Aging and an Immune Challenge Interact to Produce Prolonged, but Not Permanent, Reductions in Hippocampal L-LTP and mBDNF in a Rodent Model with Features of Delirium

Abstract Aging increases the risk of abrupt declines in cognitive function after an event that triggers immune system activation (e.g. surgery, infection, or injury). This phenomenon is poorly understood, but rodent models may provide clues. We have previously shown that aging (24-mo-old) F344xBN rats generally do not show significant physical or cognitive impairments. However, their brains mount an exaggerated inflammatory response to signals triggered by a peripheral immune challenge (an intraperitoneal injection of Escherichia coli or laparotomy). Their hippocampal levels of the proinflammatory cytokine IL-1β are significantly elevated for at least 8 d, but generally less than 14 d, after infection or surgery. This IL-1β elevation is mirrored by prolonged deficits in a hippocampus-dependent long-term memory task. In contrast, young (3-mo-old) counterparts exhibit only transient elevations in IL-1β that drop to near baseline levels within 24 h. We previously demonstrated that theta burst–evoked late-phase long-term potentiation (L-LTP)—a BDNF-dependent form of synaptic plasticity—is impaired in hippocampal area CA1 of aged animals 4 d after infection. Also, levels of mature brain-derived neurotrophic factor (mBDNF)—the protein isoform required for stabilization of L-LTP—are reduced in hippocampal synaptoneurosomes of aged animals at the same time point. In this study, we investigated whether the deficits in L-LTP and mBDNF persist in parallel with the elevation in IL-1β and impairment in memory. This was the case, consistent with the idea that an exaggerated brain inflammatory response may compromise memory consolidation in part by altering availability of mBDNF to stabilize memory-related synaptic plasticity.


Introduction
When we think about age-related cognitive decline, we tend to think of gradual decrepitude or overt neurodegenerative disease, as in Alzheimer's disease. However, cognitive decline is not always gradual. Rapid decline can be triggered by activation of the peripheral immune system. Proinflammatory cytokines (e.g., IL-1␤ and TNF-␣) produced by peripheral immune activation can communicate with the brain via both humoral and neural routes, triggering a cascade of effects in the CNS including microglial activation and de novo production of proinflammatory cytokines (Maier et al., 2001;Konsman et al., 2002;Dantzer et al., 2008). Interestingly, aging has been shown to sensitize the brain inflammatory response to a variety of experimental immune challenges [e.g., Escherichia coli, surgery, lipopolysaccharide (LPS)], increasing the size and duration of the resulting spike in proinflammatory cytokines in the hippocampus Chen et al., 2008;.
At 24 mo, Fisher 344/Brown Norway (F344xBN) rats are generally healthy, aging but not senescent. We have previously shown that a single i.p. injection of E. coli produces prolonged elevations in IL-1␤ in the hippocampi of aging 24-mo-old F344xBN rats, but not in 3-mo-old rats . The exaggerated elevation in IL-1␤ does not impair the initial learning of the test tasks or formation of short-term memories. Instead, it is associated with profound and specific deficits in tasks requiring consolidation of hippocampus-dependent long-term memory . As the levels of IL-1␤ drop, these deficits fade. Similarly, blocking IL-1␤ signaling in the brain with an intra-cisterna magna infusion of an IL-1 receptor antagonist (Frank et al., 2010) blocks the memory deficits.
Previously, we examined the effects of age and infection on memory-related synaptic plasticity and levels of hippocampal BDNF (and related proteins) at a single time point, 4 d after the E. coli injection. This time point was chosen for several reasons: (1) both the young and aged animals have recovered from the overt symptoms of illness (e.g., fever, loss of appetite, etc.; Barrientos et al., 2006); (2) levels of hippocampal IL-1␤ are still significantly elevated in the aged rats but have returned to near preinfection levels in the young rats ; and (3) the aged rats show significant deficits in hippocampus-dependent long-term memory, but the young rats do not (Barrientos et al., 2006). We measured a BDNF-dependent, memory-related, long-term form of synaptic plasticity, theta burst-evoked L-LTP in hippocampal area CA1. Deficits in theta-frequency LTP in area CA1 have been shown to distinguish cognitively impaired from unimpaired aged Fischer 344 rats (e.g., Tombaugh et al., 2002). We found that a recent history of infection was associated with reduced theta burst L-LTP in the young rats and that aging greatly exacerbated this effect (Chapman et al., 2010). We also found that levels of mature BDNF (mBDNF, the cleaved protein isoform required for long-lasting forms of memory and LTP; Pang et al., 2004;Barnes and Thomas, 2008) were significantly reduced in the hippocampal synaptoneurosomes prepared from aged rats 4 d after E. coli injection (Cortese et al., 2011). Like the deficit in long-term memory (Frank et al., 2010), the deficits in L-LTP and mBDNF could be prevented by interfering with IL-1␤ signaling in the brain (Chapman et al., 2010;Cortese et al., 2011).
In this study, we extended our examination of theta burst L-LTP and mBDNF to longer time periods (8, 14 and 21 d after infection). The goal was to determine if the deficits in synaptic plasticity and mBDNF would resolve, and if they did, to compare the time courses of their recovery with those of the alterations in IL-1␤ and hippocampus-dependent long-term memory. The results show that the changes in L-LTP and mBDNF paralleled the changes in IL-1␤ and memory over time. This suggests that prolonged inflammatory responses in the brain might affect memory-related plasticity of hippocampal synapses, in part by modulating levels of mBDNF and downstream effectors required to stabilize synaptic plasticity.

Experimental animals
The animals in this study were 3-and 24-mo-old male Fisher 344/Brown Norway F1 hybrid rats from National Institute on Aging Aged Rodent Colony. They were housed in pairs with ad libitum access to water and food and were maintained on 12-h light-dark cycle. The animals were allowed to acclimate to the animal facility for a minimum of 10 d before the experiments were begun. All experiments complied with protocols approved by the University of Colorado and Temple University Animal Care & Use Committees.

The infection model
Stock E. coli cultures (15746; ATCC) were thawed and cultured in 40 ml brain-heart infusion (BHI; Difco Laboratories) at 37°C overnight. The number of bacteria in individual cultures was extrapolated from previously determined growth curves. The cultures were centrifuged at 3000 rpm for 15 min, the supernatants were discarded, and the bacterial pellets were suspended in sterile PBS to achieve a final dose of 1.0 ϫ 10 10 colony-forming units (CFU)/mL in 250 l. All animals were given an intraperitoneal injection of 250 l of either E. coli or vehicle (sterile PBS).

Electrophysiology
Bipolar stimulating (FHC: CBBRC75) and ACSF-filled glass recording (A-M Systems: 603000) electrodes were placed in stratum radiatum to record field excitatory postsynaptic potentials (fEPSPs) from Schaffer collateral-CA1 synapses. All stimuli were set to evoke fEPSP slopes equal to one-third of the maximum in each slice. Test stimuli were delivered every minute, and test responses were recorded for 30 min before starting the experiment to ensure stability. Slices were then tetanized using a theta-burst protocol: 12 bursts of four pulses at 100 Hz, delivered 200 ms apart. The same stimulus intensity was used for tetanization and evoking test responses. Field EPSP recordings were normalized to pre-tetanus baselines and averaged for each group. Error bars indicate SEM. These data were further analyzed by factorial ANOVA, followed by Turkey's HSD post hoc tests (Graph-Pad Prism 7).

Synaptoneurosome preparation
Rats were decapitated, and hippocampi were collected 8 or 14 d after E. coli or saline injection. Tissue was minced in 500 l homogenization buffer (HB) with protease and phosphatase inhibitors [in M: 1 Tris, 1 sucrose, 0.5 EDTA, 0.25 EGTA, 0.5 NaF, 1 benzamidine, and 0.1 AEBSF (4-(2aminoethyl)benzenesulfonyl fluoride)] and homogenized with a glass tissue grinder and a Teflon pestle. The homogenate was centrifuged at 960 ϫ g for 15 min to pellet nuclear material and unbroken cells. The remaining supernatant was further centrifuged at 10,000 ϫ g for 15 min, yielding an S2 cytosolic supernatant and a P2 crude synaptoneurosomal pellet (pre-and postsynaptic components). The synaptoneurosomal pellet was washed gently in 100 l HB, homogenized with a 0.5-ml plastic pestle in 100 l HB and 10 l of 10ϫ sodium chloride-TRIS-EDTA (1ϫ final concentration), and sonicated. The final P2 fraction obtained using this procedure is enriched for presynaptic and postsynaptic proteins, terminal mitochondria, and cytoplasm and synaptic vesicles (Booth and Clark, 1978;Whittaker, 1993). Synaptic enrichment was confirmed using synaptic markers synaptophysin and postsynaptic density 95 (PSD95). Protein content was determined by the BCA protein assay (Bio-Rad).

Western blots
All procedures used here have been previously described (Cortese et al., 2011). Synaptoneurosomal samples were denatured in 4ϫ Laemmli buffer and heated at 70°C for 5 min. The resulting protein samples (40 g each) were loaded onto 4 -12% NuPage Bis-Tris SDS-polyacrylamide gels (Invitrogen) and transferred onto polyvinylidene fluoride membranes (Millipore). Membranes were blocked in 5% milk/ PBST (PBS with Tween 20) at room temperature for 30 min.
Secondary antibodies were purchased from GE Health care and Bio-Rad and were diluted in the range of 1:5000 -1:10,000. Incubations were at room temperature for 1 h, followed by 3 ϫ 10 min washes. Super Signal West Pico Chemiluminescent (Pierce) was applied, and blots were exposed to autoradiography film (Denville Scientific). Blots were then stripped in Restore Western Blot Stripping Buffer (Pierce) for 15 min, washed 3 ϫ 10 min in PBST, and subjected to standard Western blotting conditions. ImageJ was used to quantify the protein bands, and all bands were normalized to their actin controls. For TrkB, PLC␥, and ERK, the ratio of the phosphorylated form to total expression of each protein was determined. We have previously found that the combined effects of age and infection uniquely disrupt BDNF-dependent memory and synaptic plasticity (Barrientos et al., 2006;Chapman et al., 2010) and also reduce mBDNF (and related proteins) 4 -5 d after infection (Cortese et al., 2011). For the protein level time course, we therefore used an unpaired t test (Graph-Pad QuickCals) to determine if the level of the protein of interest in the aged ϩ E. coli group differed from the level of the protein in the other groups. The p value listed for each protein (or phosphorylation state ratio) is for an unpaired t test comparing the mean of the aging ϩ E. coli group to the mean of the combined values of the other test groups.

Aging and a peripheral immune challenge interact to reduce theta burst-evoked L-LTP
In an earlier report (Chapman et al., 2010), we examined the impact of age and infection on synaptic function at New Research Schaffer collateral-CA1 synapses in hippocampal slices from aged and young rats, 4 -5 d after an i.p. injection of E. coli or saline. We found no significant differences between groups in basal synaptic transmission or earlyphase long-term potentiation (E-LTP). We used two different stimulus protocols to induce late-phase longterm potentiation (L-LTP): either four trains of highfrequency stimulation, which induces robust activation of numerous plasticity-related signaling cascades (Bliss et al., 2007), or a more naturalistic theta burst stimulation, which mimics theta frequency burst firing of CA1 neurons during spatial exploration (O'Keefe, 2007). We found that four-train L-LTP was not significantly affected by age or infection. However, full expression of theta burst L-LTP was suppressed by a recent history of infection, and aging greatly exacerbated this effect.
The immune challenge-evoked elevations in IL-1␤ and the deficits in long-term memory both last Ͼ8 d, but typically Ͻ14 d, in aged animals . It seemed plausible that this might also be true of the deficits in theta burst L-LTP.

Theta burst-evoked L-LTP was recovering in aged animals 14 d after infection
The effects of age and infection were subtler at 14 d. Input-output curves indicated no significant difference across the four groups (P age, infection ϭ 0.77 at 5 V, 0.78 at 7 V, 0.73 at 10 V, 0.60 at 12 V, and 0.66 at 15 V; Fig. 1B Fig. 2B). However, the group means and graphs suggest some remaining reduction in the L-LTP of aged E. coli animals; Tukey's post hoc tests indicated that the aged E. coli group differed from young saline (p ϭ 0.0169) and young E. coli (p ϭ 0.0220). This was not the case when the aged E. coli group was compared to the aged saline group (p ϭ 0.0542). Together, these results suggest significant, but incomplete, recovery in the capacity for L-LTP at 14 d.

Theta burst-evoked L-LTP had returned to control levels in aged animals 21 d after infection
We extended our investigation to 21 d to determine if the E. coli evoked deficits in L-LTP in the aged rats would fully resolve (Fig. 2C). There was no significant difference in post-tetanic potentiation at 21 d (aged/vehicle vs. aged/E. coli: p ϭ 0.9081; aged/vehicle ϭ 232.7 Ϯ 23.9%, and aged/E. coli ϭ 237.8 Ϯ 23.3%). The results show normal levels of L-LTP in aged E. coli animals at this time point (aged/vehicle vs. aged/E. coli: p ϭ 0.8232; percentage baseline 3 h after tetanus: aged/vehicle ϭ 144.2 Ϯ 6.9%, and aged/E. coli ϭ 148.4 Ϯ 14.3%).

Levels of the mature BDNF protein isoform were significantly reduced in hippocampal synaptoneurosomes prepared from aged rats 8 d, but not 14 d after infection
The forms of long-lasting memory and synaptic plasticity compromised by age and infection are highly dependent on BDNF (Tyler et al., 2002;Chao, 2003;Lu, 2003;Bramham and Messaoudi, 2005). We have therefore hypothesized that aging and infection might compromise production or processing of BDNF protein, reducing the availability of BDNF for memory-related plasticity processes at synaptic sites (Cortese et al., 2011). BDNF is synthesized as a precursor, proBDNF, which undergoes post-translational cleavage to produce mature BDNF (mBDNF), the protein isoform required for long-lasting forms of memory and LTP (Pang et al., 2004;Barnes and Thomas, 2008).
We previously demonstrated that levels of the mBDNF protein were significantly reduced in synaptoneurosomes prepared from the hippocampi of aged rats 4 -5 d after injection of E. coli (Cortese et al., 2011). In this study, we examined later time points-8 and 14 d after injection-to determine if levels of mBDNF in aged animals would recover as levels of IL-1␤ dropped toward pre-infection baselines . Western blot analysis with an antibody against the mature domain of BDNF (Lee et al., 2001) supported this hypothesis. At 8 d, levels of mBDNF (Fig. 3A) were still significantly reduced in hippocampal synaptoneurosomes from the aged E. coli group compared to the other groups (t (18) ϭ 2.3427, p ϭ 0.0308). In contrast, levels of mBDNF were back to normal at 14 d (Fig. 4A), showing no statistical significance (t (14) ϭ 0.0936, p ϭ 0.9267). Meanwhile, Western blot analysis with an antibody against a specific proBDNF signal revealed no significant difference at 8 d ( Fig. 3A; t (14) ϭ 0.1983, p ϭ 0.8457) or 14 d ( Fig. 4A; t (10) ϭ 0.4676, p ϭ 0.6501).

Age and infection interact to reduce activation of TrkB and downstream signaling systems, but this effect is not permanent
Mature BDNF binds to the tropomyosin-related kinase B receptor (TrkB), triggering a cascade of phosphorylation events, starting with the receptor, which can activate downstream signaling pathways including the phospholipase C-␥1 (PLC␥1) and the Ras/extracellular signalregulated kinase (ERK) pathways (Patapoutian and Reichardt, 2001;Segal, 2003). These pathways ultimately lead to the transcription and translation events required for L-LTP (Finkbeiner et al., 1997;Minichiello, 2009).
We previously reported significantly reduced levels of mBDNF in synaptoneurosomes prepared from the hippocampi of aged rats 4 -5 d after injection of E. coli (Cortese et al., 2011). Consistent with the decreased availability of mBDNF, we also found significantly reduced activation of TrkB and the PLC␥1 and ERK downstream signaling pathways (Cortese et al., 2011). Here, we examined the impact of age and infection on activation of TrkB and downstream signaling 8 and 14 d after injection.
Analysis of Western blots using an antibody against phosphorylated TrkB (pTrkB) and an antibody against Aging and a peripheral immune challenge interact to produce prolonged, but temporary, reductions in L-LTP. Hippocampal slices were collected from young (3 mo) and aged (24 mo) rats 8, 14, or 21 d after injection of E. coli or saline (vehicle). L-LTP was induced in Schaffer collateral-CA1 synapses using theta-burst stimulation (12 bursts of 4 pulses at 100 Hz, delivered 200 ms apart). fEPSP slopes were normalized to pretetanus baselines, averaged, and plotted for each group. Error bars indicate SEM. Insets show representative traces before and 3 h after tetanus. A, L-LTP is severely impaired in slices from aged, but not young, rats 8 d after E. coli injection. B, L-LTP is still reduced but recovering in aged rats at 14 d. C, The L-LTP is back to baselines at 21 d. New Research total TrkB (tTrkB; sc-8316 antibody; Santa Cruz Biotechnology) showed that the ratio of pTrkB/tTrkB was significantly reduced in synaptoneurosomes from aged E. coli rats at 8 d compared to the other groups ( Fig. 3B; t (10) ϭ 2.2692, p ϭ 0.0466). At 14 d (Fig. 4B), levels of phospho-TrkB were back to baselines in the aged E. coli (t (10) ϭ 0.0470, p ϭ 0.9635).

Discussion
We have previously demonstrated that in 24-mo-old F344xBN rats, a single i.p. injection of E. coli triggers an exaggerated hippocampal production of IL-1␤ ) that is associated with profound deficits in contextual fear conditioning, a hippocampus-dependent memory task (Barrientos et al., 2006), in theta burstevoked L-LTP (Chapman et al., 2010), and in mBDNF/ TrkB signaling (Cortese et al., 2011). Blunting the effects of IL-1␤ in the brains of aged animals using the IL-1 receptor antagonist IL-1Ra blocks all of these deficits (Chapman et al., 2010;Frank et al., 2010;Cortese et al., 2011). We have also determined that the elevation in IL-1␤ and the associated memory deficits do subside, but slowly-they last more than a week, but typically Ͻ2 weeks ). Here we extend these observations, further exploring the strength of these correlations over time and asking if the infection-induced deficits in theta burst L-LTP and mBDNF will also subside and follow the same time course of recovery as the alterations in IL-1␤ and memory.
Our principle new findings are that (1) theta burst L-LTP remained profoundly compromised in aged animals 8 d after E. coli injection, but the much milder suppression observed in young animals 4 -5 d after injection (Chapman et al., 2010) had resolved; there were also still significant deficits in mBDNF levels and signaling in the aged animals at this time point; (2) theta burst LTP in the aged animals showed significant, but incomplete, recovery 14 d after the E. coli injection, and mBDNF levels and signaling in aged animals were no longer significantly impaired; and (3) 21 d after the E. coli injection, theta burst LTP in the aged animals had completely recovered. Thus, the exaggerated elevation of IL-1␤ is precisely mirrored by the deficits in memory and in mBDNF/TrkB signaling: as levels of hippocampal IL-1␤ decline, memory and mBDNF/ TrkB signaling recover. There was a slight lag in the full recovery of theta burst L-LTP, consistent with reports of a critical threshold level of BDNF being required to set the conditions necessary for full expression of BDNFdependent forms of long-lasting synaptic plasticity such as theta burst L-LTP (Korte et al., 1995(Korte et al., , 1996Patterson et al., 1996;Pang et al., 2004).
Taken together, these results (summarized in Fig. 5) are consistent with the hypothesis that the exaggerated hippocampal inflammatory response produced by age and an infection might decrease availability of BDNF at hippocampal synapses, and thus contribute to deficits in forms of long-lasting memory and synaptic plasticity that require BDNF for their complete expression.
Many studies have examined the effects of normal aging on memory, synaptic plasticity, and BDNF signaling, with varied results. It is now recognized that variability in cognitive and synaptic functioning, and in BDNF signaling, increases with increasing age in individuals and populations. Aging is frequently, though not always, associated with some degree of cognitive decline and with disruptions in related forms of synaptic plasticity; there appears to be considerable variability depending on the experimental protocols used and the species, strains, and ages of the subjects (Landfield and Lynch, 1977;Gage et al., 1984;Barnes and McNaughton, 1985;Deupree et al., 1991;Diana et al., 1995;Gallagher et al., 2003;Tombaugh et al., 2005;Lynch et al., 2006;Sharma et al., 2015). Data from human autopsy studies and animal Figure 5. A summary of the effects of age and infection at multiple time points after injection of E. coli or saline. Memory ϭ hippocampus-dependent long-term memory; IL-1␤ ϭ levels of proinflammatory cytokine interleukin-1␤ in hippocampal synaptoneurosomes; L-LTP ϭ theta burst-evoked L-LTP in the hippocampal CA1 area; and BDNF ϭ levels of mature BDNF and activity of related proteins in hippocampal synaptoneurosomes. Upward arrows indicate an increase, and downward arrows show a reduction. Three arrows represent severe deficits, and one arrow means impairments to a lesser degree. Horizontal lines indicate baseline values. Data summarized for day 4 are drawn from earlier publications: Memory and IL-1␤ (Barrientos et al., 2006), L-LTP (Chapman et al., 2010, and BDNF (Cortese et al., 2011). models examining variability in cognitive functioning with aging suggest that when deficits in hippocampusdependent memory occur, they do not arise from a loss of hippocampal neurons, or initially even from a loss of synapses, but rather from more subtle alterations in synaptic efficacy (Lister and Barnes, 2009). For example, in hippocampal area CA1, the basic mechanisms for synaptic modification persist in old age, but the threshold for producing long-lasting, memory-related plasticity increases. High-frequency stimulation protocols can still induce L-LTP, but milder, more naturalistic types of stimulation are less likely to do so (Lynch et al., 2006). Because BDNF is a key mediator of synaptic efficacy in circuits critical for cognition (Bramham and Messaoudi, 2005;Leal et al., 2015), it has long been suspected that disruption of BDNF signaling systems might play a significant role in aging-associated cognitive decline. Somewhat surprisingly, it now appears that basal levels of BDNF and its receptor TrkB in the brain do not change very much as a result of aging alone (Pang and Lu, 2004), although significant changes are seen in some neurodegenerative diseases (Zuccato and Cattaneo, 2009).
Clearly, age is not the only important variable in agerelated cognitive decline. The present results add to a growing body of evidence suggesting that much of this variability arises from complex interactions of age with genetics, lifestyle, and life history. Aging sensitizes the brain immune response Chen et al., 2008;, and increases the vulnerability of systems for memory-related plasticity to immune challenges. This may represent an important source of variability in cognitive function in the aging brain.
Aberrantly elevated levels of proinflammatory molecules such as IL-1␤ can compromise memory and synaptic plasticity. Interleukin-1␤, its receptor, and the natural IL-1 receptor antagonist are all present at relatively high levels in the hippocampus (Lechan et al., 1990;Takao et al., 1990;Ban et al., 1991). This expression pattern suggests that IL-1 signaling may play a significant role in modulating hippocampal functions, and that memory-related plasticity processes in the hippocampus may be particularly vulnerable to dysregulated IL-1 signaling. This may be particularly true in aging, since sensitivity to IL-1␤ is augmented in aged hippocampal synapses (Prieto et al., 2015). Low basal levels of IL-1␤ appear to be required for long-term memory and synaptic plasticity in the healthy hippocampus (Yirmiya and Goshen, 2011). However, performance on hippocampusdependent memory tasks can be seriously compromised by manipulations that result in too much IL-1␤. These include intraventricular (Oitzl et al., 1993) and hippocampal (Barrientos et al., 2002) IL-1 administration, multiweek elevation of IL-1␤ in the hippocampi of transgenic mice (Hein et al., 2010), and elevation of endogenous IL-1␤ evoked by infections (Gibertini et al., 1995;Barrientos et al., 2006;Chen et al., 2008) or psychological stressors (Pugh et al., 1999). Similarly, in young rodents, experimental elevation of IL-1␤ can block full expression of LTP in several areas of the hippocampus (Lynch, 2010). Application of high levels of IL-1␤ to rodent hippocampal slices reduced LTP in areas CA1 (Bellinger et al., 1993;Ross et al., 2003) and CA3 (Katsuki et al., 1990) and in the dentate (Cunningham et al., 1996;Coogan and O'Connor, 1997). In vivo LTP in the dentate was inhibited by intraventricular injection of IL-1␤ (Murray and Lynch, 1998;Kelly et al., 2003) or an i.p. injection of LPS, a potent endotoxin that triggers strong immune responses (Lynch, 2004;Barry et al., 2005).
The memory and plasticity processes compromised by excess IL-1␤ are highly dependent on BDNF, and there is increasing evidence that experimental elevation of proinflammatory cytokines in the brain can diminish the availability of BDNF-potentially from both neuronal and microglial (Parkhurst et al., 2013) sources-for memoryrelated processes (Patterson, 2015). Infusing IL-1␤ into the hippocampus decreases its capacity for transcription of BDNF after fear learning (Barrientos et al., 2004), while infusion of IL-1Ra protects it during social isolation stress . Perhaps not surprisingly, intraperitoneal injection of high levels of IL-1␤ or LPS produced an acute (within 4 h) reduction in hippocampal BDNF mRNA (Lapchak et al., 1993). However, expression of specific activity-and plasticity-associated BDNF mRNA transcripts, and the capacity to recruit these transcripts after fear learning, was still reduced in the hippocampi of aged rats 4 d after i.p. E. coli (Chapman et al., 2012). Aberrantly elevated levels of cytokines also appear to compromise production of the BDNF protein and downstream signaling. Levels of BDNF protein in the hippocampus showed a dose-dependent reduction 7 h after i.p. LPS (Guan and Fang, 2006). A high dose of LPS injected i.p. into young mice is reported to produce a small (15%) reduction in both proBDNF and mature BDNF in brain synaptoneurosomes 3 d later (Schnydrig et al., 2007). Intraperitoneal injection of E. coli produces a large reduction in mBDNF and TrkB signaling in hippocampal synaptoneurosomes from aged rats 4 -5 d later (Cortese et al., 2011). There are also indications that excessive IL-1␤ may sometimes interfere with the neuroprotective effect of BDNF-induced signal transduction, in addition to compromising its plasticity-related functions (Tong et al., 2008(Tong et al., , 2012Cortese et al., 2011;Chapman et al., 2012).
The hypothesis that exaggerated brain inflammatory responses might disrupt BNDF-dependent synaptic plasticity and neuroprotective processes has broad implications for understanding, preventing, or treating cognitive dysfunction in a variety of disorders associated with neuroinflammation or dysregulated brain immune responses, but may be particularly informative in the context considered here. Very few studies have focused on the mechanisms of acute cognitive decline (termed delirium) following an inflammatory event, despite its clinical prevalence and association with markedly increased risk of progression to and acceleration of dementia (Fong et al., 2009;Cunningham, 2011). The immune challenge-triggered cognitive decline we model here in rodents resembles that observed in human delirium. There is a common aging-associated vulnerability, and the pathology shares a similar trajectory and time course; there may well be elements of a common etiology.