Sniffing Out Schizophrenia
Neurons in the nose could be the key to early, fast, and accurate diagnosis, says a TAU researcher
A debilitating mental illness, schizophrenia can be difficult to diagnose. Because physiological evidence confirming the disease can only be gathered from the brain during an autopsy, mental health professionals have had to rely on a battery of psychological evaluations to diagnose their patients.
Now, Dr. Noam Shomron and Prof. Ruth Navon of Tel Aviv University’s Sackler Faculty of Medicine, together with PhD student Eyal Mor from Dr. Shomron’s lab and Prof. Akira Sawa of Johns Hopkins Hospital in Baltimore, Maryland, have discovered a method for physical diagnosis — by collecting tissue from the nose through a simple biopsy. Surprisingly, collecting and sequencing neurons from the nose may lead to “more sure-fire” diagnostic capabilities than ever before, Dr. Shomron says.
This finding, which was reported in the journal Neurobiology of Disease, could not only lead to a more accurate diagnosis, it may also permit the crucial, early detection of the disease, giving rise to vastly improved treatment overall.
From the nose to diagnosis
Until now, biomarkers for schizophrenia had only been found in the neuron cells of the brain, which can’t be collected before death. By that point it’s obviously too late to do the patient any good, says Dr. Shomron. Instead, psychiatrists depend on psychological evaluations for diagnosis, including interviews with the patient and reports by family and friends.
For a solution to this diagnostic dilemma, the researchers turned to the olfactory system, which includes neurons located on the upper part of the inner nose. Researchers at Johns Hopkins University collected samples of olfactory neurons from patients diagnosed with schizophrenia and a control group of non-affected individuals, then sent them to Dr. Shomron’s TAU lab.
Dr. Shomron and his fellow researchers applied a high-throughput technology to these samples, studying the microRNA of the olfactory neurons. Within these molecules, which help to regulate our genetic code, they were able to identify a microRNA which is highly elevated in those with schizophrenia, compared to individuals who do not have the disease.
“We were able to narrow down the microRNA to a differentially expressed set, and from there down to a specific microRNA which is elevated in individuals with the disease compared to healthy individuals,” explains Dr. Shomron. Further research revealed that this particular microRNA controls genes associated with the generation of neurons.
In practice, material for biopsy could be collected through a quick and easy outpatient procedure, using a local anesthetic, says Dr. Shomron. And with microRNA profiling results ready in a matter of hours, this method could evolve into a relatively simple and accurate test to diagnose a very complicated illness.
Early detection, early intervention
Though there is much more to investigate, Dr. Shomron has high hopes for this diagnostic method. It’s important to determine whether this alteration in microRNA expression begins before schizophrenic symptoms begin to exhibit themselves, or only after the disease fully develops, he says. If this change comes near the beginning of the timeline, it could be invaluable for early diagnostics. This would mean early intervention, better treatment, and possibly even the postponement of symptoms.
If, for example, a person has a family history of schizophrenia, this test could reveal whether they too suffer from the disease. And while such advanced warning doesn’t mean a cure is on the horizon, it will help both patient and doctor identify and prepare for the challenges ahead.
Scientists Identify Critical Link In Mammalian Odor Detection
Researchers at the Monell Center and collaborators have identified a protein that is critical to the ability of mammals to smell. Mice engineered to be lacking the Ggamma13 protein in their olfactory receptors were functionally anosmic – unable to smell. The findings may lend insight into the underlying causes of certain smell disorders in humans.
“Without Ggamma13, the mice cannot smell,” said senior author Liquan Huang, PhD, a molecular biologist at Monell. “This raises the possibility that mutations in the Ggamma13 gene may contribute to certain forms of human anosmia and that gene sequencing may be able to predict some instances of smell loss.”
Odor molecules entering the nose are sensed by a family of olfactory receptors. Inside the receptor cells, a complex cascade of molecular interactions converts information to ultimately generate an electrical signal. This signal, called an action potential, is what tells the brain that an odor has been detected.
To date, the identities of some of the intracellular molecules that convert odor information into an action potential remain a mystery. Suspecting that a protein called Ggamma13 might be involved, the research team engineered mice to be lacking this protein and then tested how the ‘knockout’ mice responded to odors.
Importantly, because the Ggamma13 protein plays critical roles in other parts of the body, the Ggamma13 ‘knockout’ was confined exclusively to smell receptor cells. This specificity allowed the researchers to characterize the effect of Ggamma13 deletion on the olfactory system without interference from changes in other tissues.
Both behavioral and physiological experiments revealed that the Ggamma13 knockout mice did not respond to odors. The findings were published in The Journal of Neuroscience.
In behavioral tests, control mice with an intact sense of smell were able to detect and retrieve a piece of buried food in less than 30 seconds. However, mice lacking Ggamma13 in their olfactory cells required more than 8 minutes to perform the same task. Both sets of mice were able to quickly locate the food when it was placed in plain sight.
A second set of experiments measured olfactory function on a physiological level. Using olfactory tissue from knockout and control mice, the researchers recorded electrical responses to 15 different odors. Responses from the Ggamma13 knockout mice were greatly reduced, suggesting that the olfactory receptors of these mice were unable to translate odor signals into an electrical response.
Together, the findings demonstrate that Ggamma13 is essential for mammals to smell odors and extend the current understanding of how olfactory receptor cells communicate information about odors to the brain. Future studies will seek to identify how Ggamma13 interacts with other molecules within the olfactory receptor.
“Loss of olfactory function can greatly reduce quality of life,” said Huang. “Our findings demonstrate the significant consequences when just one molecular component of this complex system does not function properly.”
Proust phenomenon: The notion that odours can trigger memories from the distant past, especially those charged with emotional significance. This occurs because of the unique connections of the olfactory system within the brain; it is the only sense that has direct contact with the limbic system (responsible for neural processes that trigger emotion, mood, motivation, and sexual behaviour).
Fun Fact: Your olfactory bulb is a bitch.
This little piece of shittery has, and will continue to be, the downfall of nations and love in general.
Why you ask? Well, when you smell something that is strongly linked to a memory of yours your olfactory bulb pieces that smell together with that memory and shoots it straight up into your brain. Like an emotional bullet every time you smell something that reminds you of “them”. That’s probably what happened to Lancelot. He was over Guinevere and then he smells a piece of grass that reminds him of her and BOOM he’s destroying a utopian society.
So when I have to sit in his room to help his roommate study, it’s like a million little bullets of emotionally loaded, beautifully intoxicating scents.
Basically, it hurts.
Explaining the Olfactory System
Molecules from the environment constantly interact with our olfactory systems. Mammals are able to reliably differentiate between literally thousands of distinct odors, a truly remarkable feat when the neurophysiological basis of this is considered. There are approximately 1000 different types of odorant receptors, additionally the genes that encode for olfactory receptors are the largest mammalian gene family (3-5% of all genes).
The olfactory system and its mechanisms can be divided essentially into two distinct sets, the peripheral and the central olfactory systems. As the nomenclature implies, the peripheral system is composed of all necessary apparatus outside the cranium, and the central olfactory system is composed of all apparatus within the central nervous system. This essay seeks to explain the basis of olfactory function and its remarkable features.
The cells specialized for scent are the olfactory sensory neurons, located within the neuroepithelium, in the back of the nasal cavity below the cribriform plate.
The olfactory neurons are unique in that they have a very finite life span; about 30-60 days; they are continuously replaced from the body’s population of basal stem cells. A study noted that the olfactory bulb and the hippocampus are the only known instances of adult neurogenesis.
The study highlights the means by which the neurons in the olfactory bulb are generated, eliminated, and replaced and the importance of understanding this system for the possible future production of anti-neurodegenerative disease therapy.
The olfactory neuron itself is a bipolar nerve cell; from the apical pole of each neuron a single dendrite extends and expands into a larger ‘knob’ from which 5-20 cilia project into the layer of mucus that coats the epithelium. The aforementioned cilia are particular and specialized for odor detection; they possess specified receptors for the detection of odorants while also having the transduction apparatus necessary for the amplification of chemical initiated signals to generate action potentials in the neuron’s axon. A single axon from the basal pole of each neuron extends to the olfactory bulb, the axons converge together in the olfactory bulb to form ‘tangles’ which together form what is called the glomulerus, the axons in this collection contact with specialized cells called mitral cells which thus project their axons into specialized regions of the brain. These specialized regions of the brain include the anterior olfactory nucleus, the amygdala, and the piriform cortex.
Essentially the sensation and perception of scents is accomplished by differing sensitivities of individual neurons to different odorants, which respond with depolarization and subsequent generation of action potentials. Higher concentrations of odorant molecules, logically, stimulate a larger number of olfactory neurons leading to a perceived ‘stronger’ scent. The olfactory sensory neurons are also remarkably effective at becoming desensitized, that is, after sufficient receptor exposure to its ligand, a receptor can be inactivated.
This inactivation is due to phosphorylation of the receptor by a protein kinase, following this an olfactory neuron might adapt to varying concentrations of an odorant molecule by adjusting its sensitivity to cAMP, similar to the method of light adaptation in the visual system. An increase in cAMP opens cyclic nucleotide-gated channels that allow for the influx of sodium and calcium, these ions then depolarize the neuron.
The stimulation of an olfactory neuron, put simply is the binding of an odorant molecule to its receptor, which subsequently causes the receptor to interact with a G-protein, the G-protein’s GTP-coupled alpha-subunit then stimulates a second-messenger pathway that increases the concentration of cAMP, this opens cyclic nucleotide-gated cation channels, leading to an influx of these ions into the cell, this changes the membrane potential of the cilia’s membrane and results in neuronal activity.
A notable characteristic of the olfactory system is that the odorant information is encoded spatially in the olfactory bulb. Experiments suggest that the glomeruli act as functional units, and that the information encoded by different odorants is in fact located in a precise point-to-point location on different glomeruli. Using labeling methods that monitored neural activity over the entire olfactory bulb it was shown that each odorant molecule usually stimulates numerous glomeruli. It has been found that olfactory neurons that express the same receptor will converge on just a few glomeruli; this finding suggests that each distinct glomerulus receives inputs from only one specific type of receptor – a high degree of specialization. Further investigation hypothesizes that an odorant that is able to stimulate numerous glomeruli in fact may activate numerous receptors, and that the different odorant molecules that stimulate the same glomerulus must activate the same receptor. Consequently the lack of a specific receptor produces, a ‘chemosensory deficit’ referred to as anosmia which renders the individual unable to detect a specific class of molecule.