2007_02_01_archive

Mothers aren't always right

When I was a child, my mother told me never to head the ball during a

soccer game. She believed the impact would kill brain cells, thus

leading to an irreversible drop in my neuron count because the brain

is incapable of forming new neurons after birth. Luckily, she was

wrong. Like my overprotective mother, many people are under the

impression that we are born with all of the neurons we will ever have;

in fact, until about a decade ago, most scientists were under the same

impression. This was a logical assumption, as mature neurons do not

divide and are thus incapable of generating new neurons, and

anatomical studies have shown that the size and structure of the brain

remain constant from soon after birth. The assumption that new neurons

are not added to the adult brain became one of the central tenets of

neuroscience.

The story of how this dogma was overturned is a fascinating one,

filled with drama and subterfuge, but I will investigate that saga in

a later post. What you need to know is that since the mid-90s, it has

been accepted that adult neurogenesis (the process by which new,

functional neurons are generated) exists in restricted regions of the

mammalian brain. These regions harbor "adult neural stem cells," which

appear to be cells that, unlike mature neurons, continue to divide,

producing cells that mature into new neurons in adults. [Note: These

cells are vastly different from the embryonic stem (ES) cells that are

the subject of political controversy; they are probably only able to

generate neurons in any significant numbers, while ES cells can

generate many different cell types. They also appear to be capable of

only a limited number of divisions, while ES cells are quite

proliferative. Also, just to clarify, the name's a bit misleading

because they're not only present in adults, but in children and

fetuses too.]

The majority of studies of mammalian neurogenesis have been conducted

in mice and rats, in which at least 2 regions of the brain have these

stem cells and thus retain a robust capacity for adult neurogenesis

(although the rate of neurogenesis drops sharply as we age). These

regions are the hippocampus, which is primarily associated with memory

formation, and the "subventricular zone" (SVZ), which lines the

ventricles (the fluid-filled chambers deep in the brain).

The primary destination of the new cells in the SVZ, it is believed,

is the olfactory bulb, which receives sensory neurons from the nose

and is thought to be involved in discriminating odors. This migration

of cells from the SVZ (deep inside the brain) to the olfactory bulb

(at the front of the brain) is not trivial; it is possibly the most

complex and lengthy migratory routes exhibited in the nervous system.

This route is called the rostral migratory stream (RMS), and contains

"chains" of cells destined to become neurons (called neuroblasts),

moving unidirectionally towards the olfactory bulb. So, "stem cells"

in the SVZ give rise to neuroblasts that migrate along the RMS to the

olfactory bulb, where they become neurons.

This image shows the RMS of a rodent, with stem cells and

neuroblasts (1,2) migrating along the RMS (3) to the olfactory bulb

(4). From Ming and Song, ARN 2005.28:223-250.

As for most biological phenomena, the knowledge about adult

neurogenesis in humans is far less complete. In 1998, compelling

evidence for adult neurogenesis was finally found for humans, although

this phenomenon appeared to be limited to the hippocampus. For a long

time, evidence for new neurons added to the adult human olfactory bulb

was lacking. Many rationalized this conclusion with the assumption

that rodents are more dependent on their sense of smell than we

humans, and thus require the birth of new olfactory bulb neurons

throughout life.

Unfortunately, the techniques for studying neurogenesis in humans is

limited and highly debated. Each group of researchers has their own

favored techniques, and is often highly critical of those used by

others. In brief, these methods involve determining whether a neuron

is "new" by using different ways to figure out when it last divided;

in other words, when it was "born." Each technique has its drawbacks

and must be complemented with other techniques (for example, proving

that the recently-divided cell is, in fact, a neuron). So although a

number of groups have found evidence for new neurons in the human

olfactory bulb, their results were called into question and have not

been widely accepted. Basically, evidence has been found for the birth

of cells in the SVZ, but it continues to be a matter of debate as to

whether these cells can form new neurons and integrate into a

functional neural network. There has been some controversial evidence

for the existence of "new" neurons in the olfactory bulb, but no one

has yet been able to show a way for the cells to travel from the SVZ

to the olfactory bulb. In short, no one had found the equivalent to

the rodent RMS.

A study that was released yesterday in Science claims to have

identified the human rostral migratory stream (RMS), and corroborated

evidence for new neurons in the olfactory bulb (although, in poor

form, they failed to cite the paper which first published this

evidence). This group injected terminally ill cancer patients (30,

randing from age 20-80) with a chemical called BrdU, which marks all

dividing cells (unfortunately, it can also mark cells that are damaged

and/or dying, so it's not perfect). After the patients died, the

researchers analyzed their brains, and were able to locate cells

containing BrdU in the olfactory bulb. This demonstrated that after

the BrdU injection, a new cell was born and found its way to the

olfactory bulb (thus distinguishing it from neurons that had been

around for the life of the person). As I mentioned, this had been

shown before, but no one knew how such cells managed to migrate to the

olfactory bulb.

The real significant finding came when the the group sectioned the

brains "sagitally," which exposes the plane that we would see from the

side. They stained the tissue for a protein that marks neuroblasts,

and found the cells distributed along a path that began at the SVZ

and, in an intriguingly circuitous route, ended at the olfactory bulb,

as in the picture on the right (adapted from Swaminathan, Sci Am

2007). These cells were at various stages of development (likewise in

rodents, the neuroblasts are thought to mature as they travel along

the RMS), and had the appearance of migrating cells. They then used

magnetic resonance imaging (MRI) in 6 living patients to locate a

"tube" which they believe ensheaths the RMS.

So there's an RMS, so what? If this finding is true, this has many

therapeutic implications. Because these cells are naturally found in

the adult brain, they may prove to be the ideal source for cell

replacement in neurodegenerative disease and the injured brain (as

opposed to grafting in embryonic stem cells from another human).

Ideally, if we identify the signals that are guiding the new cells to

the olfactory bulb, we might be able to direct their migration to an

area that had been damaged by stroke.

Another intriguing question, and matter of intense debate in the field

of adult neurogenesis, is why we need new neurons in our olfactory

bulbs. Why here (and the hippocampus), and not other regions of the

brain? One of the initial intellectual barriers to accepting that

neurogenesis occurs in adults is that neuroscientists could not

conceive of why or how one would add a new cell to a functional

neuronal circuit. Now, hippocampal neurogenesis has been linked to the

action of antidepressants and, in theory, to certain aspects of memory

formation, but the reasons for olfactory bulb neurogenesis are far

more elusive. Perhaps the addition of new neurons helps discriminate

new odors from those we have perceived before? Maybe it's involved in

associating certain smells with certain memories? Rodents have

increased addition of neurons to their olfactory bulbs when pregnant;

it would be interesting if a similar phenomenon occurred in pregnant

women, and if this would be associated with innate feelings of

compassion for the new babe.

Reference: Curtis MA et al. "Human neuroblasts migrate to the

olfactory bulb via a lateral ventricular extension." Science 2007

(DOI: 10.1126/science.1136281)

Posted by Madam Fathom at 1:38 PM 0 comments Links to this post

Labels: neurogenesis, olfactory bulb, rms, svz

Wednesday, February 7, 2007

How a chicken can run around with its head cut off

When's the last time you walked? Most of us, excepting those with

disabilities, probably walked relatively recently. Walking is a

routine behavior that's very routine, learned at an early age and

performed without much mental effort. So a more difficult question:

when's the last time you thought about what our bodies do when we

walk? If you take the time to consider the behavior, walking is a

tremendously complex task.

When we walk, we activate hundreds of muscles in an extremely precise,

sequential manner. We need to alternate our legs, alternate our

flexors (the muscles that bend a joint, e.g. quads) with our extensors

(muscles that straighten a joint, e.g. hamstrings), bend our

hip/knee/ankle/foot at the appropriate times, and do all of this with

relative fluidity. When neuroscientists initially sought to understand

the neural mechanisms underlying walking behavior, one of the major

issues was whether it required conscious control.

To explore this issue, there was a pretty easy (if a bit blunt)

solution: remove the cortex. So in the early 1900s, there were a

number of studies performed in which the cortices of neonatal cats

were removed. These "decorticate" cats matured into adults, and were

able to stand and walk around. Thus, the researchers concluded that

walking does not require descending input from the cortex.

[Importantly, certain other brain structures, such as the basal

ganglia, were left intact. Damage to the basal ganglia can result

in a phenomenon called "obstinate progresson," which is an

amusingly fitting name for the behavior. A cat with severe

obstinate progression will walk, and walk, and walk...and

walk....even if it walks into a wall, its legs will continue to

make walking movements!]

How does this work? There's been a fair bit of progress since the

early days of decorticate cats. We now understand that the motor

system is arranged in a hierarchy, as illustrated in the figure below.

First, we make the decision to start walking (this requires the

brain). The brain then gives the command ("start walking") to a

different part of the nervous system: a circuit of neurons located in

the spinal cord called the "central pattern generator," or CPG. Once

activated, the CPG activates the relevant muscles and essentially

takes care of all of the details. So that is the general strategy for

locomotion: when we decide to walk, our brains "recruit" the

appropriate CPG, and this CPG is responsible for activating the

appropriate muscles at the appropriate time. And thus, although we

consciously decide to start and stop walking, we don't need to think

about it in between. Once initiated, the motion persists without

cortical input.

[Side note: Precise patterns of muscle contractions aren't just

involved in walking, but in all coordinated, rhythmic movements,

including swimming, flying, breathing, chewing, even sneezing. (So

someone unable to walk and chew gum at the same time has a defective

spinal cord, not poor intellectual capacity).]

So the brain's (largely) out of the equation...how does the CPG handle

locomotion? As I said, the CPG is a "neural circuit"... just like a

computer circuit, a neural circuit has a number of units that

communicate with each other to modulate the output (with walking, the

output activates specific leg muscles). To simplify things, we can

ignore the majority of muscles, such as those controlling the bending

of the knee, ankle, and foot (and don't forget about our arms, which

are coordinated with our legs when we walk), and think of 4 targets of

the CPG output: the right and left hamstring, and the right and left

quadricep. The important elements of walking are alternating left and

right, and alternating flexor and extensor.

Consider a stride in which your right foot is on the ground and your

left hip is bending to make the next step. In this case, the left quad

is activated, while the right quad is not, nor is the left hammy.

However, the hammy of our "stationary" foot is activated, to help

straighten the right hip and propel us forward. So when thinking about

the neuronal components underlying these properties, one can imagine

that when the motor neuron (which is a neuron that innervates

(directly communicates with) a muscle) innervating the left quad is

active, the CPG ensures that the motor neurons innervating the right

quad and left hammy are inhibited, while the motor neuron activating

the right hammy is active.

The walking CPG can be translated to other activities: what about

hopping? When we decide to hop, our brain activates the locomotor CPG

accordingly. Since we want to move both legs together, the CPG

coordinates the output such that the quads are activated together, and

the hamstrings are activated together, but neither hamstring is ever

activated when a quad is activated. So, you can see that a single

circuit that controls the quads and hamstrings is flexible and

adaptable.

[In a follow-up post, I'll go into the network logic of the CPG, and

speculate how the CPG is able to coordinate the motor neurons with

such precision...the knowledge in mammals is far from complete, but

there have been some interesting recent studies!]

So, the infrastructure of the motor system is arranged such that the

brain doesn't have too much responsibility when it comes to routine,

rhythmic behaviors. Once it activates the appropriate spinal cord

circuit to take care of the important details, it can move on to more