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Neuroscience Breakthroughs Since Graduate School - Part 4: Neurons

Updated: Jan 24



The brain uses a sophisticated communication and command-and-control system that monitors and manages interactions between roughly 100 billion neurons, each with 5,000-10,000 synaptic connections, for as many as 500 trillion synapses in adults. Neuroscientists have learned a great deal more about neuronal function since graduate school. The most important findings are that the adult human brain creates new neurons, silent synapses may mediate neuroplasticity in adulthood, the lymphatic system extends to the brain, networks of neurons exhibit mirroring properties, neurons can release more than one neurotransmitter (NT), release NTs outside of a synapse, conduct two-way conversations, modulate NT release and action, talk to the astrocytes that enclose the synapse, and electrically communicate almost instantaneously. Research has expanded our understanding of the roles of astrocytes in regulating neuron growth, function, signaling, information processing, synapse formation and elimination, and brain waves.



The Chemical Synapse


Neurons communicate through the release of over 200 neurochemicals and ions. Axon terminal buttons release neurochemicals across a 20-50-nm fluid-filled gap between presynaptic and postsynaptic structures called a synaptic cleft and into the extracellular fluid surrounding the neuron (Bear et al., 2020). Chemical synapses produce short-duration (millisecond) and long-duration (seconds to days) changes in the nervous system. Synapse animation without sound © 3Dme Creative Studio/Shutterstock.com.




They are functionally asymmetrical because the presynaptic neuron sends a chemical message and the postsynaptic neuron receives it. They are structurally asymmetrical because the presynaptic element (axon) contains vesicles containing neurotransmitters, and the postsynaptic element (dendrite) doesn’t. Neurotransmitter (NT) release from a terminal button is called exocytosis (Breedlove & Watson, 2020). Chemical synapse graphic © rob9000/Shutterstock.com.

Chemical Synapse


In the graphic below, an axon terminal button releases NTs into the synaptic cleft. Neurotransmitters briefly form covalent bonds with receptors on a dendritic spine and then disengage after they initiate small graded potential changes (e.g., EPSPs or IPSPs) or more diverse, gradual, and long-lived actions (e.g., creating second messengers inside the target neuron). Chemical synapse graphic © nobeastsofierce/Shutterstock.com.


Chemical synapse


Neuroscientists have learned a great deal more about neuron-to-neuron communication since graduate school. The most important findings are that the adult brain creates new neurons, silent synapses may mediate neuroplasticity in adulthood, the lymphatic system extends to the brain, neuronal networks exhibit mirroring properties, and neurons can release more than one NT, release NTs outside of a synapse, conduct two-way conversations, modulate NT release and action, talk to astrocytes that enclose synapses, and electrically communicate almost instantaneously.



Neurogenesis


Neuroscience has challenged the doctrine that the adult human brain does not create new neurons. There is a consensus that neurogenesis occurs in the hippocampus (Eriksson et al., 1998) and olfactory bulb (Lim & Alvarez-Buylla, 2016). However, neurogenesis outside the hippocampus remains controversial. Animal research has yielded evidence of functionally significant neurogenesis in the amygdala, caudate nucleus and putamen (striatum), cortex, hypothalamus, and substantial nigra (Jurkowski et al., 2020). The graphic below was retrieved from sci.news.


Note. Neural stem cells giving rise to neurons are green, and an adult hippocampal neuron is red.



Silent Synapses


Silent synapses are inactive due to the absence of glutamate AMPA receptors. Researchers studying adult mice discovered these synapses on the ends of threadlike filopodia. The simultaneous firing of two neurons connected by a silent synapse causes missing AMPA receptors to appear on the filopodia cell membrane and remodel it to resemble a dendritic spine (Vardalaki et al., 2022). The next step is to determine whether the adult human brain also contains silent synapses. If it does, they are a potential target for increasing cognitive flexibility in the elderly.


Holly Barker (2022) writing for The Scientist, explained:


The study may explain how the brain is able to learn new things without having to sacrifice existing connections, the researchers say. The ability of the brain to use different synapses 'solves the plasticity versus flexibility dilemma,' says Harnett. If all the brain’s synapses are flexible, then you can’t preserve old information. But if they’re all stable, then it is difficult to learn new things, he says. Instead, the brain employs both: spiny synapses for stability and filopodia for flexibility.
But instead of distinct categories, Harnett’s group are beginning to think about dendritic projections as existing on a continuum, from filopodia on one end to mature spines at the other. 'It is a spectrum of maturity, strength, and plasticity,' says study author Dimitra Vardalaki, a PhD candidate in Harnett’s lab.

The filopodia photomicrograph © 2022 Gloria Mancinelli, Cells in Motion Interfaculty Centre.


filopodia on neurites



The Glymphatic System


The belief of an absence of conventional lymphatic vessels in the CNS contributed to the concept that the brain, in spite of its high metabolic rate, represents an immune privileged region. This idea left questioned how cerebral interstitial fluid is cleared from waste products. It was generally thought that clearance depended on cerebrospinal fluid (CSF), acting as a pseudo-lymphatic system (Natale et al., 2021).

The human brain contains a recently-discovered glymphatic system. This astrocyte-controlled lymphatic system removes cellular debris, proteins, and wastes (Xie et al., 2013). The flushing of toxic substances may protect us from neurological disorders like Alzheimer’s (Breedlove & Watson, 2020).


In the diagram below: (1) cerebrospinal fluid (CSF) flows from the subarachnoid space to travel outside pulsing arteries, (2) CSF enters the brain via aquaporins and collects waste, and (3) CSF enters the perivascular space surrounding capillaries and is removed by venous circulation. The glymphatic system graphic from Natale et al. (2021) was published in Frontiers in Neuroscience.


Glymphatic System



Mirror Neurons


Researchers discovered primate neurons with motor and visual properties in the premotor cortex. The mirror properties are due to a neuron's connections and not its construction. The cortex graphic © Vasilisa Tsoy/Shutterstock.com.


Premotor area


These mirror neurons fired when primates grasped and manipulated objects, and another primate or human performed the same action (Di Pelligrino et al., 1992; Rizzolatti & Craighero, 2004). Mirroring extends across species, including facial expressions.


Note. Image from Gross L. Evolution of neonatal imitation. PLoS Biol. Investigators have speculated that the human mirror neuron system (MNS) may mediate empathy, imitation learning, language, social cognition, and theory of mind (Buccino et al., 2006; Rajmohan & Mohandas, 2007; Schmidt et al., 2021). Heyes et al. (2021) summarized the state of our knowledge about the MNS.


For action understanding, multivoxel pattern analysis, patient studies, and brain stimulation suggest that mirror-neuron brain areas contribute to low-level processing of observed actions (e.g., distinguishing types of grip) but not to high-level action interpretation (e.g., inferring actors’ intentions). In the area of speech perception, although it remains unclear whether mirror neurons play a specific, causal role in speech perception, there is compelling evidence for the involvement of the motor system in the discrimination of speech in perceptually noisy conditions. For imitation, there is strong evidence from patient, brain-stimulation, and brain-imaging studies that mirror-neuron brain areas play a causal role in copying of body movement topography. In the area of autism, studies using behavioral and neurological measures have tried and failed to find evidence supporting the 'broken-mirror theory' of autism.


Neurotransmitter Co-Release


Dale's law proposed that a neuron releases only one NT. However, researchers have found increasing evidence of NT co-release (Svensson et al., 2019). A neuron can store different NTs in separate types of vesicles (Hökfelt et al., 2003).


Neurons can also store multiple NTs in the same vesicles (e.g., ATP and glutamate), although they may not release them simultaneously (Merighi et al., 2011; Xia et al., 2009). LDCV graphic from Merighi (2018) was published in Frontiers in Cellular Neuroscience.


Neurons store multiploe NTs

Note. The red and green spheres represent co-stored neuropeptides synthesized by the Golgi apparatus in the cell body and transported via microtubules to the axon terminal.



Extra-Synaptic Transmission: Think Outside the Cleft


Neurons release NTs outside of classical synapses. These mechanisms include release from terminal buttons into the extracellular space, axonal varicosities, and retrograde transmission.



Volume Transmission


Volume transmission involves NT release and eventual binding to a receptor outside the synaptic cleft (Coggan et al., 2005). Graphic adapted from the American Scientist.


Volume Transmission



Axonal Varicosities


Axons can release NTs into the extracellular space through varicosities (swellings) along their length, analogous to drip irrigation (Breedlove & Watson, 2020). The graphic below, published by Giachello et al. (2012) in Neuroplasticity, shows diagrams of three types of axonal varicosities and corresponding electron microscopic images.

Note. Schematic representation of the three most common varicosities observed in invertebrate neuronal cultures. It is easier to visualize varicosities in invertebrates than in mammals.


Most neurons that release norepinephrine do not do so through terminal buttons on the ends of axonal branches. Instead, they usually release them through axonal varicosities, beadlike swellings of the axonal branches (Carlson & Birkett, 2019, pp. 82-83).