Why do I procrastinate? I'll figure it out later

Procrastination

If you are a chronic procrastinator, you're not alone. Habitual procrastination plagues around 15-20% of adults and 50% of college students. For a chronic procrastinator, repeated failure to efficiently complete important tasks can lead to lower feelings of self-worth. In certain contexts, it can also result in very tangible penalties. For example, a survey in 2002 found that around 40% of American tax-payers procrastinated on their taxes, resulting in errors due to rushed filing that cost an average of $400 per procrastinator. More importantly, we tend to procrastinate when it comes to medical care (both preventive and therapeutic), which can involve very real costs to our well-being.

Why is the urge to procrastinate so strong? It sometimes seems that we are compelled to procrastinate by a force that is disproportionate to the small reward we may get from putting off a task we're not looking forward to. According to Gustavson et al., the authors of a study published last week in Psychological Science, a predisposition to procrastinate may have its roots in our genes.

Previous research has suggested a potential link between a tendency to procrastinate and an impulsive nature. Gustavson et al. explored this possible connection by observing the traits of procrastination and impulsivity in a group of 181 identical and 166 fraternal twins. Because identical twins share 100% of their genes and fraternal twins only share around 50% of their genes, if a trait is shared by identical twins more frequently than it is by fraternal twins, it suggests the trait has a significant genetic basis (for more on twin studies see this post).

The investigators reported a significant correlation between procrastination and impulsivity (r = .65). The group also reported that their genetic model determined that procrastination and impulsivity were perfectly correlated (r = 1.0), suggesting that the genetic influences on procrastination and impulsivity might be completely shared. In other words, according to this study, there are no genetic influences on procrastination that aren't also affecting impulsivity.

But why would these two traits be associated with one another? Procrastination involves putting things off, while impulsivity involves doing them on a whim. Gustavson et al. suggest that both procrastination and impulsivity involve a failure in goal management and a deficit in the ability to guide behavior effectively using goals. The authors refer to a hypothesis proposed by procrastination researcher Piers Steel that suggests impulsivity may have been adaptive to our ancient ancestors when survival depended more on thinking and acting quickly. In today's much safer world, however, planning for events yet to come has superceded impulsivity in terms of importance.

Thus, like many of our other bad habits, procrastination may have its roots in a behavior that was at one point adaptive and is now outdated. So, if it feels like your desire to procrastinate is driven by a force much stronger than your willpower, it may be so. If Gustavson et al. are correct, the impetus for procrastination lies in genetic programming that dates back to the Pleistocene era.

Gustavson, D., Miyake, A., Hewitt, J., & Friedman, N. (2014). Genetic Relations Among Procrastination, Impulsivity, and Goal-Management Ability: Implications for the Evolutionary Origin of Procrastination Psychological Science DOI: 10.1177/0956797614526260

It's All About Timing: Circadian Rhythms and Behavior

Anyone who has ever tried to drastically alter his or her sleep schedule (e.g. going from working days to working nights) knows that it is one of the more difficult biological tasks we can take on. Even altering one’s sleep patterns by a couple of hours (such as the shift experienced by cross-country travelers) can be disruptive, and enough to make us feel tired, mentally unclear, and grumpy. But why are we so inflexible when it comes to our daily routine? Why are our otherwise diverse bodies so sensitive to an adjustment of our biological clocks by just a few hours? Perhaps it is because millions of years of evolution have led to a daily body clock so fine-tuned that this sensitivity is adaptive.

Circadian (from the Latin for “around” and “day”) rhythms are endogenous biological patterns that revolve around a daily cycle. They are found in all organisms that have a lifespan that lasts more than a day. They are adaptive in the sense that they allow an organism to anticipate changes in their environment based on the time of day, instead of just being a passive victim to them. Thus, to foster that readiness, they usually involve the coordination of a number of physiological activities, such as eating/drinking behavior, hormonal secretion, locomotor activity, and temperature regulation.

A major nucleus of the mammalian brain, located in the hypothalamus and called the suprachiasmatic nucleus (SCN), is responsible for acting as the master time-keeper in mammals. When the SCN is lesioned (i.e. in rodents), it results in a complete disruption of circadian rhythms. The animals will demonstrate no adherence to a daily schedule, sleeping and waking randomly (although still sleeping the same total amount of time each day).

The SCN receives information from ganglion cells in the retina, which keep it appraised of whether it is light or dark out, and maintain its synchrony with a diurnal schedule. It is not, however, completely dependent on visual input for keeping time. A number of other environmental cues, such as food availability, social interaction, and information about the physical environment (other than light) are thought to play an important role in the SCN’s ability to maintain regular daily rhythms.

Although the SCN is the center for circadian rhythms, it seems that many individual cells are not directly controlled by the SCN. Instead, they are thought to maintain their own time-keeping mechanisms. Known as peripheral oscillators, these cells are present in a number of organs throughout the body, and can be sensitive to environmental cues as well as the signals of the SCN.

So, how do the neurons of the SCN actually “keep time”? They appear to be controlled by a cycle of gene expression that consists of a natural negative feedback mechanism. The following is a simplified version of this mechanism. Cells in the SCN produce a protein known as CLOCK (circadian locomotor output cycles kaput). This protein binds together with another, BMAL1, and they act as a transcription factor, driving the synthesis of the proteins period (PER) and cryptochrome (CRY). When large amounts of PER and CRY have been created, they form a complex and inhibit the activity of CLOCK/BMAL1---thus inhibiting their own production. Gradually, PER and CRY proteins degrade, allowing CLOCK and BMAL1 to begin promoting the production of PER and CRY again. The cycle consistently takes around 24 hours to complete before it repeats, allowing the clock in the SCN to oscillate on a regular circadian rhythm.

Disorders of the SCN can result in disruptive sleep problems, such as advanced sleep phase syndrome (early sleep and wake times) or delayed sleep phase syndrome (preference for evenings and delayed falling asleep). More attention is now being focused on the role a dysfunctional circadian system may play in already identified behavioral problems. A recent review in PloS Genetics examines the potential influence circadian rhythm disturbances may have in disorders like depression, schizophrenia, and even autism.

Circadian disruptions are present in all major affective disorders, including depression, bipolar disorder, and schizophrenia. Although the exact role circadian rhythms play in these disorders is not yet known, it may be substantial. This is supported by the influence changes in sleep patterns can have on the alleviation of primary symptoms of these disorders. For example, sleep deprivation has been demonstrated to have an antidepressant effect (albeit short-lived) in patients. And some affective disorders, such as seasonal affective disorder, seem to have a basis in the length of the day, and shape emotional states.

Autism spectrum disorders (ASD) are correlated with low melatonin levels, and a gene responsible for the synthesis of melatonin is considered a susceptibility gene for autism. Mice with a mutant form of this gene demonstrate deficits in social interaction, anxiety, and increased occurrence of seizures. It is postulated that behavioral problems in ASD may be influenced by the failure of an individual’s circadian clock to effectively take note of social and environmental cues.

Variants of a number of time-keeping genes, such as PER1, CLOCK, and CRY have been found to be associated with behavioral disorders. It has yet to be determined if these variations are causative, contributive, or unrelated to the disorders. Keeping in mind how influential a disturbance of circadian rhythms can be in our daily lives, however, it seems logical to investigate the possibility of their contribution to pathologies.

Barnard, A.R., Nolan, P.M., Fisher, E.M. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing. PLoS Genetics, 4 (5), e1000040. DOI:10.1371/journal.pgen.1000040

Read more about the suprachiasmatic nucleus: Know your brain - Suprachiasmatic nucleus

Changes in Gene Expression and Addiction

As I discussed in a post last week, addiction seems to correspond to abnormalities in dopamine (DA) transmission throughout the reward areas of the brain. Specifically, initial uses of a drug tend to correlate with low levels of dopamine receptor availability in the nucleus accumbens (NAc), while long-term use affects DA transmission throughout the entire striatum (the NAc is located in the ventral portion of the striatum, or the part nearer the front of the brain).

The striatum is a subcortical region of the brain, and part of the mesocorticolimbic DA pathway, which is integral to the evaluation and appreciation of rewards (like drugs). Striatum is from Latin, and means striped. It is so named because the entire region has a striped appearance, due to the alternating bands of gray and white matter that make it up.

The changes that occur in the striatum are postulated to be responsible for the long-lasting behavioral changes that drug addicts can experience, such as cravings for drug use, an inability to enjoy previously rewarding experiences, and proneness to relapse. It has been suggested that these changes must be preceded by some sort of synaptic remodeling in order to have such a long-lasting effect, and those synaptic changes could be a result of fluctuations in DA transmission. How exactly they occur, however, has yet to be elucidated.

A study to be published in an upcoming issue of Nature may shed some light on the mechanism behind these changes. It involves gene expression, and a phosphoprotein known as DARPP32 (dopamine-and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa).

A phosphoprotein is a protein that has had a phosphate group attached to it, through a process known as phosphorylation. Phosphorylation is an important event in cells, as it often is the catalytic process that activates enzymes and receptors. Dephosphorylation can “turn off” these enzymes, and involves proteins called phosphatases.

When dopamine 1 receptors (D1R) are stimulated, they in turn activate DARPP32, which inhibits a phosphatase known as protein phosphatase 1 (PP1). This signaling cascade affects the phosphorylation of numerous proteins in the cytoplasm and nucleus of a cell.

In the Nature study, the researchers found that the administration of amphetamine, cocaine, or morphine to mice caused DARPP32 to accumulate in the nuclei of striatal neurons. Further studies of neural cultures indicated that dopamine prevents a specific DARPP32 phosphorylation site, Ser97, from being phosphorylated. Ser97 appears to be responsible for exporting DARPP32 from the nucleus of the cell, thus DARPP32 builds up inside the nucleus.

When DARPP32 accumulates in the nucleus, it causes the phosphorylation of a histone, H3. Histones are proteins that DNA winds around to make chromatin, the protein and DNA complex that makes up chromosomes. Phosphorylation of histones often affects chromatin structure, and gene expression as a result.

Mice with mutations in the Ser97 site demonstrated long-lasting aberrations in their behavioral responses to drugs and other rewards. They showed decreased acute locomotor responses to morphine administration, along with a reduced locomotor sensitization to cocaine. Their motivation to obtain a food reward was also diminished.

Thus, this signaling pathway may be responsible for one of the most potent behavioral changes in addiction, when euphoria achieved from the drug diminishes along with the pleasure once obtained from other rewards. This change can contribute to compulsive drug seeking, as an addict obsessively continues to seek the pleasure once associated with their drug of choice. If altered gene expression is responsible for these changes, it would help to explain why they can persist for such a long period of time after the cessation of drug use—sometimes continuing to affect the behavior of an addict for years, and often making their efforts to stay sober much more difficult.

Hox Genes and Neurodevelopment

In the 1980s, scientists knew surprisingly little about the role genes play in the development of an embryo. The discovery of a particular group of genes, however, known as Hox genes, drastically improved our understanding of embryology. At the same time it revolutionized genetics and developmental biology.

In the 1890s, an English biologist named William Bateson was repeatedly amazed when he came across “freaks” of nature in his studies. These included examples like a moth born with wings where its legs should be, or an insect born with legs for antennae. In 1915, another biologist, Calvin Bridges, gave a name to these aberrations, calling them homeosis (meaning the transformation of one body part into another). Bridges had noticed homeosis in fruit flies that were born with an extra pair of wings. Intrigued, he kept this strain alive through selective mating.

In the 1980s, scientists were finally able to isolate the gene that was causing the extra wing mutation in the fruit fly. They traced it back to a small group of genes, which they called Hox genes. They found that, by manipulating these genes, they could create virtual monsters, such as flies with legs that came bursting out of the middle of their heads.

The creation of these monsters, however, helped to elucidate the function of Hox genes. Hox is short for homeobox, which is the name for the DNA sequence that these genes have in common. Hox genes become active in early embryonic development. Their job is to designate which parts of the embryo will turn into which body parts (legs, wings, head, etc.). Hox genes are so specific that, if one that controls limb development is transplanted to the head of the embryo, a limb will grow out of the head.

Scientists began to find these types of master control genes in every embryo, regardless of the organism. Even more surprisingly, the genes are considerably similar across species. Scientists found they could replace a defective Hox gene in a fly with one from a mouse without any ill effects. Hox genes and other master control genes are present in humans as well, and play the same role in embryonic development. This congruity across species indicates that Hox and master control genes are probably an ancient evolutionary mechanism, developed before much speciation took place, but still present and active.

While understanding Hox and master control genes has led to great advancements in the comprehension of embryonic development, the development of the brain has still remained a little unclear. Specifically, scientists have had trouble figuring out how specialized neurons in our brain are formed in one region, then migrate to the areas they eventually have to settle in in order to function properly.

A study published online this week in PloS Biology may shed some light on the issue, however, and Hox genes are an important part of the explanation. The authors of the study investigated pontine (from the pons) neurons in mice. Pontine neurons are formed in the rear of the brain and then must migrate in the brainstem to eventually become part of the precerebellar system. This is an area that is necessary for coordinated motor movement, and provides the cerebellum with its principal input. So the question is, once these pontine neurons are formed, how do they “know” they have to travel to the precerebellar region?

The researchers who conducted this study found Hox genes to be the guide that leads the neurons to their appropriate resting place. A specific Hox gene, Hoxa2, was found to influence neuronal migration, preventing them from going astray through the influence of a pathway of molecular signaling. The Hoxa2 gene regulates the expression of a particular receptor, known as Robo. The receptor binds to a chemical called Slit, which prevents the neurons from being drawn toward other chemoattracants. This allows the neurons to ignore outside influences and to travel directly to the precerebellar region, where they belong. When the scientists knocked out the Hoxa2 gene, the pontine neurons were unable to resist being drawn to chemoattractants and often didn’t reach their final destination.

This adds some insight into the process of neuronal migration, something that has been problematic to neuroscientists for years. It is just the beginning of the story, however. Not all of the neurons reacted to Hoxa2, suggesting there may be other Hox genes involved in brain development. Thus, scientists will continue to search for other Hox genes that are part of the process. The success of this study, however, at least provides an indication that Hox genes, some of the most highly conserved in our bodies, may also be responsible for some of the most important aspects of brain development.

 

Geisen, M.J., Meglio, T.D., Pasqualetti, M., Ducret, S., Brunet, J., Chedotal, A., Rijli, F.M., Zoghbi, H.Y. (2008). Hox Paralog Group 2 Genes Control the Migration of Mouse Pontine Neurons through Slit-Robo Signaling. PLoS Biology, 6 (6), e142. DOI:10.1371/journal.pbio.0060142

microRNAs and Schizophrenia

Over the past twenty years, our understanding of gene expression has grown tremendously. As is often the case, however, with that increased level of comprehension has come a realization that the process is even more complex than originally thought. Thus, the relatively simple model of mRNA being transcribed from DNA, then traveling to ribosomes where it is translated into proteins (with the help of tRNA and rRNA), is now thought to be just a rough summary of the process. A number of other molecules, such as transcription factors (TFs) and microRNAs (miRNAs), are also involved in the expression of genes.

TFs are proteins that bind to sections of DNA and control the transfer of genetic information from DNA to RNA. They are integral to development, management of the cell cycle, responding to environmental changes, and intercellular communication. miRNAs are small, single-stranded RNA molecules that are transcribed by DNA but not translated into proteins. They are complementary to a particular section of mRNA, and by binding to mRNA can suppress gene expression. TFs and miRNAs can control anywhere from dozens to hundreds of genes in the human genome, with some estimates being much higher.

Fully understanding the role of TFs and miRNAs is essential for uncovering the etiology of genetically based disorders. Recently researchers at Columbia University Medical Center (CUMC) found that changes in miRNA levels can result in cognitive and behavioral deficits. They believe miRNAs could be involved in the development of schizophrenia in humans.

In the past, a higher incidence of schizophrenia has been correlated with a deletion of a small part of chromosome 22, at a location designated as q11.2. One of the genes in that chromosomal section is called Dgcr8. It plays an integral role in miRNA production. Thus, the researchers at CUMC hypothesized that the absence of Dgcr8 and the resultant reduction in miRNAs might be part of the etiology of schizophrenia.

They engineered a strain of mice that lacked the Dgcr8 gene. As they predicted, the mice were found to exhibit the same behavioral and neuroanatomical deficits seen in people with schizophrenia.

While this is an important step in understanding one of the most perplexing disorders medicine has ever had to confront, it is not exactly heartening. miRNAs have widespread effects on gene expression throughout the brain. This may help to explain why schizophrenia has been so difficult to decipher, as it is probably the result of a number of genetic aberrations. Unfortunately, though, it is further indication that schizophrenia is very complex, and much more investigation will be needed to fully comprehend its origin.