We are searching data for your request:
Upon completion, a link will appear to access the found materials.
What is accumulation and release centre of neurohormones?
Is it hypothalamus?
The neurohormones in most mammals include oxytocin and vasopressin, both of which are produced in the hypothalamic region of the brain and secreted into the blood by the neurohypophysis (part of the pituitary gland).
A second group of neurohormones, called releasing hormones, also originates in the hypothalamus. The members of this group, however, are transmitted within the neural cells to a second locus in the brain, from which they pass in the bloodstream to the adenohypophysis, which also is a part of the pituitary gland. There they either stimulate or inhibit the release of the various adenohypophysial hormones.
A third group of neurohormones includes the enkephalins and other endorphins. The endorphins are effective in relieving pain, a property apparently related to their function as neurotransmitters, passing nerve impulses from one neuron to another. Their neurohormonal activity is manifested by their stimulation of the secretion of somatotropin and vasopressin by an indirect process involving a site (other than the secretory neuron) in the central nervous system.
An Overview of the Hypothalamus
The hypothalamus plays a significant role in the endocrine system. The function of the hypothalamus is to maintain your body’s internal balance, which is known as homeostasis. To do this, the hypothalamus helps stimulate or inhibit many of your body’s key processes, including:
- Heart rate and blood pressure
- Body temperature
- Fluid and electrolyte balance, including thirst
- Appetite and body weight
- Glandular secretions of the stomach and intestines
- Production of substances that influence the pituitary gland to release hormones
- Sleep cycles
- Anti-diuretic hormone (ADH): This hormone increases water absorption into the blood by the kidneys.
- Corticotropin-releasing hormone (CRH): CRH sends a message to the anterior pituitary gland to stimulate the adrenal glands to release corticosteroids, which help regulate metabolism and immune response.
- Gonadotropin-releasing hormone (GnRH): GnRH stimulates the anterior pituitary to release follicle stimulating hormone (FSH) and luteinizing hormone (LH), which work together to ensure normal functioning of the ovaries and testes.
- Growth hormone-releasing hormone (GHRH) or growth hormone-inhibiting hormone (GHIH) (also known as somatostain): GHRH prompts the anterior pituitary to release growth hormone (GH) GHIH has the opposite effect. In children, GH is essential to maintaining a healthy body composition. In adults, it aids healthy bone and muscle mass and affects fat distribution.
- Oxytocin: Oxytocin is involved in a variety of processes, such as orgasm, the ability to trust, body temperature, sleep cycles, and the release of breast milk.
- Prolactin-releasing hormone (PRH) or prolactin-inhibiting hormone (PIH) (also known as dopamine): PRH prompts the anterior pituitary to stimulate breast milk production through the production of prolactin. Conversely, PIH inhibits prolactin, and thereby, milk production. Thyrotropin releasing hormone (TRH): TRH triggers the release of thyroid stimulating hormone (TSH), which stimulates release of thyroid hormones, which regulate metabolism, energy, and growth and development.
A disease or disorder of the hypothalamus is known as a hypothalamic disease. A physical injury to the head that impacts the hypothalamus is one of the most common causes of hypothalamic dysfunction.
Hypothalamic diseases can include appetite and sleep disorders, but because the hypothalamus affects so many different parts of the endocrine system, it can be hard to pinpoint whether the root cause of hypothalamus disorders is actually related to another gland.
In particular, the hypothalamus and pituitary gland are so tightly connected that it’s often difficult for doctors to determine whether the condition is associated with the hypothalamus or pituitary gland. These are known as hypothalamic-pituitary disorders. However, there are hormone tests that help shed light on which part of the body is the root cause.
The hypothalamus is arguably the most essential of the endocrine system. By alerting the pituitary gland to release certain hormones to the rest of the endocrine system, the hypothalamus ensures that the internal processes of your body are balanced and working as they should.
In traditional drug delivery systems such as oral ingestion or intravascular injection, the medication is distributed throughout the body through the systemic blood circulation. For most therapeutic agents, only a small portion of the medication reaches the organ to be affected, such as in chemotherapy where roughly 99% of the drugs administered do not reach the tumor site.  Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. For example, by avoiding the host's defense mechanisms and inhibiting non-specific distribution in the liver and spleen,  a system can reach the intended site of action in higher concentrations. Targeted delivery is believed to improve efficacy while reducing side-effects.
When implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease.
Increasing developments to novel treatments requires a controlled microenvironment that is accomplished only through the implementation of therapeutic agents whose side-effects can be avoided with targeted drug delivery. Advances in the field of targeted drug delivery to cardiac tissue will be an integral component to regenerate cardiac tissue. 
There are two kinds of targeted drug delivery: active targeted drug delivery, such as some antibody medications, and passive targeted drug delivery, such as the enhanced permeability and retention effect (EPR-effect).
This ability for nanoparticles to concentrate in areas of solely diseased tissue is accomplished through either one or both means of targeting: passive or active.
Passive Targeting Edit
In passive targeting, the drug's success is directly related to circulation time.  This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system (RES), thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time.  To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time. 
Active Targeting Edit
Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to.  Researchers can then utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand.  The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles.
Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging.  Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process.
Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive.  Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH.  Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is hypoxia, which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors. 
By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug. It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue.  However, an emerging field known as nanotoxicology has concerns that the nanoparticles themselves could pose a threat to both the environment and human health with side effects of their own.  Active targeting can also be achieved through peptide based drug targeting system. 
There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic, biodegradable,  and must avoid recognition by the host's defense mechanisms  .
The most common vehicle currently used for targeted drug delivery is the liposome.  Liposomes are non-toxic, non-hemolytic, and non-immunogenic even upon repeated injections they are biocompatible and biodegradable and can be designed to avoid clearance mechanisms (reticuloendothelial system (RES), renal clearance, chemical or enzymatic inactivation, etc.)   Lipid-based, ligand-coated nanocarriers can store their payload in the hydrophobic shell or the hydrophilic interior depending on the nature of the drug/contrast agent being carried. 
The only problem to using liposomes in vivo is their immediate uptake and clearance by the RES system and their relatively low stability in vitro. To combat this, polyethylene glycol (PEG) can be added to the surface of the liposomes. Increasing the mole percent of PEG on the surface of the liposomes by 4-10% significantly increased circulation time in vivo from 200 to 1000 minutes. 
PEGylation of the liposomal nanocarrier elongates the half-life of the construct while maintaining the passive targeting mechanism that is commonly conferred to lipid-based nanocarriers.  When used as a delivery system, the ability to induce instability in the construct is commonly exploited allowing the selective release of the encapsulated therapeutic agent in close proximity to the target tissue/cell in vivo. This nanocarrier system is commonly used in anti-cancer treatments as the acidity of the tumour mass caused by an over-reliance on glycolysis triggers drug release.  
Micelles and dendrimers Edit
Another type of drug delivery vehicle used is polymeric micelles. They are prepared from certain amphiphilic co-polymers consisting of both hydrophilic and hydrophobic monomer units.  They can be used to carry drugs that have poor solubility. This method offers little in the terms of size control or function malleability. Techniques that utilize reactive polymers along with a hydrophobic additive to produce a larger micelle that create a range of sizes have been developed. 
Dendrimers are also polymer-based delivery vehicles. They have a core that branches out in regular intervals to form a small, spherical, and very dense nanocarrier. 
Biodegradable particles Edit
Biodegradable particles have the ability to target diseased tissue as well as deliver their payload as a controlled-release therapy.  Biodegradable particles bearing ligands to P-selectin, endothelial selectin (E-selectin) and ICAM-1 have been found to adhere to inflamed endothelium.  Therefore, the use of biodegradable particles can also be used for cardiac tissue.
Artificial DNA nanostructures Edit
The success of DNA nanotechnology in constructing artificially designed nanostructures out of nucleic acids such as DNA, combined with the demonstration of systems for DNA computing, has led to speculation that artificial nucleic acid nanodevices can be used to target drug delivery based upon directly sensing its environment. These methods make use of DNA solely as a structural material and a chemical, and do not make use of its biological role as the carrier of genetic information. Nucleic acid logic circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus such as a specific mRNA have been demonstrated.  In addition, a DNA "box" with a controllable lid has been synthesized using the DNA origami method. This structure could encapsulate a drug in its closed state, and open to release it only in response to a desired stimulus. 
Targeted drug delivery can be used to treat many diseases, such as the cardiovascular diseases and diabetes. However, the most important application of targeted drug delivery is to treat cancerous tumors. In doing so, the passive method of targeting tumors takes advantage of the enhanced permeability and retention (EPR) effect. This is a situation specific to tumors that results from rapidly forming blood vessels and poor lymphatic drainage. When the blood vessels form so rapidly, large fenestrae result that are 100 to 600 nanometers in size, which allows enhanced nanoparticle entry. Further, the poor lymphatic drainage means that the large influx of nanoparticles are rarely leaving, thus, the tumor retains more nanoparticles for successful treatment to take place. 
The American Heart Association rates cardiovascular disease as the number one cause of death in the United States. Each year 1.5 million myocardial infarctions (MI), also known as heart attacks, occur in the United States, with 500,000 leading to deaths. The costs related to heart attacks exceed $60 billion per year. Therefore, there is a need to come up with an optimum recovery system. The key to solving this problem lies in the effective use of pharmaceutical drugs that can be targeted directly to the diseased tissue. This technique can help develop many more regenerative techniques to cure various diseases. The development of a number of regenerative strategies in recent years for curing heart disease represents a paradigm shift away from conventional approaches that aim to manage heart disease. 
Stem cell therapy can be used to help regenerate myocardium tissue and return the contractile function of the heart by creating/supporting a microenvironment before the MI. Developments in targeted drug delivery to tumors have provided the groundwork for the burgeoning field of targeted drug delivery to cardiac tissue.  Recent developments have shown that there are different endothelial surfaces in tumors, which has led to the concept of endothelial cell adhesion molecule-mediated targeted drug delivery to tumors.
Liposomes can be used as drug delivery for the treatment of tuberculosis. The traditional treatment for TB is skin to chemotherapy which is not overly effective, which may be due to the failure of chemotherapy to make a high enough concentration at the infection site. The liposome delivery system allows for better microphage penetration and better builds a concentration at the infection site.  The delivery of the drugs works intravenously and by inhalation. Oral intake is not advised because the liposomes break down in the Gastrointestinal System.
3D printing is also used by doctors to investigate how to target cancerous tumors in a more efficient way. By printing a plastic 3D shape of the tumor and filling it with the drugs used in the treatment the flow of the liquid can be observed allowing the modification of the doses and targeting location of the drugs. 
As we get older, many different types of errant and unwanted proteins, the chemical byproducts of metabolism, build up and accumulate between our cells. Collectively these are known as forms of amyloid, a term that might be familiar to you in connection with Alzheimer's disease, but there are many other types of amyloid beyond that implicated in the destruction that Alzheimer's brings to the brain. For example, the work of the Supercentenarian Research Foundation implicates a different form of amyloid in the deaths of the oldest old. Those people who - though good genes, good lifestyle choices, and good luck - manage to evade heart disease, cancer, and all the other common forms of age-related death are done in by amyloid in the end.
As one of the obvious and known forms of biochemical and structural change that occurs with aging, the buildup of amyloids is a target for the Strategies for Engineered Negligible Senescence (SENS):
Extracellular junk is aggregates of stuff that do not have any function and should ideally have been cleared out of the body, but have proven resistant to destruction. Extracellular junk is different from extracellular cross-linking - it refers only to substances that do not have any function, not even a biophysical one. Most of this junk is termed "amyloid" of one variety or another. You may have heard of one form of amyloid - Abeta, the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's.
A strategy for reversing the accumulation of such material is being pursued by several scientific teams, including researchers with Elan Pharmaceuticals: vaccination to stimulate the cells of the immune system to clear out the material. . the cells may eventually encounter problems in fully digesting this material - but, if so, its degradation can still be engineered by [a bioremediation approach using enzymes discovered in bacteria].
As you might know, it is in fact not so clear-cut exactly how varying forms of amyloid cause their contributions to the damage and disease of aging. Under the SENS mindset, we should still proceed as rapidly as possible to establish ways to reduce amyloid buildup to youthful levels. It doesn't matter that we don't know all the details: the sum total of what we would like to achieve is to restore an aged biochemistry to the same state it was in when it was young. We know that increased amyloid is a change that occurs with aging, and we can see how to reverse it, so the most effective course of action is to build the necessary therapies as soon as we can, even if that means doing so in advance of a complete understanding of how amyloid damages us.
On the topic of the mechanisms by which amyloid is destructive to your cells, your metabolism, and ultimately your health and life, I noticed a recent paper I should point out, though you might prefer the popular science release format instead:
It was believed that amyloid fibrils - rope-like structures made up of proteins sometimes known as fibres - are inert, but that there may be toxic phases during their formation which can damage cells and cause disease. [But] scientists at the University of Leeds have shown that amyloid fibres are in fact toxic - and that the shorter the fibre, the more toxic it becomes.
"This is a major step forward in our understanding of amyloid fibrils which play a role in such a large number of diseases," said Professor Sheena Radford of the Astbury Centre for Structural Molecular Biology and the Faculty of Biological Sciences. "We've revisited an old suspect with very surprising results. Whilst we've only looked in detail at three of the 30 or so proteins that form amyloid in human disease, our results show that the fibres they produce are indeed toxic to cells especially when they are fragmented into shorter fibres."
Amyloid deposits can accumulate at many different sites in the body or can remain localised to one particular organ or tissue, causing a range of different diseases. Amyloid deposits can be seen in the brain, in diseases such as Parkinson's and Alzheimer's, whereas in other amyloid diseases deposits can be found elsewhere in the body, in the joints, liver and many other organs. Amyloid deposits are also closely linked to the development of Type II diabetes.
Which is not terribly surprising, but it is still good support for the SENS approach of forging ahead. The only path to rapid success in engineering ways to reverse the damage of aging is to start early.
Xue, W., Hellewell, A., Gosal, W., Homans, S., Hewitt, E., & Radford, S. (2009). Fibril Fragmentation Enhances Amyloid Cytotoxicity Journal of Biological Chemistry, 284 (49), 34272-34282 DOI: 10.1074/jbc.M109.049809
Why not just find the fountain of youth and be done with it
Turmeric dissolves Amyloid in the joints and the brain.
Please tell us more about systemic enzymes with the ability to dissolve amyloid.
There was no mention in this article about the work being done, to discover and utilize the supposed enzymes that destroy amyloids. I have read that cemeteries are devoid of these amyloid materials due to enzymes and bacteria that must be breaking them down. Furthermore no mention was made of so called chaperone chemicals that may help to carry the unwanted materials out of the body by chelation or other such mechanisms.
It is a pity to see that you are not even paying attention to this very important thing called NUTRITION, with respect to aging. I mean, do you think centenarians don't get enough nutrients and somehow avoid these effects when compared with the average Joe? Come on, wake up, I get that you're holding on for biotechnology in some transhumanist hope that you can switch the aging button off, but that just isn't how the body works. The body works with nature.
a paper show that amyloid in the brain is beneficial.
Hi. I have a question: what's the difference between the junk between cells and the cross-links that form in the extracellular matrix? Thanks.
@David: Cross-links and amyloids are two broad categories of junk between cells, with different origins and which cause different types of harm. Amyloids are proteins that misfold, changing their characteristics in ways that cause them to precipitate into clumps and strands, while cross-links are sugar compounds that glue structural proteins together.
I have tried a pill that cystic fibrosis patients take to extend their quality of life. It is protease a really nice feel good pill. Best pill I've ever taken. Can these enzymes be what also boosts the system?
You don't need to investigate soil bacteria to find agents that dissolve amyloid. Nattokinase is a natural product, produced in Natto which is an oriental fermented food. When taken in a relatively high dose, for a long period of time, it can destroy amyloid deposits in the human body.
Hmmm. I would bet solid money that Ketones dissolve amyloids like crazy. Having used acetone and MEK to remove some pretty nasty industrial glues, I cannot but wonder if this is why ketosis is so therapeutic for many? So, regular annual 2- week water fasts, low carb, moderate protein, raw fruits, and include exogenous ketones, nattokinase, protease?
I have noticed that both ginger and turmeric cannot be kept in plastic bags, as they soften/ dissolve them. so suspect these also dissolve amyloids. I would look at bromelain and papain too? Surely someone could just mix these substances up in a few test tubes and take a quick peek at what happens in vitro? Then try in vivo?
The HPA axis is also modulated by another axis that initiates in the hypothalamus – the hypothalamic-pituitary-gonadal axis (HPG axis). This axis is only included as it has become clear in the last decade that gonadal hormones strongly influence how the body responds to cortisol and how much and when cortisol is produced. The fact that significantly more women than men suffer from depression and anxiety is probably due to this interaction. It is thought that estradiol elevates cortisol levels for longer periods, turning healthy acute stress responses into pathogenic chronic responses.
Postpartum depression, where the endocrine organ of the placenta causes huge alterations in maternal stress hormone levels, may also be the specific result of HPA axis dysfunction. Furthermore, women with chronic stress seem to find it harder to start a family. As nearly all psychiatric disorders involve HPA axis dysregulation of the stress response, both axes are being studied in depth. Perhaps the specific diagnosis of HPA axis depression is not so far away.
III. ARE GREYING AND PIGMENTATION GENETICALLY CONTROLLED?
Given the considerable phenotypic overlap between mouse mutants with a hair pigmentation phenotype (Nakamura et al., 2013 ) and the hair pigmentation abnormalities seen in human patients with corresponding genetic abnormalities, at least some shared essential genes in melanogenesis and melanocyte differentiation, such as tyrosine protein kinase kit (c-kit), MITF, tyrosinase-related proteinase 1 (TRP-1), TRP-2/DCT, paired box gene 3 (PAX3), SRY-box 10 (SOX10), biogenesis of lysosome-related organelles complex 3 (BLOC-3), and neurofibromin 1 (NF1), have been identified (Nordlund et al., 2008 Pingault et al., 2010 Sleiman et al., 2013 Feng, Sun & Wang, 2014 Kubasch & Meurer, 2017 Saleem, 2019 ). The role of genes in human greying remains poorly understood, but there are clear trends in greying onset within kinships and between populations. The age of greying onset is linked to geographic ancestry, and significant greying is considered premature when it occurs before 20 years of age in Caucasians, before 25 years in populations of Asian ancestry and before 30 years of age in populations with African ancestry (Tobin, 2009 Sonthalia, Priya & Tobin, 2017 Kumar, Shamim & Nagaraju, 2018 ). Men also grey faster than women, but in distinct scalp regions (Panhard, Lozano & Loussouarn, 2012 ).
Although ethnic and sex differences suggest a genetic component in the age of greying onset, heritability itself seems to vary regionally in a twin-controlled study of heritability within Danish and British Caucasians, the onset of greying was highly heritable (Gunn et al., 2009 ). By contrast, in another larger study of facial and scalp hair features across an ethnically diverse Latin American cohort, hair greying had the lowest heritability of all traits studied (Adhikari et al., 2016 ), with greying-associated single nucleotide polymorphisms (SNPs) explaining only 6.7% of the observed phenotypic variation. A comparison of individual HFs on the same scalp – which consequently share the same genetic makeup and exposome – indicates a high level of HF-to-HF heterogeneity, and typically early-greying HFs undergo depigmentation decades before other HFs on the same head (Panhard, Lozano & Loussouarn, 2012 ). This is perhaps most evident in so-called steel/salt and pepper-headed individuals, which can remain a life-long feature. Intra-individual and inter-follicular heterogeneity strongly argues against a solely genetic pathobiology of greying, as it necessarily implicates modifiable factors that operate at the single-HF organ level.
So far, only a single SNP has been significantly associated with greying in an admixed Latin American population with European ancestry. The SNP is in the interferon regulatory factor 4 gene (IRF4) (Adhikari et al., 2016 ), and mechanistically would be expected to affect the HFPU directly. Since IRF4 and MITF act cooperatively to activate transcription of tyrosinase (TYR) in cultured human melanoma cells (Praetorius et al., 2013 ), this presumptive driver of human greying (Adhikari et al., 2016 ) would be associated with reduced tyrosinase activity in the HFPU, rather than in MSC maintenance, since the bulge is constitutively tyrosinase-negative. However, functional evidence that IRF4 really playes an important role in human hair graying is still missing. In a separate study, an HFPU-centric model of greying onset is also suggested by changing patterns of expression of melanogenesis genes during premature greying. In a small sample population, reduced expression of HFPU-resident melanogenic enzymes was accompanied by an increase in their corresponding, complementary inhibitory microRNAs (Bian et al., 2019 ). Overall, whilst loss of HF niche-resident MSCs is very likely responsible for the irreversibility of hair greying, the process invariably requires and begins with primary changes in melanogenesis, melanosome transfer and/or HF melanocyte survival within the anagen HFPU.
As critical as MITF and tyrosinase are for the control of melanocyte function and melanogenesis (Levy, Khaled & Fisher, 2006 Ganesan et al., 2008 Vachtenheim & Borovanský, 2010 Chen et al., 2018 ), neither the human nor mouse HFPU appear to be controlled by a single master gene. Instead, the importance of metabolites, co-factors, pH and other biochemical determinants of the local activity of melanogenesis enzymes, as well as reactive oxygen species (ROS) production and scavenging (Schallreuter et al., 1994 Wood et al., 2004 , 2009 Slominski et al., 2005 b) cannot be overemphasized. Furthermore, the HFPU is subject to a flux of numerous regulatory inputs that jointly ensure its appropriate function, mediating hair cycle-associated changes in HFPU activity and modulating melanin production, melanocyte survival, migration, and proliferation/apoptosis ratios. Currently recognized regulators of the human HFPU are summarized in Fig. 3.
How exactly the expression/activity of these regulators is altered in greying human HFs compared to their fully pigmented counterparts in vivo remains unknown, but ex vivo studies on micro-dissected and organ-cultured human scalp HFs are revealing how these regulators may influence HFPU activity in vivo. Additionally, given the general role of autophagy in skin ageing (Eckhart, Tschachler & Gruber, 2019 ), that a certain level of autophagic flux in the anagen hair matrix is required for anagen maintenance of human scalp HFs ex vivo (Parodi et al., 2018 ), and that functional autophagy appears crucial for melanocytes to cope with cellular stress and oxidative damage (Zhou et al., 2018 Kim et al., 2019 Qiao et al., 2020 ), it is conceivable that insufficient autophagic flux within the HFPU may contribute to hair greying.
Both thyroid hormones [triiodothyronine (T3) and tetraiodothyronine (T4)] (Van Beek et al., 2008 ) and the central neuroendocrine regulator of the hypothalamic–pituitary–thyroid (HPT) axis, thyrotropin-releasing hormone (TRH), which is produced within human scalp HFs (Slominski et al., 2002 b Gáspár et al., 2010 ), stimulate melanin production in the HFPU of human anagen VI HFs (Gáspár et al., 2011 ). Pigmentation is also regulated by the activity of an intrinsic hypothalamus–pituitary–adrenal (HPA) axis within the follicle, such that upstream corticotropin-releasing hormone (CRH), its receptor, as well as downstream adrenocorticotropic hormone (ACTH), alpha melanocyte-stimulating hormone (α-MSH), and the melanocortin receptors are all produced within the HF itself and promote pigmentation (Slominski et al., 1999 , 2004 a, 2004 b Ito et al., 2005 Kauser et al., 2005 , 2006 Van Beek et al., 2008 Meyer et al., 2009 Gáspár et al., 2011 ).
Study of hair pigmentation in knockout mice unable to synthesize downstream HPA hormones suggests that their action is secondary to TRH, which promotes pigmentation in their absence (Slominski et al., 2005 a) likely via the melanocortin receptor (Schiöth et al., 1999 Slominski et al., 2002 b), although this is yet to be verified in the human HF. Whilst known aspects of neuroendocrine regulation of hair pigmentation have been reviewed in detail elsewhere (Slominski et al., 2004 b Paus et al., 2014 ), the extent to which changes in these hormonal axes intrinsic to the HF affect the greying process has not been systematically investigated. This also applies to cytokines and growth factors such as nerve growth factor (NGF), stem cell factor (SCF) and hepatocyte growth factor (HGF) that protect human HFs from pigment loss ex vivo (Botchkareva et al., 2001 Campiche et al., 2019 ).
Hormonal stimulation of human melanocytes by the intrinsic HPA-like axis (Price et al., 1998 ), or by TRH (Gáspár et al., 2011 ) promotes MITF expression and it is likely that reduced intrafollicular production of and stimulation by melanotropic hormones may result in lowered MITF activity within the HFPU of greying human HFs, ultimately causing insufficient melanogenesis and melanosome transfer (Slominski et al., 2004 b Paus, 2011 ). As illustrated in Fig. 4, a reduction of these melanotropic HPA hormones can be observed in the hair bulb epithelium of grey/white human scalp HFs, while hair pigmentation-stimulatory drugs such as fluoxetine have been suggested to up-regulate intrafollicular α-MSH expression in some white human scalp HFs ex vivo (Chéret et al., 2020 ). This provides further circumstantial support for the concept that a relative decline in the intrafollicular production of key melanotropic neurohormones contributes to the greying process (Paus, 2011 Paus et al., 2014 ).
A fundamentally important concept is that HF cycling controls HFPU activity, and thereby hair greying, insofar as defective hair shaft pigmentation can only occur during anagen (there is currently no evidence that isolated it changes in HFPU activity can regulate HF cycling). It therefore deserves emphasis that some recently discovered, potent intrafollicular regulators of human HF cycling also regulate the HFPU and its melanin production in a hair cycle-independent manner, namely P-cadherin (Samuelov et al., 2012 , 2013 ), TRH (Gáspár et al., 2010 , 2011 ), and peripheral clock activity [i.e. circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), Period1] (Al-Nuaimi et al., 2014 Hardman et al., 2015 ). The roles of such dual regulators that independently impact upon human anagen duration and intrafollicular melanin production have not been systematically dissected in the context of greying.
What is accumulation and release centre of neurohormones? - Biology
We use both!
All mammals generate heat and have ways to retain it within their bodies. They also have physiological methods to balance heat gain, retention of body heat and heat loss so that they can maintain a constant body temperature. As a result, they are not dependent on absorbing heat from their surroundings and can be active at any time of day or night, whatever the external temperature. Most other animals (except birds) rely on external sources of heat and are often relatively inactive when it is cold.
The heat that mammals generate is released during respiration . Much of the heat is produced
by liver cells that have a huge requirement for energy. The heat they produce is absorbed by the blood flowing through the liver and distributed around the rest of the body.
In humans, body temperature is controlled by the thermoregulatory centre in the hypothalamus. It receives input from 2 sets of thermoreceptors :
- Receptors in the hypothalamus monitor the temperature of the blood as it passes through the brain (the core temperature ), that remains very close to the set point, which is 37 °C in humans. This temperature fluctuates a little, but is kept within very narrow limits by the hypothalamus.
- Receptors in the skin (especially on the trunk ) monitor the external temperature .
Both sets of information are needed so that the body can make appropriate adjustments.
Our first response to encountering hotter or colder condition is voluntary:
- if too hot, we may decide to take some clothes off, or to move into the shade
- if too cold, we put extra clothes on or turn the heating up!
It is only when these responses are not enough that the thermoregulatory centre is stimulated. This is part of the autonomic nervous system, so the various responses are all involuntary.
When we get too hot, the heat loss centre in the hypothalamus is stimulated when we get too cold, it is the heat conservation centre of the hypothalamus which is stimulated.
- Vasoconstriction - muscles in the walls of arterioles that supply blood to capillaries near the skin surface contract. This narrows the lumens of the arterioles and reduces the supply of blood to the capillaries so that less heat is lost from the blood.
- Shivering - the involuntary contraction of skeletal muscles generates heat which is absorbed by the blood and carried around the rest of the body.
- Raising body hairs - muscles at the base of hairs in the skin contract to increase the depth of fur so trapping air close to the skin. Air is a poor conductor of heat and therefore a good insulator. This is not much use in humans, but is highly effective for most mammals.
- Decreasing the production of sweat - this reduces the loss of heat by evaporation from the skin surface.
- Increasing the secretion of adrenaline - this hormone from the adrenal gland increases the rate of heat production in the liver.
- Vasodilation - the muscles in the arterioles in the skin relax, allowing more blood to flow through the capillaries so that heat is lost to the surroundings.
- Lowering body hairs - muscles attached to the hairs relax so they lie flat, reducing the depth of fur and the layer of insulation.
- Increasing sweat production - sweat glands increase the production of sweat which evaporates on the surface of the skin so removing heat from the body.
The behavioural responses of animals to heat include resting or lying down with the limbs spread out to increase the body surface exposed to the air. We respond by wearing loose fitting clothing, turning on fans or air conditioning and taking cold drinks.
When the environmental temperature decreases gradually:
- The hypothalamus releases a hormone which activates the anterior pituitary gland to release thyroid stimulating hormone ( TSH ).
- TSH stimulates the thyroid gland to secrete the hormone thyroxine into the blood.
- Thyroxine increases metabolic rate , which increases heat production especially in the liver.
When temperatures start to increase again, the hypothalamus responds by reducing the release of TSH by the anterior pituitary gland so less thyroxine is released from the thyroid gland.
Brain Cell Research on Misfolded Proteins May Lead to New Therapies
Scientists have discovered how misfolded proteins in brain cells — those carrying mutations associated with Parkinson’s disease — spread to nearby healthy cells, a study reported.
These findings support the development of therapies that may prevent Parkinson’s progression, the researchers noted.
Parkinson’s disease is thought to be triggered by the misfolding of a protein known as alpha-synuclein. This is supported by the observation that mutations in the SNCA gene, which encodes alpha-synuclein, cause familial disease.
Misfolded alpha-synuclein forms aggregates, or clumps, and accumulates in nerve cells (neurons) in the brain that generate dopamine, a signaling molecule that plays a role in motor function. Eventually, aggregated alpha-synuclein spreads to other brain cells in regions involved in cognition, sleep, and mood.
Current therapies aim to ease symptoms by replacing the missing dopamine. Still, long-term treatment can lead to involuntary movements known as dyskinesia, and to fluctuations in motor symptoms that impact quality of life. As such, there is a need to find therapies to stop the disease from spreading, thus halting progression.
“Most current therapies centre around increasing the release of dopamine, but that works for a brief period and has a lot of side effects,” Scott Ryan, PhD, a professor in the department of molecular and cellular biology at the University of Guelph, in Canada, said in a press release.
“Reduced quality of life can be a huge burden on patients, their families and the health-care system,” added Ryan, who led the study.
Alpha-synuclein aggregation, accumulation, and subsequent toxicity have been associated with impaired autophagy — the cellular process by which cells degrade and release unnecessary or damaged components.
“Regular protein turnover [recycling] is part of a healthy cell,” said Morgan Stykel, a PhD candidate at the university and the study’s lead author.
“With Parkinson’s disease, that system is not working properly,” Stykel noted.
However, the underlying mechanisms of this impairment remain unclear.
To learn more, the researchers used stem cells to create neurons with and without Parkinson’s to examine the effects of alpha-synuclein mutations.
Two stem cell lines were created, each with a mutation associated with Parkinson’s (A53T and E46K), to understand how dopamine-producing neurons clear alpha-synuclein clumps.
The first set of experiments found that, compared with control cells, alpha-synuclein was aberrantly modified by phosphate molecules — called phosphorylation — in both mutant cell lines. Those findings were “consistent with the form of [alpha-synuclein] associated with pathological [disease-causing] aggregates in human synucleinopathy brain,” the researchers wrote.
Additionally, the impact of this altered phosphorylation in mutant cells led to the accumulation of cell structures called multivesicular bodies (MVBs) over controls, which strongly suggested “an attempt by these neurons to increase transport of [alpha-synuclein aggregates],” they added. Of note, MVBs are a type of cellular vesicle that carry content that can be degraded or released into the extracellular space.
In the nervous system, the autophagy protein LC3B normally targets misfolded proteins to be degraded. Experiments showed LC3B and abnormally phosphorylated alpha-synuclein were elevated in the mutant cells as compared with the controls and were localized together.
Notably, in mutant cells, LC3B and alpha-synuclein were found to directly interact with each other and to together form aggregates leading to the inactivation of LC3B.
Most alpha-synuclein associated with LC3B was seen on the surface of MVBs. That led to the alpha-synuclein’s release from cells by exosomes — tiny sacs within cells that carry components to be secreted.
Moreover, the increased secretion of aggregated alpha-synuclein by exosomes spread to other neighboring healthy neurons. There, it promoted further clumps of alpha-synuclein instead of being degraded by cell compartments called lysosomes that contain digestive enzymes.
Finally, the overproduction of the mature form of LC3B in mutant cells reduced the levels of secreted alpha-synuclein to those seen in normal cells, which demonstrated that “restoring LC3B function in SNCA mutant neurons promotes clearance of intracellular [aggregates] and reduces the level of [alpha-synuclein] secreted via exosomes,” the researchers wrote.
“Normally, misfolded proteins are degraded,” Ryan said. “We found a pathway by which synuclein is being secreted and released from neurons instead of being degraded.”
“We hope to turn the degradation pathway back on and stop the spread of disease,” Ryan said
The investigators noted their findings could help develop new therapies.
“We may not be able to do anything about brain regions that are already diseased, but maybe we can stop it from progressing,” said Ryan. “We might be able to turn the degradation pathway back on and stop the spread of the disease.”
Retrograde Signaling in the Nervous System: Dorsal Root Reflexes
William D. Willis , in Handbook of Cell Signaling , 2003
The neurotransmitter released at synapses in the spinal cord by most dorsal root ganglion cells is glutamate [ 8 ]. However, many small caliber primary afferent fibers, such as nociceptors, also contain and release peptides, such as substance P and/or calcitonin gene-related peptide [ 9 ]. Transmitter release is triggered by the invasion of synaptic terminals by nerve impulses, which cause the opening of voltage-gated calcium channels, Ca 2+ influx into the presynaptic terminals, and exocytosis of synaptic vesicles that contain neurotransmitter [ 4, 8 ]. Note, however, that this neurotransmitter release mechanism is present not only in the central terminals of dorsal root ganglion cells within the spinal cord but also in the terminals of these sensory neurons in the periphery [ 10 ]. This implies that the propagation of nerve impulses in the antidromic direction in sensory neurons will result in the release of transmitter substances in peripheral tissue. What would be the consequence of such an event?
Bayliss [ 11 ] stimulated the distal stump of a cut dorsal root electrically so that nerve impulses were conducted toward the periphery. The antidromically propagated action potentials in the sensory axons resulted in vasodilation in the skin. Antidromic vasodilation produced in this manner is accompanied by plasma extravasation, which leads to neurogenic edema [ 12, 13 ]. For antidromic vasodilation and neurogenic edema both to occur, the electrical stimuli have to activate unmyelinated nociceptive sensory axons (C-fibers), although finely myelinated (Aδ) fibers can contribute to antidromic vasodilation [ 14–16 ]. Treatment of neonatal rats with capsaicin prevents antidromic vasodilation, indicating that the sensory fibers involved are capsaicin sensitive [ 13, 17 ]. The vasodilation is attributable chiefly to the release of calcitonin gene-related peptide, although release of substance P probably also contributes, and the neurogenic edema to substance P release [ 10 ].
Foundation for a Drug-Free World. The Truth About Drugs. Why do People Take Drugs? Available from URL: http://www.drugfreeworld.org/drugfacts/drugs/why-do-people-take-drugs.html (accessed September 2016).
Lewis PC. Tobacco: what is it and why do people continue to use it? Medsurg Nurs 2008 17: 193-201.
Beauchamp GA, Winstanley EL, Ryan SA, Lyons MS. Moving beyond misuse and diversion: the urgent need to consider the role of iatrogenic addiction in the current opioid epidemic. Am J Public Health 2014 104: 2023-9.
Boys A, Marsden J, Strang J. Understanding reasons for drug use amongst young people: a functional perspective. Health Educ Res 2001 16: 457-69.
Bye A. Experiments with cocaine and heroin addicts - are they predictive? Curr Opin Pharmacol 2014 14: 74-80.
National Institute on Drug Abuse. Drugs, Brains and Behavior: the Science of Addition. Drug Abuse and Addiction. What is Drug Addition? Available from URL: https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/drug-abuse-addiction (accessed September 2016).
Foster K, Spencer D. ‘It’s just a social thing’: drug use, friendship and borderwork among marginalized young people. Int J Drug Policy 2013 24: 223-30.
Torregrossa MM, Corlett PR, Taylor JR. Aberrant learning and memory in addiction. Neurobiol Learn Mem 2011 96: 609-23.
Volkow ND, Baler RD. Addiction science: uncovering neurobiological complexity. Neuropharmacology 2014 76 Pt B: 235-49.
Koob GF. Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 2003 27: 232-43.
Milton AL, Everitt BJ. The persistence of maladaptive memory: addiction, drug memories and anti-relapse treatments. Neurosci Biobehav Rev 2012 36: 1119-39.
Anonymous Alcoholics. Alcoholics Anonymous. 4th ed. NY: A.A. World Services, Inc. 2001 .
Latt N, Konigrave K, Saunders JB, Marshall EJ, Nutt D. Addiction Medicine. USA: Oxford University Press 2009 .
Sporns O. Networks of the Brain. Cambridge, MA: The MIT Press 2010 .
Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. 3rd ed. NY: McGraw-Hill Medical 2015 .
Gardner EL. Brain-reward mechanisms. In: Lowinson JH, Ruitz P, Millman RB, Langrod JG, editors. Substance Abuse - A Comprehensive Textbook. 4th ed. PA: Lippincott Williams & Wilkins 2005. p. 48-97.
Wise RA. Addictive drugs and brain stimulation reward. Annu Rev Neurosci 1996 19: 319-40.
Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol 1989 40: 191-225.
Richard JM, Castro DC, Difeliceantonio AG, Robinson MJ, Berridge KC. Mapping brain circuits of reward and motivation: in the footsteps of Ann Kelley. Neurosci Biobehav Rev 2013 37: 1919-31.
National Institute on Drug Abuse Volkow ND. Drugs, Brains, and Behaviour - the Science of Addiction. How Science has Revolutionized the Understanding of Drug Addiction. Available from URL: https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/preface (accessed September 2016).
Miendlarzewska EA, Bavelier D, Schwartz S. Influence of reward motivation on human declarative memory. Neurosci Biobehav Rev 2016 61: 156-76.
Bowirrat A, Oscar-Berman M. Relationship between dopaminergic neurotransmission, alcoholism, and reward deficiency syndrome. Am J Med Genet B Neuropsychiatr Genet 2005 132B: 29-37.
Spanagel R, Weiss F. The dopamine hypothesis of reward: past and current status. Trends Neurosci 1999 22: 521-7.
Müller CP, Homberg JR. The role of serotonin in drug use and addiction. Behav Brain Res 2015 277: 146-92.
Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry 2003 8: 373-82.
Yager LM, Garcia AF, Wunsch AM, Ferguson SM. The ins and outs of the striatum: role in drug addiction. Neuroscience 2015 301: 529-41.
Volkow ND, Wang GJ, Fowler JS, Tomasi D. Addiction circuitry in the human brain. Annu Rev Pharmacol Toxicol 2012 52: 321-36.
Quintero GC. Role of nucleus accumbens glutamatergic plasticity in drug addiction. Neuropsychiatr Dis Treat 2013 9: 1499-512.
Salgado S, Kaplitt MG. The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg 2015 93: 75-93.
Kosten T, Scanley B, Tucker K, et al. Cue-induced brain activity changes and relapse in cocaine-dependent patients. Neuropsychopharmacology 2006 31: 644-50.
Volkow ND, Fowler JS, Wang GJ, et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 1993 14: 169-77.
Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002 159: 1642-52.
Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry 2004 12: 305-20.
Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol 1954 47: 419-27.
Wise RA. Brain reward circuitry: insights from unsensed incentives. Neuron 2002 36: 229-40.
Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 1988 85: 5274-8.
Nestler EJ, Barrot M, Self DW. DeltaFosB: a sustained molecular switch for addiction. Proc Natl Acad Sci USA 2001 98: 11042-6.
Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001 2: 695-703.
Koob G, Le Moal M. Addiction and the brain antireward system. Annu Rev Psychol 2008 59: 29-53.
Davey CG, Yücel M, Allen NB. The emergence of depression in adolescence: development of the prefrontal cortex and the representation of reward. Neurosci Biobehav Rev 2008 32: 1-19.
Damez-Werno D, LaPlant Q, Sun H, et al. Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens. J Neurosci 2012 32: 10267-72.
Olsen CM. Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology 2011 61: 1109-22.
Quello SB, Brady KT, Sonne SC. Mood disorders and substance abuse disorders: a complex comorbidity. Sci Pract Perspect 2005 3: 13-21.
Volkow ND. The reality of comorbidity: depression and drug abuse. Biol Psychiatry 2004 56: 714-7.
Dell’Osso L, Carmassi C, Mucci F, Marazziti D. Depression, serotonin and tryptophan. Curr Pharm Des 2016 22: 949-54.
Naranjo CA, Tremblay LK, Busto UE. The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry 2001 25: 781-823.
Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006 59: 1151-9.
Belujon P, Grace AA. Hippocampus, amygdala and stress: interacting systems that affect susceptibility to addiction. Ann N Y Acad Sci 2011 1216: 114-21.
Smagin GN, Heinrichs SC, Dunn AJ. The role of CRH in behavioral responses to stress. Peptides 2001 22: 713-24.
Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981 213: 1394-7.
Rainnie DG, Bergeron R, Sajdyk TJ, Patil M, Gehlert DR, Shekhar A. Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J Neurosci 2004 24: 3471-9.
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999 160: 1-12.
Silberman Y, Winder DG. Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: an update and future directions. Alcohol 2015 49: 179-84.
Yohn NL, Bartolomei MS, Blendy JA. Multigenerational and transgenerational inheritance of drug exposure: the effects of alcohol, opiates, cocaine, marijuana, and nicotine. Progr Biophys Mol Biol 2015 118: 21-33.
Han C, McGue MK, Iacono WG. Lifetime tobacco, alcohol and other substance use in adolescent Minnesota twins: univariate and multivariate behavioral genetic analyses. Addiction 1999 94: 981-93.
Agrawal A, Lynskey MT. Are there genetic influences on addiction: evidence from family, adoption and twin studies. Addiction 2008 103: 1069-81.
Bierut LJ, Dinwiddie SH, Begleiter H, et al. Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch Gen Psychiatry 1998 55: 982-8.
Li MD, Cheng R, Ma JZ, Swan GE. A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 2003 98: 23-31.
Ball D. Addiction science and its genetics. Addiction 2008 103: 360-7.
Charbogne P, Kieffer B, Befort K. 15 years of genetic approaches in vivo for addiction research: opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 2014 76 Part B: 204-17.
Agrawal A, Pergadia ML, Saccone SF, et al. An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project. Arch Gen Psychiatry 2008 65: 713-21.
Ducci F, Goldman D. The genetic basis of addictive disorders. Psychiatr Clin North Am 2012 35: 495-519.
Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G. Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 2012 198: 79-121.
Conner BT, Hellemann GS, Ritchie TL, Noble EP. Genetic, personality, and environmental predictors of drug use in adolescents. J Substance Abuse Treat 2010 38: 178-90.
Grandy DK, Miller GM, Li JX. “TAARgeting Addiction”—The alamo bears witness to another revolution. Drug Alcohol Depend 2016 159: 9-16.
Saccone SF, Hinrichs AL, Saccone NL, et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 2007 16: 36-49.
Mathews R, Hall W, Carter A. Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value. Addiction 2012 107: 2069-74.
Hall W. Avoiding potential misuses of addiction brain science. Addiction 2006 101: 1529-32.
Hall WD, Gartner CE, Carter A. The genetics of nicotine addiction liability: ethical and social policy implications. Addiction 2008 103: 350-9.
Kim JK, Samaranayake M, Pradhan S. Epigenetic mechanisms in mammals. Cell Mol Life Sci 2009 66: 596-612.
Youngson NA, Whitelaw E. Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 2008 9: 233-57.
Vassoler FM, Sadri-Vakili G. Mechanisms of transgenerational inheritance of addictive-like behaviors. Neuroscience 2014 264: 198-206.
Caldji C, Hellstrom IC, Zhang TY, Diorio J, Meaney MJ. Environmental regulation of the neural epigenome. FEBS Lett 2011 585: 2049-58.
Maze I, Nestler EJ. The epigenetic landscape of addiction. Ann N Y Acad Sci 2011 1216: 99-113.
Renthal W, Nestler EJ. Epigenetic mechanisms in drug addiction. Trends Mol Med 2008 14: 341-50.
Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 2011 70: 687-702.
Cheng MF. Hypothalamic neurogenesis in the adult brain. Front Neuroendocrinol 2013 34: 167-78.
Aguado T, Monory K, Palazuelos J, et al. The endocannabinoid system drives neural progenitor proliferation. FASEB J 2005 19: 1704-6.
Fontaine CJ, Patten AR, Sickmann HM, Helfer JL, Christie BR. Effects of pre-natal alcohol exposure on hippocampal synaptic plasticity: sex, age and methodological considerations. Neurosci Biobehav Rev 2016 64: 12-34.
Feldman DE. Synaptic mechanisms for plasticity in neocortex. Ann Rev Neurosci 2009 32: 33-5.
Fuhrmann D, Knoll LJ, Blakemore SJ. Adolescence as a sensitive period of brain development. Trends Cogn Sci 2015 19: 558-66.
Squeglia LM, Tapert SE, Sullivan EV, et al. Brain development in heavy-drinking adolescents. Am J Psychiatry 2015 172: 531-42.
Lubman DI, Cheetham A, Yücel M. Cannabis and adolescent brain development. Pharmacol Ther 2015 148: 1-16.
Winters K, Arria A. Adolescent brain development and drugs. Prev Res 2011 18: 21-4.
Di Chiara G. Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol 1999 375: 13-30.
Diekhof E, Falkai P, Gruber O. Functional neuroimaging of reward processing and decision-making: a review of aberrant motivational and affective processing in addiction and mood disorders. Brain Res Rev 2008 59: 164-84.
Conflicts of interest
The author declares no external funding sources, commercial or non-commercial affiliations, or conflicts of interest.
This submission was handled by Dr. Hilary P. Grocott, Editor-in-Chief, Canadian Journal of Anesthesia.