Despite where you live in the world, your ethnicity or social status, everyone had to deal with a pervasive way of isolation, that practically we have never been faced with, and all of the sudden our lives changed for “good” or worse. At the moment there was “no time” to analyze what the effects were going to be, that’s what the mainstream media incongruently tried to explain!
However, as social animals, we need to be in contact, we were craving that social bonding just a few months under the lockdown measures applied, and what was happening inside of us? what kind of biological effects were boiling up and become repressed or hidden?
Well, to begin with, there are several hormones that are regulated and controlled by the circadian cycles of our bodies, to name the most relevant ones, that will also have an effect in many metabolic processes let’s start with: oxytocin, serotonin, cortisol and dopamine.
All of these hormones have specific roles in terms of your inner health, to make this metabolic adventure more interesting, we will go analyze those five and the main effects they’re having in your body.
Oxytocin. The hormone of love, as it is popularly known, this hormone is one of the biggest helpers in terms of linking multiple pathways in the brain, in our activation and modulates the hypothalamic–pituitary adrenal (HPA) axis, especially in response to disruptions in homeostasis, and coordinates demands on the immune system and energy balance (1).
Research suggests that oxytocin interacts closely with the neural pathways responsible for processing motivationally relevant stimuli. In particular, oxytocin appears to impact dopaminergic activity within the mesocorticolimbic dopamine system, which is crucial not only for reward and motivated behavior but also for the expression of affiliative behaviors.
While historically considered a prosocial hormone, research suggests oxytocin promotes both positive (i.e. maternal behaviors, pair-bonding, altruism, trust) and negative social interactions (i.e. aggression, territoriality) depending on the context (2).
As validated by several sources of research, this small in size (because it has only 9 amino acids in its composition), this amazing molecule is everywhere in our system, trying as best as possible to fulfill several roles, which happens to resemble the nature of the feminine side, protecting the offspring as much as possible, from energy regulatory pathways to immune messenger regulations, as well as helping controlling your motivation-reward system in the brain.
Our nurturing hormone is one of the unrecognized stars of the metabolic pathway show! Several times during this chronic isolation periods, probably you felt a craving for more sugary foods, didn’t you? Well, it all has to do with the regulation of certain kind of adipocytes (fat cells) in your body that are called BAT (Brown Adipocyte Tissue) these fat cells are the ones that you want more in your body as they can be easily taken up by your catabolic (slicing) pathways to be converted into smaller molecules of energy and regulate also other systems such as your temperature, but related to the craving of sugar, they will allow other forms of energy to be used! If these pathways are disrupted by the low amount of oxytocin due to lack of social bonding, as a coping mechanism you’ll crave sugar and more fatty food!
In terms of your immunity, oxytocin not only regulates the glucocorticoid (glucose steroid hormones) response, which intimately linked with the reduction of your immune system responses, when someone is one to receive a transplant of an organ, doctors use glucocorticoids to lower the rejection response of your body to the new organ. Hence, as you can now understand, oxytocin is key to maintaining homeostasis in your immune system, additionally regulating several pathways that involve the release of interleukins (immune signal molecules), reduce inflammation, control the differentiation of T and B cells (immune cells that allow memory for your immune system and the ones that produce antibodies, respectively) and it also regulates the limbic system, which happens to be the system in charge of your emotions!
Last but not least, oxytocin is extremely important and is linked to the regulation of dopamine, which is the most important neurotransmitter to regulate the reward/motivation response, that is also linked to your affiliate behaviors and helps you to sustain a “good vibe” to have a purpose in your life! So, if you reflect in this last idea, isolation measures took us out of the certainty, routines and bonding behaviors that we all had, if you take that away, for sure your motivation will go very low, for a couple of weeks at least, extend those symptoms to the fact that many of this regulation processes were completely disrupted by the lack of oxytocin, and you have the perfect equation to depress people! Now, link that to the fact that oxytocin dysregulation is also linked to behaviors of territoriality and aggression, and you have a second pervasive symptom, more divisiveness, anger and awkward new behaviors of how to interact with people again!
Serotonin. A biogenic amine synthesized from the essential amino acid tryptophan. Because serotonin cannot cross the blood-brain barrier, it functions differently in neuronal and non-neuronal tissues. In the CNS, serotonin regulates mood, behavior, appetite, and energy expenditure.
Most peripheral serotonin (5-hydroxytryptamine, 5-HT) is synthesized by enterochromaffin cells (EC) in the gut, where it acts locally or enters the circulation. In the bloodstream, most 5-HT is taken up by platelets, with free 5-HT levels being low in peripheral blood. In addition to the gut, 5-HT is synthesized in other peripheral metabolic tissues, including pancreatic β-cells and adipocytes. 5-HT directly regulates energy metabolism in metabolic tissues. It promotes proliferation and insulin secretion in pancreatic β-cells, induces lipolysis and suppresses UCP1-dependent adaptive thermogenesis in adipocytes, induces lipogenesis and gluconeogenesis while suppressing glucose uptake in hepatocytes.
Intracellular 5-HT was shown to covalently bind to the small GTPases, RAB3A and RAB27A, via “serotonylation”, with inhibition of this binding resulting in impaired insulin secretion. Intracellular 5-HT was also shown to protect β-cells from mitochondrial stress by reducing their burden of reactive oxygen species (ROS) (3).
Evidence of the relevance of serotonin is as well, immensely varied in terms of the multiple functions that it will perform, in addition to being a precursor of melatonin, which is a hormone intricately linked to your sleep cycles!
Therefore, let’s begin to unravel how this hormone has been affected by isolation, this neurotransmitter is closely linked to your mood, the popular messages are that this is the neurotransmitter of happiness. Far from that, this magical molecule is implied in regulating your mood by allowing you to buffer the reactive oxygen species ROS species of your body through the protection of your β-cells in the pancreas that in turn deal with regulating metabolic pathways to produce molecules that will regulate these stress compounds.
Moreover, serotonin allows you to develop two pathways that cope with stress adversity: 1) a passive pathway that allows you to “adapt and tolerate to the source of pain” and 2) an active pathway that “actively dealing with a source of psychological pain by changing one’s relationship to it” (4).
This is the key to how this neurotransmitter is protecting you from external experiences, that at the same time will have an effect in your mood regulation, if we are able to have strategies and mechanisms to cope with adversity and uncertainty, which are two of the main promoted emotions during the lockdown phases, if you have a disrupted mechanism that is affecting the release and production of serotonin, there’s consequently a defective system that allows you to cope with those adverse experiences and uncertainty, which will keep you in a low mood and probably will prime you to develop anxiety as an alternative coping mechanism.
Appetite and energy expenditure are also affected as a result of the low production of serotonin, and these mechanisms work by turning the proliferation and release of insulin by pancreatic β-cells, this effect will have as a consequence a complete disruption of two other hunger hormones leptin and ghrelin which are intimately linked to your energy and hunger sensor mechanisms in the brain, meaning that it will affect your satiation signal mechanisms, as well as the feeling that you’re still hungry or simply leading to binge eating behaviors. In addition to that, your metabolic pathways that are in charge of lipolysis and lipogenesis, using your fats or generating fats, respectively, will be upside down leading to gain weight and store fat! If this dysregulation mechanism continues, let’s say for almost two years, as it conveniently happened in many countries, that can easily predispose you to develop diabetes, obesity and hypertension to mention the most three common chronic diseases that will first start to be triggered.
Cortisol. It was named the “stress hormone” because it augments in alarm reaction; however, a low increment of this hormone is not dangerous for health in that cortisol regulates numerous organ functions in the body.
Cortisol has a distinct circadian rhythm, regulated by the central pacemaker localized in the suprachiasmatic nucleus, which activates the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol levels are at the lowest levels at around midnight, start to decrease at 02:00–03:00 and peak in the morning, declining back to nadir throughout the day. The lack of this rhythm may result in many diseases. In fact, we may observe it in adrenal insufficiency, but the lack of this rhythm might even lead to cancer. If the individual is overactive the stress vulnerability in- creases due to unresolved stress responses and could induce mood disorders although most individuals using appropriate coping strategies show resilience in the face of stress.
HPA axis hyperactivity and consequent glucocorticoids (GC) resistance might represent the link between chronic stress and major depressive disorder (MDD), diabetes, and metabolic syndrome. The immune system could response if an individual is exposed to social conflict, evaluation, rejection, or exclusion especially if these conditions appear as dangerous. However, this ancestral host defense mechanism is able to increase the risk for viral infection and inflammation-related disease. Sympathetic nervous system (SNS) and HPA axis would act together by releasing NE. In particular, it has been proposed (Cole et al., 1998; Lee et al., 2000) that NE would be capable to suppress transcription of antiviral type I interferon (IFN) genes and up-regulate transcription of the proinflammatory immune response genes IL-1, TNF, and IL-6. (5).
The results of a study indicated that greater social isolation in this sample was associated with delayed post-task recovery of systolic blood pressure, larger total/HDL cholesterol ratio response to stress in socially isolated men, and a higher CAR and greater total cortisol output over the day in both men and women.
The finding that socially isolated men had greater cholesterol reactivity to stress may be particularly important for health as men are at a higher risk of coronary artery disease in middle age. We found a significant effect of social isolation on the rise in cortisol after waking (6).
Extensive research, in terms of this “stress hormone”, which has a lot more functions than just regulating the stress in our bodies, is shedding light in the extremely important functions that cortisol has to regulate inflammatory processes. This amazing hormone, is in charge of regulating inflammation at the level of your visual system, in the nervous system it performs its most known function of buffering stress reactions and helping us to control our responses to stressors, at the cardiovascular level, it allows us to have anti-inflammatory processes, helps cardiomyocytes survival and increments blood pressure to allow vascular tone, as well as having anti-angiogenesis properties, meaning it helps to control the spread of more vascular avenues in case we have some uncontrolled cellular growth, that usually happens in many cancerous diagnoses.
In the immune system, it helps the spread of pro-inflammatory cytokines, regulates the maturation of immune cells and the migration to the adequate sites to fight infections, as well as helping in apoptotic processes that are also involved in predisposition to several types of cancer. At the respiratory system, it suppresses the spread of cytokines and chemokines, as well as protecting cell adhesion molecules, all of these mechanisms are helping the lungs to fight with respiratory infections. And the most known functions at the metabolic/energetic system allow the maintenance of proper calcium levels, protects against inflammatory signals, regulates glucose and lipid homeostasis.
As you can read, several of these functions are related to fighting infections, as well as helping your body to stay healthier, more energized and ready to be resilient in case any stress alarms become activated.
Finally, we’re approaching our last neurotransmitter that will round the effects of all these post-isolation symptoms, to help you understand and start creating an action plan to recover your full health.
Dopamine. It is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys.
In the brain, dopamine functions as a neurotransmitter — a chemical released by neurons (nerve cells) to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release.
Dopamine neurons of the ventral midbrain play an essential role in Pavlovian associative processes by providing a teaching signal relating to the value and saliency of stimuli. In addition to their role in reinforcement learning, dopamine plays a critical role in fear conditioning. Several studies have demonstrated that subsets of dopamine neurons are activated by threatening or noxious stimuli, as well as threat-predictive stimuli following fear conditioning.
Genetic suppression of the capacity of dopamine neurons to engage phasic increases in firing promotes sustained generalized fear and anxiety following exposure to moderate intensity threat. Additionally, enhancement or suppression of dopamine receptor signaling in the central nucleus of the amygdala (CeA) can either promote or diminish fear discrimination (7).
All drugs of abuse increase striatal dopamine levels and, following extended access, produce adaptations in the dopamine system that are associated with behavioral hallmarks of addiction, such as compulsive responding for the drug. While it had been established that food consumption can increase striatal dopamine and that intermittent access to sugar can produce neural adaptations and binge-like behavior, extended access to a high-fat and high-sugar diet, which causes obesity, also leads to adaptations in the dopamine system and the emergence of addictive-like behaviors, including reward deficits and compulsive responding for food (8).
There are multiple direct and indirect mechanisms by which a high-fat and sugar diet may impact dopamine signaling and eventually lead to adaptation and behavioral change. Overconsumption can produce neural plastic changes that have long-term influences on dopamine signaling. Nutrients and their metabolites can directly influence neural afferent signals that regulate dopamine release, and they can cross the blood brain barrier (BBB) themselves or activate hormonal signals to impact dopamine signaling. In these instances, adaptations occur in the absence of increased adiposity or the onset of glucose intolerance. Diet can also affect dopamine signaling indirectly by producing excess weight or obesity and glucose intolerance, which in turn promote numerous pathophysiological processes that could promote alterations in dopamine signaling (8).
Last but not least, dopamine is an extremely important neurotransmitter that allows us to have motivation for life, regulates our reward response to several behaviors, help us to cope as well with stress stimuli and stimulates resilience in our lives by helping us to regulate the fear response. Moreover, several energetic systems will be impacted by the dysregulation of the dopaminergic system, creating addictive/toxic cycles that will foster the consumption of processed food leading to develop chronic diseases, such as obesity, diabetes, hypertension and several types of cancer.
To compile all the effects of many of these hormones and neurotransmitters have a very clear influence in all the behaviors that people are showing, now that many of the lockdown and isolation measures are being lifted.
Episodes of anxiety, depression, aggressiveness, divisiveness, lack of motivation to interact socially, due to being extremely isolated for almost two years, disrupted metabolic signals and pathways that for many people were and are still reflecting very poor health choices that obviously are just leading them to have weaker immunity and feed the fear cycle for a following pandemic or new strain emergence, the feeling of being stuck at what they do or simply not feeling a sense of joy for their lives.
All of these post-traumatic symptoms, will continue, if you don’t realize that you own the power of your health, it is not dictated by mainstream media or any type of measure that they have been able to impose, continuing this cycle of fear and paying attention to external stressors that have been totally incongruent and now exposed to have no scientific explanation is just reinforcing a Pavlovian behavior to extend the stress conditions in your body that eventually will turn epigenetic mechanisms, turning on the gene expression to develop any of the chronic diseases just mentioned above.
Be aware, wake up and reclaim your life slowly, without rush, to start coming back to a more human, normal way of living that encompasses some social activities, that activate your body by exercising and activating your own pharmacy of health, allow yourself to meditate, journal or walk in nature to reflect on some of your deepest fears that you have, download them to weaken their emotional power, and finally, believe that your life and inner emotions are your own production, they can’t never be dictated by any media stream platform or external events that obviously you can’t control!
It is time for you and for everyone to awaken to the truth that we control what we think, feel and the emotions that we allow to be played in our minds, you’re free to tune in a different channel of vibration. And your most reliable, powerful and loving guidance is right in your heart, claiming for your attention to allow the healing process to begin!
References.
1) Carter, C. S., & Porges, S. W. (2013). The biochemistry of love: an oxytocin hypothesis. EMBO reports, 14(1), 12–16.
2) Love, T. M. (2014). Oxytocin, motivation and the role of dopamine. Pharmacology Biochemistry and Behavior, 119, 49-60
3) Choi, W., Moon, J. H., & Kim, H. (2020). Serotonergic regulation of energy metabolism in peripheral tissues, Journal of Endocrinology, 245(1), R1-R10.
4) Carhart-Harris, R.L., & Nutt, D.J. (2017). Serotonin and brain function: a tale of two receptors. Journal of Psychopharmacology (Oxford, England), 31, 1091 - 1120.
5) Zefferino, R., Di Gioia, S., & Conese, M. (2021). Molecular links between endocrine, nervous and immune system during chronic stress. Brain and behavior, 11(2), e01960.
6) Nina Grant, M.Sc., Mark Hamer, Ph.D., Andrew Steptoe, D.Sc. (2009). Social Isolation and Stress-related Cardiovascular, Lipid, and Cortisol Responses. Annals of Behavioral Medicine, Volume 37, Issue 1, February, Pages 29–37
7) Jo, Y. S., Heymann, G., & Zweifel, L. S. (2018). Dopamine neurons reflect the uncertainty in fear generalization. Neuron, 100(4), 916-925.
8) DiFeliceantonio, A.G., Small, D.M. Dopamine and diet-induced obesity. Nat Neurosci 22, 1–2 (2019).