#gene-environment interactions

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Ever wondered about what Parkinson's Disease is about? Interested to know how this disease may be worsened by environmental factors? I am doing research on the gene-environment research between alpha-synuclein (a protein involved in Parkinson's) and cadmium (a heavy metal found in batteries and ironically, phosphate fertilizers).

Made for the Sigma Xi Student Research Showcase 2015. Special thanks to staffers at the Oberlin Media Center for giving me some tips, and to everyone who has given constructive feedback on this video.

The term epigenetics was introduced in the 1940s by Conrad Waddington, who defined it as: ‘‘the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being.’’ However, with the growth and evolution of genetics, the term gained a narrower and more specific sense.

Today, epigenetics is widely known and referred to as:

‘‘the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence.’’

Common epigenetic modifications include: (the most common being methylation)

Histone variants

Posttranslational modifications of amino acids on the amino-terminal tail of histones

Covalent modifications of DNA bases

Besides covalent modifications of DNA, histones and their posttranslational modifications have also been implicated in the organization of chromatin structure and regulation of gene transcription.

Short article about epigenetics and the controversy surrounding its definition here.

Sources:

Dupont, Armant and Brenner. 2009. Semin Reprod Med. Epigenetics: Definition, Mechanisms and Clinical Perspective. 27 (5): 351-7.

Attention-Deficit/Hyperactivity Disorder

In the US, ADHD has a prevalence of around 5-12% during childhood. Approx. 5 million children and adolescents in the US have ADHD, while only 2 million are being treated (mostly through psychostimulants). ADHD has long been characterized by its well-known pervasive behavioral symptoms: hyperactivity, impulsivity and inattention, which begin in childhood. There are 2 types of ADHD according to the DSM-IV: Hyperactive/Impulsive ADHD and Inattention ADHD.

Hyperactive/Impulsive ADHD Symptoms: ADHD 1

Fidgeting/squirming

Inability to remain seated

Restless

Loud and noisy (difficulty playing quietly)

Excessive talking

Impulsive

Intrusive 

"Always on the go"

Inattention Symptoms: ADHD2

Careless errors

Inattention to detail

Sustains attention poorly

Appears to not be listening

Disorganized

Trouble following through with directions/obligations

Loses needed objects

Dislikes sustained mental effort

Easily distracted 

Forgetful

In order for criteria to be met, +6 of the symptoms mentioned above (according to ADHD type) need to be present for 6 months or more and cause impairments in more than 1 setting (social, academic, occupational). These symptoms must also not be attributable to any other condition (i.e. depression, anxiety, substance use, etc)  and can cause impairment in children by the age of 7. Other characteristics that are important in the understanding and diagnosis of ADHD patients include: age, sex, comorbidity with other psychiatric disorders, intelligence, prematurity, exposure to toxins during early life, locomotor hyperactivity, differences in delay aversion, reward salience, motor inhibition tasks, error processing and working memory compared to controls. Moreover, ADHD is a disorder that's characterized by high intra-subject variability (which is thought to be mediated by competition among functional neural networks). 

Although the underlying cause of ADHD is currently unknown, there is a belief that both genetic (mostly dopaminergic and noradrenergic genes) and environmental factors (i.e. parental smoking, brain injury) play a role in ADHD. Moreover, some have suggested that gene-environment interactions account for about 70-80% of ADHD cases. 

ADHD has strongly been linked to developmental, volumetric and functional differences in several brain structures/areas. For example, brain imaging studies of children with ADHD have found smaller sizes in the corpus callosum, caudate nucleus, and right frontal cortex. Overall, the brains of children with ADHD are significantly smaller and that the brain volume reduction in ADHD is widespread and also affects the cerebrum and cerebellum. Other studies from different disciplines have implicated disruption of the frontostriatal pathway and other circuitry in diverse areas like the prefrontal cortex, the basal ganglia and the cerebellum. Additionally, other studies have found delayed cortical maturation in children with ADHD-meaning that they take longer and are slower to develop compared to normal brains.

More recently, disruptions in other brain networks and their relation to ADHD are starting to be explored. The diagram above is taken from Castellanos et. al (2008). Dr. Castellanos is an NYU clinician who employs neuroimaging techniques like fMRI to study differences in brain circuitry and wiring in patients with ADHD. In the ADHD brain, the precuneus (red part towards the posterior end of the brain), which is involved in high-level integration of posterior association processes with anterior executive function, appears to be enlarged. ADHD related differences in brain regions are shown at the right. The authors suggest that functional circuits linking the anterior cingulate cortex to the precuneus and posterior cingulate cortex and their long range connections should be considered as dysfunctional center in the ADHD brain. 

Sources:

Castellanos et. al. 2008. Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biological Psychiatry. 63 (3): 332-7. 

Castellanos and Tannock. 2002. Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes. Nature Reviews Neuroscience. 3: 617-626. 

Castellanos, XF. 2011. The Restless Brain: Spontaneous Brain Fluctuations and Variability in ADHD. Disorders of the Nervous System Lecture.