Our focus so far has been on how neuroscientists study the individual and collective activity of neurons and how neuronal activity relates to behavior. Neurons are regulated by genes, DNA segments that encode the synthesis of particular proteins within cells. Genes control the cell’s production of chemicals, so it is possible to relate behavior to genes and to chemicals inside and outside the cell. Chemical and genetic approaches require sophisticated technologies that have seen major advances in the past decade.

The brain contains a wide mixture of chemicals ranging from neurotransmitters and hormones to glucose and gases, among many others. Abnormalities in amounts of these chemicals can cause serious disruptions in behavior. Prime examples are Parkinson disease, characterized by low dopamine levels in the substantia nigra, and depression, correlated with low serotonin and/or noradrenaline production. The simplest way to measure brain chemistry in such diseases is to extract tissue postmortem from affected humans or laboratory animals and undertake traditional biochemical techniques, such as high-performance liquid chromatography (HPLC), to measure specific chemical levels.

Fluctuations in brain chemistry are associated not only with behavioral dysfunction but also with ongoing healthy behavior. For example, research over at least the past 30 years shows that dopamine levels fluctuate in the nucleus accumbens (a structure in the subcortical basal ganglia) in association with stimuli related to rewarding behaviors such as food and sex. Changes in brain chemistry can be measured in freely moving animals using two methods, cerebral microdialysis and cerebral voltammetry.

235

Microdialysis, which can determine the chemical constituents of extracellular fluid, is widely used in the laboratory. The technique has found clinical application over the past decade. A catheter with a semipermeable membrane at its tip is placed in the brain, as illustrated in Figure 7-22. A fluid flows through the cannula and passes along the cell membrane. Simple diffusion drives extracellular molecules across the membrane along their concentration gradient.

Fluid containing the molecules from the brain exits through tubing to be collected for analysis. The fluid is removed at a constant rate so that changes in brain chemistry can be correlated with behavior. For example, if a rat is placed in an environment in which it anticipates sex or a favored food, microdialysis will record an increase in dopamine within the basal ganglia regions of the caudate nucleus and putamen, known as the striatum.

Microdialysis is used in some medical centers to monitor chemistry in the injured brain. The effects of TBI or stroke can be worsened by secondary events such as a drastic increase in the neurotransmitter glutamate. Such biochemical changes can lead to irreversible cell damage or death. Physicians are beginning to use microdialysis to monitor such changes, which can then be treated.

Cerebral voltammetry works on a different principle. A small carbon fiber electrode and a metal electrode are implanted in the brain, and a weak current is passed through the metal electrode. The current causes electrons to be added to or removed from the surrounding chemicals. Changes in extracellular levels of specific neurotransmitters can be measured as they occur.

Because different currents lead to changes in different compounds, it is possible to identify levels of different transmitters, such as serotonin or dopamine, and related chemicals. Voltammetry has the advantage of not requiring the chemical analysis of fluid removed from the brain, as microdialysis does, but it has the disadvantage of being destructive. That is, the chemical measurements require the degradation of one chemical into another. Thus this technique is not well suited to clinical uses.

Most human behaviors cannot be explained by genetic inheritance alone, but variations in gene sequences do contribute significantly to brain organization. About 1 in 250 live births are identical twins, people who share an identical genome. Identical twins often have remarkably similar behavioral traits. Twin studies show strong concordance rates that support genetic contributions to drug addiction and other psychiatric disorders. But twin studies also show that environmental factors and life experience must be involved: concordance for most behavioral disorders, such as schizophrenia and depression, is far less than 100 percent. Life experiences are acting epigenetically to alter gene expression.

Genetic factors can also be studied by comparing people who were adopted early in life and usually would not have a close genetic relationship to their adoptive parents. Here, a high concordance rate for behavioral traits would imply a strong environmental influence on behavior. Ideally, an investigator would be able to study both the adoptive and biological parents to tease out the relative heritability of behavioral traits.

236

With the development of relatively inexpensive methods of identifying specific genes in people, it is now possible to relate the alleles (different forms) of specific genes to behaviors. A gene related to the production of a compound called brain-derived neurotrophic factor (BDNF) is representative. BDNF plays an important role in stimulating neural plasticity, and low levels of BDNF have been revealed in mood disorders such as depression. The two alleles of this gene are BDNF Val 66Met and BDNF Val 66Val.

Joshua Bueller and his colleagues (2006) showed that the Met allele is associated with an 11 percent reduction in hippocampal volume in healthy participants. Other studies have associated the Met allele with poor memory for specific events (episodic memory) and a high incidence of dementia later in life. However, the Val allele is by no means the better variant: although Val carriers have better episodic memory, they also have a higher incidence of neuroticism and anxiety disorders, as illustrated in Clinical Focus 7-3, Cannabis Use, Psychosis, and Genetics. The two alleles produce different phenotypes because they influence brain structure and functions differently. Other genes that were not measured also differed among Bueller’s participants and may have contributed to the observed difference.

An individual’s genotype exists in an environmental context fundamental to gene expression, the way genes become active or not. While epigenetic factors do not change the DNA sequence, the genes that are expressed can change dramatically in response to environment and experience. Epigenetic changes can persist throughout a lifetime and even across multiple generations.

237

Changes in gene expression can result from widely ranging experiences, including chronic stress, traumatic events, drugs, culture, and disease. A study by Mario Fraga and his colleagues (2005) stands as a powerful example of gene–experience interactions. The investigators examined epigenetic patterns in 40 pairs of identical twins by measuring two molecular markers related to gene expression.

Although twins’ patterns of gene expression were virtually identical when measured in childhood, 50-year-old twins exhibited differences so remarkable as to make them as different epigenetically as young non-twin siblings! The specific cause or causes of such differences are unknown but thought to be related to lifestyle factors, such as smoking and exercise habits, diet, stressors, drug use, and education, and to social experiences, such as marriage and child rearing, among others. The epigenetic drift in the twins supports the findings of less than 100 percent concordance for diseases in identical twins.

The role of epigenetic differences can also be seen across populations. Moshe Szyf, Michael Meaney, and their colleagues (e.g., 2008) have shown, for example, that the amount of maternal attention mother rats give to their newborn pups alters the expression of certain genes in the adult hippocampus. These genes are related to the infants’ stress response when they are adults. (Maternal attention is measured as the amount and type of mother–infant contact; a difference of up to 6 hours per day can exist between attentive and inattentive mothers.)

A subsequent study by the same group (McGowan et al., 2009) examined epigenetic differences in hippocampal tissue obtained from two groups of humans: (1) suicides with histories of childhood abuse and (2) either suicides with no childhood abuse or controls who died of other causes. The epigenetic changes found in the abused suicide victims parallel those found in the rats with inattentive mothers, again suggesting that early experiences can alter hippocampal organization and function via changes in gene expression.

Experience-dependent changes in gene expression are probably found not only in the hippocampus but throughout the brain as well. For example, Richelle Mychasiuk and colleagues (2011) found that stressing pregnant rat dams led to wide changes in gene expression in their offspring, in both the frontal cortex and the hippocampus. However, the investigators found virtually no overlap in the altered genes in the two brain regions: the same experience changed different brain regions differently.

Epigenetic studies promise to revolutionize our understanding of gene–brain interactions in healthy brain development and brain function. They will also help researchers develop new treatments for neurological disorders. For example, specific epigenetic changes appear to be related to the ability to make a functional recovery after stroke.

Chemical and Genetic Measures of Brain and Behavior

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

Answers appear in the Self Test section of the book.