Snapshot: What is the balance beam test?

When you think of a balance beam, you might think of gymnastics. For humans, a balance beam is a surface where we perform jumps, flips, and other athletic feats. Whether it’s a child taking their first class, or an Olympic athlete going for gold, the balance beam requires both balance and coordination. When a scientist puts a mouse through the balance beam test, they don’t ask them to do this kind of complicated routine, but they are testing those same abilities.

Little Black Mouse on a White Background
Little Black Mouse on a White Background. Photo used under license by Michiel de Wit/

The equipment setup for the balance beam test is simple: two platforms with a beam running between them plus lots of padding underneath so the mouse doesn’t get hurt if it falls off. Over multiple days, the scientist will train the mouse to run across the beam from one platform to another. Once the mouse has been trained, it will go through multiple official test runs. In these tests, the scientist will measure the time it takes for the mouse to cross the beam. They will also count the number of times one of its paws slips off the beam during the crossing. You can see some videos of mice doing the test here.

Mice that have problems with balance and coordination usually take longer to cross the balance beam and have more paw slips during the crossing. The mice might take longer to cross because they are clinging to the beam to try to stay on. Their paws might slip more because they cannot coordinate their movements properly. The scientist can also compare the measurements from the first day of training with the measures taken during the official runs. This shows how well the mouse learned to stay on the beam. This is useful because learning how to do a task and performing the task are two different things. Some parts of the brain are more important for learning, while others are more important for doing the task. Thus, telling those two aspects apart can be useful.

Mouse cossing a balance beam connecting two platforms

A typical balance beam setup, with two platforms and a beam between them. Image by Amy Smith-Dijak.

The balance beam test has been used to understand balance and coordination in both healthy mice and mouse models of disease. In healthy mice, scientists studying the basic biology of balance and coordination use this assay to test if changing the way particular parts of the brain work changes the mouse’s performance. For diseases in which lack of balance and coordination are major features, such as spinocerebellar ataxias, this test is a simple way to check how fast the disease progresses in mouse models. The assay can further be used to test possible treatments for these diseases: better scores after the treatment indicate that the therapy helped the mice improve their balance and coordination.

To sum it up, the balance beam test is a simple and effective assay to measure a mouse’s balance and coordination. Its use helps scientists to understand the basic biology of balance and coordination, as well as uncover why they are impaired in some diseases. Using the balance beam test on mouse models of disease that underwent different treatments, scientists can further measure if the therapy would improve the mouse’s balance and coordination. Therefore, the balance beam test might even help to find new treatments for motor coordination diseases.

If you would like to learn more about the balance beam test, take a look at these resources by the Maze Engineers and Creative Biolabs.

Snapshot written by Dr. Amy Smith-Dijak and edited by Dr.Larissa Nitschke.

2 Minuti di Scienza: Come si misura clinicamente la gravità dei sintomi in pazienti atassici

Il coordinare facilmente ed efficacemente movimenti  come il parlare e il camminare è essenziale nello svolgimento della vita quotidiana. L’abilità di orchestrare questi movimenti con successo è generalmente chiamata “coordinazione mootoria”. Anche se i pazienti di SCA in genere sono in grado di iniziare movimenti coorporei, la loro abilitá di eseguirli in modo agevole e preciso è alterata. Per esempio, è possibile notare l’incordinazione motoria in pazienti atassici che non riescono a camminare lungo una linea retta, o nella difficoltà che hanno nel deglutire. Questi ed altri problemi motori possono notevolmente inficiare la vita quotidiana. Poter valutare fino a che punto un paziente sia in grado di fare questi movimenti offre un’ indicazione della gravità della patologia in ciascun individuo affetto dalla malattia.

Black pencil lying on top of paper that has scoring chart on it
Immagine ottenuta da Pixabay,

A differenza di ciò che analisi cliniche di routine misurano, come la pressione sanguigna o i livelli di zucchero nel sangue, non esiste una semplice misura per quantificare i movimenti umani. Per sopperire a questa carenza, sono state sviluppate numerose unità di misura con l’intento di assegnare una quantificazione standard as esami di coordinazione motoria.  Una di queste misure è la Scala per la Valutazione e la Classificazione dell’Atassia (SVCA). Un medico esperto (generalmente un neurologo) analizza la capacità del paziente di portare a termine alcuni comandi ( come ad esempio alzarsi in piedi o camminare) e poi, usando la SVCA, assegna  un voto per ogni comando. La procedura dura  circa 15-20 minuti, e in genere include i seguenti esami:

Continue reading “2 Minuti di Scienza: Come si misura clinicamente la gravità dei sintomi in pazienti atassici”

Snapshot: What is the Hippocampus?

How do you remember your name? Thank your hippocampus, a part of the brain that lies buried in the cerebrum and plays an important role in memory. The hippocampus looks like a seahorse when removed from the brain and hence the name (derived from Hippokampus, the Greek word for seahorse). Our brain consists of two hippocampi, one in each brain hemisphere.

One of the most striking feature of the hippocampus was observed by the Nobel laureate, Santiago Ramón y Cajal, in the 19th century. Cajal recorded his microscopic observation of the hippocampus in the form of beautiful hand drawings:

A very detailed sketch of the hippocampus on paper. The drawing looks very old.
The hippocampus, ink on paper – original drawing by Cajal. See more of Cajal’s drawings in this blog post by Margaret Peot.

He documented that neurons were arranged in unique layers in the hippocampus, a ground-breaking observation that proved to be useful several years later in studying how these neurons communicate with each other and form a circuit (think of it like a logic gate) for collecting and storing memories.

What is the function of the hippocampus?

In the 1950s, a patient named Henry G. Molaison, referred to as patient H.M., suffered from a severe form of epilepsy and went through a surgical procedure where a portion of his brain was removed in an effort to treat epilepsy. His surgery was of moderate success. He managed mild epilepsy for the next 58 years, however, he tragically lost the ability to form new memories as most of his hippocampi were removed during surgery.

H.M. served as the longest case study in history to understand the formation of memory in humans. The hippocampus is important for formation of new memories that we experience, known as explicit memory. This mostly involves remembering facts or events and over a period of time they get stored away permanently as long-term memory by a process called memory consolidation.

From H.M.’s case study it was clear that he was unable to form new memories as he lost the ability to consolidate them for future use. However, some of his long-term memory before the surgery such as events from his childhood or facts about his parents remained intact. This was fascinating for scientists as they were able to conclude that the hippocampus is necessary for memory consolidation but not for memory retrieval – a process required for recollecting memories from the place it was stashed away (this storage space could be in other brain regions), as in the case of H.M.’s older memories before his surgery.

The hippocampus also acts like a GPS in our brain and is important for another type of memory called spatial memory. Groups of cells in the hippocampus called “place cells” co-ordinate with another group of cells called the “grid cells” that exist in another brain region, and help us remember directions and navigate the space around us. The scientists who discovered these cells, John O’Keefe, May Britt-Moser and Edvard Moser were awarded the 2014 Nobel Prize in Physiology and Medicine.

How is the hippocampus affected in neurological disorders?

Many neurological disorders have ties to dysfunction/degeneration of the hippocampus.  Most notably is Alzheimer’s disease (AD), with one of the earliest AD disease symptoms being the loss of spatial memory and short-term memory. A previous article summary in our website also explores how an ataxia related gene increases the risk for Alzheimer’s disease.

If you would like to know more about the story of H.M. and how he transformed our understanding of memory, you can learn more by reading “Permanent Present Tense” by Suzanne Corkin.

If you would like to learn more about the hippocampus, take a look at these resources by Medical News Today and Verywell Mind.

Snapshot written by Dr. Chandana Kondapalli and edited by Dr. Hayley McLoughlin.

Snapshot: What is Neurofilament light protein (NfL)?

Nerve cells (aka neurons) are unique cells in that they have long, and thin extensions called axons which form connections with and talk to other neurons. This particular shape of neurons determines how quickly they can get their messages to other cells. You can think of the axons in the brain like the wires connecting all the components of a dense electrical network.

NfL stands for Neurofilament light protein (Not to be confused with the national football league!). Neurofilaments are proteins found in our neurons. They are important for helping these cells hold their structure and size. We know this is important for their ability to send messages to other neurons. NfL is the smallest unit of three types of neurofilaments (light, medium and heavy). There is a lot of NfL found in the axons of neurons.

A large neuron with long interconected axons
A cortical neuron stained green with antibody to NfL. Image courtesy of GerryShaw on Wikimedia.

How do you measure NfL levels?

Like other proteins, NfL levels can be measured in fluids using tools known as immunoassays. These tools make use of antibodies generated by the immune systems to capture and count the protein of interest. It has been possible to measure NfL in cerebrospinal fluid (CSF) – the clear fluid that surrounds the brain and has lots of brain proteins – since 2005. In recent years, immunoassay technology has improved significantly, permitting the quantification of proteins previously too low in concentration to detect. One of these technologies is Single Molecule Array (Simoa) and has made it possible to measure NfL reliably in blood.

Why is NfL used as a biomarker?

Biomarkers are biological characteristics that can be measured and that tell us about a particular biological or disease process or response to a therapy. They can be used to make drug development more efficient. NfL is released into CSF after brain injury and also in many neurodegenerative diseases. This makes it a biomarker of neuronal injury. The problem with CSF is that it requires a safe but relatively invasive medical procedure called a lumbar puncture or spinal tap to collect. It would be a lot easier for both patients and doctors if we could get the same information from a blood test. Being able to quantify NfL – a brain protein – in blood, and more importantly, that it reflected what was happening in the brain was very exciting for many diseases.

In neurodegenerative diseases with effective disease modifying therapies (such as Multiple Sclerosis and Spinal Muscular Atrophy), a lowering of NfL reflects the clinical benefit in response to these therapies. In another genetic neurodegenerative disease caused by a CAG expansion, Huntington’s disease, NfL increase has been shown to be the earliest detectable change in asymptomatic gene carriers who are very far from their predicted age of disease onset. Many results like these suggest that NfL could help monitor disease even before symptoms appear, decide when to start therapies, and tell us if a drug is improving the health of neurons.

What NfL research is being done in ataxia research?

So what about ataxias? You will be pleased to know that Ataxia researchers have also jumped on the NfL band wagon. We previously wrote an article on two independently published studies in SCA3 which showed in many patients that NfL levels increased as Ataxia severity got worse, they were correlated with a measure of clinical severity (SARA) and increased with the level of brain loss (atrophy). One of the studies showed NfL levels increased with a higher number of CAG repeats in someone’s SCA3 mutation. There is also work using mouse models of SCA3 to understand this biomarker further. Two studies have now shown that NfL is also increased in Friedreich’s ataxia. With more research, NfL could potentially be used to design better clinical trials for ataxias and to monitor disease.

If you would like to learn more about NfL, take a look at this article by NeurologyLive.

Snapshot written by Dr. Lauren Byrne and edited by Dr. Gülin Öz.

2 minuti di Scienza: Cosa sono I nucleotidi antisenso?

I nucleotidi anti-senso (anche noti come ASOs o AON, dall’inglese Antisense oligonucleotides) sono piccole molecole che possono essere usate per prevenire o alterare la produzione di proteine. Le proteine sono la forza lavoro della cellula, e dirigono la maggior parte dei processi cellulari. Le proteine sono prodotte in due fasi: nella prima un gene che codifica per una proteina viene convertito in una molecola che contiene specifiche istruzioni, l’RNA messaggero (mRNA). L’ mRNA trasferisce l’informazione contenuta nei geni al compartimento che assembla le proteine. Qui, l’mRNA è infine trasformato in proteina. Gli ASOs sono corte sequenze di DNA a singolo filamento, complementari alla sequenza di uno specifico mRNA. In base a diversi tipi di modifiche chimiche della loro sequenza, gli ASOs possono determinare due tipi di effetti sull’ mRNA complementare. Alcune modifiche fanno si che gli ASO distruggano l’mRNA e, di conseguenza, causano la perdita della proteina corrispondente. Altre modifiche, invece, permettono agli ASO di mascherare certi tratti dell’mRNA bersaglio, causando la produzione di una versione alterata della proteina.

Come funzionano gli ASO nel corpo umano. Autore della figura Larissa Nitschke, creato con BioRender.

La maggior parte delle Atassie spinocerebellari (dall’inglese Spinocerebellar Ataxias, SCAs) sono causate dall’accumulazione di una proteina tossica in una specifica regione del cervello. Per questo motivo, il principale obiettivo del trattamento delle SCAs con gli ASOs è inibire la produzione della proteina tossica. Un esempio di questa applicazione degli ASO è il lavoro del Prof. Harry Orr all’ Università del Minnesota. Il suo gruppo di ricerca studia l’Atassia spinocerebellare di tipo 1 (SCA1), causata dall’accumulo tossico della proteina Ataxina-1. Iniezioni di ASOs in modelli animali di SCA1 riducono i livelli di Ataxina-1 e migliorano l’incoordinazione motoria tipica della SCA1. Un altro modo di usare gli ASOs per il trattamento delle SCAs è la modifica dell’informazione trasmessa dall’mRNA per produrre una versione alterata della proteina. Questo approccio è stato testato nel caso della Atassia spinocerebellare di tipo 3 (SCA3), nella quale un’espansione nel gene Atxn3 rende la proteina Ataxina 3 tossica. Il gruppo del Dr. van Roon-Mom, in Olanda, per esempio, ha usato gli ASOs per rimuovere esclusivamente la porzione espansa della proteina Atxn3, lasciando intatta il resto della struttura proteica e la sua funzione.

Entrambi gli studi, così come altri studi portati avanti per altre SCAs, hanno evidenziato il potenziale uso degli ASOs come strumenti terapeutici per le SCAs. Mentre la ricerca sugli ASOs per le SCAs è per lo più nella fase preclinica, il trattamento con gli ASO per altre malattie, come la Distrofia Muscolare di Duchenne e l’atrofia muscolare spinale, è stato già approvato dall’ente statunitense Food and Drug Administration. Ulteriori studi clinici saranno necessari per misurare il beneficio terapeutico degli ASOs in pazienti di SCAs.

Per saperne di più sugli oligonucleotidi antisenso, leggi questo articolo alla pagina  HDBuzz sugli ASOs in via di sviluppo per la malattia di Huntington.

“2 minuti di Scienza” scritto da Dr. Larissa Nitschke, revisionato da Dr. Hayley McLoughli, tradotto in italiano da Dr. Antonia De Maio. Pubblicato per la prima volta il 31 Maggio 2019.