Several studies have shown that hippocampal place cells encode not only where we are, but where we’re going.  For example, rats can be trained in a maze where they start at one end, run down an alley, and are presented with a fork in the road: they can go left or right.  While the rat is still running down the alley, some hippocampal neurons begin to fire if the rat is going to turn left, and others fire if the rat is going to turn right.  Thus, just by observing which group of neurons is firing, researchers can predict what the rat is about to do.  Presumably, such “prospective encoding” by neurons helps rats (and us) plan a sequence of actions that will help us get where we want to be in the future.

A recent study by Pamela Kennedy and Matthew Shapiro shows that this prospective encoding is not limited to purely spatial information.  In their study, the rat is always placed at one end of a long alley and, at the far end, has a choice of entering a white goal box or a black goal box.  The location of these boxes can vary. On some days, the rat is deprived of water, making it thirsty; if the rat runs into the white goal box, it will find water there.  On other days, the rat is deprived of food, making it hungry; if the rat runs into the black goal box, it will find food there.  (After the testing session, the rats are generally allowed free access to food and water – it’s only right before the testing that they are made hungry or thirsty.)

Kennedy and Shapiro found that some hippocampal place cells fired when the rat was running down the long alley – but only if the rat was thirsty and intending to head for the water-associated goal box.  Other neurons also fired when the rat was running down the alley – but only if the rat was hungry and intending to head for the food-associated goal box.  Because the location of the goal boxes varied, this wasn’t purely spatial information (“when you reach the end of the alley, turn left”); rather, these neurons seemed to encode what goal the rat was seeking (“when you reach the end of the alley, turn towards the white to obtain water”).

Assuming that similar encoding happens in the hippocampus of other mammals, including humans, such neurons could be an important component helping our brains to retrieve particular memories that are especially relevant to our current goals, allowing us to select among possible actions based on our memories of how well those actions helped us achieve particular goals in the past.

Further reading:

Pamela J. Kennedy & Matthew L. Shapiro (2009). Motivational states activate distinct hippocampal representations to guide goal-directed behaviors. Proceedings of the National Academy of Sciences, vol. 106, no. 26, pp. 10805-10810.

One thorny question has always been whether this age-associated impairment reflects a failure of learning or of retention.  Are older people less able to learn (encode) new information – or do they successfully learn the information but then fail to retain it, perhaps due to accelerated forgetting?

A new study in mice suggests that the age-related impairment is one of learning, not forgetting.  Louis Matzel and colleagues tested young mice against mice aged 19-21 months (a ripe old age for mice).  Unsurprisingly, the elderly mice were slower than young mice on several kinds of learning tasks.  But, with extended training, this deficit could be overcome, so that the overtrained elderly mice performed as well as their younger counterparts.

The new twist in this study was that both groups of mice were tested on their learning after an interval of 30 days.  The younger mice tended to remember well.  The older mice who had been overtrained could also remember well.  Only the elderly mice whose initial training had been incomplete showed poor performance on the retention test.  This suggests that, once the elderly mice do learn the information, they do not forget it at a higher rate than young mice.  The trick is to use overtraining to get the information properly stored in the first place.

Obviously, mice are not people; but some important facts about learning and memory that have been observed in mice turn out to be true in other mammals too, including humans.  In this case, the conclusion would be that elderly individuals may need a little longer to get new information safely stored in the brain.  But once safely stored, that information may be no more vulnerable to forgetting than in a younger brain.

Further reading:

L. D. Matzel and others (2009). “Age-related impairments of new memories reflect failures of learning, not retention.” In, Learning and Memory, vol. 16, no. 10, pp. 590-594.

One counterargument often made by those who believe in ginkgo’s beneficial effects is that these studies were simply too short, and that the benefits of ginkgo only emerge if taken over a period of years.

Now, a new report seems to lay even that objection to rest.

Published in the prestigious  Journal of the American Medical Association (JAMA) in December 2009, this latest study followed over 3000 non-demented elderly individuals, randomly assigned to take either ginkgo or placebo twice daily.  Importantly, this was a double-blind study, meaning that during the study, neither the participants nor the researchers who evaluated them knew which individuals were taking which type of pill.  This procedure prevents the participants and researchers from (even inadvertently) allowing their beliefs about ginkgo’s efficacy, or lack thereof, from influencing the results.

Participants were followed for a median of over 6 years, and checked for rates of change on various cognitive measures, including tests of memory, attention, and executive function.  Unsurprisingly, the participants on placebo showed a mild annual decline on these measures – but the participants on ginkgo showed just as much decline.

The researchers also conducted genetic testing, particularly for presence of the APOE-E4 allele, a naturally-occurring genetic variant that increases a person’s risk for developing Alzheimer’s.  Some have suggested that, perhaps, the protective effects of ginkgo depend on whether an individual carries this genetic variant.  But, again, the results of this long-term study showed no evidence of any beneficial effects, either on carriers or non-carriers of the APOE-E4 allele.

In sum, long-term usage of ginkgo had little or no effect on protecting against memory decline in non-demented elderly individuals.  As of now, the bulk of scientific evidence points overwhelmingly in the same direction: arguing against any beneficial effects of ginkgo biloba, either in protection against cognitive decline, or in protection from Alzheimer’s, or in improving memory function in individuals who already have Alzheimer’s.

Further Reading:

B. E. Snitz and others (2009). Ginkgo biloba for preventing cognitive decline in older adults: A randomized trial. In Journal of the American Medical Association (JAMA), vol. 302, no. 24, pp. 2663-2670.

In healthy adults, sleep is known to affect consolidation: the process whereby information accumulated during the day is slowly integrated into the brain’s long-term networks, where it can become a lasting memory.  In research studies, volunteers who learn a new skill or memorize new facts can sometimes perform better the next morning – after a good night’s sleep allows them to consolidate the information – than they did the day before.

The relationship between a good night’s sleep and good memory in healthy adults raises the possibility that sleep deprivation in schizophrenia may be a contributing cause to some of the cognitive disturbance in that disorder.

In fact, sleep complaints are common among patients with schizophrenia, and can include difficulty falling asleep and staying asleep.  Even the type of sleep may be affected. During the course of a night, normal adults cycle through several stages of sleep, including periods of rapid eye movement (REM) sleep and “slow wave sleep” (SWS).  One theory is that SWS may help stabilize or reinforce memories, while REM sleep helps these new memories become integrated into brain networks. Some patients with schizophrenia show almost a complete abolition of SWS, and a few studies have now shown that those patients with less SWS tend to be the same ones who show the poorest recall of information learned prior to sleep.

In their review of these studies, Manoach and Stickgold suggest that healthy adults use sleep to help automate recently-learned information and skills, so that performance can be faster and less dependent on voluntary attention.  In effect, while we sleep, the brain figures out how to perform familiar tasks on “auto-pilot” so that we can focus our attention on other things.  Patients with a breakdown of normal sleep-dependent consolidation would be correspondingly less able to automate tasks, meaning that they would have to spend more attention on these tasks – making it harder to carry out complex tasks with high attentional demands.  This in turn might be the root cause of many of the cognitive deficits observed in schizophrenia.

The idea that sleep may be responsible for much of the cognitive impairment in schizophrenia is still highly theoretical. There is much more work to be done in this area, but the early results are suggesting a new way to understand at least some of the cognitive impairments in schizophrenia – which in turn may suggest that treating sleep disturbances might help provide relief from some of the symptoms of this devastating disorder.

Further reading:

D. S. Manoach and R. Stickgold (2009) Does abnormal sleep impair memory consolidation in schizophrenia? In, Frontiers in Human Neuroscience, vol. 3:21 (available online at: www.ncbi.nlm.nih.gov/pmc/articles/PMC274129).

R. Stickgold & M. P. Walker (2007) Sleep-dependent memory consolidation and reconsolidation. Sleep Medicine, vol. 8, pp. 331-343.

Until recently, the only gene known to be associated with late-onset AD was APOE, a gene associated with clearing cholesterol from the bloodstream.  APOE comes in three common variants, known as E2, E3, and E4.  People carrying E4 are about three times more likely to develop late-onset AD than those carrying E3; people carrying E2 are at a slightly reduced risk for the disease.  But the link between APOE and AD is not terribly strong; many people carrying E2 still develop AD, while some carrying E4 never do.  Apparently, other genetic or environmental factors must play a role too.

Now, two large-scale studies have identified three additional genes that appear to play a role in determining an individual’s risk for late-onset AD.  One study conducted by researchers in France considered over 15,000 elderly people with and without AD, and found that the people with AD were much more likely to have specific variants on genes known as CLU and CR1.  These genes may help regulate how the body clears beta amyloid, the protein that accumulates in the brains of people with AD; variants of these genes that are less effective at this task may contribute to an individual’s susceptibility to the disease.  A second study out of the UK examined over 16,000 people with and without AD, and replicated the findings with CLU as well as identifying a third genetic variant, on the PICALM gene, that also occurred more often in individuals with AD.

CLU, CR1, and PICALM join APOE as significant risk factors for the common, late-stage form of AD.  Together, the four genes may account for as much as 40-50% of AD cases.  Knowing the genetic variants associated with a disease is a long way from being able to prevent or cure that disease, but it’s an important step: now, researchers at least have some idea of where to begin targeting their efforts.

Further reading:

D Harold and others (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. In, Nature Genetics, vol. 41, pp. 1088-1093.

JC Lambert and others (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. In, Nature Genetics, vol. 41, pp. 1094-1099.

There are times when such distraction can have serious consequences, such as when we’re driving a car.  The statistics are clear: car accidents are much more likely if drivers are distracted, such as by talking on a cell phone.  Now research is beginning to show us why.

A recent study examined the performance of drivers using a computerized driving simulator, while those drivers were conversing either with in-car passengers (who could see the same driving simulator), or via cell phones.  As several prior studies have shown, drivers’ performance suffered during cell phone conversations compared to in-car conversations; the cell-phone-using drivers showed slowed reaction times (such as speed of braking responses) and poorer avoidance of road and traffic hazards.  One reason appeared to be “conversation suppression”: in-car passengers tended to slow their rates of conversation as the driver approached a hazard.  This could free up attention and other brain resources, allowing the driver to focus with the hazards of the road.  In contrast, cell-phone conversants (who could not see the road, and thus could not judge approaching hazards) did not tend to suppress conversation at those critical moments.

Importantly, this particular study considered hands-free phone usage.  Several states in the US now ban or restrict drivers from using handheld cell phones, but allow hands-free phones.  But many studies now suggest the real issue isn’t whether the driver is physically holding the phone; the real issue is that a conversant who is not in the same car as the driver doesn’t suppress conversation when a road hazard appears.

The bottom line from a growing body of studies seems to be a consistent warning that cell phone usage (whether handheld or hands-free) while driving can seriously impair a driver’s performance.   The good news: talking to an in-car passenger may actually improve driver performance, because passengers often spontaneously provide alerting comments, helping the driver notice and attend to looming hazards or changes in road conditions.

Further reading:

S. G. Charlton (2009) Driving while conversing: Cell phones that distract and passengers who react. Accident Analysis and Prevention, vol. 41, pp. 160-173.

Y. Ishigami and R. M. Klein (2009) Is a hands-free phone safer than a handheld phone? Journal of Safety Research, vol. 40, pp. 157-164.

As we sleep, we (like rats) cycle through several “stages,” including rapid-eye movement (REM) sleep, which is believed to be when we dream, and several kinds of non-REM sleep.

A recent study has suggested that REM is particularly important for neurogenesis in the hippocampus.  One group of rats were given four days of REM deprivation, by putting the rats in a small chamber where the floor was a treadmill that automatically activated whenever the rats entered REM sleep – forcing them to step forward to avoid being carried into the wall of the chamber.  (Non-REM sleep didn’t activate the treadmill.) For comparison, a group of control rats were placed in the same type of chamber, but treadmill activation was unrelated to sleep cycle.

The REM-deprived rats showed much less neurogenesis than controls. Both groups showed similar amounts of total sleep, and similar levels of stress hormones, indicating that the stress of being periodically awoken was similar for the REM-deprived and control rats. This study therefore suggests that REM sleep is particularly important for the birth and survival of new neurons in the adult brain.

There are two important implications of this study.  The first is that it adds to a growing literature suggesting that relatively short-term periods of sleep deprivation (equivalent to a few nights’ insomnia or intentional wakefulness) can significantly affect the brain.  This is a cautionary finding for those of us who routinely don’t get a full night’s sleep.

The second implication is that not all sleep is equal.  This study also adds to a growing literature suggesting that REM sleep has some special functions, particularly contributing to learning and memory.  Many medications, including some over-the-counter sleeping aids, disrupt REM sleep.  If REM sleep is indeed important for neurogenesis, then disrupting REM may disrupt neurogenesis – which might in turn have consequences for a person’s learning and memory abilities.

Further Reading:

R. Guzman-Marin et al. (2008). Rapid eye movement sleep deprivation contributes to reduction of neurogenesis in the hippocampal dentate gyrus of the adult rat. Sleep, 31(2):167-175.

Two of the keynote lectures stick in my mind.  The first was a talk by Richard Morris, the eminent British researcher who studies how brains form new memories.  Since 2009 marks SfN’s 40^th anniversary, Morris gave a brief overview of SfN’s history, reminding us all how far the science of neuroscience has come in that time.  Some of the researchers attending the 2009 meeting had not yet been born in 1969, and many of the seminal papers which we now take for granted had not yet been published. A salient example is Bliss & Lømo’s (1973) article documenting long-term changes in neurons as a result of experience: a phenomenon termed long-term potentiation (LTP) which is now generally believed to be one of the fundamental ways in which the brain encodes new learning.  Modern research methods such as functional neuroimaging (fMRI and PET) and genetic mapping, not to mention information-sharing via the Internet, were not yet available in 1969. In the past 40 years, we’ve developed new tools to diagnose diseases and new methods to treat them, as well as a broader understanding of how the brain works and why it sometimes doesn’t. Looking back now on how much we’ve learned in the last 40 years, one can’t help but wonder what we might learn in the next 40 years – and whether some of today’s most terrifying and incurable disorders, such as schizophrenia, Alzheimer’s, and epilepsy, could join polio and smallpox as relics of the past.

Against this vision of past and future, SfN attendees face a present reality in which competition for research funding is perhaps as fierce as it has ever been.  At the National Institutes of Health (NIH), the federal institution that is the major funder of biomedical research in the US, only about 20% of submitted research proposals actually receive funding.  The situation would have been much worse during the economic downturn, but for a large injection of stimulus funds provided by the Recovery Act (ARRA), which allowed many labs to continue their research (and to maintain and hire laboratory staff).  There is concern about what will happen when that infusion of money runs out. Francis Collins, NIH’s director, addressed SfN attendees and stressed that researchers themselves have a responsibility not only to conduct research, but also to communicate to the broader public why that research matters, and why in times of budgetary crisis, scientific research is an investment in the future of our species and our planet that our society must continue to support.  With luck, this year’s SfN meeting attendees came away charged with that vision as much as with inspiration for new and exciting research directions.

In the last few years, there have been intriguing suggestions that low-to-moderate alcohol consumption may also protect against age-related cognitive decline, and even against Alzheimer’s disease.  One study considered mice that had been specially bred to develop beta amyloid plaques in their brains; beta amyloid plaques are a hallmark of Alzheimer’s disease in humans.  Some of the mice were given moderate amounts of cabernet sauvignon in their water supply for a period of about 7 months; others were given plain water. The group given wine showed less accumulation of plaques in their brain, and also showed much less decline in memory function than their counterparts.  The implication is that some (or some combination) of the chemical compounds in wine – specifically red wine – helps the brain combat plaque accumulation. 

And what about in humans?  A study published late last year in the Journal of the American Geriatric Society followed nearly 6,000 community-dwelling elderly adults for three years.  Each individual’s baseline alcohol consumption was recorded at the start of the study: about 42% of the women and 71% of the men were alcohol drinkers.  As would be expected, most of the volunteers showed some mild cognitive decline over the course of the study.  But female drinkers showed less decline than female nondrinkers on the Mini-Mental Status Exam or MMSE, a standard test of general cognitive function.  No such differences were observed between male drinkers and non-drinkers.  The authors’ conclusion: low-to-moderate alcohol consumption may help slow cognitive decline in elderly women.  This echoes an earlier study from 2005 which found a similar effect: that elderly women who drink about one serving of alcohol a day may have a slightly reduced risk of cognitive decline.  It’s not clear why women appear to benefit more than men, although one possibility is that, since women are at greater statistical risk of Alzheimer’s then men, more of the women are in a position to benefit from the plaque-busting properties of red wine.

There’s an obvious and serious caveat: the current findings do not represent an invitation to heavy drinking.  Long-term intake of large amounts of alcohol damages the brain, and is associated with a host of other health complications.  Current US guidelines suggest that women drink no more than two to three units a day (one unit is approximately one small glass of wine), while men (who typically have larger body weights) should drink no more than three or four units per day.  (These are general guidelines, and don’t apply to everyone; some individuals should drink much less or not at all.)

Nevertheless, for those who enjoy an occasional glass of wine, there now seems to be a reasonable cause to rejoice: modest amounts of red wine may not only pleasure the palate, but may also help protect the aging brain.

Further Reading:

J. Wang and others (2006). “Moderate consumption of cabernet sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer’s disease.” In, “FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology,” vol. 20, no. 13, pp. 2313-2320.

D. J. Stott and others (2008). “Does low to moderate alcohol intake protect against cognitive decline in older people?”In, Journal of the American Geriatric Society, vol. 56, no. 12, pp. 2217-2224.

M. J. Stampfer and others (2005). “Effects of moderate alcohol consumption on cognitive function in women.” In, New England Journal of Medicine, vol. 352, no. 3, pp. 245-253.

Caloric restriction also improves learning and memory in animal.  For example, a standard test of learning in rats is to place the rat in a shallow pool. Somewhere in the pool is a little platform, hidden just below the surface of the water. Rats are actually quite competent swimmers, and will swim around until they stumble across the platform; then they’ll climb out of the water.  With repeated trials, healthy rats learn the location of the platform quickly, and as soon as they’re placed in the pool, they rapidly swim to the platform and climb up.  It’s a skill that declines with age, so that older rats have a harder time learning to locate the hidden platform than younger rats do. Rats given lifelong CR – provided with only 60% as much food as a healthy rat would normally choose to eat – show less decline with age than animals given free access to food. 

A recent study suggests that caloric restriction might improve learning and memory in humans, too.  Two groups of healthy elderly individuals were assigned to follow either a “standard” diet or a calorie-restricted diet for 3 month.  At the end of that period, unsurprisingly, the CR group had lost weight.  More surprisingly, the CR group showed a significant improvement – almost 30% — in their memory scores.  The group on a regular diet showed no change from their baseline scores.

So, should we all start cutting back drastically on our caloric intake?  Here, the question gets complicated.  Obviously, there are many health benefits to maintaining a healthy diet, managing our cholesterol levels and keeping blood pressure in check.  But severe caloric restriction, with caloric reductions as dramatic as in the studies above, can have risks. The obvious risk is malnutrition. When reducing caloric intake, there may also be reduced intake of nutrients and vitamins that the body needs to function; as a result, calorie-restricted diets should only be attempted under medical supervision and with proper care to ensure that the body is still getting adequate supplies of nutrients and vitamins. 

Anecdotally, I’ve talked to two people who study caloric restriction in animals, and after seeing the dramatic positive effects, they had decided to attempt extending their own longevity in the same way. (They both had the medical background needed to attempt CR responsibly, without risking their health.) They reported feeling continually hungry, irritable, overtired, and cold.  In the end, they decided, a longer life wasn’t worth it if one was going to be miserable the whole time.

Instead, these and other researchers are focusing on the mechanisms involved – trying to understand exactly why CR produces the cognitive benefits it does.  Maybe, if we understood that, there would be a way to produce the same effects – in a more painless way than near-starvation.

Further reading:

J. Stewart and others (1989). The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the 8-arm radial and the Morris water mazes. In, Neurobiology of Aging, vol. 10, pp. 669-675.

A. V. Witte and others (2009). “Caloric restriction improves memory in elderly humans.” In, Proceedings of the National Academy of Sciences (USA), vol. 106, no. 4, pp. 1255-1260.