Norepinephrine

Norepinephrine

Colloquially called adrenaline – a powerful activator in the brain

When we speak of adrenaline we think of high stress situations, positive and often negative. Norepinephrine is the neurotransmitter that is related to adrenaline, but not to be confused with the hormone, and it is related to attention, action, but also plasticity and learning.

adrenaline brain

The Sabre-Toothed Tiger jumps out from behind a bush and turns its large yellow eyes onto our friendly cavemen. The tiger gives a low rumbling growl and takes a cautious small step forward, seemingly ready to pounce at an instant. Our caveman, shocked, stands focusing on the tiger his whole body has been rocketed into a high state of alert and tension. His heartbeat has accelerated, his pupils have dilated, his senses have all pricked up and he has laser sharp vision. At this precise moment he is frozen waiting for the slightest abrupt movement which will spur his body into action. Either to launch is rudimentary spear at the tiger or evade and try to escape.

This is often how the primitive roots of our flight or fight response are portrayed – with a threat scenario. Slightly unrealistically: Neolithic man did not live in the same time period as sabre-toothed tigers, and we are adapted to live in the savannah, more likely, than the jungle. Nevertheless, it is easy to imagine, and we have all experienced these periods of shock or tension from simple activities like being surprised by a person jumping from behind a wall, to having a near car crash, to receiving shocking news. Our system activates and all sorts of bodily functions kick off a string of automated reactions. They sympathetic nerve system preparing the system, in very short periods of time, for heightened vigorous activity.

Adrenaline is usually associated with this, it is. But I’d like to give you a brief review of another major neurotransmitter and modulator, norepinephrine also known as noradrenaline. Whereas adrenaline is the hormone signalling responses across the body stimulated by the hypothalamic-pituitary-adrenocortical system norepinephrine is the neurotransmitter that may or may not be associated with the adrenaline response. Chemically they are similar.

norepinephrine brain

So, what does norepinephrine do in the brain? Well, if we take a quick sidestep into ADHD, we can see that there are a number of approaches to deal with ADHD but there are two main classes of drugs to help with attention deficits. One is related to the dopamine system which includes the famous, or infamous, Ritalin, a selective dopamine reuptake inhibitor. The others are related to stimulation and often target the norepinephrine system such as atomoxetine.

Norepinephrine is released mostly in the brain stem specifically in the Locus Coeruleus. Some of you may remember that this is an area that we focused on way back in lbR-2021-01 and is involved in attention. This norepinephrine circuit basically projects throughout the whole cortex as you can see from the diagram above. However, what you will also notice is that there are some similarities to Dopamine which I reviewed in last month’s issue lbR-20201-09.

So, the question is are dopamine and norepinephrine similar, different, or collaborative in their function?

The answer seems to be an irrevocable – probably interrelated! A review in 2020 noted how their functions are similar and they seem to operate in parallel on similar topics – however, we saw last month that dopamine is very strongly involved in the encoding of reward and motivation. It is therefore suitable to conjecture that adrenaline has an arousal and attention function and this complements dopamine. This thereby also stimulates encoding of significance be that of positive or particularly of negative and stressful events which are particularly powerful in the brain. The review also notes norepinephrine’s importance in plasticity and how this also functions in parallel with dopamine.

So, in summary, norepinephrine is a key transmitter that has wide-reaching impacts on the brain and operates closely with dopamine to guide attention, encode and interpret emotional significance, and in guiding learning

References

Norepinephrine

Mather, M., Clewett, D., Sakaki, M., and Harley, C. W. (2016). Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory. Behav. Brain Sci. 39. doi:10.1017/S0140525X15000667.

Moret, C., and Briley, M. (2011). The importance of norepinephrine in depression. Neuropsychiatr. Dis. Treat. 7. doi:10.2147/NDT.S19619.

Saboory, E., Ghasemi, M., and Mehranfard, N. (2020). Norepinephrine, neurodevelopment and behavior. Neurochem. Int. 135. doi:10.1016/j.neuint.2020.104706.

Schwarz, L. A., and Luo, L. (2015). Organization of the locus coeruleus-norepinephrine system. Curr. Biol. 25. doi:10.1016/j.cub.2015.09.039.

van der Linden, D., Tops, M., and Bakker, A. B. (2021). The Neuroscience of the Flow State: Involvement of the Locus Coeruleus Norepinephrine System. Front. Psychol. 12. doi:10.3389/fpsyg.2021.645498.

Dopamine vs Norepinephrine

Ranjbar-Slamloo, Y., and Fazlali, Z. (2020). Dopamine and Noradrenaline in the Brain; Overlapping or Dissociate Functions? Front. Mol. Neurosci. 12. doi:10.3389/fnmol.2019.00334.

The Amygdala

The Amygdala

Fear, or emotions, or attention?

The Amygdala is one of those brain areas that gets a lot of attention. A lot. In fact, it may be one of the most famous areas of the brain – in no short part due to its role in fear and what Daniel Goleman called the “Amygdala Hijack” to describe situations in which emotionality takes over your brain – or supposedly at least. But the amygdala is a little misrepresented – let’s clear up its reputation.

amygdala brain

SM are the initials of a patient, who according to the case in a well-cited paper by Feinstein et al. in 2010, exhibits little to no fear. What is special about SM is that she has severe damage to both her Amygdalae. And though at the time there was known to be a strong relationship between fear and Amygdala function, SM’s rare condition enables the study of this in real world scenarios.

She was put through a series of situations and her fear measured. For example, she had consistently expressed a fear of spiders and snakes in previous interviews and so she was taken to an exotic pet store and presented with snakes and spiders to document her response. Surprisingly despite her insistence she is “afraid “ of these, she showed no fear at all. In fact, she showed the opposite: curiosity, reaching out to touch the snakes and spiders and stroke them!

In addition to this she was taken to, ostensibly, America’s most haunted house. The Waverly Hills Sanatorium Haunted House, showing no fear on a tour in contrast to other participants, and researchers, on the same tour. Her fear and emotional response were also collected systematically in everyday life with an emotional diary and through structured interviews. She indeed seemed to show no fear or to experience threat.

One notable experience also points to a key role of the Amygdala or absence of this in SM. She lived in a city and one of her walking routes home passed through a parking lot. On one occasion she was held up at knifepoint and robbed. For many this may have been a traumatic experience – but moreover it would almost certainly have led to avoiding this parking lot or walking home at night through this place. Also, the place would be expected to trigger negative memories. Not so with SM. She continued to walk across the parking lot unabated and unaffected by her negative experience there. This shows a key role of the Amygdala, and maybe underestimated with the focus on fear processing, namely that of learning.

In fact, a recent study did just this. They attempted to connect the amygdala to learning and not through triggering the emotional impact. Emotions trigger large networks in the brain and so it is difficult to disentangle the effects of different regions in the brain. In these experiments by Bass et al. in 2021 they used Deep Brain Stimulation to simulate the Amygdala (or not) in rats when encountering objects. They showed that the stimulation increased the memory of objects without observably activating emotions.

fear brain amygdala

Illustration such as this are used in research into Fear – just looking at this picture consistently shows activation patterns in the amygdala.

Illustration such as this are used in research into Fear – just looking at this picture consistently shows activation patterns in the amygdala.[/caption]This puts the Amygdala at the crossroads of memory and learning and particularly Pavlovian conditioning – so relating positive or aversive stimuli with contexts. This was clearly missing in SM whose experience in the parking lot did not lead to her having aversive reactions to said parking lot. Though we have outlined this clear relationship to fear there have been just as many relationships to positive emotions and the Amygdala. This is why many researchers see it as a salience processing unit rather than a fear centre. It shows us what is important and hence where to focus our attention, or not, and what to learn or not.

However, though there is also strong activation in the Amygdala to positive or appetitive cues, cases such as in SM do not show much dysfunction of positive emotions. So, it seems the Amygdala is involved in all emotional processing, but rewarding and positive experiences rely on other networks whereas fear and threat are strongly related to, or even dependent on, the Amygdala.

This key function of the Amygdala can be seen in its location and connections: it sits in the limbic system close to the hippocampus, itself considered a memory centre, but also close to the thalamus and prefrontal cortex. It is split into different subsections, simply three. The medial, the middle bit, is connected strongly to the olfactory centres (smell), the basolateral, to the frontal and cerebral cortex, and the central & anterior to the brain stem, hypothalamus, and sensory centres.

brain amygdala

Amygdala and neighbouring structures

 

All of these seem to make sense – connecting sensory input to emotional and hormone release in the hypothalamus, and to the frontal regions to control attention and close to the hippocampus to guide learning, not to mention sensory centres to build associations. Of notable interest, and little discussed is the connections to the olfactory centre. Though the majority of research is into visual stimuli, particularly of faces to which the amygdala can be more responsive than other areas of the brain supposedly specialised in faces (the FFA reviewed in lbR-2021-08).

A recent piece of research shows why – the sense of smell is one of our fastest systems to respond – harking back to a time when our sense of smell was much more important in everyday life and more than in modern society. Iravani et al. from the Karolinska Institute in Sweden showed in a recent piece of research that the olfactory system is a high-speed circuit and particularly to aversive smells which influence our avoidance behaviours. This is often also unconscious.

So, this paints a clearer picture of the function of the Amygdala as an emotional attention centre that is especially reactive and necessary for threat and aversive contexts and drives learning, memory, and conditioning. However, the role of the Amygdala may have unintentionally been tainted by Daniel Goleman’s 1995 description of the “Amygdala Hijack”. This term has been used by many an aspiring neuroleadership expert or coach.

Simply put, Goleman, at the time, painted picture whereby the amygdala reaction essentially hijacked the rational brain and rendered us at the whims of our emotionality. This is an oversimplified description which is appealing to a broader audience but does have some truth in it. Even as an aspiring neuroleadership expert I found the term a little oversimplified – however, it was also useful to describe to lay audiences how emotionality can take over the brain. The fact is, threat is a basic survival instinct and so can, and will, activate many stress systems in the body. However, how to engage and deal with this and is not clearly identified with the term amygdala hijack.

The SCOAP model that regular readers will be familiar with, goes some way to explain this in more detail – Firstly, different concepts can trigger a negative reaction (e.g. self-esteem threat but also loss of control or loss of orientation). Secondly, this can be very individualised. Thirdly, some people respond to threats much stronger than others. Fourthly, many of these are also conditioned responses. Fourthly we are looking at broad networks in the brain and body. So yes, the Amygdala hijack could be a way to describe the emotional response we have, but is too simplified to be useful and misconstrues how the amygdala and brain functions together. SCOAP is a much better way to formulate this and explore – for those who want to learn more.

But back to our two almond-shaped structures in our brain. They are widely researched, seem to have an oversized influence on brain functions, do activate strongly to threat and fear, and control response to this, and control aversive and avoidance behaviours – in fact so much so that political affiliation can be accurately predicted by looking at amygdala activation as I outline in the earlier article on fear in society.

So, the amygdala it is a powerful brain region related to primal networks – and also positive learning, and sometimes being afraid and cautious of threat is very good thing. As SM didn’t learn, sometimes it is good to avoid dangerous places. But too much fear is not good thing either. So, we may need to use our prefrontal to exert some top-down influence on our amygdala or at least refocus on positives. And that will also lower stress. And lead to higher wellbeing

References

Case of SM

Feinstein, J. S., Adolphs, R., Damasio, A., and Tranel, D. (2010). The Human Amygdala and the Induction and Experience of Fear. Curr. Biol. 21, 1–5. doi:10.1016/j.cub.2010.11.042.

Olfactory response

Iravani, B., Schaefer, M., Wilson, D. A., Arshamian, A., and Lundström, J. N. (2021). The human olfactory bulb processes odor valence representation and cues motor avoidance behavior. Proc. Natl. Acad. Sci. U. S. A. 118. doi:10.1073/pnas.2101209118.

Amygdala and memory and learning

Bass, D. I., Partain, K. N., and Manns, J. R. (2012). Event-specific enhancement of memory via brief electrical stimulation to the basolateral complex of the amygdala in rats. Behav. Neurosci. 126. doi:10.1037/a0026462.

Article on DANA website: https://www.dana.org/article/beyond-emotion-understanding-the-amygdalas-role-in-memory/

Steinberg, E. E., Gore, F., Heifets, B. D., Taylor, M. D., Norville, Z. C., Beier, K. T., et al. (2020). Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning. Neuron 106. doi:10.1016/j.neuron.2020.03.016.

Review

LeDoux, J. (2007). The amygdala. Curr. Biol. 17, R868-74. doi:10.1016/j.cub.2007.08.005.

Amygdala and fear

Hardee, J. E., Thompson, J. C., and Puce, A. (2008). The left amygdala knows fear: laterality in the amygdala response to fearful eyes. Soc. Cogn. Affect. Neurosci. 3, 47–54.

Murray, E. A. (2007). The amygdala, reward and emotion. Trends Cogn. Sci. 11, 489–497. doi:10.1016/j.tics.2007.08.013.

Michely, J., Rigoli, F., Rutledge, R. B., Hauser, T. U., and Dolan, R. J. (2020). Distinct Processing of Aversive Experience in Amygdala Subregions. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 5. doi:10.1016/j.bpsc.2019.07.008.

Behaviour and stress

Zhang, W. H., Zhang, J. Y., Holmes, A., and Pan, B. X. (2021). Amygdala Circuit Substrates for Stress Adaptation and Adversity. Biol. Psychiatry 89. doi:10.1016/j.biopsych.2020.12.026.

Yang, Y., and Wang, J. Z. (2017). From structure to behavior in basolateral amygdala-hippocampus circuits. Front. Neural Circuits 11. doi:10.3389/fncir.2017.00086.

Gründemann, J., Bitterman, Y., Lu, T., Krabbe, S., Grewe, B. F., Schnitzer, M. J., et al. (2019). Amygdala ensembles encode behavioral states. Science (80-. ). 364. doi:10.1126/science.aav8736.

Krabbe, S., Gründemann, J., and Lüthi, A. (2018). Amygdala Inhibitory Circuits Regulate Associative Fear Conditioning. Biol. Psychiatry 83. doi:10.1016/j.biopsych.2017.10.006.

Šimić, G., Tkalčić, M., Vukić, V., Mulc, D., Španić, E., Šagud, M., et al. (2021). Understanding emotions: Origins and roles of the amygdala. Biomolecules 11. doi:10.3390/biom11060823.

Kim, J., Zhang, X., Muralidhar, S., LeBlanc, S. A., and Tonegawa, S. (2017). Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors. Neuron 93. doi:10.1016/j.neuron.2017.02.034.

Mothers Can Pass on Stress to Future Generations

Mothers Can Pass on Stress to Future Generations

Quick Hits
Daily brief research updates from the cognitive sciences

baby mother brain stress

I presume you’re not just talking about stressed mothers stressing out their kids and/or grandchildren?
Not precisely. I’m talking about passing on stress activation patterns in DNA genetically.

Oh, that doesn’t sound good!
No, it isn’t good. We have known for quite a while that so-called epigenetic changes seem to be passed on to offspring.

What’s epigenetic?
All genes need to be activated and can be activated in different ways. Epigenetic markers are not a change in genes but how the existing genes are activated or not.

Ok, and this can be passed on?
Yes, the researchers from the University of Iowa, found out the precise mechanism. Clever things they are. But it is complicated. Basically instead of cleaning the hard drive, so to speak, and resetting genes, a protein released stops this “cleaning of the hard drive” and instead of the genes being reset the stress is passed on. Specifically in this case being present in unfertilised eggs.

And what changes?
In this case, Quote: “One of these newly silenced genes encodes the insulin receptor, which is central to metabolic changes with diabetes in humans, and which, when silenced, alters an animal’s physiology, metabolism, and stress resilience.”

Is this big news
Well, as I said, we already knew some of these things can be passed on. For example previous research has shown parents who have been though periods of starvation add an “eating” gene activation and this is passed on to children who are more likely to become obese. Read about that here.

Oh wow? So we should look after ourselves because the damage we do to yourselves can be passed on to our children.
Precisely!

Andy Habermacher

Andy Habermacher

Andy is author of leading brains Review, Neuroleadership, and multiple other books. He has been intensively involved in writing and research into neuroleadership and is considered one of Europe’s leading experts. He is also a well-known public speaker speaking on the brain and human behaviour.

Andy is also a masters athlete (middle distance running) and competes regularly at international competitions (and holds a few national records in his age category).

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Reference

Srijit Das, Sehee Min, Veena Prahlad.
Gene bookmarking by the heat shock transcription factor programs the insulin-like signaling pathway.
Molecular Cell, 2021
DOI: 10.1016/j.molcel.2021.09.022

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