2-Minute Neuroscience: Long-Term Potentiation (LTP)

Long-term potentiation, or LTP, is a process by which synaptic connections between neurons become stronger with frequent activation. LTP is thought to be a way in which the brain changes in response to experience, and thus may be an mechanism underlying learning and memory. In this video, I discuss one type of LTP: NMDA-receptor dependent LTP. I outline the mechanism underlying NMDA-receptor LTP and describe how it is thought to strengthen synaptic connections where it occurs.

Know your brain: Midbrain

Where is the midbrain?

The midbrain is one of the three subdivisions of the brainstem; it is the most rostral of these subdivisions, or the one that is closest to the top of the brainstem. The midbrain connects the brainstem to the diencephalon at a location sometimes called the midbrain-diencephalon junction.

What is the midbrain and what does it do?

Although it is a relatively small section of neural tissue, the midbrain contains a long list of nuclei, tracts, nerves, and other structures---each with its own diverse catalog of functions. Thus, any attempt to define all of the actions of the midbrain in a just a few sentences, paragraphs, or even pages is inherently inadequate. Rather than attempt to do that, I will simply discuss some of the most prominent anatomical features of the midbrain and some of their putative functions.

One of the most noticeable external features of the midbrain is the presence of four bumps on its posterior surface (the side that faces the back of the brain). Those bumps are indicative of the presence of four large underlying clusters of neurons; the upper pair of those clusters are known as the superior colliculi and the lower pair are known as the inferior colliculi. The superior colliculi are thought to be involved in directing behavioral responses toward stimuli in the environment, while the inferior colliculi are best known for their role in auditory processing.

The anterior surface of the midbrain is marked by the presence of the crura cerebri (plural for crus cerebri), two large bundles of axons that travel along the base of the midbrain as they stretch from the pons to the cerebral hemispheres. They contain fibers that are part of important motor pathways like the corticospinal and corticobulbar tracts. The crura cerebri are sometimes called the cerebral peduncles, although this term is generally used to refer to a larger area that includes the crura cerebri as well as much of the rest of the midbrain.

The midbrain is often divided into three regions. At the level of the midbrain, the fourth ventricle has narrowed to form the cerebral aqueduct, a channel that connects the fourth ventricle with the third ventricle. The region of the midbrain posterior to the cerebral aqueduct is called the tectum, which means "roof" in Latin. The tectum consists primarily of the superior and inferior colliculi.

The area of the midbrain anterior to, or in front of, the cerebral aqueduct is called the tegmentum. The tegmentum contains a variety of ascending and descending tracts that pass through the midbrain, such as the medial lemniscus and the anterolateral tracts. Fibers from the superior cerebellar peduncles, the major efferent pathway from the cerebellum, decussate in the midbrain. Some of these fibers project to a midbrain nucleus called the red nucleus, which is thought to play an important role in motor coordination.

There are several other important nuclei and neuronal clusters in the midbrain tegmentum. For example, the midbrain tegmentum contains nuclei for two cranial nerves: cranial nerve III (oculomotor nerve) and cranial nerve IV (trochlear nerve). It also contains neurons that are part of the raphe nuclei---clusters of serotonin-producing neurons found in the brainstem that send serotonin throughout the central nervous system. Additionally, one of the largest collections of dopamine-producing neurons in the brain, the ventral tegmental area, is located in the midbrain tegmentum.

The third region of the midbrain is made up of two structures called the basis pedunculi. They cover the anterolateral portions (to the front and toward the sides) of the brainstem. The basis pedunculi include the crura cerebri (discussed above) as well as the substantia nigrae, which---like the ventral tegmental area---contain large collections of dopamine-producing neurons.

Finally, the area surrounding the cerebral aqueduct is called the periaqueductal gray, or PAG. The PAG has long been recognized for its role in pain inhibition, although it is also thought to be involved in many other functions ranging from emotional responses to the production of vocalizations.

References:

Haines DE. Fundamental Neuroscience for Basic and Clinical Applications. 4th ed. Philadelphia, PA: Elsevier; 2013.

Vanderah TW, Gould DJ. Nolte's The Human Brain. 7th ed. Philadelphia, PA: Elsevier; 2016.

History of neuroscience: Camillo Golgi

By the second half of the 19th century, scientists were beginning to develop a better understanding of the overall function of the nervous system. Discoveries like Paul Broca's identification of Broca's area and Fritsch and Hitzig's description of the motor cortex, for example, had led researchers to a deeper appreciation of the functional specialization of different parts of the brain. What was still missing by the 1870s, however, was an awareness of some of the most fundamental information about the basic building blocks of the nervous system: neurons.

In fact, the word neuron (along with the terms axon, dendrite, and synapse) would not be introduced until the 1890s, and at the middle of the 19th century there was some debate about whether the brain was even made up of distinct cells like other tissues in the body. This was because when one viewed brain tissue under a microscope, nerve cells appeared to have many extensions that stretched out to other cell bodies, seeming to make contact with them. In this way, the brain looked as if it consisted of a collection of uninterrupted processes that formed an expansive net of cellular entities. This view of the structure of the brain came to be called reticular theory, as the word reticulum is Latin for "net."

The main obstacle that prevented researchers from being able to describe the true structure of neurons was the lack of a stain that allowed for the clear differentiation of neurons under the microscope. Because cells are not distinctly colored like they often are in textbooks, their clear borders are difficult to discern against a similarly colorless fluid background (even under the microscope). Microscopists must rely on dyes or stains, which selectively color cells or individual components of cells so they stand out and are able to clearly be seen.

Before the 1870s, the most widely used stain in brain science was a substance called carmine, a reddish stain that could be obtained from certain insect species (it is still used today as a coloring agent in a variety of products ranging from cosmetics to yogurt). Carmine was recognized as a staining agent in the 1850s. Its discovery was a major breakthrough, as prior to its widespread use staining was not even a regular practice nor was its utility fully appreciated. The carmine stain, however, still did not allow brain scientists to attain a perfectly clear picture of neurons, instead leading to the view that supported reticular theory as discussed above. 

This was the context when Camillo Golgi made his contributions to the field in the 1870s. Golgi was a thirty-year old physician working at a small, little-known hospital in northern Italy. He did not have the benefit of using the laboratory facilities of a large research institution. Instead, he created a makeshift laboratory in a kitchen of the hospital. The laboratory consisted of not much more than his microscope, which he mostly used in the evening by candlelight.

a pyramidal neuron stained with a golgi stain

It was in that hospital kitchen that Golgi developed a new method of staining that would revolutionize the way people looked at the brain. The stain involved soaking cells in a solution of silver nitrate, and although Golgi was not the first to attempt to stain cells with silver, his method was a tremendous improvement over past efforts.

The silver staining method caused neurons to appear dark against a yellow background (for this Golgi initially called the method the "black reaction"), but the essential feature of the stain for making it useful in visualizing neurons was that it only caused about 3% of the neurons in a tissue sample to be darkened. This was important because if all neurons were stained, the abundance of cells in any sample would cause the whole sample to appear black. Due to its selectivity, the silver stain allowed for the visualization of a selection of neurons in such detail as had never been possible before.

Golgi used his new stain to make a number of important observations about the nervous system. He provided more detailed descriptions of neurons, including the first good descriptions of axon collaterals, or branches that extend off of the main processes of axons. He described two types of neurons in the brain, one that has long a long axon that can stretch from the grey matter of the brain to other parts of the brain or nervous system, and another that has a short axon. These neurons have since been named Golgi I and Golgi II cells, respectively. He detailed ways in which glial cells can be differentiated from neurons and described the structure of the cortex, corpus callosum, and spinal cord. He discovered sensory receptors in muscle that detect muscle tension; these are now known as Golgi tendon organs. And of course he was the first to describe in detail the protein- and lipid-packaging cellular organelle now called the Golgi apparatus. 

Despite all of Golgi's achievements, his contribution of the silver stain may have been the most significant, as it allowed later researchers to appreciate the true structure of neurons for the first time. Golgi's stain (with some refinement) would be used by neuroscientists like Santiago Ramon y Cajal to prove that neurons did not fuse together to form a net, and instead were independent of one another (just like other cells in the body); Cajal's observations on the structure and organization of neurons would soon come to be known as neuron doctrine, and it would supplant reticular theory in the minds of most of the scientific community. Golgi and Cajal would share the 1906 Nobel Prize in Physiology or Medicine for their important contributions to neuroscience.

Although Golgi's stain had helped Cajal to disprove reticular theory, Golgi refused to accept the evidence that suggested neurons were independent of one another. In his Nobel Prize acceptance speech, Golgi railed against the neuron doctrine, shocking much of the audience to whom the evidence in support of it was distinctly clear. Even though he was incredibly stubborn on this point, however, Golgi's obstinance does not overshadow the significant contributions he made to neuroscience and biology as a whole.

Finger S. Minds Behind the Brain. New York, NY: Oxford University Press; 2000.

2-Minute Neuroscience: Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder characterized by a progressive loss of motor function. ALS affects upper motor neurons and lower motor neurons. As these motor neurons stop working, muscles also begin to atrophy; this can eventually lead to respiratory failure, which is often the cause of death in ALS patients. The pathophysiology of ALS is not completely understood, but similar to other neurodegenerative diseases like Alzheimer's disease it is characterized by clusters of dysfunctional proteins within neurons. In this video, I discuss ALS symptoms and pathophysiology.

Know your brain: Mammillary bodies

Where are the mammillary bodies?

The mammillary bodies are part of the diencephalon, which is a collection of structures found between the brainstem and cerebrum. The diencephalon includes the hypothalamus, and the mammillary bodies are found on the inferior surface of the hypothalamus (the side of the hypothalamus that is closer to the brainstem). The mammillary bodies are a paired structure, meaning there are two mammillary bodies---one on either side of the midline of the brain. They get their name because they were thought by early anatomists to have a breast-like shape. The mammillary bodies themselves are sometimes each divided into two nuclei, the lateral and medial mammillary nuclei. The medial mammillary nucleus is the much larger of the two, and is often subdivided into several subregions.  

What are the mammillary bodies and what do they do?

The mammillary bodies are best known for their role in memory, although in the last couple of decades the mammillary bodies have started to be recognized as being involved in other functions like maintaining a sense of direction. The role of the mammillary bodies in memory has been acknowledged since the late 1800s, when mammillary body atrophy was observed in Korsakov's syndrome---a disorder characterized by amnesia and usually linked to a thiamine deficiency. Since then a number of findings---anatomical, clinical, and experimental---have supported and expanded upon a mnemonic role for the mammillary bodies.

The mammillary bodies are directly connected to three other brain regions: the hippocampus via the fornix, thalamus (primarily the anterior thalamic nuclei) via the mammillothalamic tract, and the tegmental nuclei of the midbrain via the mammillary peduncle and mammillotegmental tract. Two of the three connections are thought to primarily carry information in one direction: the hippocampal connections carry information from the hippocampus to the mammillary bodies and the thalamic connections carry information from the mammillary bodies to the thalamus (the tegmental connections are reciprocal). 

These connections earned the mammillary bodies the reputation of being relay nuclei that pass information from the hippocampus on to the anterior thalamic nuclei to aid in memory consolidation. This hypothesis is supported by the fact that damage to pathways that connect the mammillary bodies to the hippocampus or thalamus is associated with deficits in consolidating new memories. Others argue, however, that the mammillary bodies act as more than a simple relay, making independent contributions to memory consolidation. Both perspectives emphasize a role for the mammillary bodies in memory but differ as to the specifics of that role.

Further supporting a role for the mammillary bodies in memory, there is evidence from humans that suggests damage to the mammillary bodies is associated with memory deficits. Several cases of brain damage involving the mammillary bodies as well as cases of tumor-related damage to the area of the mammillary bodies suggests that mammillary body damage is linked to anterograde amnesia. Indeed, mammillary body dysfunction has been identified as a major factor in diencephalic amnesia, a type of amnesia that originates in the diencephalon (Korsakoff's syndrome, an amnesia that is seen primarily in long-term alcoholics, is one type of diencephalic amnesia).

Experimental evidence from animal studies also underscores the importance of the mammillary bodies in memory. Studies with rodents and monkeys have found deficits in spatial memory to occur after damage to the mammillary bodies or the mammillothalamic tract. 

In addition to involvement in memory functions, there are cells in the mammillary bodies that are activated only when an animal's head is facing in a particular direction. These cells are thought to be involved in navigation and may act somewhat like a compass in creating a sense of direction.

Vann SD, & Aggleton JP (2004). The mammillary bodies: two memory systems in one? Nature reviews. Neuroscience, 5 (1), 35-44 PMID: 14708002