Biology ︱ Professor Dr Thomas Heinbockel

The endocannabinoid system regulates the Understanding the connection between the and the nose to achieve a response: in this case, recognise a smell.

The recent discovery of ince the 1960s, researchers have important systems within our entire dynamics are comparable with those endogenous cannabinoids has been curious about the effects of bodies, responsible for maintaining of neurotransmitters and can modulate kickstarted a whole area of S drugs on the body. One of those everything in balance. Essentially, if the neuronal interactions on a similarly research into their function. drugs under investigation was cannabis, endocannabinoid system is disrupted, fast timescale.” Cannabinoids have been widely and by the late 80s, researchers knew it can affect the whole body as it controls studied in the and about receptors in the brain which could many of our day-to-day functions, RETROGRADE SIGNALLING of the brain but their bind to certain compounds in cannabis including our of smell. It has been From this work, researchers were able role in other regions, including known as cannabinoids. This began to found that the endocannabinoid system to establish that, once they’re released, the olfactory system, are largely explain how cannabis (or cannabinoids is responsible for many of our bodily endocannabinoids find the receptors a mystery. Professor Thomas to be more precise) can affect the functions, from sleeping and appetite, to on nearby neurons and force them to Heinbockel and his team from brain, but also raised some interesting fertility and , to name just a few. reduce release of neurotransmitters. Howard University College of questions: why would we have these This is known as a retrograde signalling. Medicine research cannabinoids receptors if cannabinoids only came Our understanding of the Endocannabinoids can operate this way in the olfactory system to from external sources? endocannabinoid system has significantly in various regions in the brain, including understand more about how progressed in areas of the brain such as the hippocampus, cerebellum, neocortex Discovered by accident, the the nose communicates with Finally, in 1992, researchers came up the hippocampus and the amygdala, but and amygdala, but the olfactory system the brain. with an answer: it turned out that these the study of this system in the olfactory remains a mystery. endocannabinoid system has turned out receptors are more important than pathway is still in its early days. For Prof to be one of the most important systems previously thought; we have our own Thomas Heinbockel at Howard University Neurons in the brain can largely be forms of cannabinoids produced in the College of Medicine, the olfactory system separated into two groups. Some cause within our entire bodies. body. Due to the history of cannabis in is an ideal place for investigating how the small electrical currents in neighbouring this research, this system was named the endocannabinoid system regulates the cells and are known as excitatory However, when the child gets really continue on their excitable streak for a endocannabinoid system. Discovered by connection between the brain and the neurons as they ‘excite’ other neurons; excitable they start throwing their toys while. Like the excitable child throwing accident, the endocannabinoid system nose to achieve a response: in this case, others stop neighbouring neurons from at the parent, preventing the parent toys, when an external tufted neuron has turned out to be one of the most recognise a smell. “Understanding the generating a current, and are called from calming the child down and they is excited by another neuron, it starts endocannabinoid system in action may inhibitory neurons. It’s important to shed light on how endocannabinoids lead have a balance of these neurons in the to altered sensory ,” says Prof brain – if your brain is too excitable this Heinbockel. can cause seizures, like in epilepsy. If your brain is full of inhibitory neurons FAST RESPONSE then none of them would be able For Prof Heinbockel, the first step was to communicate and you wouldn’t to understand how these lipid-based be here. cannabinoids were capable of controlling the activity of neurons. Neuronal Like all areas of the brain, in the olfactory activity is typically extremely fast and system there is a mix of excitatory it was believed that lipid compounds and inhibitory neurons: the external could not compete on the same level. tufted neurons are excitatory and the Using a variety of techniques, the team periglomerular neurons are inhibitory. showed that at 22°C, endocannabinoid These neurons communicate to each synthesis and release occurs within 75- other all the time. Let’s imagine that the 190 milliseconds (ms) after the , external tufted neuron is an excitable and that value can even drop down to child and the periglomerular neuron is 50 ms at 37°C. “That’s almost an order an adult trying to control their offspring. Receptors in the brain bind to certain of magnitude faster than previously When the child is moderately excitable, Like all areas of the brain, in the olfactory compounds in cannabis known as system there is a mix of excitatory and cannabinoids. thought,” says Prof Heinbockel. “Our the parent can tell them to calm down inhibitory neurons. findings imply that lipid messenger now and again and the child does so.

www.researchoutreach.org www.researchoutreach.org As a neural circuit, the glomerular layer receives direct information from the nose. The ends of the neurons coming from the cluster in spherical structures Behind the Research called glomeruli. This layer (glomerular layer) represents the first level of synaptic processing. The next level of processing Professor Dr Thomas Heinbockel occurs in the mitral layer, followed by the deepest layer made up of granule cells E: [email protected] T: +1 443-841-4949 that connect with the mitral cells. W: https://profiles.howard.edu/profile/34601/thomas-heinbockel

The final piece of the puzzle involved understanding how endocannabinoids References regulate the output of the olfactory Research Objectives system – mitral cells. Surprisingly, Prof Professor Dr Heinbockel’s research is focused on Wang ZJ, Hu SS, Bradshaw HB, Sun L, Mackie K, Straiker Heinbockel and his collaborator found understanding brain mechanisms of information processing A, Heinbockel T. (2019) Cannabinoid Receptor-Mediated that mitral cells did not have cannabinoid and their relation to neurological and neuropsychiatric Modulation of Inhibitory Inputs to Mitral Cells in the Main receptors, suggesting that if mitral cells disorders. . J Neurophysiol. doi:10.1152/jn.00100.2018. were affected by endocannabinoids then it wouldn’t be through direct Detail Harvey JD, Heinbockel T. (2018) Neuromodulation of Synaptic Transmission in the Main Olfactory Bulb. Int J Environ Res activation. They hypothesised that mitral Public Health. 8;15(10). doi:10.3390/ijerph15102194. cells were activated in an indirect way Prof Dr Thomas Heinbockel The olfactory bulb, located in the forebrain and confirmed this by monitoring the Howard University College of Medicine Heinbockel, Thomas & Wang, Ze-Jun & A. Brown, Edward of vertebrates, receives neural input about odours detected by cells in the nasal cavity. activity of mitral cells whilst stimulating Dept of Anatomy & Austin, Paul. (2016). Endocannabinoid Signaling in Neural cannabinoid receptors with a molecule 520 ‘W’ St., N.W. Circuits of the Olfactory and . In: Cannabinoids similar to the endocannabinoid structure Washington, DC 20059 in Health and Disease, Edition: http://www.intechopen.com/ known as WIN 55. As predicted, books/cannabinoids-in-health-and-disease/endocannabinoid- signaling-in-neural-circuits-of-the-olfactory-and-limbic- …the olfactory system is an ideal place for WIN 55 excited mitral cells and when system, Chapter: 2, Publisher: InTech Open Access Publisher, investigating how the endocannabinoid cannabinoid receptors were blocked, Editors: Rosaria Meccariello, Rosanna Chianese, pp.11- mitral cells become less excitable. 3710.5772/63214. system regulates the connection between The researchers concluded that endocannabinoids released from mitral Wang ZJ, Sun L, Heinbockel T. (2012) Cannabinoid receptor- the brain and the nose. cells stop periglomerular neurons from mediated regulation of neuronal activity and signaling in glomeruli of the main olfactory bulb. J Neurosci., 32(25):8475- throwing out endocannabinoids. These send signals from the olfactory bulb to inhibiting them, allowing mitral cells to 9. doi:10.1523/JNEUROSCI.5333-11.2012. prevent the periglomerular neuron (the communicate with other areas of the brain send signals across the brain. It’s thought parent) from inhibiting the excitability of for smell recognition. that the relief of inhibition allows the Heinbockel T, Brager DH, Reich CG, Zhao J, Muralidharan S, the external tufted neuron. The external mitral cells to become more fine-tuned Bio Alger BE, Kao JP. (2005) Endocannabinoid signaling dynamics tufted neuron continues to be excited The olfactory system has a multi-layer in responding to odours. Dr Thomas Heinbockel is Professor and Interim Chair of probed with optical tools. J Neurosci., 25(41):9449-59. until its neighbouring neuron stops structure, including – in order from surface Anatomy, Howard University, Washington, DC. He worked doi:10.1523/JNEUROSCI.2078-05.2005. stimulating it. Prof Heinbockel confirmed to the centre – the glomerular layer, the Prof Heinbockel’s exciting new research on his M.S. thesis at the Max-Planck-Institute for Behavioral endocannabinoids are involved by mitral layer and the granule cell layer. shows how the olfactory system is , Starnberg/Seewiesen and completed a Ph.D. adding a drug called AM251 to block modulated by endocannabinoids, in at the University of Arizona. He was Personal Response endocannabinoid receptors. When specifically, the activity of external Research Associate in Physiology, Otto-von-Guericke- AM251 was added, the periglomerular tufted cells and mitral cells. A better University, Magdeburg, and subsequently held research neurons (the parent) inhibited the understanding of the endocannabinoid faculty appointments at the University of Maryland School What practical implications do you foresee for this excitatory activity of the external tufted system provides greater insight into how of Medicine. research? Could it be used to treat any conditions associated with the olfactory system? neuron (the child). This retrograde endocannabinoids lead to altered sensory signalling allows inhibition to be lifted for perception. This research will also be Funding On the one hand, some neurological disorders such a short period of time. Prof Heinbockel useful in understanding disorders where National Science Foundation (NSF)( IOS-1355034) as Alzheimer’s Disease and Parkinson’s Disease show strong impairment of the olfactory sense, and this acts as thinks this might be key to making neuromodulator signalling has gone an early indicator of the disease. Potentially, cannabinoids the olfactory system more sensitive. awry such as depression, addiction and Collaborator can help to overcome sensory impairments and/or even Parkinson’s disease. Drugs that mimic • Dr Alex Straiker, The Gill Center for Biomolecular Science delay disease progression. On the other hand, drug LOCATION IS ESSENTIAL or block neurotransmitters are used to and the Department of Psychological and Brain Sciences, addiction such as marijuana substance use disorder is a At this stage, Prof Heinbockel had treat these disorders, therefore research Indiana University, Bloomington, IN 47405 brain disease that afflicts many people and costs society identified that cannabinoid signalling into neuromodulator signalling will help in terms of medical and social expense. Understanding was involved in regulating the researchers create better treatments for the neurobiological mechanisms of this disease can help olfactory system, but the effect of these disorders. Additional research will to develop pharmacotherapeutic treatment strategies that could prevent drug abuse. endocannabinoids on the outputs of the A better understanding of the further unravel the complexity of signal olfactory system remained a mystery. endocannabinoid system will help to processing in the olfactory system and create better treatment of disorders such Mitral cells are vital in connecting the as depression. provide further insights into how the brain olfactory bulb to the rest of the brain, they functions as a whole.

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