BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal...

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Journal of Neuroimmunolog

BDNF mRNA expression in rat hippocampus following contextual

learning is blocked by intrahippocampal IL-1h administration

Ruth M. Barrientos*, David B. Sprunger, Serge Campeau,

Linda R. Watkins, Jerry W. Rudy, Steven F. Maier

Department of Psychology and Center for Neuroscience, University of Colorado at Boulder, Campus Box 345, Boulder, CO 80309, USA

Received 29 May 2004; received in revised form 18 June 2004; accepted 18 June 2004

Abstract

The present study examined the modulating effects of an intrahippocampal injection of interleukin-1h (IL-1h) on brain-derived

neurotrophic factor (BDNF) mRNA expression 0.5, 2, 4, and 6 h following contextual fear conditioning, a task known to increase BDNF

mRNA, in rats. Contextual fear conditioning produced a time-dependent increase in BDNF mRNA that varied by region of hippocampus. IL-

1h blocked or reduced these increases in BDNF mRNA in the CA1, CA2, and dentate gyrus regions of the hippocampus, but had no effect in

cortical regions. These data support the idea that IL-1h-produced memory deficits may be mediated via BDNF mRNA reductions in

hippocampus.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Memory consolidation; Time course; Proinflammatory cytokines; BDNF; Intrahippocampal; In situ hybridization

1. Introduction

Peripheral infection can produce severe and prolonged

declines in cognitive functioning in individuals with

neurodegenerative disorders such as Alzheimer’s disease

and Parkinson’s disease (Perry et al., 2003). Moreover,

infection and the consequent activation of immune cells

can even lead to interference with cognitive processes in

healthy humans (Reichenberg et al., 2001) and animals

(Gibertini et al., 1995), although the effects in these

subjects are of smaller magnitude and duration. Clearly,

interference with cognitive functions by peripheral infec-

tion or immune stimulation can only occur via the

activation of pathways from the periphery to the brain,

which can lead to alterations of function within the brain.

Indeed, research conducted over the past decade has

uncovered both blood-borne and neural routes by which

proinflammatory cytokines, released from activated

0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.jneuroim.2004.06.009

* Corresponding author. Tel.: +1 303 492 0777; fax: +1 303 492 2967.

E-mail address: [email protected] (R.M. Barrientos).

immune cells within peripheral organs in which immune

responses occur, can signal the brain and potently alter

neural activity (Maier et al., 2001). Thus, the activity of

the brain changes quite markedly within a short period of

time following the release of proinflammatory cytokines in

the periphery. For example, c-fos mRNA increases in

regions such as the area postrema, nucleus tractus

solitarius, and hypothalamic nuclei within 1 h (the first

timepoint examined) of injection of lipopolysaccharide

(LPS) or interleukin-1h (IL-1h) itself, with activation

spreading to other areas more relevant to cognition at

later timepoints (Brady et al., 1994; Ericsson et al., 1994).

At the neurochemical level, changes in the hippocampus

are prominent, with extracellular serotonin increasing quite

markedly within 90 min (Linthorst et al., 1995).

Interestingly, the de novo induction of proinflammatory

cytokines such as IL-1h within the brain is a key feature of

the neural cascade that is induced by peripheral infection/

immune activation (Laye et al., 1994; Nguyen et al., 1998).

This is noted because elevated levels of IL-1h within the

hippocampus are now known to impair hippocampal-

dependent memory consolidation (Barrientos et al., 2002,

y 155 (2004) 119–126

R.M. Barrientos et al. / Journal of Neuroimmunology 155 (2004) 119–126120

2003; Gibertini et al., 1995; Oitzl et al., 1993; Pugh et al.,

2001; Yirmiya et al., 2002).

Memory consolidation is thought to be dependent on

long-term potentiation (LTP), a form of synaptic plasticity

that is characterized by a persistent increase in synaptic

efficacy following tetanic stimulation (Bliss and Lomo,

1973). Importantly, inhibition of LTP results in hippo-

campal-dependent memory impairments (Morris et al.,

1986; Shimizu et al., 2000), and elevated hippocampal IL-

1h has been shown to interfere with LTP (Lynch, 1998).

Although the impact of increased hippocampal IL-1hon memory consolidation is clear, the mechanism(s) by

which IL-1h interferes with memory consolidation is

unknown. IL-1h could interfere with hippocampal func-

tion directly, or it could modulate other factors that are

important in memory consolidation. Brain-derived neuro-

trophic factor (BDNF) is an intriguing candidate in this

regard. BDNF is a neurotrophin whose expression is

required for basal neurogenesis, is important in neuro-

protective responses to insults (Lee et al., 2002), and is

critical for early-, middle-, and late-phase events involved

in synaptic plasticity (Korte et al., 1995; Messaoudi et al.,

2002; Tyler et al., 2002) and hippocampal-dependent

memory consolidation (Hall et al., 2000; Ma et al.,

1998; Mizuno et al., 2000). BDNF is rapidly induced in

the hippocampus during learning and memory tasks that

require intact hippocampal function, such as contextual

fear conditioning (Hall et al., 2000), and is necessary for

at least 4 h after training to form a long-term memory

(Alonso et al., 2002). It is noteworthy that BDNF is

required at the time of LTP induction as well (Alonso et

al., 2002; Gartner and Staiger, 2002). Thus, reductions in

hippocampal BDNF lead to both inhibition of LTP and

hippocampal-dependent memory impairments (Alonso et

al., 2002; Ma et al., 1998).

Given these data, it is interesting to note that systemic

administration of either IL-1h or LPS has been reported to

significantly downregulate BDNF mRNA in the hippo-

campus (Lapchak et al., 1993). Since peripheral IL-1h or

LPS administration increases both IL-1h mRNA (Laye et

al., 1994) and proteins (Nguyen et al., 1998) in the

hippocampus, it is possible that elevated IL-1h in the brain

decreases BDNF expression, thereby, in whole or in part,

accounting for the interference with memory consolidation.

Consistent with this possibility, we have shown that social

isolation, which elevates endogenous IL-1h protein in the

hippocampus (Pugh et al., 1999), reduces BDNF mRNA in

the hippocampus and impairs hippocampal-dependent

memory (Barrientos et al., 2003). Furthermore, an intra-

hippocampal injection of the IL-1 receptor antagonist (IL-

1ra) before social isolation prevented both the BDNF

reduction and the memory impairment produced by social

isolation (Barrientos et al., 2003). Although these data are

consistent with the idea that IL-1h-produced memory

impairments are mediated via a downregulation of BDNF

mRNA, there is no direct evidence that elevations of IL-1h

in the hippocampus would, in fact, result in a reduction of

the hippocampal BDNF mRNA increase that is produced by

a learning experience.

The present study thus examined the modulating effects

of an intrahippocampal injection of IL-1h administered

immediately after contextual fear conditioning, a task

known to increase BDNF mRNA in the hippocampus

(Hall et al., 2000). BDNF mRNA expression in the

hippocampus was examined 0.5, 2, 4, and 6 h after

conditioning. To demonstrate the specificity of IL-1h’saction in the hippocampus, we measured BDNF expres-

sion in the cortex. While it seems intuitive to measure

BDNF expression in the amygdala instead, we did not

because Hall et al. (2000) reported that there was no

increase in BDNF mRNA expression in the amygdala

associated with contextual conditioning. Thus, no modu-

lating effects of IL-1h on BDNF mRNA expression would

be expected in this region. Measuring BDNF expression

in the cortex instead further validates the specific effect of

IL-1h in the hippocampus.

Since there are no previous experiments examining the

effects of an intrahippocampal injection of IL-1h after

training on the consolidation of contextual fear memory,

such an experiment was also conducted.

2. Materials and methods

2.1. Subjects

Adult male Sprague–Dawley rats (Harlan, Indianapolis,

IN) weighing approximately 300 g at the beginning of the

experiment were housed four to a cage [52 (L)�30

(W)�21 (H) cm] at 25 8C on a 12-h:12-h light/dark cycle

(lights on at 0700 h). Cages were lined with standard

bedding and rats were allowed free access to food and

water and were given 1 week to acclimate to colony

conditions before experimentation began. All experiments

were conducted in accordance with protocols approved by

the University of Colorado Animal Care and Use

Committee. All efforts were made to minimize the number

of animals used and their suffering.

2.2. Surgery

Under halothane anesthesia, all animals were placed in

a Kopf sterotaxic apparatus and implanted with bilateral

cannulae (Plastics One, Roanoke, VA) directed at the

dorsal hippocampus (for a detailed procedure, see Bar-

rientos et al., 2002). Briefly, cannulae were placed in the

following coordinates relative to bregma: AP, �3.5 mm;

ML, F2.4 mm; and DV, �3.0 mm. Each guide cannula

was fitted with a dummy cannula that extended 1 mm

beyond the tip of the guide cannula (i.e., total length, 4

mm) to maintain patency. Rats were allowed to recover

for 4 weeks.

Fig. 1. Representative Cresyl violet-stained brain section with cannulae

track marks depicting correct placement. Microinjections were made

through guide cannulae placed AP �3.5 mm, ML F2.4 mm, DV �4.0

mm from bregma.

R.M. Barrientos et al. / Journal of Neuroimmunology 155 (2004) 119–126 121

2.3. Apparatus

Conditioning chambers were two identical Igloo coolers,

as previously described (Barrientos et al., 2002). A 2-s, 1.4-

mA shock was delivered through a removable floor of

stainless steel rods 1.5 mm in diameter, spaced 1.2 cm

center to center. Each rod was wired to a shock generator

and scrambler (Colbourn Instruments, Allentown, PA).

Chambers were cleaned with water before each animal

was conditioned or tested.

2.4. Behavioral procedures

Rats were taken two at a time from their home cage and

each was placed in a conditioning chamber. Rats were

allowed to explore the chamber for 2 min before the onset of

a 2-s footshock (1.4 mA). Another 2 min later, the rats

received a second 2-s footshock and then were removed

from the chamber. Rats then received a bilateral micro-

injection of either vehicle or IL-1h (IL-1h; see below) into

the dorsal hippocampus. For the behavioral experiment, the

rats were then tested for fear of the conditioning context 48

h later as a measure of memory, as previously described

(Barrientos et al., 2002). Briefly, rats were placed in the

context and observed for 6 min, and scored as either moving

or freezing every 10 s. Scoring was carried out by observers

blind to experimental treatment and interrater reliability

exceeded 97%.

For the in situ hybridization experiment, rats were

decapitated 0.5, 2, 4, or 6 h following microinjection. A

group that was neither conditioned nor injected was also

included to serve as basal controls. The time at which they

were decapitated was counterbalanced to account for time of

day effects. Brains were rapidly removed, frozen in cold

isopentane, and stored at �80 8C.

2.5. Microinjections

Microinjections were carried out immediately following

contextual fear conditioning as previously described (Bar-

rientos et al., 2002). Briefly, a 33-gauge microinjector

(Plastics One) attached to PE50 tubing was inserted through

the indwelling guide cannula. The distal end of the PE50

tubing was attached to a 100-Al Hamilton syringe, which

was placed into a Kopf microinjection unit (Model 5000)

that accurately dispensed the desired volume. Human

recombinant IL-1h, generously provided by the NIH Bio-

logical Response Modifier Program, was microinjected at a

dose of 10 ng in a volume of 0.5 Al per side of the

hippocampus. Vehicle controls received equivolume phos-

phate-buffered saline (PBS; pH 7.4).

2.6. In situ hybridization and histology

Sections (10 Am) were cut on a Leica cryostat through

the hippocampus, thaw-mounted onto polylysine-coated

slides, and stored at �80 8C until processing. Sections

were fixed in buffered paraformaldehyde (4%) for 1 h,

rinsed three times with 2� SSC (standard sodium citrate),

placed in 0.1 M triethanolamine containing 0.25% acetic

anhydride for 10 min, rinsed for 5 min in H2O, and

dehydrated in alcohols. The cDNA probe specific for

BDNF (795 bp fragment; courtesy of Dr. J. Herman,

University of Cincinnati Medical Center, Cincinnati, OH)

was directed at exon V, which codes for the mature

protein. It was linearized using the NHE restriction

enzyme. To generate 35S-labeled complementary RNA to

BDNF mRNA, 1 Ag of linearized plasmid DNA; 1� T3

transcription buffer (Promega); 125 AC of 35S-UTP; 4 Alof H2O; 12.5 mM dithiothreitol (DTT); 150 AM GTP,

CTP, and ATP; 20 U of RNase inhibitor; and 6 U T3

polymerase in a total volume of 25 Al were incubated for

~2 h at 37 8C. To isolate the complete complementary

RNA from single nucleotides, a Sephadex G50-50 column

was used. The 35S-labeled probe was diluted in hybrid-

ization buffer to yield an approximate concentration of

1�106 cpm/65 Al. The hybridization buffer consisted of

50% formamide, 10% dextran sulfate, 2� SSC, 50 mM

sodium phosphate buffer (pH=7.4), 1� Denhardt’s sol-

ution, and 0.1 mg/ml yeast tRNA. The radiolabeled probe/

hybridization mixture (65 Al) was applied to each slide,

and sections were coverslipped. Slides were placed in

covered plastic boxes lined with filter paper moistened

with 50% formamide/50% H2O and incubated for 12–16 h

at 55 8C. Coverslips were floated off in 2� SSC, and

slides were rinsed three times in 2� SSC. Slides were

incubated in RNase A (200 Ag/ml) for 60 min at 37 8C,followed by successive washes in 2�, 1�, 0.5�, and

0.1� SSC for 2–3 min each, with an additional incubation

in 0.1� SSC for 60 min at 70 8C. Slides were rinsed in

distilled H2O, dehydrated in alcohols, and exposed to

Kodak BIOMAX MR X-ray film for approximately 5

days.

Semiquantitative analyses were performed on digitized

images from X-ray films in the linear range of the

acquisition system. This system consisted of a Northern


Light box, model B-95 (Imaging Research, St-Catharines,

Ontario, Canada), a Sony XC-ST70 digital camera fitted

with a Navitar 7000 zoom lens, a Scion LG3 frame

Fig. 2. Mean integrated densities of BDNF mRNA expression in dorsal and ventr

following contextual fear conditioning. Intrahippocampal IL-1h significantly bloc

dorsal and ventral DG. Uninjected/unconditioned rats served as baseline controls

grabber board, and a Scion Image (ver. Beta 4.0.2; Scion,

Frederick, MD) on a Dell 8100 computer. Signal pixels of

a region of interest were defined as having a gray value of

al CA1, CA2, CA3, and DG regions of the hippocampus 0.5, 2, 4, and 6 h

ked BDNF mRNA expression in dorsal and ventral CA1, ventral CA2, and

. Bars=S.E.M.

Fig. 3. Representative in situ hybridization images depicting BDNF mRNA expression in dorsal hippocampus and anterior cortex of vehicle or IL-1h-treatedrats at 2 h following contextual fear conditioning. Largest differences can be seen in CA1 and DG regions. There were no group differences in BDNF mRNA

expression in the cortex. Uninjected/unconditioned rats served as baseline controls. Measurements were taken for ventral regions also, but are not depicted here.


3.5 S.D. above the mean gray value of a cell-poor area

close to the region of interest. The number of pixels and

the average gray values above the set background were

then computed for each region of interest and multiplied,

giving an integrated densitometric measurement. An

average of 8–12 measurements were made for each region

of interest [dorsal and ventral dentate gyrus (DG); CA1,

CA2, and CA3 regions of the hippocampus; and anterior

and posterior cortices above the hippocampus], and these

values were further averaged to obtain a single integrated

density value per region for each rat. The specificity of

the probe was confirmed in a control experiment by using

a sense probe. No specific hybridization was observed in

the sense-treated sections (data not shown).

Slides that underwent in situ hybridization were later

stained with Cresyl violet to determine proper cannulae

placement into the hippocampus. To verify cannulae

placement in rats that participated in the behavioral

experiment, rats were anesthesized with Nembutal and

decapitated, then brains were removed, sliced, and stained

with Cresyl violet. Slides were then examined under a

light microscope to verify that the cannulae were placed in

the hippocampus. Only rats with proper cannulae place-

ment (as seen in Fig. 1) were included in the statistical

analyses of each experiment.

Fig. 4. Mean integrated densities of BDNF mRNA expression in anterior and poste

There was very little BDNF mRNA expression in these cortical regions compared

IL-1h-treated rats. Bars=S.E.M.

3. Results

3.1. Experiment 1

BDNF mRNA levels are shown in Fig. 2. In general,

there was a large rise in BDNF mRNA in all hippocampal

regions at 2 h following contextual fear conditioning,

compared to basal levels as measured in unconditioned/

uninjected control rats. These elevated levels gradually

declined at 4 and 6 h. At 6 h, levels appeared to be no

different than in unconditioned/uninjected controls. Impor-

tantly, hippocampal administration of IL-1h blocked or

reduced the conditioning-induced increase. A 2�4�8

ANOVA revealed a significant main effect of Drug

[F(1,400)=27.4, Pb0.0001], a significant main effect of

Time [F(3,400)=8.85, Pb0.0001], and a significant main

effect of Brain Region [F(7,400)=7.83, Pb0.0001]. There

was also a signif icant Drug�Time interact ion

[F(3,400)=1.38, Pb0.0001], a significant Drug�Brain

Region interaction [F(7,400)=2.764, Pb0.01], a significant

Time�Brain Region interaction [ F (21,400)=8.596,

Pb0.0001], and a significant Drug�Time�Brain Region

interaction [F(21,400)=1.611, Pb0.05]. A representative

photomicrograph of each condition at the 2 hr time point is

presented in Fig. 3.

rior cortical regions 0.5, 2, 4, and 6 h following contextual fear conditioning.

to hippocampal regions, and there were no differences between vehicle- and

Fig. 5. Mean percent freezing during the contextual fear test. IL-1h-treatedrats showed a significant memory impairment compared with vehicle-

treated rats. *Pb0.05. Bars=S.E.M.


Individual ANOVAs for each brain region revealed

significantly higher BDNF mRNA in the vehicle-treated

groups than in the IL-1h-treated groups, in the dorsal CA1

[F(1,50)=19.99, Pb0.0001] and ventral CA1 [F(1,50)=6.65,

Pb0.013 regions], ventral CA2 region [F(1,50)=8.48,

Pb0.01] and dorsal DG [F(1,52)=4.85, Pb0.04], and ventral

DG [F(1,50)=6.00, Pb0.02]. There was no significant main

effect of Drug in the dorsal CA2, dorsal and ventral CA3, or

anterior and posterior cortical regions.

The pattern of results was quite different in the cortical

areas (see Fig. 4). In both cortical areas, BDNF mRNA

expression was very low compared to any hippocampal

region and there were no effects of intrahippocampal IL-1h.There was a significant time effect in both the anterior

[F(3,51)=6.15, Pb0.01] and posterior [F(3,51)=13.54,

Pb0.0001] cortical areas. In these areas, BDNF mRNA

expression was highest at 0.5 h and gradually declined down

to basal levels at 6 h.

3.2. Experiment 2

The results of the behavioral experiment are shown in

Fig. 5. An ANOVA revealed a significant difference in

freezing behavior between IL-1h-treated rats (n=8) and

vehicle-treated rats (n=10) [ F(1,16)=6.11, Pb0.03].

Vehicle-treated rats froze significantly more of the time

(69%) than did IL-1h-treated rats (43%).

4. Discussion

To our knowledge, this is the first direct evidence that

elevated IL-1h in the hippocampus reduces BDNF mRNA

expression in most regions of the rat hippocampus following

a hippocampal-dependent learning task, and that it does so

in a time-dependent manner.

IL-1h did not reduce BDNF mRNA in cortical regions,

although it should be remembered that IL-1h was injected

into the hippocampus, not cortex. These data also support

previous findings that contextual fear conditioning induces a

large and rapid increase in BDNF mRNA in the hippo-

campus (Hall et al., 2000). However, we found the increase

to occur 2 h—not 0.5 h—following contextual fear

conditioning, as did Hall et al. (2000). Perhaps the stress

associated with the microinjection that occurred immedi-

ately following conditioning delayed the rise in BDNF

mRNA. Also, since our first time point after 0.5 h was 2 h,

the rise could have occurred anytime between those time

points. Thus, the delay may not have been as long as it

appears here.

The most striking increases in BDNF following

conditioning and the most robust blockade of BDNF

increases by IL-1h occurred in the CA1 region. This was

so despite the fact that basal BDNF mRNA levels were

lower in CA1 than in most other hippocampal regions.

This result is particularly intriguing because the CA1

region gives rise to substantially greater cortical and

subcortical connections than the DG, CA3, or CA2 fields

(van Groen and Wyss, 1990), and is critically important

for hippocampal-dependent memory formation (Shimizu

et al., 2000).

Memory for the conditioning context was also signifi-

cantly impaired by the IL-1h administration. These data

support a growing body of evidence showing that elevated

levels of proinflammatory cytokines impair hippocampal-

dependent memory (Barrientos et al., 2002, 2003; Giber-

tini et al., 1995; Oitzl et al., 1993; Pugh et al., 1999,

2001; Yirmiya et al., 2002). Therefore, conditions that

result in significantly elevated levels of IL-1h in the

hippocampus are of particular concern with regards to

cognition.

The behavioral data, together with the in situ hybrid-

ization data, further support the hypothesis that IL-1h-produced memory impairments are mediated via reduc-

tions in hippocampal BDNF mRNA expression. As

discussed earlier, LTP may be a critical process for

forming short-term as well as long-term hippocampal-

dependent memories. It is known that IL-1h inhibits LTP

in the rat hippocampus (Bellinger et al., 1993; Cunning-

ham et al., 1996; Vereker et al., 2000a,b), and BDNF

reductions could also be involved in the mediation of this

interference. For example, BDNF is required for the

induction of LTP in CA1 neurons (Alonso et al., 2002;

Gartner and Staiger, 2002; Korte et al., 1995). Therefore,

IL-1h-mediated BDNF reductions may precede the IL-1h-mediated LTP inhibition.

In addition, IL-1h also causes a profound decrease of

glutamatergic transmission, but not GABAergic inhibition,

in hippocampal CA1 pyramidal neurons (Luk et al., 1999).

Since NMDA receptor activation is necessary for LTP

(Shimizu et al., 2000), and because BDNF, through its

receptor trkB, is critically necessary to potentiate NMDA

receptor activity (Levine et al., 1998; Levine and Kolb,

2000; Sun et al., 2001), this may be another mechanism


involved in IL-1h-mediated impairment of hippocampal-

dependent memories.

BDNF-dependent forms of LTP require activation of L-

type voltage-gated calcium channels (Zakharenko et al.,

2003), and inhibiting calcium release or calcium channel

function prevents BDNF function (Balkowiec and Katz,

2002). Given these findings, it is intriguing that IL-1h has

been shown to inhibit voltage-gated calcium channel

currents in CA1 neurons (Plata-Salaman and ffrench-

Mullen, 1994), an effect that was blocked by IL-1ra.

Although the present data suggest that IL-1h decreases

BDNF mRNA expression, they do not indicate the

mechanism(s) by which this effect comes about. BDNF is

at least in part a CREB-mediated gene (Shieh et al., 1998;

Tao et al., 1998), and there are a number of ways in which

IL-1h receptor signaling could impact on CREB-mediated

transcription. For example, nuclear calcium signaling has

been shown to control CREB-mediated gene expression

(Hardingham et al., 2001) and, as discussed, IL-1h can

inhibit calcium channel currents. Alternatively, IL-1hsignaling activates the NFk-B pathway, and NFk-B com-

petes for the CREB-binding protein (Parry and Mackman,

1997) that is necessary for CREB-mediated transcription

(Kwok et al., 1994). There are other possible mechanisms as

well, but the present data do not address this issue.

Finally, the present data may be of clinical relevance

since patients with Alzheimer’s disease and AIDS dementia

complex (ADC) show both elevated levels of brain

proinflammatory cytokines (Cacabelos et al., 1991; Gallo

et al., 1991; Lombardi et al., 1999; Sheng et al., 1995) and

striking memory impairments (McArthur et al., 1999;

Salmon et al., 1988; Stern et al., 2001; Tross et al., 1988).

Moreover, BDNF is significantly diminished in the hippo-

campi in both of these populations (Boven et al., 1999;

Hock et al., 2000; Murray et al., 1994; Phillips et al., 1991).

Acknowledgements

This work was supported by NIH grants F32-MH64339

and RO1-MH65656.

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