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0:00
>> NAFTALI RAZ: Our next speaker is Carol Barnes. And she will -- her talk will be about animal models of brain adaptation and compensation in aging. So if you were not paying attention to animal studies in compensation and resilience you certainly will be after this talk. >> CAROL BARNES: Thank you.
0:24
Thanks Naftali and thanks for the invitation to be here. My role in this session is going to be to talk about parallel lines of work on brain and cognitive aging, reserve, resilience and compensation in animal models of normative aging.
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Rodent and non-human primate models provide a number of advantages for studying aging including the facts that in fact, animals other than humans do not spontaneously show the most common human neurodegenerative disease, that’s Alzheimer’s disease, and physiological, anatomical, biochemical and molecular circuits in the brain can be examined in greater detail in animals. But of course the objective of our research is to guide understanding of human brain and cognition.
1:12
So it may be fair to ask me at least two questions, and if I don’t ask myself, I think Naftali will probably ask me, so I’ll ask myself. “Why do I think that it’s even remotely reasonable to believe that there may be a correspondence between brain and cognitive aging between species?” And “What have we learned about any of the concepts that this summit is focusing on today from animal models?” Well to partially and quickly answer the first question, I’ll focus on the hippocampus,
1:44
a filo genetically ancient structure that’s well conserved across animals and critical for certain types of memory in all species who have been tested. Even turtles have lovely primordial hippocampus or archie cortex. So this was -- this slide shows what was portrayed to be true about cell loss in human temporal lobe when I first became interested in aging in the early 1970’s. By the time you are 90 your inter-mynocortical cells will be very shriveled.
2:17
But over the decades with well controlled humans, the studies of non-human primates and rodents experiments, one thing we know about the hippocampus during aging is that wide spread cell death is not the norm. In fact the numbers of principal cells such as granule cells CA3 and CA1 pyramidal cells in hippocampus do not decline spontaneously in animals at ages nearing their species-specific lifespan So not in humans, not in monkeys, not in dogs, rats or mice in which these cells have been
2:51
counted, with blind experimental designs and stereological methods. But we know that in each of these species there are memory deficits that suggest some dysfunction of internal and external hippocampal circuits. Now spatial memory is more straight forward than other kinds of memory to examine across species because it does not require language to test its functionality. And spatial memory is observed to change in -- at two years in rats, at 22 year-old monkeys
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and 65 year-old humans, each of these ages considered to be old in these respective species. However I think we need to change the definition of old in humans because I’m now well over on the other side of 65 so I think we need to discuss that but that’s for some other time.
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In this example from rats, the data is shown from Mark Lindner’s lab, shorter path lengths of animals swimming in the Morris water of maze task is not to reflect more accurate navigation and spatial memory. And older rats are worse on average than their younger counterparts.
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To the right you see data from Scott Moffet’s lab, shorter path lengths and a virtual reality navigation experiment and environment also reflects better memory of the environment and this also changes as a function of age, older people are also worse. But what you notice from these data is that in both rats and human data there are--
4:33
there's some variability with older rats and people showing some older rats and people showing quite good memory---quite good memory and some others quite poor. So, as I said previously hippocampus cell numbers don’t change with age across species so why is there a change in memory and what’s responsible for the variability and the degree of memory change? Now this cognitive variability itself suggests individual differences in the extent of brain adaptation in aging.
5:05
Now from animal work we have several clues about where to look for these brain changes. First we know that one form of synaptic plasticity that we believe is used by the brain to lay down memory traces, long term potentiation or LTP, is altered in the aging hippocampus. Now while synaptic strengthening can be induced at old synapses, and by inference these aging synapses can store information, we’ve shown that the strengthening decays more quickly
5:38
in older animals and this faster decay is correlated with how good the old rat’s -- the rat’s memory is actually regardless of age. Furthermore another kind of plasticity that reduces synaptic strength, long term depression or LTD, is easier to deduce in aging hippocampus, which was shown by Tom Foster’s lab. So from animal work one answer to the question, why memory changes with age, is that these plasticity mechanisms are altered.
6:14
Another thing we know from animal model work is that while cell numbers remain reasonably stable, synapses -- you know these important points of communication between cells that wire up critical memory circuits in the brain -- synapses are lost during aging. For example, early work by Geinismin and his colleagues and electrophysiological data from the rat suggest axon pruning and the loss of up to about a third of synapses from the medial entorhinal cortical projection into the hippocampus.
6:46
These findings have been replicated many times in animal models with a number of newer techniques. And in fact, more recently this kind of white matter pruning has been confirmed in healthy older humans including work from Craig Stark and Leila De Telidamorel’s labs where using MRI methods their data suggests a thinning of the white matter tract connecting the entorhinal cortex and the hippocampus. So we have evidence from animal models that suggest
7:16
that synaptic loss also contributes to memory decline, and presumably the degree of change in these plasticity mechanisms and loss of connections could in part explain differences in cognitive reserve and resilience between individual animals. Now I want to say a little bit more now about how animal models have contributed to conceptualizing ideas about brain compensation in aging. I’ll start with this ancient text, published in 1980, I supposed you could call it
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classic literature to be less judgmental, but the data in this manuscript combined in vivo electrophysiological recordings of synaptic potentials in young and old rats that I collected for my thesis experiments in Del Hauser University working in Graham Goddard’s lab. And because the electrophysiological measurements that I obtained were extra cellular there were some, or several alternative explanations for reduced amplitudes of the synaptic and
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pre-synaptic responses in the dentate gyrus of old rats. An exact interpretation could only be given by doing intra-cellular recordings so that I could get direct voltage measurements. So in the late 1970’s the best place to learn in vitro hippocampal slice technology was Per Anderson’s lab in Oslo. And Per said he would give me a spot in his lab if I could get a fellowship.
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I’m not sure why I thought the U.S. Government would support somebody who had been in Canada for seven years for graduate school to then go off to Norway for two more years. But I applied in 1978 for a post-doctoral fellowship in NRSA from the National Institute on Aging, which had just been established in 1976. And Zaven Katchaturian who was the neuroscience program officer -- whatever they were called in those days -- took a bet on me and I got the very first NRSA in neuroscience
9:16
from the National Institute on Aging and went off to Norway in 1979. Bruce McNaughton was also able to get an insert post doctoral fellowship from Canada to do other work in Anderson’s lab. So in Oslo, we obtained evidence consistent with the idea of a pruning of axon collaterals and synapses from the medial entorhinal cortical projection onto hippocampus granule cells in old rats in the in vitro hippocampus slice preparation and these data replicated the
9:46
in vivo recordings I had done in Halifax. Now the fiber potential is a reflection of the number of axon collaterals from layer two of the entorhinal cortex that can be activated. And you see here there’s no change in the activation threshold but evidence for a reduced number of pre-synaptic fibers in old rats. And to the right, even though the fiber potentials response was smaller in the older rats, the synaptic responses were proportionately greater in these old animals.
10:21
And it was critical that this finding held, both for extra cellular and inter cellular voltage measurements, suggesting that the remaining synapses were slightly stronger in old rats. Now this result was consistent with the idea of compensation at a single synapse level. And the plausibility of this interpretation was strengthened when in 1991 Tom Foster conducted, what I can only call heroic, quantal analysis experiments in our lab using minimal stimulation techniques.
10:56
With this method you can stimulate a single axon collateral and measure the depolarization of granule cells generated by a single synapse. So, Tom was able to then directly show that the strength of individual synapses was increased in old rats. With respect to the idea that the aging brain might actually, actively adapt in response to a primary change in the number of synaptic context. The compensation narrative when something like this,
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okay If old granule cells can lose up to a third of their synapses from the medial entorhinal cortex and we know that each granule cells needs a certain level of depolarization or activation to fire an action potential, then how do these cells transmit incoming information to circuits downstream of the hippocampus?” And the idea emerged at that time, that well the hippocampus may solve this reduced input problem by increasing the strength of the individual synapses
12:02
that remain on old granule cells. And this is how the compensation was defined in these early experiments.
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But the question is how do we know this is compensation and that synapse loss is the primary trigger for synaptic strengthening? And here you see schematic of fewer but stronger synapses onto -- in old rats onto granule cells. And the stronger synapses in old animals may well help counter balance the effect of synaptic loss. But Monica Chala in our lab, has shown that fewer old granule cells actually are activated during behavior by using gene expression activity markers to monitor self-spiking.
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So this suggests that the increase in synaptic strength is not sufficient to completely restore normal network activity during behavior, so that this compensation doesn’t mean that the circuit is back to normal completely.
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But the open question is then, how then would the network behave if there was no synaptic strengthening? The argument made is that the system might fall below some critical threshold for functional circuit out throughput. And this hypothesis directly predicts that aged animals with higher cognitive ability may have more synapses, stronger synapses or both than those animals showing low performance levels. Now the experiments to test this hypothesis have not been done, but the results could
13:35
either refute or support the compensation idea. Always good to have an experiment that could actually disprove your hypothesis, but if this was positive it would point to changes in synapses in being a primary trigger for adaptive responses in aging brains. One important thing to keep in mind, and I know that Cheryl Grady and others will have more to say about this, you can’t just look at one part of the circuit
14:05
to understand the aging brain vulnerability or adaptability, rather you need to keep in mind the complexity of the circuit exam and how perturbation of one component of the network will likely impact the regions to which it’s connected. And I’m focusing here on the input from the entorhinal cortex to the hippocampus for simplicity. And even this myopic view you can see, can become quite complex. So I’m going to give you an example now, my final example, CA3 pyramidal cells.
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There’s a reduced input from the dentate gyrus. I just told you that fewer granule cells are active during behavior. Peter Raff’s lab has showed that CA3 also receives reduced input from the entorhinal cortex. But from these facts you might have expected that CA3 cells would be less active. But we know Ian Wilson with Michaela Gallagher showed that CA3 pyramidal cells in aging rats show higher frying rates than young. Alex Tomei in my lab has shown that CA3 cells in old monkeys show
15:03
higher frying rates than young and Mike Yassa has shown that older adults show increase bold signal in CA1 region of the -- in CA3 region of the hippocampus. So could part of this explanation of this hyper excitability be the result of a compensatory strengthening of synapses from CA3 from the dentate gyrus and entorhinal cortex just like we saw for the granule cells? Again, experiments just explore these ideas have not yet been done.
15:33
Another change in CA3 circuit that could help contribute to this hyper excitability is a change in interneurons. So while it remains controversial whether a decrease in inhibitory neurons is observed in CA3 and rats and monkeys, Alex Tomei has shown that there’s a reduction in somatostatin
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neurons in associated with higher firing rates in CA3.
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I’m running out of time so I won’t go through the details of this but in fact these -- the fewer neurons is associated with greater firing rates. So what do these -- how does this change happen? We think it’s a change in chemical phenotype in these interneurons because the same numbers of neurons overall exist. But what do these data imply? Well could there be two compensatory responses to a decrease drive on the CA3 from the dentate gyrus and entorhinal cortex.
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Increased synaptic strength and decreased numbers of inhibitory cells. Is this compensation gone wrong?
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So I have several thoughts to leave you with.
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One provocative issue I raise in closing is that if our goals is to assist the aging brain to achieve an optimal state or function at older ages I think that understanding the compensatory or adaptive reactions to primary age related changes is going to be critical. Another point to raise is that the use of non-human primates is going to be important to bridge a gap between rodent and human aging and this resource is under great strain right now and I’m hoping that it will survive.
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And finally we need to fully embrace the idea that the brain is not passively sitting back during the aging process, the brain is continuously adapting and changing throughout the lifespan, making it crucial to be strategic in our attempts to modify the circuits within this really magnificent and actively adapting organ. And just quickly to say that I’m grateful to the Midnight Brain Foundation and NIA for all their years of support, thanks. [applause]
17:57
>> NAFTALI RAZ: We have time for a couple of questions, so please step to the microphone.
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>> MALE SPEAKER: When do you think these changes begin? Most of the work you’re talking about, particularly with the hyper excitability in the very olds, we’re looking at an adaptation what should we look for earlier? >> CAROL BARNES: Right, so we all – most of us don’t do longitudinal studies in our animals because you have to sacrifice them at the end so forth and implants don’t last that long, and we can’t precisely answer the question in point.
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It starts--my intuition is that we need to go earlier and earlier, you know, not only if we’re going to alter cognitive trajectories over the lifespan we need to get those manipulations in the system as early as possible so that we can optimize how we will go forward in aging. So I don’t have a pinpoint answer to that now. Katherine. >> KATHERINE: Yeah, great talk Carol. My question is similar to Tom’s. What do we think the initiating events are that we need to compensate for?
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And I think part of that will be longitudinal studies but is this going to be -- are we looking for a molecular switch, a cellular change or a network phenomenon? >> CAROL BARNES: It’s going to be cells but how they participate in the network it’s got to be, so I can’t separate those. I think there’s a number of molecular switches that might be modifiable to keep our circuits more plastic and to evolve in a more favorable way.
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And we’re all trying cognitive intervention you know, dietary interventions, lifestyle and so forth to try to see what the maximum effects would be by doing those kinds of manipulations in aging. Hi. >> RICHEY SHARRETT: Hi, fascinating talk.
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Dogs kept in peoples homes who live well beyond their natural lifespan of course do develop beta amyloid one to 42 and veterinaries see dementia very often in dogs that are 12 years old and so on. Are you quite sure that your rats, I haven’t heard anything about rodents in beta amyloid. don’t have beta amyloid. >> CAROL BARNES: Still dogs do not develop the pure classical symptoms of Alzheimer’s disease, they don’t get hyper phosphorylated tau and so forth.
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And cerebral angiopathy is one thing and these plaques are another. No rats don’t and I have a study ongoing very carefully characterizing monkeys over the lifespan that I hope to get out this summer to show that they also do show some plaques, don’t show tangles and their cognition does change.
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>> NAFTALI RAZ: I’m sorry, I think we’re out of time. So, sorry but we’ll have to save this question for the general discussion.
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