightly from 752 (9.2% of listings) to 820 (9.7%, p = 0.3), but the proportion of deceased-donor liver transplants (DDLTs) allocated to recipients with MELD ≥ 35 increased from 23.1% to 30.1% (p < 0.001). The proportion of regional shares increased from 18.9% to 30.4% (p < 0.001). Sharing of exports was less clustered among a handful of centers (Gini coefficient decreased from 0.49 to 0.34), but there was no evidence of change in CIT (p = 0.8). Total adult DDLT volume increased from 4133 to 4369, and adjusted odds of discard decreased by 14% (p = 0.03). Waitlist mortality decreased by 30% among patients with baseline MELD > 30 (SHR = 0.70, p < 0.001) with no change for patients with lower baseline MELD (p = 0.9). Posttransplant length-of-stay (p = 0.2) and posttransplant mortality (p = 0.9) remained unchanged. In the first 12 months, Share 35 was associated with more transplants, fewer discards, and lower waitlist mortality, but not at the expense of CIT or early posttransplant outcomes.