The “spectrumization” of neurological disorders
Historically and socially, psychiatric diseases have been defined as these yes-or-no disorders of the brain: he has schizophrenia, he doesn’t. He has autism, he doesn’t. For the cases that were not crystal clear, the neurologist just had to take his or her best guess as to whether or not the patient suffered from a disease, or whether the patient was within the boundaries of normal. But with the ever-increasing understanding of how absurdly complex the brain is came a shift toward a “spectrumization” of psychiatric disorders. Researchers and physicians started noticing just how similar some of these psychiatric patients were in their biomarkers, even though they had different diagnoses. Patients were no longer simply a binary diagnosis, but became a single point along a spectrum of symptoms and disorders.
With this newer view on psychiatric disorders, there is currently much more flexibility in terms of the diagnosis of an individual. The most well-known of these spectrum disorders is the autism spectrum disorders (ASD) that include Asperger’s to full blown autism to Rett’s syndrome. Side note: all of these are thought to be developmental disorders, along with schizophrenia, demonstrating just how ridiculously important the proper development of the nervous system is. I’ll write more on this later since neurodevelopment is just so ridiculously interesting. Each of these autism spectrum disorders has some or many overlapping symptoms with one another (behavioral, electrophysiological, genetic etc.), with varying degrees of severity. However, each disorder still has its own unique symptom or combination of symptom(s) that make it its own disorder. This is true for mood disorders (depression, bipolar, etc.) and other psychiatric disorders too (different symptoms of schizoprenia and schizoid disorders for example). I am sure that our classification scheme for psychiatric disorders will change as the research into these fields becomes even more fruitful.
It isn’t wholly surprising that this trend has developed. We know the brain to be a very densely packed mess of highly connected cells that communicate with each other using a myriad of different chemical compounds. The effect of subtle but significant changes in the wiring and firing patterns of these neurons can be quite large, and similar changes between individuals at the level of neuronal connections can lead to similar changes at a higher level such as behavior. What complicates matters is that in many instances the same abnormalities at the circuitry level can be caused by different molecular and genetic underpinnings, and that very similar circuit level differences can in fact lead to vastly different behavioral outputs. Most psychiatric illness diagnoses are at the level of behavior currently, but there is a huge push in neuroscience research to find reliable biomarkers that are not as subjective as behavioral tests.
This of course stems from the belief that all thoughts, feelings, emotions, and consciousness are firmly rooted in the physical world ie our neurons within our brain. If you are a believer in dualism (a la Descartes) then this obviously does not apply, but I find it very difficult to believe in dualism with our current understanding of our nervous system, as limited as it may be. If the thoughts of an individual are irrational, delusional and/or fly in the face of reason and evidence, then it follows that something must be different in the substrate responsible for these thoughts when compared with a “normal” substrate. But, how does one define a brain as being normal? This is a tough question that I don’t have a good answer for, as it is a mix of both biological and social criteria that defines a “normal” brain. But, I imagine that there is quite a broad spectrum of what can be categorized as “normal”, just as there are broad spectrums for the various diseases as well.
This is a confocal image of a mouse hippocampus, specifically the dentate gyrus region of the hippocampus. The red staining is against a protein that is expressed in mature neurons, while the neurons marked with green are transgenically expressing green fluorescent protein (GFP). The reason why you only see a few green neurons as opposed to the red staining which marks so many more neurons is because this transgenic mouse strain’s neurons only express green in neurons that have undergone some form of electrical activity. This image was taken after a learning and memory task, so presumably these green neurons are the ones directly responsible for encoding the new memories that were learned, since they were the ones that have been activated as determined by the GFP expression being turned on in these cells.
Taken from Matsuo et al 2009 Frontiers Behav Neurosci
My brain visually stored this image as soon as I saw it because it was so striking to me. This is an image of a dissected, opened mouse retina that shows labeling of a specific subset of retinal ganglion cells (neurons within your eye that are responsible for the different qualities of vision). The transgenic labeling shows that these neurons have dendritic arborizations which point in a single direction (downward/ventral). Most likely due to this one-sidedness of their projections, this class of cells is responsible for recognizing only movement in the upward direction. The thin streaks that are also labeled (and where the arrow is pointing) are the axons of these cells, all converging near the center of your eye to form the optic nerve, which then sends visual information to be processed by your visual cortex.
Image taken from Sanes et al 2008 Nature
One of the difficulties in fluorescent imaging of neurons has been that light penetration of the excitation lasers needed to observe fluorophores does not penetrate deeply enough. The laser scatters the deeper you go due to the tissue itself scattering light, which renders clear imaging impossible at very deep levels in the cortex and other brain structures deeply embedded in the brain. However, if the brain were clear, then light would be able to penetrate much deeper and clearer images can be taken at much deeper parts of the brain.
Recently, a group at Riken has been able to get around this issue by developing a reagent that turns tissue clear and, thus, amenable to imaging. Left is a mouse embryo that has been soaked in saline (salt water), while right is a mouse embryo that has been soaked in their reagent known as Scale. It is pretty clear from this photo that they have made the tissue of the mouse embryo transparent! This is not usable in living tissue yet since the reagents used are pretty harsh to the tissue, but the group is developing something in hopes of applying it to living tissue. Think of the possibilities!
From Riken
For those of you who don’t believe there is beauty in science. This is a dissociated hippocampal neuron with an antibody stain against MAP2, a common cell body and dendritic marker. Billions of these guys make up the human brain through trillions of synaptic connections. Neurons really are beautiful.
Image taken from our own lab.
Sleep, and why we need it
One of the most enigmatic behaviors we engage in occurs every night (or, for some of us, every morning or afternoon too). Sleep has long been observed and practiced evolutionarily speaking, but the exact functions of sleep are still unknown to us. Some claim that sleep is not necessary since there are people who do not sleep for decades but are still fine, while others say that sleep is critical for every single biological function ranging from physical recovery to memory processing. We do have some ideas as to why organisms sleep, but what is the main function or functions of sleep and how do we test this?
To test the possible functions of sleep, most of the research has been done on human subjects since many of the readouts from these tests have to deal with cognitive functions. One cannot very easily ask a mouse whether it feels less alert or whether it doesn’t remember things as well (although there are tests that indirectly address these cognitive functions). As you may know from personal experience, sleep deprivation has been shown to have some pretty negative effects on your brain’s functioning, including attention span, memory acquisition, memory consolidation, memory retention, etc. the list goes on… These brain functions have been implicated in sleep due to studies that test the effects of sleep-deprivation on humans or animals, and reporting back whether or not deficits are present in different behavioral tasks. Using a wide range of techniques from fMRI brain imaging to single neuron recordings, we are pretty confident in claiming that if you lack sleep you will not function optimally in many memory-associated behaviors.
One pretty cool model for sleep that has arisen from these sleep-deprivation studies is that sleep functions to “dampen” or weaken the synaptic connections. The “synaptic homeostasis model” is pretty straightforward: when we are awake our synaptic connections increase, and when we are asleep our brain downscales these connections back to a proper, functional level which would free up more “space” for subsequent newer connections. Thus, when sleep does not occur, neuronal connections and neuronal circuits would essentially saturate and hinder any new learning that might be attempted. Other bodies of research strongly implicate sleep in proper consolidation of long term memory. Both of these ideas have come about from sleep deprivation studies, but in order to convincingly show sleep’s normal role is for these functions, we have to be able to induce sleep. (Sidenote: this is a pretty important point in science, in that for a model or hypothesis to be correct it cannot truly be supported by loss of function experiments alone, but also must be supported by gain of function experiments.)
Recently, we have finally been able to control the sleeping and waking of a model organism—the fruit fly aka Drosophila melanogaster. Surprisingly, sleep or a sleep-like state has been observed in Drosophila, and even as low on the evolutionary ladder as the nematode C. elegans. Drosophila in particular have provided lots of insight into our understanding of sleep, from behavior to circuitry underlying sleep. Since these model organisms are particularly amenable to genetic manipulations, it is no surprise that Drosophila is the first organism where we are able to manipulate sleep through the use of tricky genetic tools.
On the left is an electron micrograph image of a whole fly, when you are looking head-on at the head. On the right is an image of the fly brain with all neurons in red, in the same orientation as the left EM. The green is labeling a subset of neurons that make up important olfactory memory structures, and you can clearly see the morphology of a single one of these neurons
This paper is the first paper to functionally manipulate a neuronal circuit and actually induce sleep in flies. This now provides us with a great tool to study the effects of sleep and not just sleep deprivation! They determined this by first expressing a special type of temperature-sensitive cation channel in a very specific structure of the fly brain (fan-shaped bodies). When placed in a hot environment, the channels would open and allow cations such as Na+ to flow in, and the net effect was that it induced sleep in the flies.
Next, they tested the synaptic homeostasis model for sleep mentioned above by housing the flies in a “socially enriched” environment. This environmental condition has previously been shown to increase the number of synaptic terminals, and when the researchers on this paper tested the flies’ long term memory after being raised in this environment, they found that memory was impaired when they tried to test the flies after training them. However, if they induced sleep right before training the animals, they found that the flies were now able to retain the memory! In effect, this strongly supports and corroborates the existing data regarding sleep’s effects on synaptic homeostasis
To test the effect of sleep on memory consolidation, they trained the flies using a behavioral protocol that shouldn’t induce long term memory formation. But, if they induced sleep right after training the flies, the flies then were able to form long term memories from their training! So now we have good, positive evidence for the functional role of sleep not only from sleep deprivation studies, but from sleep-induction studies. This is the first paper that has ever been able to really cleanly show an endogenous function for sleep, and it’s actually quite exciting to me.
From these results, you can make your own decision as to whether or not you should change your sleeping pattern, or whether you want to pull an all-nighter next time to study. Keep in mind that this has only been shown in Drosophila so far, but I am hopeful that data from other model organisms such as transgenic mice will provide even further support.
I realize that many of the topics I post about pertain to memory, but I do think it is one of the “holy grails” of neuroscience which is why so much effort and research is devoted to better understand it.
Cryptochrome, the magnetic-field-sensitive molecule
This is kind of a strange finding, one with interesting possible implications. A recent paper came out in the journal Nature that looks at this gene known as CRY2, which is a gene that encodes a molecule in the class known as cryptochromes. (For those of you who don’t know, Nature is a scientific journal that is one of the very top journals, alongside Cell and Science.)
Birds and turtles are among the many organisms that we know of which use the Earth’s magnetic field for navigation purposes, but for a long time we were unsure of exactly how this sensory perception was accomplished, since in humans and mice/rats it has always been assumed that there was no magneto-sensory perception. Then this class of molecules named cryptochromes was discovered, and unsurprisingly, a functional significance was found for these molecules in the brain (specifically the retina of the eye). In birds, these molecules were found in photoreceptors of their eyes and shown to be incredibly important for navigation (maybe through the actual perception of light by the bird, although we can’t exactly ask birds directly how they see things..). Do humans have this molecule as well?
We do in fact have a subtype of crytochrome molecules, ones that are supposed to be non-light-sensitive. There exist two types of these—a class that is sensitive to blue light that is found in Drosophila and other invertebrates and a class that is not sensitive to blue light that is found in vertebrates like us. Both types serve to regulate circadian rhythms, as the sleep-wake cycle is heavily dependent on light and an internal biological clock, but the mechanism of their action is most likely different. The actual sensation of magnetic fields is thought to be mediated by light-sensitive chemical reactions involving cryptochrome, but since our type of cryptochrome is insensitive to light we are thought to be unable to sense magnetic fields (can you?). Interestingly, hCRY2 (mentioned above; human CRY2) is very highly expressed in the retina, but again supposedly this molecule is insensitive to light.
This paper aims to challenge this notion. By creating a transgenic fly line that expresses hCRY2, they show that this molecule is in fact sensitive to magnetic fields in a light-dependent fashion. To do this, they first knocked out all of the endogenous cryptochrome molecules in a line of Drosophila melanogaster (scientific name for fruit fly), and saw that it had deficits in its light-dependent magnetosensitivity—as expected. Then, in this fly line with knocked out cryptochrome, they express hCRY2 to see if any of the deficits would be rescued, and in fact they were. These results suggest that the human variant hCRY2 is in fact capable of sensing magnetic fields in a light-dependent manner.
The authors are wise in not directly claiming that this evidence shows humans are sensitive to magnetic fields, because simply put there is still only very minimal evidence that we as a species have magnetosensitivity. Rather, it is a good first step in at least demonstrating that a molecule in our genome is at least capable of magnetosensation.
As to whether or not I believe this claim for human magnetosensitivity, I’m a skeptic but do not think it is impossible. Until further tests show this molecule still retains its photosensitivity and magnetosensitivity in a “human background”, and in fact is functionally significant, I would be hesitant to make any bold claims.
Although this is a somewhat older finding, this still fascinates the hell out of me. A man in Europe who leads a pretty average life one day goes to the hospital to get a leg problem checked out. They take a scan of his brain, and the doctors are completely perplexed. On the top and bottom left you can see a horizontal and sagittal section of his brain as viewed by CT scan. For comparison, a normal patient’s brain CT scan is in the top and bottom right. That huge, gaping hole there should be filled with brain matter, but it’s completely devoid of any neurons. Somehow, this individual is able to live just fine with a hugely shrunken cortex! The plasticity of our brains are pretty damn impressive.
Image taken from newscientist.com
The sensory cortex homunculus. This little guy on the right’s body part proportions are drawn according to the relative representation of each body part in the sensory cortex (left). Notice the huge representation of the hands, tongue and face relative to the trunk.
Food for thought: why might our hands be so highly represented in the sensory cortex?
Taken from Purves et al
