Cobbers on the Brain

In the world of modern science, we get a lot of absolutes. Something is or it isn’t, it works, or it doesn’t.  Unfortunately, in the absence of these absolutes, there is preliminary research, or new findings that often contradict each other. Such was this case concerning this foray into autism and neural connectivity.  The connection between neural connection, coined, “functional connectivity” and ASD has been examined frequently throughout the last decade.  This connectivity is measured using fMRI to examine the brains activity, and patterns of connectivity.  These bio-markers if found could do wonders in the way of diagnosing and treating autism, earlier and more specifically than previously. This is important as the current methods of diagnosis are the Autism Diagnostic Observation Schedule, and the Autism Diagnostic Interview.  While these have proven effective, diagnosis can be a long process due to lack of proper resources, and properly trained clinical staff.

These fMRI’s have shown multiple contradictory results, and while that may seem somewhat dark, there may be a reason for that.  Autism at its core is an individualistic ailment, and each person, and where they may or may not place on the Autism Spectrum is truly unique.  Each individual’s combination of various experiences and genetic makeup could certainly be to blame for the vast differences in connectivity patterns.  One manner of thinking is that maybe, autism is just a deviation from the typical pattern of brain activity, while exactly what that deviation may be is yet to be fully understood.

In terms of connectivity itself, some work shows this deviation from “normal” as an underconnectivity between distant brain regions, as well as an overconnectivity in those nearby.  The weakened signal from those distant regions, in turn with the interference due to the over-connection of adjacent results in these issues. Researchers mentioned “noisier patterns of connectivity” in brains of people with autism than in controls.  The more severe the deviation that was seen from this control, the more severely a person’s symptoms presented.   From this, we can see that while we cannot currently say if this is an over-connectivity or under-connectivity issue, it is certainly conceivable from the information gathered that there is an impairment of neural connectivity in ASD.

While each individual’s unique place on the Autism Spectrum is just that, unique, already we have separated the spectrum into several different ailments.  If it is found there is a similarity in functional connectivity between individuals in similar areas on the spectrum, that could be a major breakthrough for ASD.  Developing biomarkers that are repeatable may help a lot of children get the treatment, and progression they personally need much earlier in their life!  With many of these studies seemingly contradictory, it’s important to recognize that while different, they may all be correct. Autism and its impacts are unique in nearly every aspect for the individual. Why would the connections within their brains be any different?

Autism Spectrum Disorder (ASD) is incredibly common, with about one in every 59 children being diagnosed, yet varies widely in its manifestation. Diagnosis of ASD is typically made by age two developmental medical check-ups and is based on behavioral observations. Some characteristic behaviors include eye contact avoidance, limited or lack of language development, delay in language acquisition, repetitive body movements,

Nothing in ASD makes sense except in the light of various genetic and epigenetic mutations resulting in problems with synaptic transmission. Dysregulation in gene networks forming the synaptic transmission supporting system is implicated in the development of ASD, but no specific single gene modulation is sufficient to cause ASD symptom formation, therefore more study is needed to elucidate the specific gene-environment & gene-gene interactions giving rise to ASD symptoms.

Inside the Brain

However, before we dive into understanding what is going wrong with the synaptic transmission in ASD, we should first understand synaptic transmission more generally. Broadly speaking, synaptic transmission is how your brain sends and receives information from stimuli both internal and external. How the brain makes sense of all of these signals is still an active and exceedingly exciting area of research. Diving down to the cellular level, synaptic transmission occurs when a neuron sends an electrical signal called an action potential down its axon to the synapse, where the sending neuron physically interfaces with the dendrites of the receiving neuron.

Once at the synapse, the action potential triggers the release of neurotransmitters (figure 1). The exact neurotransmitter and how much neurotransmitter is released is a highly controlled process involving many different proteins and signaling cascades. It’s incredibly interesting, but sadly we won’t be spending any time on it today. Instead, we’ll be focusing on the receiving neuron.

Figure 1: Access for free at https://openstax.org/books/biology-2e/pages/1-introduction

Once the neurotransmitter molecules are released, they diffuse across the synapse and bind to receptors on the dendrites of the receiving cell (figure 1). These receptors then interact with a network of support proteins known as the postsynaptic density (PSD). The PSD is incredibly important in maintaining synaptic transmission. Interestingly, in ASD, deficits in several of the PSD proteins have been identified. Specifically, we’ll be looking at the Shank family of proteins. Shank1, Shank2, and Shank3 all appear in the PSD and help form a sort of molecular scaffolding system to literally support and anchor receptors in the membrane and maintain proper dendritic shape. Specifically, deficits in Shank proteins are known to cause ASD-like behaviors in mice, and analysis of ASD patient samples commonly reveals Shank protein deficits in humans.

In ASD, methylation of the promoter regions of these genes causes a decrease in protein expression (figure 2). Ok, that sentence had a lot of jargon. Let’s break it down. Methylation is a key method of epigenetic gene regulation where specific parts of a gene’s promoter region are given a methyl group by an enzyme called DNA Methyltransferase. Promoter regions are regions of DNA that do not code for protein but offer a site for transcription factors, proteins that help induce gene transcription, to bind to help start transcription of protein-coding regions. Methylation of promoter regions at specific sites known as CpG islands makes the promoter sequence more bulky than usual, thus hindering transcription factors from binding and lowering protein expression (figure 2). This decreased expression of Shank proteins hinders the receiving cell’s ability to translate the signal into action.

Figure 2: Diagram of DNA sequence with methylated CpG islands in the promoter, transcriptional start site, and protein-coding region labeled.

Conclusion

It’s becoming increasingly clear that the interaction between genes and the environment is incredibly important in understanding complex human disorders like ASD. It’s also clear that while much research has been done and every day our knowledge of these conditions is expanding, much more work needs to be done in order to translate our basic understanding of the formation and development of ASD symptoms into treatments or therapies that improve quality of life for those living with ASD. However, in the meantime, support research by reading and sharing information from scientifically valid sources, financially support charities working to improve the lives of people with ASD and their families.

Having read a number of articles within my neurochemistry course, mostly related to neurological conditions and cognitive diseases, it appears inflammation is a significant and central component. This made me wonder if inflammation is a significant factor in other conditions as well. This week’s article answered my question suggesting a link between hypothalamic inflammation and obesity. The general gist of the article explains that inflammation of the hypothalamus impairs energy balance and contributes to insulin resistance which through a number of pathways leads to the development of obesity through altered neurocircuitry.

Image indicating relationship between signaling pathways of Ghrelin, Leptin, & Insulin.

The hypothalamus is a region of the brain critical in the regulation of eating and drinking, body temperature and energy maintenance, memory and stress control, and regulator of the endocrine system. Because of its significant roles, inflammation of the hypothalamus could result in dysregulation within these functions yielding several unfavorable events such as the development of obesity.

Molecular signaling & interactions related to development of obesity

Typically within a healthy individual, there is a balance between the signaling of leptin, ghrelin, and insulin. The leptin receptor when activated stimulates a protein abbreviated as Stat through a cascade of signaling. When Stat is activated, it moves into the nucleus of the cell and activates the transcription of proteins. Stat activates a protein abbreviated as POMC ( an appetite suppressor) and inhibits another abbreviated as AgRP ( an appetite stimulator) which signals satiety and suppresses the desire to feed. When activated, the insulin receptor, also through a cascade of signaling, activates a series of proteins (abbreviated respectively as IRS1, Grb, SoS, PI3K, and Akt) that stimulate the molecule that follows leading to the final activation of Akt. Akt similar to Stat, enters the nucleus of the cell but activates a protein abbreviated as Foxo which typically blocks the activity of Stat preventing the sensation of satiety and allowing for feeding when necessary. When Foxo is activated by Akt, it leaves the nucleus of the cell and is unable to inhibit Stat which allows for the sensation of satiety when necessary and stops the feeding behavior. These pathways help to regulate the intake of nutrients and maintenance of a healthy weight. Ghrelin works similarly but ultimately stimulates AgRP to elevate hunger and encourage feeding when the body requires more energy and nutrients.

Balance vs imbalance in hypothalamic signaling in obesity

Issues arise when an individual consistently consumes a high-fat and unhealthy diet, specifically those consisting of high concentrations of saturated fatty acids. Generally speaking, unsaturated fatty acids are healthier than saturated fatty acids as saturated fatty acids can stack upon one another and lead to clots or cholesterol buildup within arteries. A general rule of distinction between these two types of fat is that saturated fats are typically solids at room temperature while unsaturated fats are typically liquid. When consistently consumed in high concentrations, saturated fatty acids activate receptors abbreviated as TNF-alpha and TLR4. These receptors also use a cascade of signaling and activate JNK which phosphorylates (in this case inhibits) IRS1 blocking insulin signaling and NF-kappa-B which activates another protein (SOCS) which inhibits both insulin and leptin signaling. With disruptions in both insulin and leptin signaling, ghrelin becomes the primary stimulator leading to increased feeding, dysregulation of the sensation of satiety, and imbalances with energy maintenance leading to increased and continued storage as fat.

The challenges of obesity are not only limited to the molecular implications but society as a whole. With increased access to unhealthy foods, increasing prices of fresh produce, and the time commitment to create a healthy and well-balanced meal, temptations sway in the direction of fast, cheap, and easy. Advancements in technology decrease the amount of energy we expend throughout the day as food can be delivered to our door, we sit for hours on end, and we pursue the use of technology and entertainment over physical labor and exercise. Obesity and so many of the conditions we face go beyond just the molecular implications and often include an environmental or societal component as well. To truly address these matters; we must confront the influencing factors, both the micro and the macro. Thanks for reading.

If you live in the US, you’re probably aware of the problem we have with obesity. Even if you don’t live in the US you most likely have the perception that all Americans are fat, which isn’t completely false. America has nearly 40% of the world’s McDonalds, and over 11,000 more restaurants than the country with the

2nd most McDonalds. Eating badly is ingrained in our culture, and in some cases, is our culture. 

With the existence of concepts such as fat shaming, some people believe that obese individuals can simply stop eating more than they have to. Now I don’t want to say that overeating isn’t a part of being overweight or being unhealthy, because it is, but are overweight individuals as in control as we think they are? Everyone has the choice of what they eat (assuming you have the income, although this isn’t a fair assumption either), but in a lot of ways, overweight people should not be fully blamed for the pounds they put on. Recent research shows that certain types of food, such as food that is high in fat, can be neurologically addictive. Because of this addictive quality, some are arguing for a place to be made in the Diagnostic and Statistical Manual (DSM V) for obesity as a mental disorder. 

It has been found that there are a number of ways in which food, specifically food that is high in fat, can have addictive qualities. In some ways this assertion is already intuitive, as you never just want to have one donut. However, we can see the effects of this addictive quality on a deeper, more scientific level than simply being aware of its effects. For instance, deficits in dopamine transmission are induced within a high fat diet. Simplified, this means you don’t feel as good over time while eating the same amount of unhealthy food; the enjoyment diminishes on a neurological level. This in many ways parallels when a tolerance has been built up through repeated drug use. 

It is commonly understood in research that obesity most likely causes increased inflammation, and inflammation may result in higher levels of obesity, though all the exact mechanisms for this loop aren’t known yet. What we do know is that obesity-related systemic inflammation reduces the integrity of brain structures involved in reward and feeding behaviors. To simplify this, this means that obesity triggers system-wide inflammation, which reduces the amount of control that we have over rewarding behaviors, including our food intake. Over time, our mental system of self-protection against resisting treats may be eroded by the fact that we’re eating these treats. A reduced integrity of reward systems has been found in drug addicts, where cortical brain regions involved in executive control and decision making have been heavily implicated. Through eating a high fat diet, we might be allowing our brains to think that eating more high fat items is what should occur. 

One study looked at fibrinogen (a protein that’s found in blood) as a marker for inflammation, in which more fibrinogen means more inflammation. Unsurprisingly, fibrinogen was higher among obese individuals. An interesting finding however was that volumes of the orbitofrontal cortex in obese participants were negatively associated with fibrinogen levels. One of the functions of the orbitofrontal cortex is impulse control, and so damage to this area can lead to both impulsivity and compulsivity. Just because there is a difference in volume here however doesn’t mean it’s due to fibrinogen, so researchers controlled for variables within lean subjects, and found that 9% of the variance in OFC volume could be explained by fibrinogen. This, unfortunately, doesn’t bode well for obese individuals. In the case of obesity, we might be our own worst enemies, as we may be unintentionally sabotaging our own willpower by consuming a high-fat diet.