A final point. We differ as to the nature and spread of our associative networks. And extremes of them can produce very interesting things at times. For example, most of us learned early on to associate something resembling the following with the concept of “face”:
But then someone comes along whose associate networks of neuronal projections are broader, more idiosyncratic than everyone else’s. And they teach the world that this can evoke faceness as well:
What might we call the consequence of some types of atypically wide associative nets of neurons? Creativity.
One More Round of Scaling Up
A neuron, two neurons, a neuronal circuit. We’re ready now, as a last step, to scale up to the level of thousands of neurons at once.
Consider the following slice of tissue viewed under a microscope:
It’s a homogeneous field of cells, all organized in roughly the same way. The top left corner and bottom left corner look exactly the same.
This is a liver in cross-section; if you’ve seen one part, you’ve seen it all. Boring.
If the brain were this homogeneous and boring, it would be an undifferentiated mass of tissue, with neuronal cell bodies carpeted evenly all over the place, sending out their processes every which way. Instead there’s a huge amount of internal organization:
In other words, the cell bodies of neurons that have related functions are clumped together in particular regions of the brain, and the axons that they send to other parts of the brain are organized into projection cables. What all this means, crucially, is that different parts of the brain do different things. All the regions of the brain have names (usually multisyllabic and derived from Greek or Latin), as do the subregions, and the sub-subregions. Moreover, each talks to a consistent collection of other regions (i.e., sends axons to them) and is talked to by a consistent collection (i.e., receives axonal projections from them).
You can go crazy studying all this, as I’ve seen, tragically, in the case of many a neuroanatomist who relishes all these details. For our purposes there are some key points:
Each particular region contains millions of neurons. Some familiar names at this level of analysis: hypothalamus, cerebellum, cortex, hippocampus.
Some regions have very distinct and compact subregions, and each is referred to as a “nucleus.” (This is confusing, as the part of every cell that contains the DNA is also called the nucleus. What can you do?) Some probably totally unfamiliar names, just as examples: the basal nucleus of Meynert, the supraoptic nucleus of the hypothalamus, the charmingly named inferior olive nucleus.
As described, the cell bodies of neurons with related functions are clumped together in their particular region or nucleus and send their axonal projections off in the same direction, merging together into a cable (a “fiber tract”). Here’s an example, taken from the hippocampus:
Back to that myelin wrapping around axons that helps action potentials propagate faster. Myelin tends to be white, sufficiently so that the fiber tract cables in the brain look white. Thus they’re generically referred to as “white matter.”
As can be seen, a lot of the brain is taken up by the fiber tracts—all sorts of regions are talking to one another, often distant parts.*
Suppose you have someone who has sustained an injury in one particular part of the brain, mysterious spot X. This gives the opportunity to learn something about the brain by now seeing what no longer works right in the person. Neuroscience as a field really got its starts thanks to studies of soldiers who had suffered “missile projection wounds.” Viewed in a detached manner, the endless nineteenth-century European military bloodbaths were God’s gift to neuroanatomists. The injured individual now does something abnormally. Can you conclude that spot X is the part of the brain responsible for the normal version of that behavior? Only if it’s where a cluster of neuronal cell bodies are. If spot X is a fiber tract, you’re actually learning something about the region of the brain whose neurons sent axonal projections in that fiber tract, and that region could be at the other end of the brain. So it’s important to distinguish between “neuronal nuclei” and “fibers of passage.”
Finally, back to the reference just now about a part of the brain being the center for some behavior. The examples from earlier in the chapter showed how hard it is to make sense of the function of an individual neuron without considering the network that it is part of. Same theme here, writ large. Given that every brain region is getting projections from and sending projections to a zillion other places, it is rare that an individual brain region is “the center for” anything. Instead it’s all networks where, far more often, a particular region “plays a key role in,” “helps mediate,” or “influences” a behavior. The function of a particular brain region is embedded in the context of its connections.
Thus, this concludes our Brain 101 primer.
Appendix 2
The Basics of Endocrinology
Endocrinology is the study of hormones, very different sorts of messengers from the neurotransmitters of chapter 2. As a recap, neurotransmitters are released from neurons’ axon terminals in response to action potentials. Once released, they travel a microscopic distance across the synapse and bind to receptors on dendrites of the second, postsynaptic neuron, thereby changing that neuron’s excitability.
In contrast, a hormone is a chemical messenger released from secretory cells (including neurons) in various glands. Once secreted, it enters the bloodstream, where it can influence any cells throughout the body that possess receptors for it.* So right off the bat we have key differences. First, neurotransmitters directly affect only neurons on the other side of synapses, while a hormone can potentially affect each of the trillions of cells in the body. A second difference is the time course; neurotransmitter signaling across synapses occurs in milliseconds. In contrast, many hormonal effects emerge over hours to days and can persist forever (for example, how often does puberty go away after a while?).
Neurotransmitters and hormones also differ in the scale of their effects. A neurotransmitter binds to its postsynaptic receptor, resulting in a local change in the flow of ions across the membrane of that dendritic spine. But depending on the hormone and the target cell being considered, hormones can change the activity of particular proteins, turn certain genes on or off, alter the metabolisms of cells, cause them to grow or atrophy, to divide or to shrivel up and die. Testosterone, for example, increases muscle mass, and progesterone causes the proliferation of cells in the uterus, causing it to thicken during the luteal phase. Conversely, thyroid hormone kills cells in a tadpole’s tail as the animal is metamorphosing into a frog, and a class of stress hormones can kill cells in the immune system (helping to explain how stress makes us vulnerable to getting a cold). Hormones are extremely versatile.
Most hormones are part of a “neuroendocrine axis.” Recall from chapter 2 how all roads in the limbic system lead to the hypothalamus, with its pivotal role in regulating the autonomic nervous system and hormonal systems. Here’s where that second part comes in. Neurons in the hypothalamus secrete a particular hormone that travels in a tiny, local circulatory system connecting to the pituitary, just below the base of the brain. There that hormone stimulates the secretion of a particular pituitary hormone, which enters the general circulation and stimulates the secretion of a third hormone from some peripheral gland. Here’s an example involving my three favorite hormones: during stress, hypothalamic neurons secrete CRH (corticotropin-releasing hormone), which stimulates pituitary cells to secrete ACTH (adrenocorticotropic hormone). Once in the general circulation, ACTH gets to the adrenal glands, where it stimulates secretion of steroid stress hormones called glucocorticoids (with the human version being cortisol, aka hydrocortisone). Other hormones (e.g., estrogen, progesterone, testosterone, and thyroid hormone) are released from peripheral glands as the final step of their own “hypothalamic/pituitary/peripheral gland axis.”* As a wonder
ful complication, the secretion of each particular pituitary hormone is often not under the control of only a single hypothalamic releasing hormone. Instead there are multiple types of hormones serving that function, and other hypothalamic hormones that inhibit that particular pituitary hormone’s release. For example, an array of hypothalamic hormones in addition to CRH regulates the release of ACTH, where different types of stressors produce different combinations of those hypothalamic hormones.
Not all hormones are regulated in this brain/pituitary/peripheral gland manner. In some cases there’s a brain/pituitary two-step, where the pituitary hormone exerts effects throughout the body; growth hormone generally fits this pattern. In other systems the brain sends projections down the spine and to a particular gland, helping to regulate its hormone release; the pancreas and its secretion of insulin are an example (where circulating glucose levels are the main regulator). Then there are weirdo hormones secreted from unlikely places like the heart or gut, where the brain regulates secretion only indirectly.
Hormones, like neurotransmitters, are made cheaply. They are constructed in just a few biosynthetic steps from plentiful precursors—either simple proteins or cholesterol.* Moreover, the body generates multiple types of hormones from the same precursor. For example, the numerous steroid hormones are all generated from cholesterol.
So far we’ve given short shrift to hormone receptors. They do the same general job as do neurotransmitter receptors; there is a distinctive receptor molecule for each type of hormone,* with a concave binding domain whose shape is complementary to the shape of the hormone. To trot out the same cliché as was used for neurotransmitters, a hormone fits into its receptor like a key fits into a lock. And as with neurotransmitter receptors, there’s no free lunch with hormone receptors. The various steroid hormones are structurally similar. Thus, if you’re cheap at the production end, you need subtle, fancy receptors that differentiate among those similar hormones—you do not want receptors that confuse, say, estrogen and testosterone.
Hormone/neurotransmitter similarities continue. Like neurotransmitter receptors, a hormone receptor’s “avidity” for its hormone can change. This means that the shape of the binding site changes a bit, so that the hormone now fits more or less snugly, thus increasing or decreasing the duration of the hormone’s effects. The number of receptors for a particular hormone in a cell can also change, altering the cell’s sensitivity to that hormone’s effects. The number of receptors in a target cell can be as important as the levels of the hormone itself, and there are endocrine diseases where normal levels of a hormone are secreted but, because of a mutation in the hormone’s receptor, no signal gets through. Hormone levels are akin to how loudly someone speaks. Receptor levels are akin to the acuity with which ears detect that voice.
Finally, receptors for a hormone typically occur in only a subset of cells and tissues in the body, meaning that only those are responsive to the hormone. For example, only tail cells contain receptors for thyroid hormone when tadpoles are turning into frogs. Similarly, only some types of breast cancer involve tumors whose cells are “ER positive”—i.e., they contain estrogen receptors and are responsive to the growth-promoting effects of the hormone.
This is our overview of how hormones alter the functions of target cells over the course of hours to days. Hormones were highly pertinent in chapter 7 when considering the effects of hormones in childhood and fetal life. Specifically, hormones can have permanent “organizational” effects during development, shaping how the brain is constructed. In contrast, “activational” effects persist for hours to days. These two domains interact, in that organizational hormone effects on a fetal brain influence what activational effects hormones will have on that brain in adulthood.
Back to the main text to consider specific hormones.
Appendix 3
Protein Basics
Proteins are a class of organic compounds that are the most abundant molecules in living systems. They are hugely important, since numerous hormones, neurotransmitters, and messengers of the immune system are made of protein; ditto for the receptors that respond to those messengers, the enzymes that construct or degrade them,* the scaffolding that shapes a cell, and so on.
A key feature of proteins is their shape, since the shape of a protein determines its function. Proteins that form the scaffolding of a cell have the shape of the different crossbars in scaffolding at construction sites (sort of). A protein hormone will have a distinctive shape that is unique and distinctively different from the shape of a hormone that has different effects.* And a protein receptor must have a shape that is complementary to the shape of the hormone or neurotransmitter that it binds (back to the time-honored cliché of appendix 1, namely that a messenger like a hormone fits into its receptor like a key into a lock).
Some proteins change their shape, typically moving between two conformations. Suppose you have an enzyme (again, a protein) that synthesizes a molecule of sucrose by linking a molecule of glucose to a molecule of fructose. The enzyme must have one conformation that resembles the letter V, where one end binds a glucose molecule at a particular angle, the other fructose. The binding of both triggers the enzyme to shift to its other conformation, where the two ends of the V move close enough for the glucose and fructose to be linked. The sucrose floats off, and the enzyme flips back to its original conformation.
What determines the shape and function of a protein? Any given protein is made of a string of amino acids. There are about 20 different types of amino acids—including some familiar ones like tryptophan and glutamate. Each protein’s string of amino acids is unique—like the string of letters that composes a word. Your typical protein is about 300 amino acids long, and with 20 different amino acid types, there are nearly 10400 possible sequences (that’s ten followed by four hundred zeros)—more atoms than there are in the universe.* The amino acid sequence of a protein influences the unique shape(s) of that protein. Dogma used to be that amino acid sequence determines the shape(s) of that protein, but it turns out that the shape is also subtly altered by things like temperature and acidity—in other words, environmental influences.
And what determines the sequence of amino acids that are strung together to form a particular protein? A particular gene.
DNA AS THE BLUEPRINT FOR CONSTRUCTING PROTEINS
DNA is another class of organic compounds, and just as there are roughly 20 different types of amino acids, there are 4 different “letters” (called nucleotides) that make up DNA. A sequence of 3 nucleotides (called a codon) codes for a single amino acid. If there are 4 different types of nucleotides, and each codon is 3 nucleotides long, there can be a total of 64 different codons (4 possibilities in the first place × 4 in the second × 4 in the third = 64). A few of those 64 are reserved to signal the end of a gene, and after eliminating those “stop codons,” there are 61 different codons coding for 20 different amino acids. Therefore, there is “redundancy”—almost all amino acids can be specified by more than one unique codon (an average of about 3, i.e., 61/20). Typically the different codons coding for the same amino acid differ by only a single nucleotide. For example, four different codon sequences code for the amino acid alanine: GCA, GCC, GCG, and GCT (A, C, G, and T are the abbreviations for the four types of nucleotides).* Redundancy will be important for understanding gene evolution.
The entire stretch of nucleotides that codes for a single type of protein is called a gene. The entire collection of DNA is called the genome, coding for all of the tens of thousands of genes in an organism; “sequencing” the genome means determining the unique sequence of the billions of nucleotides that make up that organism’s genome. That stretch of DNA is so long (containing roughly twenty thousand genes in humans) that it has to be broken into separate volumes, called chromosomes.
This produces a spatial problem. The DNA library is found in the center of the cell, in the nucleus. Proteins, however, occur all over the cell, are constructe
d all over it (just think of proteins in the axon terminals of a spinal neuron in a blue whale, terminals that are light-years away from that neuron’s nucleus). How do you get the DNA information out to where the protein is made? There is an intermediary that completes the picture. The unique nucleotide sequence in DNA that codes for a particular gene is copied into a string of similar nucleotide letters in a related compound called RNA. Any given chromosome contains a staggeringly long stretch of DNA, coding for one gene after another; in contrast, this stretch of RNA is only as long as the particular gene. In other words, a more manageable length. That RNA is then shipped to wherever it is supposed to be in the cell, where it then directs which amino acids are strung together in which sequence to form a protein (and there are amino acids floating around in a cell, ready to be grabbed for the protein-construction project). Think of RNA as a photocopy of a single page out of this vast twenty-thousand-page-long DNA encyclopedia. (And multiple copies of the cognate protein can be made from the instructions in a photocopy page of RNA. This sure helps in circumstances where copies of the protein must wind up in each of the thousands of a single neuron’s axon terminals.)
This produces what is termed the “central dogma” of life, a concept first framed in the early 1960s by Francis Crick, half of the renowned Watson and Crick, who discovered the “double helix” structure of DNA (with more than a little purloined help from Rosalind Franklin, but that’s another story). Crick’s central dogma holds that the nucleotide sequence of DNA that composes a gene determines how a unique stretch of RNA is put together . . . which determines how a unique stretch of amino acids are put together . . . which determines the shape(s) of the resulting protein . . . which determines that protein’s function. DNA determines RNA determines protein.* And implicit in that central dogma is another critical point: one type of gene specifies one type of protein.
Behave: The Biology of Humans at Our Best and Worst Page 71
