They identify neural circuits that are altered in Huntington’s disease

Huntington’s disease is a genetically based neurodegenerative disorder that causes motor, cognitive, and psychiatric alterations in affected individuals. Understanding the alterations of the neural circuits in this disorder is essential to be able to design therapeutic approaches. In the case of patients, this disease is associated with dysfunction of some neuronal pathways in the brain, specifically, the corticostriate circuit.

Now, a study has identified new alterations in other neural circuits in mouse models with which this pathology is studied, which significantly alters the lives of patients.

The research has been led by Mercè Masana, professor at the Faculty of Medicine and Health Sciences of the University of Barcelona (UB) and member of the Institute of Neurosciences of the UB (UBneuro), the August Pi i Sunyer Institute of Biomedical Research (IDIBAPS ) and the Center for Network Biomedical Research on Neurodegenerative Diseases (CIBERNED), in Spain. In the work, whose first author is the researcher Sara Conde Berriozabal, the experts Jordi Alberch, Manuel José Rodríguez and Guadalupe Soria (UB, UBneuro, IDIBAPS), among others, also participate. The research has been carried out with the support of the UB Scientific and Technological Centers (CCiTUB) and the IDIBAPS Magnetic Resonance Imaging Unit.

An inherited disorder that affects brain neurons

Huntington’s disease is a rare and hereditary pathology that usually manifests itself in adults between the ages of 35 and 50, although there are also juvenile forms of the pathology. It is caused by a mutation in the gene called IT15 or HTT that codes for the huntingtin protein (HTT). Traditionally, the motor disorder most associated with the disorder was chorea —a nervous disease that causes abnormal and involuntary movements—, but there are also other disorders that are not motor and that usually appear before.

This disorder is associated with dysfunction of corticobasal circuits in the brain. In earlier work, published in the academic journal eLife in 2020, the team characterized one of the neural circuits involved in the development of the disease in animal models: the connection from the secondary motor cortex (M2) to the dorsolateral striatum (DSL) nucleus. .

In patients, the brain area most affected from the onset of the disease is the premotor cortex —the M2 cortex in mice— which is involved in cognitive functions and perception processes. In the case of animal models, M2 is related to deficits in motor learning. In addition, it is also known that this cortical area is capable of projecting neuronal axons to various brain regions beyond the striatum.

Now, the new work identifies for the first time that the M2 cortex sends different axonal projections to another anatomical structure of the brain —the superior colliculus (SC)—, which are profoundly damaged and could be related to the symptoms of the disease.

In the framework of the work, the functional magnetic resonance technique revealed reduced functional connectivity between the left M2 cortex and all the brain regions analyzed in mouse models of the disease. By applying other innovative methodologies to control and modulate neural activity—ontogenetics, electrophysiology, photometry, and chemogenetics—the team discovered that lack of M2 cortical activity could be responsible for the altered responses in Huntington’s models.

The administration of fluorescent sensors in the M2 cortex (in yellow) has allowed us to understand how the aberrant activity of this cortex is related to alterations in the integration of visual stimuli. (Image: University of Barcelona. CC BY)

Understanding alterations in the brain circuit

Identifying the different modifications and functions of the M2 cortex circuit —beyond the corticostriate pathway— provides data that is decisive for delving into the symptoms of Huntington’s disease and other neurodegenerative pathologies (Parkinson’s, etc.). In addition, a deeper understanding of the role of the superior colliculus and its neural circuits—involved in the rapid movements present in many neurological disorders such as Huntington’s disease—may provide new insights to delay the onset and severity of symptoms in motor disorders. .

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The study is titled “M2 cortex circuitry and sensory-induced behavioral alterations in Huntington’s Disease: role of superior colliculus”. And it has been published in the academic journal Journal of Neuroscience. (Source: UB)