Apical and basilar dendrites of pyramidal neurons

Scheibel and Scheibel used Golgi staining to study arrangements of dendrites in the spinal cord, and later, the neocortex. Dendrodendritic synapses were found in bundles of basal and apical dendrites of pyramidal neurons. It is unknown whether apical dendrites and basal dendrites are two separate systems with different tasks, or just apparently different for reasons of the construction of the network.

APICAL DENDRITES

The cortex is filled with pyramidal cells, a type of neuron with a large cell body and very long dendrites extending in the basal and apical directions. The apical dendrites of pyramidal cells are oriented towards the pia of the brain, as shown in the figure below. Cell bodies in Layer 6 have dendrites that form a bundle extending to Layer 1.

From Dendrites

A cross-section of apical dendrites is shown in the box (figure above), with an arrow pointing to the region where dendritic membranes are closely opposed. Microtubule, mitochondria, and other proteins are stained at the site of communication between two dendrites.

The next figure shows apical dendrite bundles in cat visual cortex, cut in cross-section (the lower half of the figure).

From Dendrites

Each white spot represents a dendrite; where two white spots touch is the place of dendritic membrane contact. These constellations of dots are sometimes called puncta or puncta adherentia by histologists to refer to an ambiguous structure, but in many cases puncta resemble dendrites in cross-section.

BASILAR DENDRITES

The basilar dendrites of pyramidal neurons are very long. Scheibel and Scheibel were impressed with the length of the Betz cell basilar dendrites, and suggested that the great length of the dendrites was a unique feature for which these cells evolved. In mice, rats, and cats, giant pyramidal cells of Betz and large solitary cells of Meynert in visual cortex have long basilar dendrites organized into bundles. As shown in the figure below, cat cortex had thick patches of basilar dendrites in layer 5 and layer 2/3. In human cortex, basilar dendrite bundles can reach a length of 2000-3000 um, with diameters of 12-40 um.

From Dendrites

Part C of Figure 2 (below) shows a close-up view of a dendrite bundle, which contains 6-10 basilar dendrite shafts and varies in total diameter from 7-8 um to 1-3 um. It appears to change as individual dendrites are added or subtracted along its length.

From Dendrites

The length of basilar dendrites permits Mountcastle's columns to link to each other, as shown in the figure below. Gap junction coupling at dendrite bundles could serve as an averaging mechanism, uniting the neurons involved into an assembly.

From Dendrites

Studies on ventral horn motoneurons had led to a presumptive relationship between onset of reciprocal flexor-extensor activity in the muscle masses of the leg and the appearance of bundling in motoneuron dendrites. The onset of dendritic bundles with the development of discrete items of output performance could have implications for non-motor memory as well. Scheibel and Scheibel surmised that age-related problems with cognitive association skills could be due, as shown in the figure below, to a loss of the large dendrite bundles within basilar shafts of giant pyramidal neurons.

From Dendrites

Senility may be associated with dendrite retraction and less thickness of basilar dendrite bundles. The figures (above, below) are from Golgi-impregnated sections of human cortex at different stages of aging. In particular, there is a loss of horizontal lengths (basilar dendrites) during aging rather than vertical (apical) dendrites. The decline of effective dendrite connectivity may be an important contribution for the fading of human consciousness.

From Dendrites

Like the dendrite bundles in spinal cord, thalamic reticular nucleus, and raphe, dendrite bundles formed by the apical and basilar dendrites of pyramidal neurons appear to make direct dendrodendritic connections. It has been estimated that the dendritic bundles of the rabbit neocortex are characterized by such a close packing that about 20% of the surface of every dendrite is common to adjacent dendrite surfaces, separated by the extracellular space only. There are no intervening glia between the dendrites, and no post-synaptic specializations that resemble axon-synapses machinery, thus gap junctions appear to be the primary means of communication between two or more dendrites in a bundle, although it is controversial whether adult pyramidal neurons have significant numbers of gap junctions.

Chemical material not exceeding a molecular weight of ~1 kDa can fit through an open gap junction. There is a slight time lag as the chemical moves from one cell to another, but this is how low molecular weight messengers such as cyclic AMP move through gap junction-connected cells, allowing two or more cells to synchronize their metabolic state. If many gap junctions are open, millions of cells in the network can be coupled at once. This may contribute to an ancient way of communicating between cells that does not depend on synaptic activity. While axons are busy firing, dendrites are synchronizing subthreshold activities and debris with neighboring neurons.

Dendrite bundles in particular seem to serve as one collecting system for many afferent influences. Dendrites contain a large surface area for the interplay of fractional changes in membrane potentials. It is generally believed that the current paths of individual neurons that summate in the extracellular space in and around the dendrites gives rise to summed extracellular potentials, the EEG, and rhythmic EEG potentials.

From Dendrites

Reference

Roney K. J., A. B. Scheibel and G. L. Shaw. 1979. Dendritic bundles: survey of anatomical experiments and physiological theories. Brain Res. 180, 225-271.

Dendrite bundles in spinal cord

Virtually all neurons within the central nervous system and certainly the pyramidal neurons in cortex have extensive dendritic trees, which in fact contain most of the membrane of the cells.

Dendrites participate in very old forms of cell-to-cell communication, which pre-date axon potentials. Suppose two cells want to communicate for the first time. Whereas hundreds of proteins are needed to form a chemical synapse between two cells, just one protein, connexin, must be expressed in the dendrite region of each cell in order to form a gap junction synapse, then information can be transferred from dendrite to dendrite.

The tendency of neuroscientists to explain what is happening in the brain in terms of action potentials fired and received is due partly to work on the axon by Hodgkin and Huxley. Dendrites are often regarded as receiving stations for axons, or structural components of the cell that support axons. However, dendrites have primary sensory functions, for example, the dendrites of internal retinal ganglion cells are sites of phototransduction. Dendrites typically represent regions of excitable cell membrane, which initially served an important function in gathering sensory information.

“We thus find a type of response of excitable tissue occurring over a range from the protozoan slime mold to the mammalian cortex which in essential respects is distinct from the all-or-none response of nerve, and probably is the more primitive process.” (M.H. Clare, 1955)

Dendrites in spinal cord

Enormously long dendrites of motoneurons were first identified in the ventral spinal cord of reptiles and amphibians. Ramon y Cajal illustrated these dendrodendritic bundles in the ventral commissure of spinal cord (below).

From Dendrites

In 1970, Scheibel and Scheibel used the Golgi staining technique to show dendrite bundles in the ventral commissure of cat spinal cord (below).

From Dendrites

The next figure shows a motoneuron dendrite bundle in the cat spinal cord. There are electrotonic synapses, or gap junctions, between motoneuron dendrites.

From Dendrites

The first electrophysiological demonstration of gap junctions took place in spinal motoneuron dendrites of toadfish (Pappas et al, 1966).

What is the function of dendrite bundles?

In early 1970s, Scheibel and Scheibel began to study dendrite bundles with the Golgi staining technique. Investigations in the ventral spinal cord of cat revealed dendrites of motoneuron pools innervating muscles of antagonistic function. In kittens, bundles are not present at birth but develop near the end of the second week, when kittens start using hind limbs for weight bearing and walking.

From Dendrites

A gain in dendrite bundle thickness coincided with the kittens' use of coordinated limb movements, so the authors suggested that dendrite bundles may serve as reservoirs harboring central programs necessary to the inception of movement in the antigravity (weight-bearing) muscles of the lower extremities and back. At birth in kittens, motoneuron dendrites are poorly developed, and motor behavior is minimal, but at 12 days, lengthening of dendrites is apparent, and at 4-5 months, dendrite bundles are dense and well-developed, at which time the animals can make coordinated limb movements for jumping and running. It was also found that a loss in motor strength with aging was associated with a loss of dendritic bundles, and re-exertion of effort.

In addition to spinal cord, bundled dendrites are found in the thalamus, cortex, hypothalamus, and reticular formation.


References

Pappas G. D. and M. V. Bennett 1966. Specialized junctions involved in electrical transmission between neurons. Annals of the New York Academy of Sciences, 137, 495-508.

Scheibel M. E. and A. B. Scheibel 1970. Organization of spinal motoneuron dendrites in bundles. Experimental Neurology, 28, 106-112.

Scheibel M. E. and A. B. Scheibel 1970. Developmental relationship between spinal motoneuron dendrite bundles and patterned activity in the hind limb of cats. Experimental Neurology, 29, 328-335. 10.1016/0014-4886(70)90062-2

Scheibel M. E. and A. B. Scheibel 1971. Developmental relationship between spinal motoneuron dendrite bundles and patterned activity in the forelimb of cats. Experimental Neurology, 30, 367-373. 10.1016/S0014-4886(71)80015-8

Scheibel M. E. and A. B. Scheibel 1973. Dendrite bundles in the ventral commissure of cat spinal cord. Experimental Neurology, 39, 482-488. 10.1016/0014-4886(73)90032-0

LD50, lethal dose 50

Terrence McKenna explains the concept of LD50.

"We want to take an excursion here and learn a little pharmacology. If you're going to talk about pharmacology, there is one concept that you should get straight, and that's called LD50. It means "lethal dose 50". What does this mean? Well, you have 20 rats and you give them a certain amount of, let's say, mescaline. When half the rats die, that dose, expressed as milligrams per kilogram of body weight, is called the LD50. And when pharmacologists assess the danger in a drug, they ask the following question, "what is the relation of the LD50 to the effective dose?", and if the LD50 of a drug is only 20 times the effective dose, that's considered an incredibly toxic, dangerous, and dubious drug. A good drug is a drug where the LD50 is 200 times more than the effective dose. In the case of LSD, the LD50 for man has never been determined. That's how safe LSD is. We're talking about lethality here, not you know. So people say, "Well are there unsafe psychedelics?" Well, yes, you just look up the LD50s, line them up, and see which ones have the better ratios. By that measurement, by that standard, LSD is the most desirable. But the LD50 of psilocybin is very impressive. You can take 100 times the effective dose of psilocybin and expect to live. Mescaline, not. Mescaline has a bad profile. As an amphetamine, if you took 20 times the effective dose of mescaline, you would probably die. Of course, an effective dose of mescaline is nearly a gram of pure material, 700 milligrams. If you took 20 times 700 milligrams you would be taking nearly 2/3 of an ounce of mescaline..." (Terrence McKenna)

The LD50 of LSD varies from species to species. Rabbit is the most sensitive species known, with LD50 of 0.3 mg/kg i.v. The LD50 for rats is ten times higher at 16.5 mg/kg i.v. Mice tolerate 46-60 mg/kg i.v. LSD (Passie et al, 2008). An intraperitoneal dose of LSD 5.0 mg/kg reportedly caused death in a rat within 30-45 minutes and was associated with cardiac irregularities and general rigidity of musculature (Sylar et al, 1971). A too high dose of LSD typically causes animals to expire by paralysis, bradycardia, or respiratory failure; these effects probably involve centers in the caudal brain stem.

In an experiment with Macacus rhesus, one animal received 240 ug/kg and the other 140 ug/kg, which are enormous doses of LSD. In terms of a 70 kg person, the animals received 168 and 98 hits of LSD. These doses did not produce an excited behavior in monkeys as small doses do, but instead produced sedation. The monkeys became quiet and more sluggish around the cage, and did not jump about the cage as they did before. The monkeys lived.


Reference

Passie, T., J.H. Halpern, D.O. Stichtenoth, H.M. Emrich and A. Hintzen 2008. The pharmacology of lysergic acid diethylamide: A review. CNS Neurosci. Ther. 14, 295-314.

Sklar, S., K.A. Nieforth and M. Malone 1971. Synthesis and preliminary screening of N-ethyltryptamine derivatives related to reserpine and lysergic acid. J. Pharm. Sci. 60, 304-306.

Hydrophobic interactions 1. Meyer and Overton: Loss of consciousness by volatile gases depends upon molecular orbital parameters

What distinguishes an anesthetic drug from an inert molecule?

Many inert drugs are soluble in water, whereas anesthetic drugs such as halothane, nitric oxide, and LSD are soluble in fats like olive oil. That's the main difference. Most inert molecules like sugars and amino acids cannot absorb to a van der Waals surface because they are too engaged in strong interactions with water. Most inert molecules are covered by a hydration shell.

One of the most remarkable discoveries of the century was made by Meyer and Overton, who related the effective dose of anesthetic gases to their lipid-water coefficient. They were the first to show a quantitative relationship between physicochemical and biological data in aliphatic systems. This research occurred before protein crystallography, and one idea that emerged from their discovery is that the hydrophobic properties of a drug (e.g. its lipid-water coefficient) are more fundamental for biological activity than a drug's steric properties.

In 1965, Agin and colleagues extended the work of Overton and Meyer, by showing that the biological activity of an anesthetic drug (to block electrical activity) depends on its molecular orbital parameters. A large group of structurally diverse anesthetic drugs were studied. For each drug, the researchers assayed the minimum blocking concentration (MBC) of electrical activity with experiments involving isolated muscle fibers of the frog, Rana pipiens. Ionization potential and polarizability were calculated with standard methods. Then they did correlations and found that over an 8-fold concentration range of activity, there was a close relationship between a drug's log(MBC) and the product of its polarizability and ionization potential.

From Lipophilicity, log P

Agin and colleagues only studied local anesthetics that were considered neutral or possessed only small dipole moments, thus the major contribution to the energy of drug-tissue interaction is assumed to be from the drug's dispersion energy. The inescapable conclusion from their work is that the biological activity of local anaesthetic gases is related to dispersion energy.



References

Agin, D., L. Hersh and D. Holtzman 1965. The action of anesthetics on excitable membranes: A quantum-chemical analysis. Proc. Natl. Acad. Sci. U. S. A. 53, 952-958.