House of Mind

The Neuromuscular Junction (NMJ) is a specialized synapse that serves to transmit electrical impulses (action potentials) from the motor neuron nerve terminal to the skeletal muscle. Basically, the NMJ allows for efficient and reliable communication between the motor neuron nerve and the muscles required for contraction and movement. The primary chemical messenger in this synapse, which consists of the presynaptic region (containing the nerve terminal), the synaptic cleft and the postsynaptic surface, is acetylcholine. These regions are defined by the differential localization of specific proteins, which underlie their distinct anatomical features and their physiological roles. 

Now it’s time to briefly sum up what goes on in the NMJ, as shown in the diagram above. 

1. The action potential (or electrical impulse signal) reaches the nerve terminal in the presynaptic region. The hallmark feature of the nerve terminal is that it contains the synaptic vesicles, along with the proteins that help vesicle function. These vesicles are aligned near their release site, called an active zone. 

2. When action potentials reach the nerve terminal they activate calcium channels, which open up and facilitate the influx of calcium into the presynaptic terminal, which in turn commences the process of vesicular release into the synaptic cleft. 

3. The increase in intracellular calcium concentration triggers the fusion of the synaptic vesicles with the nerve terminal membrane. The mechanism of synaptic vesicle fusion involves conformational changes in multiple docking proteins both on the vesicle and the nerve terminal’s plasma membrane. 

4. Once fused with the nerve terminal membrane, the vesicle releases its contents into the extracellular space, also known as the synaptic cleft. The chemical or neurotransmitters (in this case, acetylcholine) released then bind to their corresponding receptors on the postsynaptic surface (also known as the motor end plate in the NMJ). 

5 & 6. Acetylcholine binds to its receptors and opens ligand-gated Na+/K+ channels. These structures are designed to optimize cholinergic neurotransmission in order to produce an end plate potential (EPP). The EPP is simply the net synaptic depolarization caused by the release of acetylcholine triggered by the nerve action potential. The EPP is a function of the miniature endplate potential (MEPP) amplitude, which represents the depolarization of the postsynaptic membrane produced by the contents of a single vesicle, and quantal content (number of transmitter vesicles released by a nerve terminal action potential. The EPP serves to open the voltage-gated Na+ channels in the postsynaptic region, which in turn results in an action potential that triggers muscle fiber contraction. These changes in the postsynaptic region potential result in muscle stimulation and contraction.

7. Acetylcholinesterase degrades acetylcholine so that it (choline) can be re-uptaked and recycled to produce new acetylcholine molecules. It’s activity terminates synaptic transmission. 

Sources:

Hughes, Benjamin W., et. al. 2006. Molecular architecture of the neuromuscular junction. Muscle & Nerve. 33(4): 445-461. DOI 10.1002/mus.20440

Motor Systems: Control of Movement and Behavior. 2008. Available at: http://www.colorado.edu/intphys/Class/IPHY3730/09motorsystems.html

Acetylcholine

• The major source of acetylcholine in the brain is the pedunculopontine tegmental nucleus. The basal forebrain is another source one of cholinergic neurons (i.e. ACh neurons originate from the medial septum, diagonal band of Broca, nucleus basalis, and more). 
• The basal cholinergic forebrain is affected in neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease and dementia with Lewy bodies. Deficits in cholinergic neurotransmission have been associated with the neuropsychiatric effects present in some of these diseases. 
• Acetylcholine is synthesized from acetyl co-enzyme A and choline via choline acetyl transferase (CAT).
• Acetylcholine exerts its multiple effects via 2 receptors: muscarinic (mAChR) and nicotinic (nAChR) receptors. Both of these receptors are found pre- and postsynaptically in glutamatergic and gabaergic neurons. 
• nAChRs are ligand-gated ion channels that are divided into 2 subtypes depending on their distribution. Those that are found in the neuromuscular junction skeletal muscle are called nicotinic muscle (nM) while those that are found elsewhere within the nervous system are called nicotinic neuronal (nN). 
• mAChRs are G-protein coupled receptors that include 2 classes of receptors: M1-like and M2-like receptors. M1-like receptors activate phospholipase C and inhibit potassium currents. In contrast, M2-like receptors inhibit adenylyl cyclase and presynaptic calcium channels to activate potassium channels. 
• The action of acetylcholine is terminated via acetylcholinesterase which hydrolyzes it.
• Acetylcholine is one of the neurotransmitters that can also function as a neuromodulator. When it is not re-uptaked by the postsynaptic cell, it modulates synchronization of neural networks, among other things.
• ACh has a great number of physiologic effects including: enhancement of attention to sensory stimuli, improving sensory processing, encoding of memory for specific stimuli, modulation of cortical function and cognition, modulation of theta and gamma oscillations (during wakefulness and REM sleep), among others. 

Sources: 

Acetylcholine as a Neurotransmitter. 2004. Available at: 

Benarroch, Eduardo E. 2010. Acetylcholine in the cerebral cortex: Effects and clinical implications. Neurology. 75: 659-665. DOI: 10.1212/WNL.0b013e3181ee267e

Hasselmo, Michael E. and Martin Sarter. 2011. Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition. Neuropsychopharmacology. 36: 52-73. doi:10.1038/npp.2010.104

The Autonomic Nervous System Divide: Parasympathetic and Sympathetic Systems

Recently, I saw a similar diagram that left it at that. Considering I’ve never talked about either of these systems, I decided to expand a bit. 

The autonomic nervous system is part of the peripheral nervous system that exerts involuntary control over the body’s organs and other systems. It is divided into two branches: sympathetic and parasympathetic. In case you haven’t noticed, the sympathetic and parasympathetic nervous systems act in an antagonistic manner and cause opposite effects on target organs. Normally, these two systems are in equilibrium (or balanced) with each other but may be affected by external factors, such as stress. 

The sympathetic nervous system is located in the spinal cord and intermingles with motor fibers. It exerts its effects on our viscera including the adrenal gland, which secretes epinephrine (among other things). The sympathetic nerves secrete norepinephrine and innervate both vessels and visceral organs, thus enabling rapid reactions that result in the effects outlined above. Another way to think about this system is to remember this phrase: fight or flight response. When faced with an emergency, this system is triggered and 

in contrast to the sympathetic nervous sytem, the parasympathetic system acts as a brake mainly through acetylcholine secretion. A key phrase for this system is rest and digest.

Finally, one must remember that the autonomic system is constantly active; it’s function is not only limited to “fight or flight” or “rest and digest” responses. 

Sources:

Baumann, N and Jean-Claude Turpin. Neurochemistry of Stress: An overview. Neurochemistry Research. 35: 1875-1879. 

Chudler, Eric H. 2011. Autonomic Nervous System. Available at: http://faculty.washington.edu/chudler/auto.html

On Lucid Dreaming and Galantamine

A while back one of my followers asked about lucid dreaming and the role of a pill called galantamine, a selective and reversible acetylcholinesterase inhibitor. At first I was skeptical (sleep and consciousness are processes that still baffle some of the world’s brightest people, along with the fact that they are hard to study) but my curiosity got the best of me and I looked into it. Below is some of the things I learned… 

Lucid dreaming is the experience and sensation of gaining conscious awareness during dreaming (Voss et. al, 2009). Some groups have suggested that lucid dreaming can be thought of as being a dissociated state of consciousness with features of both wakefulness and REM sleep. Evidence from electroencephalographic studies seem to support this idea and insinuate that lucid dreaming may involve not only instructive co-activation but also synchronization of brain circuits underlying primary and secondary consciousness (see cited paper for definitions), resulting in a “hybrid” brain state during lucid dreaming (Hobson, 2009) (Voss et. al, 2009). According to Voss (2009), the primary author of the EEG study in question, “in order to move from non-lucid REM sleep to lucid REM dreaming there must be a shift in brain activity in the direction of waking”, which is what the authors mean when they talk about lucid dreaming being a hybrid state. Additionally, findings from functional neuroimaging studies have complemented and extended EEG data by demonstrating that lucid dreaming is correlated with increased cortical activation of brain areas believed to mediate features of secondary consciousness (i.e. precuneus, frontopolar/dorsolateral prefrontal cortex, temporal cortex). 

Now that you guys have a bit of background on lucid dreaming, let’s talk about galantamine. Galantamine comes from different plant sources all around the world and is most commonly used as a plant extract. Galantamine, also known as Razadyne, belongs to a class of medications known as acetylcholinesterase inhibitors, which basically means that galantamine keeps the acetylcholinesterase enzyme from breaking down acetylcholine- a neurotransmitter that can be either excitatory or inhibitory and may also act as a neuromodulator when it is not re-uptaked by the cell (see diagram below).

Acetylcholine is present in both the peripheral and central nervous system and has roles in muscle movement (particularly in the autonomic nervous system) as well as memory, cognition, sensory enhancement, sleep and attentional mechanisms.

Clinically, galantamine is given as a supplement to many Alzheimer’s disease (AD) patients in order to treat some of the memory and cognitive symptoms. Galantamine has also been found to temporarily increased dream recall and lucidity. Nevertheless, one must remember that galantamine is NOT a cure for Alzheimer’s disease nor its symptoms. The search for current research or clinical trials on the effects of galantamine on sleep was not very fruitful. The most recent paper (Riemann, 1993) I could find on the effects of galantamine hydrobromide on sleep is outdated and presents some troubling results. Apparently, both doses utilized in the study (10mg, 15mg) promoted REM sleep, as indexed by a shortened latency to REM sleep, increased REM density (a measure of the frequency of rapid eye movements during REM sleep) and reduced slow wave sleep, also known as deep sleep or NREM sleep, mostly in the first NREM sleep cycle. An important finding was that the 15mg dose was accompanied by negative side effects including nausea, vomiting and unpleasant dreams. The group, however, found that these adverse effects can be attenuated by pretreatment with N-methylscopolamine hydrobromide, an anticholinergic agent that functions as a muscarinic antagonist. In short, the antidote blocks muscarinic acetylcholine receptors. Interestingly, sleep EEG data (for the 15mg) dose did not vary significantly between groups that had pretreatment and those who did not. More recent literature (Iraqi & Hughes, 2009) has 

So, is galantamine THE lucid dreaming pill? I hardly think so. Apart from the fact that I still believe lucid dreaming is hard to achieve, I become even more skeptical when I find reads like Iraqi & Hughes (2009) in which the relationship between galantamine and nightmares is supported. Or perhaps it was an unintentional lucid dream induction gone wrong? It seems to me that among the major caveats and unknowns in this field (sleep, consciousness) are the inability to objectively characterize a subjective experience that is already altered by the laboratory setting. Also, it seems like this would be one of the fields were individual variability between subjects can make a world of a difference… Today I cringed thinking about all the potential confounds that could alter experimental results. But still, take what’s written here for what it’s worth. I personally admire the efforts that many scientists have made in shedding some light on the subject, but I just feel we’re so far behind. And not just with sleep and dream studies… Neuroscience is a very dynamic, complex and a tricky thing. With all that said, it has been SUPER interesting to learn about all of this and share it with you guys. I hope it has been for you too.

Sources:

Galantamine. 2009. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001066/

Hobson, JA. 2009. REM sleep and dreaming: Towards a theory of protoconsciousness. Nature Reviews Neuroscience. 10:810-811. doi:10.1038/nrn2716

Hurd, Ryan. 2009. Galantamine: Reviewing the Lucid Dreaming Pill. Available at: http://dreamstudies.org/galantamine-review-lucid-dreaming-pill/

Iraqi, A. and TL Hughes. 2009. An unusual case of nightmares with galantamine. Journal of American Geriatric Society. 57 (3): 565. 

Riemann, D. et. al. 1993. Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep. Psychiatry Research. 51: 253-267. 

Voss, U. et al. 2009. Lucid dreaming: A state of consciousness with features of both waking and non-lucid dreaming. Sleep. 32 (9) :1191-1200.