"Memory, Aging and Alzheimer's: When forgetting too much becomes a problem"

Although our brains produce new neurons throughout our lives, their overall number peaks in our early twenties and then gradually declines as we age. Certain forms of memory tend to get worse with age as a consequence. Episodic memory in particular is often weaker in the elderly, making it more difficult to remember where a car was parked, or what time a friend was supposed to arrive for dinner. The good news is that other types of memory such as semantic (remembering general facts and concepts) and procedural (remembering how to do something) memories remain robust in most people well into their later years.

Unfortunately this is not the case for people suffering from an increasingly well-known disorder called Alzheimer’s disease, which severely impairs normal memory. Alzheimer’s is the most common example of a spectrum of disorders known as neurodegenerative diseases, all of which cause neurons to die off more rapidly than they would with normal aging. The prevalence of Alzheimer’s increases dramatically with age, rising from just 3% in those aged 65-74 to almost 50% among those 85 years and older.

Currently available treatments tend to focus on minimizing the symptoms of Alzheimer’s by compensating for the loss of neurons. Some of these therapies can be helpful, but scientists have not yet found a ‘cure’ for Alzheimer’s, i.e. a treatment that would actually slow or halt the neuronal loss. This is because it’s still not entirely clear why neurons die in Alzheimer’s, although thousands of laboratories across the world are bringing us closer to the answer every day. We can hope that several of the many promising therapeutic avenues currently under investigation by scientists in Montreal and elsewhere will one day provide an effective means of combating the disease for both present and future generations. (Andrew Greene, McGill University)

All are welcome to join us on Wednesday, February 23rd, at 7:00 pm at La Sala Rossa (4848 boul. St-Laurent, Montreal, QC, H2T 1R6) for an evening of questions and answers, as we discuss memory and aging with world-class experts Andrea Leblanc, Ph.D., Serge Gauthier, M.D., F.R.C.P.C., and Judes Poirier, Ph.D., C.Q. Refreshments will be provided. This is a free event! We hope to see you there!

for more information: http://sfn-montreal.ca/baw/cafe/

http://www.facebook.com/#!/event.php?eid=183243215043955

hosted by BAW Montreal as part of our 2011 Brain Awareness Week public events. 

Thank you to our sponsors .

*** Our popular Science Cafés offer the public the opportunity to meet and discuss various topics in Neuroscience in an informal setting. These Cafés feature a Question & Answer with three to four guest panelists who are experts in their fields, snacks and entertainment. Our Cafés are always free thanks to our sponsors. ***

Monogamous cheaters

In my previous post I wrote about vasopressin and oxytocin, so-called “love molecules” that promote attachment and pair-bonding in voles and humans. These molecules act on receptors found in the dopamine-reward system to enhance the dopamine “pleasure” response thereby re-enforcing monogamous activities. However, socially monogamous voles, like humans, are prone to “mistakes” or “slip-ups” with males and females frequency engaging in uncommitted sexual behaviors. Indeed, using genetic testing of offspring, researchers have found that many of the species first thought to be “monogamous” like birds and gibbons actually participate in extra-pair copulations. It’s now more exciting to find a species that is actually sexually monogamous (such as the recent discovery of a monogamous frog). Evolutionarily speaking this is not surprising; we want to get it on with as many people as possible to pass on our genes and increase genetic diversity, while at the same time having enough resources to take care of our young. Therefore, it is possible that two competing systems co-evolved in humans: one that promotes monogamy (vasopressin, oxytocin and others) and another previously uncharacterized system that promotes sleeping around with as many people as possible. This predicts that our tendencies towards infidelity and sexual promiscuity could also be genetically encoded.

Is unfaithfulness really all in the genes? A new study published recently in PLoS ONE suggests that it might be, at least in part. The authors linked a certain variant of the dopamine D4 receptor gene to the propensity towards one-night stands (but not the actual number) and the number of sexual partners in those that were unfaithful (but not to unfaithfulness per se, although there was a trend towards significance). Interestingly, people with this variant have less dopamine D4 receptors in the reward centers of the brain and these receptors show less binding to dopamine, suggesting that these individuals might need more dopamine floating around to reach the same feel-good mood. It’s not a surprise then, that this variant has also been associated with a slew of other behaviors that increase dopamine release including addictions, risky behavior and novelty-seeking.

So, what does this mean? The authors are careful to point out that the dopamine D4 receptor gene should not be labeled the “cheating gene” or the “promiscuity gene” (although it already has) since having the variant does not necessarily mean that you will sleep around or be unfaithful. Many other genetic, environmental (alcohol) and cultural influences are likely to play into an individual’s decision to sleep around or cheat. In addition, the variant may be associated with a third confounding variable like being more honest about sexual behavior, more attractive, etc. Or it may simply be associated with risky behavior and novelty-seeking, increasing the likelihood of wanting uncommitted sex.

For now, I’d hold off on sending your significant other for genetic testing.

Part 3 of 3: Stress and the Aging Brain

                 Perhaps where we see the most extensive effects of stress on the brain is in adulthood and into older age.  In rats, it has been discovered that acute and chronic stress can have very different effects.  An acute stressor (ie. something that only lasts for a short period of time) actually enhances learning and memory, up to a certain point, beyond which too much stress causes performance to deteriorate again.  A state of chronic stress, however, has been shown to have very negative effects on the brain.  Specifically, in rats, chronic stress has been associated with a shrunken hippocampus, specifically because dendrites in the hippocampal neurons begin to die off.  These rats also perform more poorly on memory tasks, especially those involving spatial memory. 

                In fact, if you expose a middle-aged rat to high levels of glucocorticoids, it will perform cognitive tasks similar to the way that a rat in old age would perform them, while reducing glucocorticoid levels in an old rat will enhance its performance.  So, could chronically high glucocorticoid levels contribute to the cognitive decline (memory and word-finding difficulties) that we know happen as we age?  Could they have anything to do with Alzheimer's Disease (AD), a disease characterised by both poor memory and reduced hippocampal volume?  The answer so far is that we're still not sure, but more and more evidence is suggesting that there is at least a correlation between chronic stress, a smaller hippocampus and the prevalence of Alzheimer's.  In monkeys, higher glucocorticoid levels have also been shown to increase Beta-amyloid in the brain, a protein that's known to be a precursor to the cell death seen in Alzheimer's Disease. 

                But why is this?  If you remember back to my first post about stress and the brain, I said that the hippocampus is one of the main mechanisms by which the HPA axis gets shut down.  If you have more and more glucocorticoids, you see hippocampus shrinkage.  This means that there's less and less hippocampal tissue to shut down the HPA axis, leading to chronically high glucocorticoid levels and consequently, a chronically shrinking hippocampus.  It's a feed-forward mechanism.  There's also the neurotoxicity hypothesis, which says that a lifetime of dealing with chronically high glucocorticoid levels may cause the hippocampus to be less able to deal with other aspects of normal aging and therefore its cells are more easily damaged and die off. 

                Don't panic yet.  There's no need to stress out about how your brain is responding to your stressful life.  You're not doomed to an ever-dwindling hippocampus.  It turns out that if you remove a chronic stressor, dendrites that had previously disappeared are actually able to grow back.  Obviously removing every stressor from our lives isn't likely to happen, so there are a few other minor changes that we can make to help us along.  Interestingly, one of the few things that we can do in order to grow new neurons (called neurogenesis, a phenomenon that neuroscientists only came to believe in fairly recently) is exercise.  Exercise has been shown to especially increase neurons in…wait for it…the hippocampus.  How convenient is that?  As if we needed another incentive to stick to our 2011 resolution to hit the gym! 

Cristina McHenry

Concordia University

Adapted from "Effects of Stress Throughout the Lifespan on the Brain, Behaviour and Cognition" by Sonia Lupien et al. and inspired by Wayne Brake's Neuropharmacology course at Concordia University.  

Part 2 of 3: Stress and the Adolescent Brain

                 Research is indicating that the adolescent brain is particularly sensitive to the effects of high glucocorticoid levels and therefore to stress as well.  During the teenage years, there appear to be high levels of glucocorticoid mRNA (a chemical that comes from DNA and encodes a type of blueprint for the creation of a specific type of protein) in the prefrontal cortex, which is an area that also undergoes development during this time.  This suggests that the functions that this part of the brain is responsible for, mainly cognition (reasoning, thinking, planning, sequencing, judgement, etc.) and emotion, are heavily affected by glucocorticoids and therefore by stress.  Many forms of psychopathology like depression and anxiety show up in adolescence, often following a period of particularly severe stress.  So all of this information is basically another way of saying that teenagers' emotions and decision-making abilities are prone to fluctuate according to any tiny little outside event…which we probably didn't need a neuroscientist to tell us, but now we know why!

                Interestingly, although the prefrontal cortex is greatly affected by stress, it seems that the hippocampus is spared in this period.  This is likely because the hippocampus finishes developing around 2 years of age.  Children who suffered abuse through late childhood and early adolescence did not show a decrease in hippocampal volume in adolescence, although interestingly they do show this decrease later on in adulthood.  More to come in my next post about what happens to the stressed brain as we age!

Adapted from "Effects of Stress Throughout the Lifespan on the Brain, Behaviour and Cognition" by Sonia Lupien et al. and inspired by Wayne Brake's Neuropharmacology course at Concordia University.  

Cristina McHenry 

Concordia University

Stress and the Brain: Part 1 of 3: The Stress Response

When the brain detects any kind of threat or stress, it sets a coordinated system into motion to counter the stress.  This is the stress response, and it involves autonomic, neuroendocrine, metabolic and immune components.  One of the most studied stress systems is the HPA (hypothalamic-pituitary-adrenal) axis.  To start off this component of the stress response, neurons in the hypothalamus release CRH (corticotrophin releasing hormone).  This then causes the pituitary gland to release ACTH (adrenocorticotropic hormone) into the circulatory system.  ACTH travels in the blood to the adrenal glands, which sit just above the kidneys, causing them to release glucocorticoids such as cortisol into the circulatory system. 

                Back in the brain, in an area called the hippocampus, there are receptors for these glucocorticoids, unsurprisingly called glucocorticoid receptors (GRs).  Once the stress has disappeared, glucocorticoids are supposed to bind to these receptors, which then function to shut down the hypothalamus, pituitary gland and ultimately the adrenal glands, putting an end to the stress response and returning the body to homeostasis.  Unfortunately, this system can go awry with chronic or particularly severe stress. 

Prenatal/Infant Stress and the Brain (check out my next 2 posts for Adolescent Stress and the Brain, as well as Stress and the Aging Brain)

            When pregnant moms-to-be are stressed, some of their glucocorticoids pass through the placental barrier and reach the fetus.  A certain level of glucocorticoids is required for proper nervous system development since they remodel the axons and dendrites of neurons and affect cell survival.  However, high levels of glucocorticoids have negative effects on brain development and later functioning.  Rats exposed to prenatal glucocorticoids have fewer receptors in the hippocampus later in life.  As I said before, these GRs function to shut down the stress response.  So if there are fewer GRs present in the hippocampus, the stress response is not shut down as effectively, leading to higher than normal levels of glucocorticoid activity later on (more on why this is important in the section on Stress and the Aging Brain). 

Higher prenatal glucocorticoid levels have three main effects on adult behaviour: learning impairments, greater sensitivity to drugs of abuse and increased anxiety and depression.  The learning impairments in particular are thought to be caused by the changes in the hippocampus, while drug sensitivity and anxiety/depression are thought to be caused by changes in the amygdala. 

In infancy and early childhood, the brain is surprisingly hyposensitive to stress.  Certain things can still affect brain development, however.  Good parenting actually results in a small decrease in the stress response to everyday occurrences (which is a good thing).  However, in cases of extreme deprivation, the HPA axis becomes seriously underactive, possibly due to a downregulation in the pituitary.  Basically, the hypothalamus releases so much CRH that the pituitary can't handle it anymore and gives up trying.  Remember that a certain level of HPA activity is needed in order for neurons to develop properly.  Luckily, this severe reduction in HPA activity can be fixed after a mere 10 weeks of proper care.   

Stay tuned for Parts 2 & 3!

Cristina McHenry

Concordia University

Adapted from "Effects of Stress Throughout the Lifespan on the Brain, Behaviour and Cognition" by Sonia Lupien et al. and inspired by Wayne Brake's Neuropharmacology course at Concordia University.  

Electricity and the brain

Part 3 of 3 : Electric currents that create the action potential

The negative voltage of the neuron attracts the positive charges on the outside, but they can not enter the neuron because the neuronal membrane prevents them. That is when another group of proteins steps in. These proteins are sensitive to the voltage of the neuron (voltage-dependent ion channels). They are specific for a single atom, have a structure that reminds us of a tube with a door that opens when a certain potential is reached. Thus, when a neuron receives a stimulus (from the 5 senses or another neuron), there is a fluctuation of the neuron’s resting potential (Figure 4). If a specific potential is reached, the voltage-dependent proteins door opens and lets in the positive charges. This movement of charges is an electrical current that can be measured in amperes, usually on the order of picoampere (10^-12 ampere).

When we think of brain electricity, there are two very important voltage-dependent channels: sodium channels (Na) and potassium channels (K). When the neuron is depolarized so as to achieve a certain potential (threshold potential), these channels open and let their specific atoms (ions) go through (Figure 4). Note that sodium channels have faster kinetics (open faster) than potassium channels ; they will open first, sodium will quickly enter the neuron and there is then an increase of positive charges inside the neuron, up until the sodium channels close. At that time, the voltage in the neuron rises to about 40millivolts (mV). Then the potassium channels come into play. They allow potassium ions to leave the neuron to eliminate the positive charges inside the neuron and allow the neuron to come back to a negative voltage. This very fast sequence of opening and closing is called the action potential. This action potential will develop in the neuron cell body and spread along the axon like a wave in water until it reaches the end where it can communicate with another neuron, allow muscle contraction, allow the release of hormones, etc..

Eric Trudel 

McGill University

Electricity and the brain

Part 2 of 3 : The neuronal membrane and the establishment of neuronal voltage

The "walls" of neurons (neuronal membrane) are composed of special fats that totally separate the interior of the neuron from the outside. If we take these special fats and place them in the tank mentioned above, they will spontaneously form a sphere with a uniform distribution of minerals (those previously dissolved in the aquarium in part 1) inside and outside the sphere (electrically neutral). We then have a draft of a neuron.

The neuronal membrane contains several proteins that distinguish neurons from all other cells. One group in particular, called pumps or exchangers, transfers one or more atoms to the other side of the membrane (Figure 3). Therefore, if we introduce this group of proteins in the membrane of the example of the aquarium above, one group of proteins will be responsible for removing the sodium atoms inside the neuron, another group will be responsible to concentrate potassium atoms inside the neuron, etc. (Table 1). The net result will be a decrease of positive charges (Na +, Ca2 +) inside the neuron and the inside will be negatively charged, thus forming a potential difference (about -60millivolt) ; this is called the resting potential.

Eric Trudel 

McGill University