What you need to know:

• The brain is a complex set of neurons working together to receive and interpret information, control and initiate behavior and actions, and serve as the focal point for intelligent thought.
• More than 50 million Americans are impacted by disorders dealing with brain dysfunction.
• Recent findings are shedding light on the complex interplay between genetic and environmental signals in the brain.
• Ongoing genomic research at HudsonAlpha include studies related to Alzheimer disease, amyotrophic lateral sclerosis, autism, Huntington disease and Parkinson disease.

The brain is the most complex component of the human body. It receives and interprets information from our senses, oversees behavior and actions, and serves as the focal point for intelligent thought. Much of what defines who we are, both as humans and as individuals, is thanks to the chemical reactions that occur within this three-pound mass of neurons and supporting cells. Historically, the functions of the brain have seemed elusive and unsolvable: Scientists and clinicians are now beginning to decipher its inner workings. These findings shed light on the interplay between genetic and environmental signals in a healthy brain and offer clues regarding brain dysfunction or disease. In this edition of “Biotech Basics” we’ll briefly look at general brain function, followed by a quick overview of common disorders of the mind. Along the way, we’ll identify areas of genomic research at HudsonAlpha to show how genomic research can “open the vault,” increasing our understanding of brain function, dysfunction and treatment.

The Brain
The brain consists of approximately 100 billion nerve cells (neurons) and perhaps up to 10 times that many supporting cells (known as glial cells). The brain can be classified into a number of different sections, based on structural or functional similarities. As noted by the National Institutes of Health, “The brain is like a committee of experts. All the parts of the brain work together, but each part has its own special properties.”

The brain is often categorized into three basic components (figure 1a): the forebrain, midbrain and hindbrain. In a nutshell, the hindbrain is responsible for unconscious yet essential functions like breathing, swallowing and blood circulation. The hindbrain also contains the cerebellum, which is important for controlling posture, balance and equilibrium. The hindbrain and midbrain (involved in visual and auditory activities) together make up the brainstem. The forebrain is responsible for receiving and processing information from the rest of the body, producing and understanding language, storing memories, controlling movement and higher-level thinking. The forebrain is most easily recognized by the cerebrum, the large structure subdivided into two symmetrical halves (or hemispheres). These communicate with each other through a thick bundle of connecting nerve fibers. The outer rim of the cerebrum is called the cerebral cortex, a thin layer of neurons where most information processing actually occurs. The forebrain can be further divided into other sections (lobes) according to their function (figure 1b):

• Frontal lobe – planning and reasoning, parts of speech and movement
• Parietal lobe – perception related to touch, pressure, temperature and pain
• Temporal lobe – recognition of sound (hearing) and memory
• Occipital lobe – vision

Deep within the cerebrum lies a region known as the “inner brain” (figure 1c). This area contains structures involved in hormone regulation (hypothalamus), emotion (limbic system), memory (hippocampus) and initiating and integrating movement (basal ganglia).

Disorders of the Mind
There are more than 600 disorders known to impact the nervous system, striking an estimated 50 million Americans each year. Some disorders affect movement while others influence personality, behavior or cognition. Many of these disorders are described below, with acknowledgements to the National Institute of Neurological Disorders and Stroke.

Alzheimer disease is an age-related, non-reversible brain disorder that develops over a period of years. The symptoms of AD begin with memory loss and confusion, gradually leading to behavior and personality changes, a decline in decision-making and language skills, and problems recognizing family and friends. AD ultimately leads to a severe loss of mental function. These losses are related to the worsening breakdown of the connections between certain neurons in the brain and their eventual death. Most cases of AD occur in individuals over the age of 60.

Amyotrophic lateral sclerosis, sometimes called Lou Gehrig’s disease, is a rapidly progressive, invariably fatal neurological disease that attacks the neurons responsible for controlling voluntary muscles. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles across the body. In ALS, these motor neurons degenerate and die. Individuals with ALS lose strength and the ability to move arms, legs and other parts of the body. When muscles in the diaphragm and chest wall fail, individuals are unable to breathe without ventilatory support.

Autism is the most common condition in a group of developmental disorders known as the autism spectrum disorders. Autism is characterized by three distinctive behaviors. Autistic children have difficulties with social interaction, display problems with verbal and nonverbal communication, and exhibit repetitive behaviors or narrow, obsessive interests. These behaviors can range in impact from mild to disabling. Initial studies have found more neurons than expected in the brains of individuals with autism and it appears that at least a portion of these neurons did not follow proper developmental signals.

Huntington disease results from genetically programmed degeneration of neurons in an area of the brain known as the striatum. This degeneration causes uncontrolled movements, loss of intellectual faculties and emotional disturbance. HD is a familial disease, passed from parent to child. According to the Huntington’s Disease Society of America, more than a quarter of a million Americans have HD or are at risk of inheriting the disease from an affected parent.

Parkinson disease belongs to a group of conditions called motor system disorders, which result from the loss of dopamine-producing neurons in the basal ganglia. The four primary symptoms of PD are tremor or trembling in hands, arms, legs, jaw and face; rigidity or stiffness of the limbs and trunk; bradykinesia or slowness of movement; and impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking or completing other simple tasks. PD usually affects people over the age of 50.

Why Genomics?
Scientists believe that as much as 80 percent of all genes are active inside the brain. Of the disorders described above, only Huntington disease has been clearly linked to mutations in a single causative gene. For the other disorders, evidence suggests that symptoms are caused by a combination of genetic and environmental risk factors, most of which are still unknown. Genome-wide approaches are needed to identify the variants in these genes that influence risk and impact clinical severity. Within the last three years, a number of potential genetic risks have been identified, many of which are now awaiting confirmation. Additional studies are examining large-scale changes such as copy number variation and the role of epigenetic modifications like DNA methylation. Many such projects are occurring at HudsonAlpha.

• Dr. Richard Myers’ lab is using next generation sequencing technology to study Parkinson disease, ALS and Huntington disease.
• Dr. Devin Absher and his team are working to identify genetic variants associated with autism.
• Drs. Rick Myers and Devin Absher are working on the genomics and genetics of three mood disorders: bipolar disorder, major depression and schizophrenia.
• In Dr. Shawn Levy’s lab, targeted sequencing techniques are identifying mutations in exons and/or RNA from genes associated with Alzheimer disease and ALS. Levy also works on a schizophrenia project.

– Dr. Neil Lamb
director of educational outreach
HudsonAlpha Institute for Biotechnology

For more information:
www.ninds.nih.gov
This is a thoroughly developed Web site, created by the National Institute of Neurological Disorders and Stroke. It includes an index of disorders, as well as an easy-to-read, downloadable overview of the human brain.

www.g2conline.org
Genes to Cognition Online is an educational Web site focusing on modern neuroscience. Be sure to check out the G2C Brain, an interactive 3-D model of the brain.

Here are a few of the support groups available:
www.alz.org – Alzheimer Association
www.alsa.org – ALS Association
www.autismspeaks.org – Autism Speaks
www.hdsa.org – Huntington Disease
www.parkinson.org – Parkinson Foundation