Are GABA Receptors Related To Anxiety in Humans Because Worms Wriggle? Building a Model of the Insular Cortex – Part 14

In the previous post I looked at GABA receptors in C.Elegans – the Nematode worm. C.Elegans has been extensively studied and there is a very sophisticated understanding of the organism’s biological machinery. What I found fascinating was that the role of the GABA receptors in C.Elegans has been clarified and has been found to play a role in movement as well as a few other functions. There are only 26 neurons in C.Elegans.

C.Elegans

The Nematode worm moves by contracting the muscles on one side of its body whilst relaxing the opposing muscles. The GABA receptors are involved in the relaxation of the muscles.

Muscle Relaxation and GABA Receptors

When people are anxious this can cause the muscles to tense. Some drugs acting at the GABA receptors in humans can reduce muscle tone. Some drugs which target these receptors can also alleviate anxiety. Which comes first? This is the chicken and egg scenario. Do you have to be anxious to have tense muscles or do you become anxious because your muscles are tense.

The James-Lange and Cannon-Bard Theories

The question of whether emotions or bodily sensations happen first is dealt with by the James-Lange and Cannon-Bard Theories. Essentially the two theories take differing positions on the question. The James-Lange theory states that emotions happen in response to information coming from the body. When the heart races you feel anxious. The Cannon-Bard theory says that  emotions and bodily responses occur independently but can be coordinated by the Thalamus.

Nematode Worms, GABA Receptors and Anxiety in Humans

Nematode worms and our ancestors diverged some 800 million years ago. In that space of time Nematodes and our species have continued to evolve. Nevertheless the conservation of the GABA receptors in both Nematodes and our species is evidence of the importance of these receptors. Some simple connections and a narrative can be constructed to account for the above.

1. Nematodes have developed GABA receptors to facilitate movement

2. GABA receptors enable Nematodes to relax muscles to steer and move in certain directions

3. GABA receptors are part of a movement apparatus

4. As species have evolved and become more complex they have become capable of conscious experience

5. The movement apparatus has been conserved but also become associated with other complex phenomenon such as conscious experience

6. In humans muscle groups oppose each other – reciprocal extensor and flexor muscle groups at the elbow are one example.

7. The underlying relationship with GABA receptors remains

8. Action through the GABA receptors relaxes muscle groups and results in accompanying sensory feedback (small variation in the GABA receptor gene may not be related to anxiety but rather it is the physiological effects that the products of these receptor gene variants have in common).

9. This sensory feedback produces an emotional response – lowering of anxiety

While the above supports the James-Lange theory we could argue that there is a bidirectional relationship. For instance a heightened state of anxiety in response to internal stimuli can increase the tension in the muscle groups.

The above is a testable hypothesis. The hypothesis makes a very specific statement about a receptor in adaptive terms. The GABA receptor facilitates movement of the organism. Whilst it may well be wrong it nevertheless contains implicit assumptions which make it testable against the evidence base. The theory in essence states that the GABA receptor function is conserved and associated with increasingly complex phenomenon. If on moving from Nematode worms to humans there was convincing evidence of loss of motor related GABA receptor function in intermediary species this would contradict the hypothesis.

 

References

Jorgensen, E.M. GABA (August 31, 2005), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.14.1, http://www. wormbook.org.

Related Resources on this Site

Developing a Model of the Insular Cortex and Emotional Regulation: Part 1

Building a Model of the Insular Cortex – Part 2: Reviewing a Model by Craig – Part 1

Building a Model of the Insular Cortex – Part 3: Reviewing a Model by Craig – Part 2

Building a Model of the Insular Cortex – Part 4: Reviewing a Model by Craig – Part 3

Building a Model of the Insular Cortex – Part 5: The Evolution of the Insular Cortex

Building a Model of the Insular Cortex – Part 6: A Recap

Building a Model of the Insular Cortex – Part 7: The James-Lange Theory

Building a Model of the Insular Cortex – Part 8: The Cannon-Bard Thalamic Theory of Emotions

Building a Model of the Insular Cortex – Part 9: Charles Darwin on the Expression of the Emotions

Building a Model of the Insular Cortex – Part 10: The Limbic System

Building a Model of the Insular Cortex – Part 11: A Second Recap

Building a Model of the Insular Cortex – Part 12: GABA receptors and Emotions

Building a Model of the Insular Cortex – Part 13: GABA receptors and Nematode Worms

What does the Insular Cortex Do Again?

Insular Cortex Infarction in Acute Middle Cerebral Artery Territory Stroke

The Insular Cortex and Neuropsychiatric Disorders

The Relationship of Blood Pressure to Subcortical Lesions

Pathobiology of Visceral Pain

Interoception and the Insular Cortex

A Case of Neurogenic T-Wave Inversion

Video Presentations on a Model of the Insular Cortex

MR Visualisations of the Insula

The Subjective Experience of Pain

How Do You Feel? Interoception: The Sense of the Physiological Condition of the Body

How Do You Feel – Now? The Anterior Insula and Human Awareness

Role of the Insular Cortex in the Modulation of Pain

The Insular Cortex and Frontotemporal Dementia

A Case of Infarct Connecting the Insular Cortex and the Heart

The Insular Cortex: Part of the Brain that Connects Smell and Taste?

Stuttered Swallowing and the Insular Cortex

YouTubing the Insular Cortex (Brodmann Areas 13, 14 and 52)

New Version of Video on Insular Cortex Uploaded

Contributors to the Model (links are to the posts in which contributions were made – these links may contain further links directly to the contributors)

Ann Nonimous

The Neurocritic

Psico-logica

Index: There are indices for the TAWOP site here and here Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk. Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

Focusing on the GABA Receptors – A Look at the Nematode: Building a Model of the Insular Cortex – Part 13

A very basic model of the Insular Cortex was developed in previous posts (see Appendix). In the open model of the Insular Cortex detailed above there is a key role for GABA receptors in determining the intensity of emotional experience. The model is a little simple at the moment and we are at a point where we can begin to add detail. A useful starting point is to take a closer look at the GABA receptor in order to reconcile the neurobiology with the assumptions in the model.

There are two types of GABA receptor – the GABAa and the GABAb receptor. The GABA receptor is found in the Nematode worm which also goes by the name Caenorhabditis elegans (using binomial nomenclature) or C.elegans for short. A video of C.elegans is shown below.

C.elegans

There are two reasons that we might want to briefly look at C.elegans in order to get a better understanding of GABA receptors.

1. C.elegans has been very well studied.

2. C.elegans is a very simple organism and researchers have a more comprehensive (although not exhaustive) understanding of the physiology of C.elegans in contrast with more complex organisms.

Reflecting point 1 above, there is an online resource which I will reference in this post – the Wormbook – an online review of C.elegans biology. This book has a creative commons license and the quotes below are from the section on GABA.

‘γ-aminobutyric acid (GABA) is an amino acid neurotransmitter synthesized by decarboxylation of glutamate by the enzyme glutamic acid decarboxylase. GABA had been long known to exist in plants and bacteria, where it serves a metabolic role in the Krebs cycle‘

Historically GABA was studied in many species and at first it was thought to be a metabolite. There were a few twists and turns in the story before GABA was convincingly established as a neurotransmitter and this is covered in Jogensen’s section of the Wormbook. In C.elegans, GABA has been found to play a role in gut function, locomotion and foraging. C.elegans has a very simple nervous system with only 26 GABA neurons.

‘These 26 GABA neurons are comprised of 6 DD, 13 VD, 4 RME, RIS, AVL and DVB (Figure 2B). These neurons fall into different classes based on their synaptic outputs: the D-type neurons, that is, the 6 DD and 13 VD motor neurons, innervate the dorsal and ventral body muscles, respectively; the 4 RME motor neurons innervate the head muscles; the AVL and DVB motor neurons innervate the enteric muscles; and RIS is an interneuron (White et al., 1986)‘

In the video of C.elegans above you can see the worms wriggling as they move across the screen. They are able to achieve this movement by relaxing some of their muscles using GABA. The unopposed muscle then steers the movement. What is fascinating about this are the many parallels with GABA function in humans. However although there are parallels with GABA receptors and GABA function in vertebrates we must remember that all species continue to adapt. Therefore even though vertebrates and C.elegans shared a common ancestor at one point, further ahead in time the function of the same gene may be lost or find an altogether different use in either lineage. Jogensen comments that

‘Nematodes and vertebrates diverged over 800 million years ago. Nevertheless the proteins governing GABA cell identity, biosynthesis and transport are conserved in the nematode and vertebrate nervous systems. Notably, studies in the nematode identified the vesicular GABA transporter and the UNC-30 homeodomain transcription factor, and subsequent genome comparisons identified the vertebrate orthologs of these genes. Although there does not appear to be a GABA-gated cation channel related to EXP-1 in the vertebrate genome, the GABAA channel and the GABAB chloride G-protein coupled receptor are both found in the vertebrate and nematode genomes‘

There are a few genes which are known to be related directly to GABA and mutations in these genes are described in the table below. There are also a few GABA related function but which are yet to be matched with genes.

Jorgensen clarifies the role of some of these gene/gene functions in C.elegans.

‘In summary, UNC-30 is required for GABA neuron specification in the D-type neurons and its expression is sufficient for conferring GABA neuron identity. However, its role in cell identity is complicated. UNC-30 is not required by all GABA neurons for GABA cell identity. How these cells regulate neurotransmitter specificity is not known. Moreover, some cells that express UNC-30 do not display GABA cell identity. Why these cells do not express GABA specific genes is not known‘

and

‘GABAA  receptors are GABA-gated chloride channels that inhibit cell activity. The GABAA receptor, that inhibits body muscle contraction during locomotion, is encoded by the unc-49 gene (Figure 6; Bamber et al., 1999; Bamber et al., 2005). The unc-49 locus encodes three distinct GABA receptor subunits by splicing a common N-terminal ligand-binding domain to one of three alternative C-terminal domains, producing the UNC-49A, UNC-49B, and UNC-49C subunits (Bamber et al., 1999). Keep in mind that these alternative gene products are all subunits of a GABAA ligand-gated ion channel and are not related to GABAB receptors. This unusual gene structure is conserved in the distantly-related nematode C. briggsae. The UNC-49B and UNC-49C subunits are expressed in the muscles and localized to synapses from the D-type GABA motor neurons (Bamber et al., 1999; Bamber et al., 2005; Gally and Bessereau, 2003). The GABA receptor at neuromuscular junctions is a heteromer composed of the B and C subunits (Bamber et al., 2005). The B subunit is required for localization of the receptor to neuromuscular junctions and the C subunit imparts specific pharmacological properties to the heteromeric receptor (Bamber et al., 2005; Bamber et al., 2003). The UNC-49A subunit is barely detectable in vivo, and does not heteromultimerize with UNC-49B or UNC-49C to form a functional receptor in vitro (Bamber et al., 1999)‘.

From the above, we therefore know that there are a number of genes involved in GABA related functions in C.elegans and that the physiological function has been well characterised but there are still pieces of the jigsaw missing. There are some useful points here but in terms of the model we will need to take a closer look at GABA and GABA receptors in humans.

References

Jorgensen, E.M. GABA (August 31, 2005), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.14.1, http://www. wormbook.org.

Related Resources on this Site

Developing a Model of the Insular Cortex and Emotional Regulation: Part 1

Building a Model of the Insular Cortex – Part 2: Reviewing a Model by Craig – Part 1

Building a Model of the Insular Cortex – Part 3: Reviewing a Model by Craig – Part 2

Building a Model of the Insular Cortex – Part 4: Reviewing a Model by Craig – Part 3

Building a Model of the Insular Cortex – Part 5: The Evolution of the Insular Cortex

Building a Model of the Insular Cortex – Part 6: A Recap

Building a Model of the Insular Cortex – Part 7: The James-Lange Theory

Building a Model of the Insular Cortex – Part 8: The Cannon-Bard Thalamic Theory of Emotions

Building a Model of the Insular Cortex – Part 9: Charles Darwin on the Expression of the Emotions

Building a Model of the Insular Cortex – Part 10: The Limbic System

Building a Model of the Insular Cortex – Part 11: A Second Recap

Building a Model of the Insular Cortex – Part 12: GABA receptors and Emotions

What does the Insular Cortex Do Again?

Insular Cortex Infarction in Acute Middle Cerebral Artery Territory Stroke

The Insular Cortex and Neuropsychiatric Disorders

The Relationship of Blood Pressure to Subcortical Lesions

Pathobiology of Visceral Pain

Interoception and the Insular Cortex

A Case of Neurogenic T-Wave Inversion

Video Presentations on a Model of the Insular Cortex

MR Visualisations of the Insula

The Subjective Experience of Pain

How Do You Feel? Interoception: The Sense of the Physiological Condition of the Body

How Do You Feel – Now? The Anterior Insula and Human Awareness

Role of the Insular Cortex in the Modulation of Pain

The Insular Cortex and Frontotemporal Dementia

A Case of Infarct Connecting the Insular Cortex and the Heart

The Insular Cortex: Part of the Brain that Connects Smell and Taste?

Stuttered Swallowing and the Insular Cortex

YouTubing the Insular Cortex (Brodmann Areas 13, 14 and 52)

New Version of Video on Insular Cortex Uploaded

Contributors to the Model (links are to the posts in which contributions were made – these links may contain further links directly to the contributors)

Ann Nonimous

The Neurocritic

Psico-logica

Index: There are indices for the TAWOP site here and here Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk. Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

GABA Receptors and Emotions: Building a Model of the Insular Cortex – Part 12

In this post we will look at the original open model of the Insular Cortex and its role in emotional regulation. In part 11 there is a summary of the posts in this series which look at the relationship between the Insular Cortex and emotional regulation. The diagram above illustrates the main themes in the series to date. We looked at the development of an open model which is contributed to by readers producing a collective ownership in keeping with the principles of the open science movement. The original model is shown below

Model of Anterior Insular Cortex Function

In the original post we looked at a number of studies as well as some assumptions about the strength of evidence for each of these assumptions. For the sake of simplicity I will leave out the detailed examination of the strength of evidence which we can always return to at a later point.

The model above is relatively straightforward. The Anterior Insular Cortex is proposed as the brain area where sensory information results in emotional output. The GABA receptors or more specifically the GABAa receptors are involved in this transformation of sensory information into emotions. The GABA receptor density acts a bit like a ‘volume button’. Increasing the receptor density decreases the intensity of the emotions and conversely decreasing receptor density increases the intensity of the emotional experience. The Benzodiazepines influence the GABAa receptor and are a well known class of pharmacological agents which are known to modify emotions such as anxiety. At this superficial level of examination therefore the model has an ecological validity which fits with clinical acumen.

The second component of the model is the integration of sensory information. This was based on an interview with scientist Lawrence Williams who looked at how temperature influenced perception of relationships. This component of the model runs much deeper though. Looking at the top diagram we can see many models of emotions. The relationship between sensation and emotions is a key feature of the Cannon-Bard and James-Lange theories. Additionally work by Craig has developed this much further. These other models may also have influenced the above indirectly as these theories will have permeated neuroscience. An important part of the work in developing this model will be clarifying the relationship with these other models and distinguishing this model of emotions from those involving other brain regions.

Related Resources on this Site

Developing a Model of the Insular Cortex and Emotional Regulation: Part 1

Building a Model of the Insular Cortex – Part 2: Reviewing a Model by Craig – Part 1

Building a Model of the Insular Cortex – Part 3: Reviewing a Model by Craig – Part 2

Building a Model of the Insular Cortex – Part 4: Reviewing a Model by Craig – Part 3

Building a Model of the Insular Cortex – Part 5: The Evolution of the Insular Cortex

Building a Model of the Insular Cortex – Part 6: A Recap

Building a Model of the Insular Cortex – Part 7: The James-Lange Theory

Building a Model of the Insular Cortex – Part 8: The Cannon-Bard Thalamic Theory of Emotions

Building a Model of the Insular Cortex – Part 9: Charles Darwin on the Expression of the Emotions

Building a Model of the Insular Cortex – Part 10: The Limbic System

Building a Model of the Insular Cortex – Part 11: A Second Recap

What does the Insular Cortex Do Again?

Insular Cortex Infarction in Acute Middle Cerebral Artery Territory Stroke

The Insular Cortex and Neuropsychiatric Disorders

The Relationship of Blood Pressure to Subcortical Lesions

Pathobiology of Visceral Pain

Interoception and the Insular Cortex

A Case of Neurogenic T-Wave Inversion

Video Presentations on a Model of the Insular Cortex

MR Visualisations of the Insula

The Subjective Experience of Pain

How Do You Feel? Interoception: The Sense of the Physiological Condition of the Body

How Do You Feel – Now? The Anterior Insula and Human Awareness

Role of the Insular Cortex in the Modulation of Pain

The Insular Cortex and Frontotemporal Dementia

A Case of Infarct Connecting the Insular Cortex and the Heart

The Insular Cortex: Part of the Brain that Connects Smell and Taste?

Stuttered Swallowing and the Insular Cortex

YouTubing the Insular Cortex (Brodmann Areas 13, 14 and 52)

New Version of Video on Insular Cortex Uploaded

Contributors to the Model (links are to the posts in which contributions were made – these links may contain further links directly to the contributors)

Ann Nonimous

The Neurocritic

Psico-logica

Index: There are indices for the TAWOP site here and here Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk. Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.