Genes and the Brain


What do your genes have to do with your brain? More than you know.

  1. Genes guide the formation of the brain and its structures in early development (more links)
  2. Genes continue to guide the development of the brain through childhood, adolescence, and early adulthood
  3. Throughout your lifetime, genes regulate activity of every brain cell, assisting in cell survival and basic neuron to neuron interaction on a microsecond by microsecond basis
  4. Genes guide the formation and differentiation of new brain neurons throughout life — and help guide them to their final destination
  5. Genes are involved in normal ageing of brain cells, as well as degenerative and disease processes
  6. Genes often determine when it is time for neurons to die
  7. And much more . . .

Proteins form the internal machinery within brain cells and the connective tissue between brain cells. They also control the chemical reactions that allow brain cells to communicate with each other.

Some genes make proteins that are important for the early development and growth of the infant brain. For example, the ASPM gene makes a protein that is needed for producing new nerve cells (or neurons) in the developing brain. Alterations in this gene can cause microcephaly, a condition in which the brain fails to grow to its normal size.

Certain genes make proteins that in turn make neurotransmitters, which are chemicals that transmit information from one neuron to the next. Other proteins are important for establishing physical connections that link various neurons together in networks.

Still other genes make proteins that act as housekeepers in the brain, keeping neurons and their networks in good working order.

For example, the SOD1 gene makes a protein that fights DNA damage in neurons. Alterations in this gene are one cause of the disease amyotrophic lateral sclerosis (ALS), in which a progressive loss of muscle-controlling neurons leads to eventual paralysis and death. The SOD1 gene is believed to hold important clues about why neurons die in the common “sporadic” form of ALS, which has no known cause.

Most of the single gene mutations that cause rare neurological disorders such as Huntington’s disease have been identified. In contrast, there is still much to learn about the role of genetic variations in common neurological disorders and conditions, like Alzheimmer’s disease and stroke. A few things are clear. First, for most people, a complex interplay between genes and environment influences the risk of developing these diseases. Second, where specific gene variations such as SNPs are known to affect disease risk, the impact of any single variation is usually very small. In other words, most people affected by stroke or Alzheimer’s disease have experienced an unfortunate combination of many “hits” in the genome and in the environment. Finally, beyond changes in the DNA sequence, changes in gene regulation – for example, by sRNAs and epigenetic factors – can play a key role in the disease.

__ http://www.ninds.nih.gov/disorders/brain_basics/genes_at_work.htm

Whenever most people think about genes and the brain, they probably think about how genes build the brain during gestation and early childhood. It is unlikely that they understand that the genes inside their brains are working at a faster rate than their fastest thoughts.

Since our brains make us who we are, and our genes make our brains what they are (in collaboration with the environment), perhaps we should make a small effort to understand how this symphony harmonises?

Despite the anatomical complexity of the brain and the complexity of the human genome, most of the patterns of gene usage across all 20,000 genes could be characterized by just 32 expression patterns. While many of these patterns were similar in human and mouse, the dominant genetic model organism for biomedical research, many genes showed different patterns in human. Surprisingly, genes associated with neurons were most conserved across species, while those for the supporting glial cells showed larger differences. __ Allen Brain Institute via ScienceDaily.com

This is an intriguing finding, although it is likely to be expanded on significantly in the near future. Specific gene expression patterns within the nearly infinite possible patterns of gene expression, can tell us a lot about what is happening inside a cell.

The adult brain bears a gene expression imprint based on embryologic origin and classic evolutionary complexity. (A) Pearson correlation heat map matrix of all brain samples. The white boxes outline the classic evolutionarily related regions of the archicortex (A) (HiF, CA1, CA3, and DG), paleocortex (P) (Amg, EntCx, and PrhCx), and neocortex (N) (Cx and MtrCx). Samples with very similar gene expression profiles corresponding to a higher correlation coefficient are denoted by dark red, and map positions corresponding to brain regions with dissimilar gene expression profiles appear dark blue. (B) Unsupervised hierarchical cluster dendrogram. (Left) The dendrogram relating structures to one another. (Right) A schematic of the developing mouse brain with the five vesicle regions color-coded. The color chart shows the derivatives of these embryonic brain vesicles in the context of the dendrogram. The hatched boxes indicate brain structures formed by inductive events. A, archicortex; P, paleocortex; N, neocortex.  http://www.pnas.org/content/102/29/10357/F1.expansion.html

The adult brain bears a gene expression imprint based on embryologic origin and classic evolutionary complexity. (A) Pearson correlation heat map matrix of all brain samples. The white boxes outline the classic evolutionarily related regions of the archicortex (A) (HiF, CA1, CA3, and DG), paleocortex (P) (Amg, EntCx, and PrhCx), and neocortex (N) (Cx and MtrCx). Samples with very similar gene expression profiles corresponding to a higher correlation coefficient are denoted by dark red, and map positions corresponding to brain regions with dissimilar gene expression profiles appear dark blue. (B) Unsupervised hierarchical cluster dendrogram. (Left) The dendrogram relating structures to one another. (Right) A schematic of the developing mouse brain with the five vesicle regions color-coded. The color chart shows the derivatives of these embryonic brain vesicles in the context of the dendrogram. The hatched boxes indicate brain structures formed by inductive events. A, archicortex; P, paleocortex; N, neocortex.
http://www.pnas.org/content/102/29/10357/F1.expansion.html


The image above demonstrates a gene expression map based upon the mouse brain — the premier research model for studying mammalian brains.

If you understand how genes, brains, and environments interact, you will know far more than most scientists working in the field. For example:

The research team studied 218 human brains and 206 chimpanzee brains to compare two things: brain size and organization as related to genetic similarity. The human brains were from twins (identical and fraternal) or siblings; the chimpanzee brains had a variety of kinship relationships, including mothers and offspring or half siblings. The study found that human and chimpanzee brain size were both greatly influenced by genetics. In contrast, the findings related to brain organization were different for chimpanzees and humans. In chimpanzees, brain organization is also highly heritable, but in humans this is not the case….

“The human brain appears to be much more responsive to environmental influences,” said Dr. Gómez-Robles. “It’s something that facilitates the constant adaptation of the human brain and behavior to the changing environment, which includes our social and cultural context.”

___ http://www.sciencedaily.com/releases/2015/11/151116181023.htm

More

With a sample size of only 218 human brains, Dr. Gomez-Robles claims to refute the findings of a study that looked at over 30,000 human brains! Anything for the cause of political correctness, I suppose.

The authors of the above study appear to be claiming that because human brains are more plastic than chimp brains, that genes somehow play a lesser role in the formation and function of human brains. Most readers can understand that gene function is even more important to a more plastic brain — such as humans have — than to a less plastic brain, such as a chimp’s.

Too many scientists are working with blinders on, preventing them from observing multiple logical levels at once.

An Example of Brain Plasticity in Neuronal Circuits Involved in Formation of “Fear Memories”

Neuronal circuits mediating contextual fear acquisition, expression and generalization. (a) Contextual fear acquisition requires a representation of the environment within the CA1 region of the ventral hippocampus. This contextual information is then relayed to the basolateral and central nuclei of the amygdala (BLA/CeA), a structure of the medial temporal lobe involved in the formation of context-US associations. Contextual fear acquisition has also been shown to depend on dorsal medial prefrontal (dmPFC) regions, including the AC, which is known to receive inputs from the ventral CA1. Output circuits involved in the genesis of conditioned fear responses include projections from the AC or AMG to the ventrolateral periaqueductal grey (vlPAG). (b) Contextual fear expression has been shown to be dependent on the prelimbic region (PL) of the dmPFC, which receives inputs from both the ventral CA1 and the BLA. Output circuits involved in the genesis of conditioned fear responses include projections from the PL or BLA/CeA to the vlPAG. (c) Contextual fear discrimination has been shown to strongly depend on precise contextual representations provided by a reciprocal circuit between the ventral CA1, the PL, and the NR, which projects back to the hippocampus. Alterations within this circuit leads to fear generalization in non-conditioned contexts. The expression of fear generalization might involve direct projections from the PL to the vlPAG or indirect connections through the BLA/CeA. Red arrows and letters indicate structures and projections involved during specific contextual fear memory phases. Gray arrows and projections indicate hypothesized functional connectivity during specific contextual fear memory phases. http://onlinelibrary.wiley.com/enhanced/doi/10.1111/gbb.12181

Neuronal circuits mediating contextual fear acquisition, expression and generalization. (a) Contextual fear acquisition requires a representation of the environment within the CA1 region of the ventral hippocampus. This contextual information is then relayed to the basolateral and central nuclei of the amygdala (BLA/CeA), a structure of the medial temporal lobe involved in the formation of context-US associations. Contextual fear acquisition has also been shown to depend on dorsal medial prefrontal (dmPFC) regions, including the AC, which is known to receive inputs from the ventral CA1. Output circuits involved in the genesis of conditioned fear responses include projections from the AC or AMG to the ventrolateral periaqueductal grey (vlPAG). (b) Contextual fear expression has been shown to be dependent on the prelimbic region (PL) of the dmPFC, which receives inputs from both the ventral CA1 and the BLA. Output circuits involved in the genesis of conditioned fear responses include projections from the PL or BLA/CeA to the vlPAG. (c) Contextual fear discrimination has been shown to strongly depend on precise contextual representations provided by a reciprocal circuit between the ventral CA1, the PL, and the NR, which projects back to the hippocampus. Alterations within this circuit leads to fear generalization in non-conditioned contexts. The expression of fear generalization might involve direct projections from the PL to the vlPAG or indirect connections through the BLA/CeA. Red arrows and letters indicate structures and projections involved during specific contextual fear memory phases. Gray arrows and projections indicate hypothesized functional connectivity during specific contextual fear memory phases.
http://onlinelibrary.wiley.com/enhanced/doi/10.1111/gbb.12181


Here, we are talking about the things that you are afraid of, the things that can trigger a phobia or panic attack or PTSD. The close interaction of gene expression, brain structure, and the environment determine how well you can function in the face of various exposures and challenges.

The image above illustrates brain circuits that are involved in fear acquisition, expression, and generalisation. But how can we extinguish long-established fears — grow beyond them? It is not easy.

A review of several studies suggests that fear extinction does not result from an erasure of the original CS-US memory, but rather from the learning of a new CS- (No-US) association that will compete with the original CS-US association (Bouton 2004). Interestingly, it has been shown that extinction learning is specific to the context in which it occurs. As a consequence, following extinction learning, presentation of the extinguished CS in a context different from the extinction context, will trigger a full recovery of conditioned fear responses, a phenomenon known as context-dependent fear renewal (Bouton 2002, 2004).

From a clinical standpoint, long-lasting recovery of conditioned fear responses following exposure therapies, an analog of extinction learning in humans, is a major obstacle in the treatment of pathological conditions such as anxiety disorders and PTSD (Yonkers et al. 2003). For example, Rodriguez et al. studied this return of fear in a systematic manner on undergraduate students showing spider phobia. They observed a greater recovery of fear when participants were tested outside the exposure context. Hence, although the exposure therapy was successful, extinction of fear strongly depended on the extinction context (Rodriguez et al. 1999). The context-dependency of extinction learning has been confirmed by other human studies, which supports the similarity of extinction processes between humans and animals (Alvarez et al. 2007; Milad et al. 2005). For clinical purposes, the understanding of the neuronal circuits involved in the contextual modulation of fear extinction and renewal processes represents an important challenge to develop efficient therapeutic approaches to fear-related pathological conditions.

… A number of studies have also revealed a strong contribution of the mPFC during fear extinction. The first evidence that the mPFC processes fear extinction was given by Ledoux and colleagues who showed that while this region was not necessary for the acquisition of fear conditioning, it is required for extinction learning (Morgan & Ledoux 1995; Morgan et al. 1993). In this study, the authors reported heterogeneous results depending on the mPFC subregion that was lesioned. Indeed, whereas dorsal mPFC lesions increased freezing responses to both CS and context, during both acquisition and extinction, vmPFC lesions (including ventral PL, medial orbital cortex and IL) specifically altered extinction learning. This result was later confirmed by other studies (Lebron et al. 2004; Morrow et al. 1999b) although some reports did not find any effect of the lesion (Gewirtz et al. 1997; Morgan et al. 2003). Hence, these data suggested sub-regional heterogeneity within mPFC, a hypothesis that was later confirmed.

it is likely that the understanding of the detailed functional role of dedicated neuronal circuits and elements within the mPFC, BLA and HPC involved in the regulation of contextual fear behavior will open new therapeutic avenues for the treatment of anxiety disorders, including PTSD and other related psychiatric conditions. For instance, recent non-invasive transcranial magnetic stimulation (TMS) approaches targeting prefrontal regions have been shown to modulate cortical inhibition in rodents likely through an action on different classes of interneurons (Funke & Benali 2011; Hoppenrath & Funke 2013; Volz et al. 2013) and to reduce core symptoms of PTSD (Bluhm et al. 2009; Grisaru et al. 1998). Although additional studies are required to fully understand how TMS might reduce PTSD core symptoms within mPFC-BLA-HPC circuits, these approaches are very promising for the treatment of pathological anxiety. __ onlinelibrary.wiley.com/enhanced/doi/10.1111/gbb.12181

mPFC: Medial Prefrontal Cortex
BLA: Basolateral Amygdala
HPC: Hippocampus

The jargon and formatting of scientific writing can be intimidating, but the act of combing through to find what you are looking for is brain-building in itself, if you pace yourself.

Free review articles from Genes, Brains, and Behavior journal, for purposes of practise.

The bottom line is that human brains are genetically programmed to be plastic — to respond in an exquisite manner to the environment. Lower species of animals lack this gene-based facility, and must rely more on instinct. They, of course, grow out of a dependent infancy much more quickly than most humans. Parenthetically, blacks of African ancestry grow out of dependent infancy more quickly than other subspecies of humans.

The false dichotomy of “nature vs. nurture,” or “genes vs. environment,” has no place in more informed discussions of gene expression and human behaviour. With a growing knowledge of “epigenetics” we are seeing deeper levels of gene-based environmental plasticity of behaviour — even spanning the generations.

A better understanding of gene-based environmental brain plasticity will allow us to grow out of our fear programming and other dysfunctional programming, in order to become who we wish to be.

More on this topic later.

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