Posts Tagged ‘ neurochemistry ’

The Memory Master

A gene that may underlie the molecular mechanisms of memory has been identified, says a new study.

Some of us feel that "yellow" and "red" are open to interpretation...

The gene’s called neuronal PAS domain protein 4 (Npas4 to its friends). When a brain has a new experience, Npas4 leaps into action, activating a whole series of other genes that modify the strength of synapses – the connections that allow neurons to pass electrochemical signals around.

You can think of synapses as being a bit like traffic lights: a very strong synapse is like a green light, allowing lots of traffic (i.e., signals) to pass down a particular neural path when the neuron fires. A weaker synapse is like a yellow light – some signals might slip through now and then, but most won’t make it. Some synapses can inhibit others, acting like red lights – stopping any signals from getting through. And if a particular synapse goes untraveled for long enough, the road starts to crumble away – until finally, there’s no synapse left.

There’s a saying in neuroscience: “Cells that fire together wire together.” (And vice versa.) In other words, synaptic plasticity – the ability of neurons to modify their connectivity patterns – is what allows neural networks to physically change as they take in new information.  It’s what gives our brains the ability to learn.

In fact, millions of neurons are delicately tinkering with their connectivity patterns right now, inside your head, as you learn this stuff. Pretty cool, huh?

Anyway, synaptic plasticity’s not exactly breaking news – scientists have been studying it in animals like squid and sea slugs since the 1970s. Neurons in those animals are pretty easy to study with electrodes and a microscope, because a) the animals are anatomically simple compared to humans, and b) some of their neurons are so huge they can be seen with the naked eye.

Studying synapses in humans isn’t quite so simple, though. For one thing, most people wouldn’t like it if you cut open their brain and started poking around while they were alive and conscious – and besides, a lot of the really interesting stuff happens down at the molecular level.

That brings up an important point: though you normally hear about genes in connection with traits – say, a “gene for baldness” and so on – these complex molecular strands actually play all sorts of roles in the body, from building cells to adjusting chemical levels to telling other genes what to do.

That’s why MIT’s Yingxi Lin and her team set out to study the functions of certain genes found in the hippocampus – a brain structure central to memory formation – the journal Science reports. The researchers taught a group of mice to avoid a little room in which they received a mild electric shock, then used a precise chemical tracking technique to isolate which genes in the mouse hippocampus were activated right when the mice learned which room to avoid.

In particular, they focused on a hippocampal region with the sci-fi-sounding name of Cornu Ammonis 3or CA3 for short:

We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning.

By “transcriptional program,” the paper’s authors mean a series of genetic “switches” – genes that Npas4 activates – which in turn make chemical adjustments that strengthen or weaken synaptic connections. In short, Npas4 appears to be part of the master “traffic conductor program” for many of the brain’s synapses.

Though they were pretty excited by this discovery (who wouldn’t be?) the researchers took a deep breath, calmed down, and double-checked their results, by testing memory formation in mice whose brains were unable to produce Npas4:

Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice.

In short, they make a pretty convincing argument that Npas4 is a necessary ingredient in a mouse’s ability – and probably our ability – to form certain types of new memories.

Exactly how that program relates to our experience of memory remains unclear, but it’s a promising starting point for fine-tuning future memory research. I don’t know about you, but I’d be thrilled to green-light such a project.

Synaptic Changes

Synapses – the junctions where neurons communicate – are constantly growing and pruning themselves – and those two processes occur independently of one another, says a new study.

A neuron shows off its fancy green glowy-ness.

As a synapse sees more and more use, it tends to grow stronger, while synapses that fall out of use tend to grow weaker and eventually die off. Collectively, these processes are known as synaptic plasticity: the ability of synapses to change their connective properties. But as it turns out, the elimination of redundant synapses isn’t directly dependent on others being strengthened – instead, it seems to be triggered by its own independent chemical messaging system.

Like many mammals, we humans are born with brains that aren’t yet particularly well-adapted for anything other than – well, adaptation. Through our brains’ extraordinary plasticity, we’re able to learn, in a few short years, everything from how to walk upright to how to argue – and as we grow older, our brains learn how to learn more quickly and think more efficiently by pruning away unneeded synapses.

But all that speed and flexibility come at a price: the balance between synaptic growth and die-back must be delicately maintained. Excessive connectivity can lead to diseases like epilepsy, while insufficient communication can result in disorders like autism.

This kind of summarizing oversimplifies the situation, of course – brain disorders rarely have just a single cause, or a clearly-defined set of symptoms. Even so, they provide grim reminders of the precise electrochemical balancing act that continues in the dark backstage of our skulls throughout each moment of every day.

And now, as the Journal of Neuroscience reports, a team led by The Jackson Laboratory’s Zhong-wei Zhang has found that synaptic growth and pruning aren’t two parts of a single process after all – they’re two processes, coordinated through two different chemical signaling systems.

The team discovered this by studying a certain type of glutamatergic synapses – i.e., synapses that use the common neurotransmitter chemical glutamate – in mouse neurons. The specific type of synaptic receptor the team studied is called the AMPAR, which is short for (get ready for this) “α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.”

The team discovered that when AMPARs of baby mice were deprived of glutamate stimulation, these receptors’ symapses didn’t grow stronger, as they did in normal mice:

Deletion of GluA3 or GluA4 caused significant reductions of synaptic AMPAR currents in thalamic neurons at P16–P17, with a greater reduction observed in GluA3-deficient mice.

No huge shock there. But what was surprising for the team was their other discovery – that even in these glutamate-deficient mice, pruning of AMPARs still proceeded normally:

Deletions of GluA3 or GluA4 or both had no effect on the elimination of relay inputs: the majority of thalamic neurons in these knock-out mice—as in wild-type mice—receive a single relay input.

Looking at this data, it’s hard to escape the conclusion that pruning of AMPARs is dependent on a separate mechanism from their strengthening. Just what that other mechanism is remains to be seen.

In short, this is another example of how even the most mundane workings of our brains continue to stun neuroscientists with brand-new revelations every day.

Chemical Parasites

A certain brain parasite actually turns off people’s feelings of fear by increasing levels of the neurotransmitter chemical dopamine, says a new study.

T. gondii, gettin' ready to blow your %@&#$ mind.

Toxoplasma gondii, a parasitic protozoan (a kind of single-celled organism), mostly likes to live in the brains of cats – but it also infects birds, mice, and about 10 to 20 percent of people in the U.S. and U.K. This might sound like science fiction, but plenty of microbiologists will assure you it’s very real.

In fact, T. gondii isn’t the only parasite that controls its hosts’ behavior – a fungus called Ophiocordyceps unilateralis makes infected ants climb to the highest point they can find, sprout fungal spore pods from their heads, then stay there and starve to death; at which point the spores are unleashed to recruit more ants for the fungus’s zombie army. Other microbes force spiders to weave cocoons for them, or make roaches lay immobile while larvae grow inside their bodies, then chew their way out. Um, yeah, so… nature is pretty frickin’ hardcore.

Anyway, back to the parasite at hand. Throughout the past few years, a University of Leeds microbiologist named Glenn McConkey has worked at the forefront of T. gondii research – in 2009, his team made the astonishing discovery that the microbe’s genome encodes instructions for producing dopamine: in essence, this bug is living cocaine, and it’s bending the minds of millions of people at this very moment.

And now, as the journal PLoS ONE reports, McConkey’s team has made a breakthrough that is, if anything, even more incredible: once the parasite has taken up residence in a brain, it triggers the production and release of dopamine at a much greater level than normal, causing infected animals (including people) to engage in impulsive, compulsive and/or fearless behavior:

In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released … Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells.

In short, by changing the electrochemical properties of dopaminergic neurons (those that deal with dopamine transmission and reception), T. gondii basically causes its host’s brain to shout “I’m awesome!” ceaselessly at top volume. You can imagine the havoc this wreaks.

If the host is, say, a mouse or a bird, impulsive and fearless behavior will typically get it gobbled up by a predator, which allows the parasite to move into a new host and spawn a new generation. But if the host happens to be a human being – well, there’s no telling what might happen. For one thing, studies have found a strong link between T. gondii infection and schizophrenia.

Thanks to Science, though, there’s hope – McConkey’s team is optimistic that these new results will help doctors diagnose T. gondii infections more quickly and accurately, and perhaps use dopamine antagonists – drugs that block dopaminergic activity – to fight some of the psychotic symptoms these crazy little guys cause.

So, I guess one big question remains: why the hell isn’t this story making front-page news? Your guess is as good as mine. Kinda spooky, isn’t it?

Stress and Balance

Our responses to threatening situations depend on two fear-regulation circuits, a recent study shows.

"I wish this job wasn't so heavy on the glutamate."

A well-balanced sense of fear is crucial to our survival: too much, and we’d descend into panic attacks every time we were startled. Too little, and we might not react when survival is crucial. As it turns out, this balance is maintained by two opposing brain circuits, both involving corticotropin-releasing hormone (CRH) and its type 1 receptor (CRHR1).

The body releases CRH in response to stressful stimuli. This substance creates some pretty interesting effects in different parts of the brain – in areas like the forebrainhippocampus, and thalamus, it triggers the release of the excitatory neurotransmitter glutamate, which contributes to anxiety behavior.

But as a new paper in the journal Science shows, CRH helps with a completely different set of responses in the midbrain – it directly triggers the release of dopamine, which reduces fear and increases confidence. This means CRH and its type 1 receptors are involved in a self-regulating circuit that can both spread and reduce feelings of stress:

These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.

In other words, these two CRH-triggered systems exist in a delicate balance – and a disruption of that balance could lead to excessive fear reactions on the one hand, or to indifference on the other.

This means it’s probably time for psychiatrists to take another look at anti-anxiety drugs that target the brain’s CRH circuits:

The over-activity of the CRH system in patients with mood disorders is not general but probably limited to certain regulatory circuits in the brain, thus causing imbalanced emotional behavior.

This means that instead of just thinking of CRH as a “stress hormone,” we should probably be looking at these regulatory circuits as whole systems, and examining their interactions with one another.

So the next time you’re feeling panicky, try to remind yourself that it’s just your glumatergic neurons acting up – and those lovely dopaminergic circuits should kick in any second.

Diff’rent Vesicles

A new discovery shows that the rules of synaptic transmission are very different from what we’d thought.

A synapse, blissfully unaware of the VAMP7s lurking in its midst.

In each neuron, tiny sacs called vesicles store neurotransmitter chemicals, and help transport them to other neurons. For decades, scientists had thought all the vesicles of a particular neurotransmitter were more or less identical – but now, they’ve discovered that only one set of vesicles are marked for transmission, while a much larger set lay mysteriously dormant.

What causes these differences, you ask? A protein with an awesome name:

We now find that the v-SNARE tetanus toxin-insensitive vesicle-associated membrane protein (VAMP7) differs from other synaptic vesicle proteins in its distribution to the two pools, providing evidence that they differ in molecular composition. We also find that both resting and recycling pools undergo spontaneous release, and when activated by deletion of the longin domain, VAMP7 influences the properties of release.

In other words, the presence of VAMP7 in a vesicle is an indicator of whether it’ll be released or not. This overturns the previous assumption that some vesicles get transmitted because – more or less – they’re in the right place at the right time. But now we know that vesicles don’t just get “discovered” like aspiring actresses – each one is born for its job, just as some of us are born to ride, run, or be wild.

As a paper published in the journal Neuron reports, a team led by UCSF’s Robert Edwards tagged various proteins with glowing (bioluminescent) molecules found in jellyfish. They found that VAMP7 levels are high in the resting pool of vesicles – the one that stays inside the neuron – but much lower in the recycling pool, which contains the vesicles that get transmitted, then recycled for later use.

Since the resting pool of vesicles can be 80 percent larger than the recycling pool, Edwards is sure it plays a significant purpose – but no one has any idea what that purpose is yet:

Resting vesicles are involved in a separate not-well-understood process in which neurons spontaneously release vesicles, which may help them adjust the types of connections they make with each other as well as the strength of those connections.

Since these vesicle differences may apply to all neurotransmitters in all neurons, it looks like we’ll need to correct some major misunderstandings about how the nervous system works. For one thing, we’ll probably need to reassess how we understand brain diseases whose symptoms stem from synaptic transmission problems.

It’s going to be really interesting to see what future research tells us about these resting vesicles, and what kinds of secret missions they get sent on when they’re not resting.

Working Off Worry

Want to get rid of gloomy thoughts? Try working some physical activity into your daily routine, says a new study.

Even adorable kitties need an endorphin boost sometimes.

For people who struggle with depression and anxiety, the research shows, exercise can be just as effective as antidepressant medication. It often prevents symptoms from getting worse – and in some cases, it even helps cure the problem.

Doctors have known for decades that a little physical activity can help distract you from your worries, boost positive feelings, and even relieve anxiety and depression. But in recent years, research has shown that exercise’s hidden effects reach much deeper: it tells your body to produce endorphins – natural chemicals that act similarly to morphine - to produce a natural high. And studies have shown that regular exercise can even make you smarter, by increasing blood flow to the brain and triggering neurogenesis – the birth of new neurons.

But as this new paper in the Journal of Clinical Psychiatry reports, a team led by UT Southwestern’s Dr. Madhukar Trivedi has discovered something even more exciting – a regular dose of exercise can work just as well as antidepressant medication:

Many people who start on an antidepressant medication feel better after they begin treatment, but they still don’t feel completely well or as good as they did before they became depressed. This study shows that exercise can be as effective as adding another medication.

In other words, patients who exercised instead of adding a second drug often improved just as much as people who did add another drug.

By the time the 12-week study was finished, almost 30 percent of the patients who exercised had achieved full remission of their depression, and another 20 percent showed significant improvement. That’s close to 50 percent of depressed patients whose moods measurably improved thanks to exercise.

It’s also intriguing that different types of exercise seem to have different effects on people with various characteristics:

Moderate exercise was more effective for women with a family history of mental illness, whereas intense exercise was more effective with women whose families did not have a history of the disease. For men, the higher rate of exercise was more effective regardless of other characteristics.

So if you’re a woman with crazy parents, you might benefit most from a quick jog on the treadmill – but it looks like I’m gonna have to run a Warrior Dash if I want to stop sulking.

Anyway, the good news is, it doesn’t take much of an investment to start seeing the benefits of exercise – most doctors recommend somewhere between 30 and 60 minutes, three times a week. Even taking a short walk on your lunch break can cheer you up.

Unless you’re perambulating on one of these things – I don’t think that counts.

Pain on the Brain

Men and women experience pain in different ways, a new study shows.

"Aaaagh, my KORs are killing me!"

The behavior of opioids – chemicals that suppress pain – differs between men’s and women’s bodies. This is because the three main types of opioid receptors in the brain and spinal cord interact very differently, depending on whether their owner is a man or a woman.

See, scientists have known for years that certain kinds of narcotic analgesics – a certain class of pain relieving drugs – are much more effective on women then on men. It was hard to understand why, though, because both men and women have mu (MOR), delta (DOR), and kappa (KOR) opiate receptors – the three main kinds – and these receptors work in essentially the same way in either gender.

But now, scientists have found that the spinal cords of female animals have almost five times as many kappa-mu heterodimers – complex molecules formed by combining KORs and MORs (commonly called KOR/MOR heterodimers) – as those of males. And not only that – the number of KOR/MOR heterodimers climbs four times higher when a woman’s body is pumping with estrogen and progesterone – two hormones crucial for regulating female body chemistry:

Spinal synthesis of estrogen is critical to the processes [of forming and using KOR/MOR heterodimers], and blockade of either estrogen receptor (ER) α-, β-, or G-protein-coupled ER1 or progesterone receptor (PR) substantially reduces KOR/MOR and eliminates mediation by KOR of spinal morphine antinociception.

In other words, a squirt of estrogen causes a sharp increase in the number of KOR and MOR receptors that get formed. This is a Big Deal, because some previous research suggests that in men, KORs and the chemicals that activate them may actually promote pain – and that their attachment to a MOR converts them to part of a pain-relieving system:

The research suggests that kappa-mu opioid receptor heterodimers could function as a molecular switch that shifts the action of kappa-opioid receptors and endogenous chemicals that act on them from pain-promoting to pain-alleviating.

To figure out what was going on with all these receptors, a team led by Alan Gintzler, a SUNY biochemist, first did some research to show that KOR and MOR opioid receptors join to form KOR/MOR heterodimers, the Journal of Neuroscience reports. This research was the first step toward understanding how these receptors interacted in the body’s pain system.

For this new study, though, the scientists injected estrogen and progesterone into the spinal cords of test animals, and determined that both chemicals were critical for the formation or KOR/MOR heterodimers, and these heterodimers’ activity in suppressing pain, as opposed to spreading it.

This discovery could go a long way toward explaining why certain pain-suppressant drugs that target MORs and KORs – such as pentazocine and nalbuphine – work well on women, but poorly on men: in spinal cords that lack the KOR/MOR heterodimer, the drugs might be activating the lonely little KORs, which – without their MOR friends, would help promote pain instead of relieving it. How rude of them.

Anyway, this new data looks like it’ll provide some encouraging ideas for future pain relief research:

The activation of the kappa-opioid receptor within the kappa-mu-opioid receptor complex could provide a mechanism for recruiting the pain-relieving functions of spinal kappa-opioid receptors without also activating their pain-promoting functions.

The researchers also point out that doctors should talk with women about where they are in their menstrual cycle before prescribing them medications like these – when estrogen and progesterone levels drop, pain relievers might turn into pain promoters.

So the moral of the story is, if you’re a guy (or a women who’s low on estrogen), some things really are gonna hurt me more than they hurt you.


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