JN Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Neurophysiol 98: 1048-1051, 2007. First published May 30, 2007; doi:10.1152/jn.00250.2007
0022-3077/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
98/2/1048    most recent
00250.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Abraham, W. C.
Right arrow Articles by Benuskova, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Abraham, W. C.
Right arrow Articles by Benuskova, L.

REPORT

"Heterosynaptic" LTD in the Dentate Gyrus of Anesthetized Rat Requires Homosynaptic Activity

Wickliffe C. Abraham, Barbara Logan1, Amy Wolff1 and Lubica Benuskova2,3

1Department of Psychology, University of Otago, Dunedin, New Zealand; 2Knowledge Engineering and Discovery Research Institute, Auckland University of Technology, Auckland, New Zealand; and 3Department of Applied Informatics, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovakia

Submitted 6 March 2007; accepted in final form 25 May 2007


ABSTRACT
 
TOP
 ABSTRACT
INTRODUCTION
 GRANTS
 REFERENCES
 
Heterosynaptic long-term depression (LTD) is conventionally defined as occurring at synapses that are inactive during a time when neighboring synapses are activated by high-frequency stimulation. A new model that combines computational properties of both the Bienenstock, Cooper and Munro model and spike timing-dependent plasticity, however, suggests that such LTD actually may require presynaptic activity in the depressed pathway. We tested experimentally whether presynaptic activity is in fact necessary for previously described heterosynaptic LTD in lateral perforant path synapses in the dentate gyrus of urethane-anesthetized rats. As predicted by the model, procaine infusion into the lateral path fibers, sufficient to transiently block neural activity in this pathway, prevented the induction of LTD in the lateral path following medial path high-frequency stimulation. These data indicate that the previously described heterosynaptic LTD in the dentate gyrus in vivo is actually a form of homosynaptic LTD, requiring presynaptic activity in the depressed pathway.


INTRODUCTION
 
TOP
 ABSTRACT
 INTRODUCTION
GRANTS
 REFERENCES
 
Traditionally, long-term depression (LTD) has been classified as being either homo- or heterosynaptic in nature (Bear and Abraham 1996Go). Homosynaptic LTD (hom-LTD) refers to depression at the same synapses as those stimulated to induce the LTD effect. In contrast, heterosynaptic LTD (het-LTD) refers to depression at synapses neighboring the activated ones but not directly activated themselves. In this latter case, the stimulated synapses typically exhibit homosynaptic LTP simultaneously with the het-LTD, although it is not clear that this is a requirement for het-LTD induction. In the hippocampus, hom-LTD has been observed in all excitatory pathways tested. Het-LTD has been more elusive, with the bulk of reports arising from in vivo studies of perforant path synapses in the dentate gyrus (Abraham and Goddard 1983Go; Doyere et al. 1997Go; Levy and Steward 1979Go). Intriguingly, het-LTD is difficult to obtain in dentate gyrus synapses in vitro (Hanse and Gustafsson 1992Go), whereas hom-LTD is more readily observed (Wu et al. 2001Go).

One difference between in vivo and in vitro dentate gyrus preparations may be the degree of resting activity in the presynaptic axons. Typically resting activity is low in the slice preparation and certainly in the dentate gyrus the perforant path axons are expected to be completely quiescent as their cell bodies of origin in the entorhinal cortex have been cut off during slice preparation. In contrast, entorhinal cortical neurons afferent to the dentate gyrus exhibit resting activity on the order of 2–8 Hz in the anesthetized preparation (Dickson et al. 1994Go; Gloveli et al. 1997Go). Could such ongoing activity contribute to het-LTD induction in vivo? In a recent computational model of dentate synaptic plasticity that merges principles of the Bienenstock, Cooper, and Munro (BCM) model (Bienenstock et al. 1982Go) and spike-timing dependent plasticity, we observed that simulated het-LTD in the lateral perforant path synapses could be readily induced when the medial perforant path was given LTP-inducing stimulation (Benuskova and Abraham 2007Go). However, induction of such apparent het-LTD may in fact have required activity in the depressed pathway during medial path high-frequency stimulation (HFS) because this model incorporates a parameter for ongoing synaptic activity in the lateral path at a rate of 8 Hz as observed experimentally (Frank et al. 2001Go). The results from this modeling prompted us to address more carefully the role of resting activity in het-LTD through experimental hypothesis testing and further modeling. Our results indicate that apparent het-LTD in vivo is in fact a form of hom-LTD, dependent on activity in the depressed pathway.

Adult male Sprague-Dawley rats (2–4 mo) were anesthetized with urethan (1.5 g/kg ip) and prepared for stereotaxic implantation of medial and lateral path stimulation electrodes plus an extracellular field potential recording electrode in the dentate hilus, as previously described (Christie and Abraham 1992Go) and as approved by the University of Otago Animal Ethics Committee. The lateral path stimulating electrode was glued to a 30-gauge stainless steel cannula such that it projected ~0.5 mm below the cannula. The cannula was attached via polyethylene tubing to a syringe pump (Harvard Apparatus, Holliston, MA) for microinjection of either procaine (200 mg/ml) or phosphate-buffered saline (PBS) vehicle. The medial and lateral path electrode positions were adjusted to maximize evoked field potentials with the electrophysiological signatures of each pathway, including waveshape and paired-pulse responses, as previously described (Abraham and Goddard 1983Go; Abraham et al. 2001Go).

Low-frequency baseline stimulation (150–600 µA, 150-µs pulse duration) alternated between the two perforant pathways at 15-s intervals. When the responses were stable for 30 min, either PBS or procaine (0.25 µl) was injected into the lateral path over a 2.5-min period. HFS, consisting of 50 trains (400 Hz, 25 ms, 250-µs pulse duration) given in sets of five trains at 0.1 Hz (1 min between sets), was given to the medial path 5 min after solution injection. Test shocks at the baseline intensity and frequency were resumed for a further 60-min recording period. The slope of the field excitatory postsynaptic potentials (fEPSPs) was measured for both the medial and lateral path responses and expressed as a percentage change from the average baseline value prior to injection. Statistical comparisons between groups were made by Student's t-test, with a significance level set at 0.05. All data are expressed as means ± SE.

For modeling heterosynaptic plasticity in the dentate gyrus, we used the computational model described in Benuskova and Abraham (2007)Go, in which one model neuron represents the whole population of experimentally tested granule cells. The model neuron is the Izhikevich spiking neuron (Izhikevich 2003Go) with two input pathways, the lateral and medial perforant paths. Each input is characterized by a certain number of input fibers engaged by stimulation and by the synaptic weight of each fiber. Synapses modify according to a spike-timing-dependent plasticity (STDP) rule. We made the size of STDP windows for LTP and LTD changeable as a function of the previous average of postsynaptic activity of the model granule cell according to the relation proposed for the BCM moving LTD/LTP threshold (Bienenstock et al. 1982Go). Less average activity in the past leads to a bigger timing window for potentiation and a smaller window for depression, and vice versa.

In the model's control condition, where simulated ongoing activity was present at both input pathways, medial HFS led to medial path LTP and lateral path het-LTD (Fig. 1, A and B), similar to that observed experimentally (Abraham et al. 2001Go). The requirement for presynaptic activity to generate LTD in the lateral path following medial path HFS was tested by setting the lateral path resting and evoked activity parameters to zero for a 5-min period prior to the simulated HFS and for the subsequent testing period. As can be seen in Fig. 1A, this parameter change had no influence on the induction of LTP in the medial path but completely prevented the development of LTD in the lateral path (Fig. 1B) as detected by monitoring the total synaptic weights corresponding to the medial and lateral paths, respectively. Thus in the model, induction of apparent "heterosynaptic" LTD in the lateral path actually is dependent on activity in that pathway.


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		FIG. 1. Results of the computational modeling showing the summed perforant path synaptic weights on a simulated dentate gyrus granule cell before and after high-frequency stimulation (HFS) of the medial perforant path. A: weight changes in the medial path synapses comparing conditions when the lateral path resting activity is either normal (control) or set to 0 from t = 40–100 min (no lateral activity). The initial reduction in the medial path response early in the HFS period probably reflects a competition between long-term depression and potentiation (LTD and LTP) processes that is initially won, on average, by LTD. This initial response reduction is not observed experimentally, however. B: similar data as in A but for the lateral path synapses. Note the loss of lateral path LTD when resting activity in that pathway is set to zero. For these simulations, the model used was the same as that described in Benuskova and Abraham (2007)Go with the scaling factor equal to 5,000 and no hard limits on maximal or minimal values of the synaptic weights.

 
To experimentally test the need for presynaptic activity in the lateral path to induce LTD in vivo, the local anesthetic procaine was injected into the lateral path component of the angular bundle through a cannula attached to the stimulating electrode. The injection was considered to have successfully blocked lateral path presynaptic activity selectively if the fEPSP response to lateral path test pulse stimulation was reduced by ≥85%, whereas the medial path response was not reduced at all. HFS was given to the medial path during maximal inhibition of the lateral path response (Fig. 2). As expected, procaine delivery had no effect on the degree of LTP elicited in the medial path measured 60-min post-HFS compared with saline vehicle-treated controls (37 ± 5%, n = 7 vs. 37 ± 4%, n = 7, respectively, n.s.; Fig. 2A). In contrast, the degree of lateral path response suppression in the same animals at this time point was reduced in the procaine-treated group (–10 ± 6%, n = 7) compared with the control group (–24 ± 3%, n = 7; P < 0.05; Fig. 2B). When a second medial path HFS was delivered, the control group showed no further lateral path LTD. Likewise, the second HFS in the procaine group generated no LTD; rather, the lateral path response continued to return toward baseline (–5 ± 8%, n = 6).


Figure 2
View larger version (17K):
[in this window]
[in a new window]

  		FIG. 2. Experimental data in which procaine was used to transiently silence presynaptic activity in the lateral path. A: medial path field excitatory postsynaptic potential (fEPSP) responses after medial path HFS, comparing the saline-treated group (control) with the procaine-treated group. Injections were made into the lateral perforant path (see B, thick arrow). A 2nd tetanus (HFS2) failed to induce further LTP for both groups. Data are means ± SE percent change from baseline. Scale bars: 2 mV, 5 ms. B: similar data as in A but showing the suppressive effect of procaine injection on lateral path-evoked responses and its inhibition of LTD compared with saline-injected controls, seen after procaine wash-out. A 2nd tetanus also failed to induce LTD in the procaine group and produced no further LTD in the control group. Inset: waveforms are averages of 10 sweeps taken just before injection (1) and 60 min post-HFS1 (2).

 
The residual response suppression noted in the procaine-treated group was not a reduced degree of LTD but rather a result of the slow washout of procaine because a third group of animals given procaine but no HFS showed a similar degree of slow recovery from the response suppression (–11 ± 3%, n = 6; Fig. 3, A, B, and D). Thus procaine during the HFS appeared to completely block het-LTD. What was still uncertain was whether resting activity was sufficient to preserve the het-LTD or whether the stimulus-evoked activity also was necessary because both would be blocked by procaine. To test this, we simply stopped stimulating the lateral path during and for 40 min after medial path HFS, a procedure that should have left relatively undisturbed the resting activity in the lateral path, although this could not be directly verified in the present experiment. In the absence of procaine, stopping lateral path stimulation did not prevent LTD from occurring (–17 ± 5%, n = 6; Fig. 3, C and D), but as this was slightly less than the control level of LTD, it remains possible that evoked activity contributed to a small portion of the full LTD in control animals.


Figure 3
View larger version (17K):
[in this window]
[in a new window]

  		FIG. 3. A and B: comparison of the medial (A) and lateral (B) path responses for the procaine plus medial path HFS group with a procaine injection only group. Note that recovery of the lateral path responses from the procaine injection is equivalent for the 2 groups, indicating that medial path HFS generated no LTD in the procaine-treated lateral path. C: turning off the lateral path stimulation (during time between the 2 thick arrows) during and after medial path HFS did not significantly affect lateral path LTD compared with the control group. D: summary histogram illustrating the inhibition of lateral path LTD by procaine treatment, and lack of LTD inhibition when lateral path test pulses were turned off instead. Asterisk, P < 0.05 compared with control group, Student's t-test.

 
One intriguing finding was that a second HFS given to the original procaine group after washout failed to elicit lateral path LTD (Fig. 2B). We considered that this reflected either a residual effect of the procaine itself or else a persistent effect of the temporary loss of lateral path resting activity. However, neither interpretation was correct as the procaine control group that did not receive medial path HFS until 60 min after washout did show normal LTD after receiving an HFS (–35 ± 7%, n = 4; Fig. 3B). This suggests that the continued lack of LTD in the original procaine group was a metaplastic effect of the first HFS, which prevented LTD induction 60 min later in much the same way as it prevented further LTP induction (Fig. 2A) (Frey et al. 1995Go). An alternative view to the metaplasticity explanation is that LTD is conditional on generation of LTP in the stimulated pathway (Doyere et al. 1997Go), perhaps as a method of normalizing overall synaptic input to the postsynaptic neurons. However, we currently believe this interpretation to be less likely as LTP and LTD are not generally tightly coupled in the hippocampus given the many examples of LTP (e.g., present experiment) and LTD (many studies of homosynaptic LTD) being induced in isolation.

Taken together, the findings from both the computational modeling and the electrophysiological experimentation strongly support the view that so-called "het-LTD" in the dentate gyrus in vivo actually is a form of hom-LTD that requires presynaptic activity in the depressed pathway during the period of LTD induction. In the case of the modeling, this is not surprising because the model does not include a parameter that would permit LTD induction in the absence of presynaptic activity. However the model was instructive because it demonstrated that resting activity in one pathway is in principle sufficient to induce LTD when local conditions are altered by the HFS in a separate pathway. In the model, medial path HFS generates a period of time when the lateral path activity is decorrelated with granule cell firing and thus more susceptible to spike-timing-dependent LTD. The experimental work confirmed that resting activity in the to-be-depressed synapses is necessary for LTD induction as block of resting activity in the lateral path by procaine (gauged by the loss of stimulus-evoked responses) was sufficient to prevent LTD. In contrast, procaine delivery had no effect on medial path LTP, nor on the metaplastic inhibition of LTP and LTD induction by a second HFS. One cautionary note to these interpretations is that the present experiments were conducted in urethan-anesthetized animals. We predict that similar mechanisms account for het-LTD in awake animals, but this remains to be tested.

The presence of ongoing presynaptic activity in vivo raises the question of why it does not cause hom-LTD under these resting conditions and therefore occlude further depression as induced experimentally. In the model, as noted in the preceding text, the modification threshold has settled at a point where LTD and LTP are balanced and no net change occurs (Benuskova and Abraham 2007Go). HFS leads to desynchronization of medial and lateral path presynaptic activity and therefore reduced co-occurrence of presynaptic activity and postsynaptic spiking during the STDP window for potentiation. Net LTD thus occurs. This may explain the pattern of results in vivo, but other interpretations are also possible. For example, there may be a modifiable threshold for LTD (Artola and Singer 1993Go) that is driven to the right by spontaneous activity until such activity is incapable of inducing LTD. Hom-LTD in this case would require more synchronized and therefore depolarizing presynaptic activity than occurs spontaneously to be induced (see also Kerr and Abraham 1995Go). To cross this LTD threshold, it may take the medial path HFS to drive the threshold transiently to the left and thereby permit basal activity to elicit LTD. Alternatively, it is conceivable that lateral path activity is increased transiently through polysynaptic activation of this pathway during medial path HFS.

The requirement for presynaptic activity to induce "het-LTD" helps explain why it has been easier to observe in the dentate gyrus of intact animals than in the dentate gyrus slice preparation for which there have been no reports of het-LTD to our knowledge. This mechanism also appears to contribute to het-LTD described in polysynaptic visual pathways of anesthetized kittens (Tamura et al. 1992Go). Het-LTD has been reported, however, in hippocampal CA1 slices, particularly under conditions of very strong stimulation and postsynaptic depolarization (Abraham and Wickens 1991Go; Scanziani et al. 1996Go). It may be that under these conditions there is a very large shift in the modification threshold such that very low levels of resting activity in CA3 pyramidal cells, or even spontaneous release of transmitter at the Schaffer collateral terminals, is sufficient to elicit the LTD. Alternatively, under these conditions a true het-LTD at nonactive synapses may be generated through sufficient calcium mobilization postsynaptically, as theorized by Artola and Singer (1993)Go or else a diffusible signal for LTD induction is released by neighboring cells (Scanziani et al. 1996Go).

The LTD evoked in the present experimental study appears to be a hybrid form of LTD akin to previously described associative LTD (Christie and Abraham 1992Go; Debanne et al. 1994Go; Stanton and Sejnowski 1989Go). Here presynaptic activity is normally insufficient to cause plasticity, but it has the capability to do so when conditions are associatively altered by activity in a second pathway, in this case medial path HFS. In our model, the key alteration induced by the HFS is a decorrelation of lateral path presynaptic activity and granule cell postsynaptic activity (Benuskova and Abraham 2007Go). Regardless of the actual mechanism, these findings point to a complex dynamism of the plasticity properties of perforant path synapses that is a function of activity in all the afferent pathways.


GRANTS
 
TOP
 ABSTRACT
 INTRODUCTION
 GRANTS
REFERENCES
 
This work was supported by grants from the New Zealand Health Research Council, the University of Otago Research Committee, National Institute of Neurological Disorders and Stroke Grant NS-021184, and the Slovak Grant Agency VEGA 1/2045/05.


FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: W. Abraham, Dept. of Psychology, Box 56, University of Otago, Dunedin, New Zealand (E-mail. cabraham{at}psy.otago.ac.nz)


REFERENCES
 
TOP
 ABSTRACT
 INTRODUCTION
 GRANTS
 REFERENCES
 
Abraham WC, Goddard GV. Asymmetric relations between homosynaptic long-term potentiation and heterosynaptic long-term depression. Nature 305: 717–719, 1983.[CrossRef][Medline]

Abraham WC, Mason-Parker SE, Bear MF, Webb S, Tate WP. Heterosynaptic metaplasticity in the hippocampus in vivo: a BCM-like modifiable threshold for LTP. Proc Natl Acad Sci USA 98: 10924–10929, 2001.[Abstract/Free Full Text]

Abraham WC, Wickens JR. Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus. Brain Res 546: 336–340, 1991.[CrossRef][Web of Science][Medline]

Artola A, Singer W. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends Neurosci 16: 480–487, 1993.[CrossRef][Web of Science][Medline]

Bear MF, Abraham WC. Long-term depression in the hippocampus. Annu Rev Neurosci 19: 437–462, 1996.[CrossRef][Web of Science][Medline]

Benuskova L, Abraham WC. STDP rule endowed with the BCM sliding threshold accounts for hippocampal heterosynaptic plasticity. J Comp Neurosci 22: 129–133, 2007.[CrossRef][Web of Science][Medline]

Bienenstock EL, Cooper LN, Munro PW. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J Neurosci 2: 32–48, 1982.[Abstract]

Christie BR, Abraham WC. Priming of associative long-term depression by theta frequency synaptic activity. Neuron 8: 79–84, 1992.

Debanne D, Gahwiler BH, Thompson SM. Asynchronous pre- and postsynaptic activity induces associative long-term depression in area CA1 of the rat hippocampus in vitro. Proc Natl Acad Sci USA 91: 1148–1152, 1994.[Abstract/Free Full Text]

Dickson CT, Trepel C, Bland BH. Extrinsic modulation of theta field activity in the entorhinal cortex of the anesthetized rat. Hippocampus 4: 37–51, 1994.[CrossRef][Web of Science][Medline]

Doyere V, Srebro B, Laroche S. Heterosynaptic LTD and depotentiation in the medial perforant path of the dentate gyrus in the freely moving rat. J Neurophysiol 77: 571–578, 1997.[Abstract/Free Full Text]

Frank LM, Brown EN, Wilson MA. A comparison of the firing properties of putative excitatory and inhibitory neurons from CA1 and the entorhinal cortex. J Neurophysiol 86: 2029–2049, 2001.[Abstract/Free Full Text]

Frey U, Schollmeier K, Reymann KG, Seidenbecher T. Asymptotic hippocampal long-term potentiation in rats does not preclude additional potentiation at later phases. Neuroscience 67: 799–807, 1995.[CrossRef][Web of Science][Medline]

Gloveli T, Schmitz D, Empson RM, Heineman U. Frequency-dependent information flow from the entorhinal cortex to the hippocampus. J Neurophysiol 78: 3444–3449, 1997.[Abstract/Free Full Text]

Hanse E, Gustafsson B. Long-term potentiation and field EPSPs in the lateral and medial perforant paths in the dentate gyrus in vitro: a comparison. Eur J Neurosci 4: 1191–1201, 1992.[CrossRef][Web of Science][Medline]

Izhikevich EM. Simple model of spiking neurons. IEEE Trans Neur Netw 14: 1569–1572, 2003.[CrossRef]

Kerr DS, Abraham WC. Cooperative interactions among afferents govern the induction of homosynaptic LTD in the hippocampus. Proc Natl Acad Sci USA 92: 11637–11641, 1995.[Abstract/Free Full Text]

Levy WB, Steward O. Synapses as associative memory elements in the hippocampal formation. Brain Res 175: 233–245, 1979.[CrossRef][Web of Science][Medline]

Scanziani M, Malenka RC, Nicoll RA. Role of intercellular interactions in heterosynaptic long-term depression. Nature 380: 446–450, 1996.[CrossRef][Medline]

Stanton PK, Sejnowski TJ. Associative long-term depression in the hippocampus induced by hebbian covariance. Nature 339: 215–218, 1989.[CrossRef][Medline]

Tamura H, Tsumoto T, Hata Y. Activity-dependent potentiation and depression of visual cortical responses to optic nerve stimulation in kittens. J Neurophysiol 68: 1603–1612, 1992.[Abstract/Free Full Text]

Wu J, Rush A, Rowan MJ, Anwyl R. NMDA receptor- and metabotropic glutamate receptor-dependent synaptic plasticity induced by high frequency stimulation in the rat dentate gyrus in vitro. J Physiol 15: 745–755, 2001.




This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
P. J. Sjostrom, E. A. Rancz, A. Roth, and M. Hausser
Dendritic Excitability and Synaptic Plasticity
Physiol Rev, April 1, 2008; 88(2): 769 - 840.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
98/2/1048    most recent
00250.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Abraham, W. C.
Right arrow Articles by Benuskova, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Abraham, W. C.
Right arrow Articles by Benuskova, L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the The American Physiological Society.