Astrocyte Pathology in the Prefrontal Cortex as New Cause of Cognitive Dysfunction?

New research indicates that astrocytes may play a role in cognitive dysfunction (at least in rats). Here is a brief description of astrocytes from Wikipedia:

Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They are the most abundant cell of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.

Again, from Wikipedia, here is a list of the functions astrocytes perform in the brain:

Previously in medical science, the neuronal network was considered the only important one, and astrocytes were looked upon as gap fillers. More recently, the function of astrocytes has been reconsidered,^[3] and are now thought to play a number of active roles in the brain, including the secretion or absorption of neural transmitters and maintenance of the blood–brain barrier.^[4] Following on this idea the concept of a "tripartite synapse" has been proposed, referring to the tight relationship occurring at synapses among a presynaptic element, a postsynaptic element and a glial element.^[5]

• Structural: They are involved in the physical structuring of the brain. Astrocytes get their name because they are "star-shaped". They are the most abundant glial cells in the brain that are closely associated with neuronal synapses. They regulate the transmission of electrical impulses within the brain.
• Glycogen fuel reserve buffer: Astrocytes contain glycogen and are capable of glycogenesis. The astrocytes next to neurons in the frontal cortex and hippocampus store and release glycogen. Thus, Astrocytes can fuel neurons with glucose during periods of high rate of glucose consumption and glucose shortage. Recent research suggests there may be a connection between this activity and exercise.^[6]
• Metabolic support: They provide neurons with nutrients such as lactate.
• Blood–brain barrier: The astrocyte end-feet encircling endothelial cells were thought to aid in the maintenance of the blood–brain barrier, but recent research indicates that they do not play a substantial role; instead, it is the tight junctions and basal lamina of the cerebral endothelial cells that play the most substantial role in maintaining the barrier.^[7] However, it has recently been shown that astrocyte activity is linked to blood flow in the brain, and that this is what is actually being measured in fMRI.^[8][9]
• Transmitter uptake and release: Astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP, and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca²⁺-dependent manner.^[10] (This has been disputed for hippocampal astrocytes.)^[11]
• Regulation of ion concentration in the extracellular space: Astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space.^[12] If this function is interfered with, the extracellular concentration of potassium will rise, leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium is well known to result in epileptic neuronal activity.^[13]
• Modulation of synaptic transmission: In the supraoptic nucleus of the hypothalamus, rapid changes in astrocyte morphology have been shown to affect heterosynaptic transmission between neurons.^[14] In the hippocampus, astrocytes suppress synaptic transmission by releasing ATP, which is hydrolyzed by ectonucliotidases to yield adenosine. Adenosine acts on neuronal adenosine receptors to inhibit synaptic transmission, thereby increasing the dynamic range available for LTP.^[15]
• Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow.^[16]
• Promotion of the myelinating activity of oligodendrocytes: Electrical activity in neurons causes them to release ATP, which serves as an important stimulus for myelin to form. However, the ATP does not act directly on oligodendrocytes. Instead, it causes astrocytes to secrete cytokine leukemia inhibitory factor (LIF), a regulatory protein that promotes the myelinating activity of oligodendrocytes. This suggest that astrocytes have an executive-coordinating role in the brain.^[17]
• Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a glial scar, repairing the area and replacing the CNS cells that cannot regenerate.^{[citation needed]}
• Long-term potentiation: Scientists debate whether astrocytes integrate learning and memory in the hippocampus. It is known that glial cells are included in neuronal synapses, but many of the LTP studies are performed on slices, so scientists disagree on whether or not astrocytes have a direct role of modulating synaptic plasticity.

This is an important addition to previous research demonstrating the role of astrocyes in developmental disorders:

• Barker, AJ, Ullian, EM. (2008). New roles for astrocytes in developing synaptic circuits. Communicative & integrative biology; 1(2): 207–11. PMID 19513261. 
• Sloan, SA, Barres, BA. (Mar 29, 2014). Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Current opinion in neurobiology; 27C: 75–81. PMID 24694749.

Here is a summary of the new research, followed by the abstract for the article, which is, of course, hidden behind a paywall.

A new cause of mental disease?

Thursday 24 July 2014
Researched and Written by Catarina Amorim

Astrocytes, the cells that make the background of the brain and support neurons, might be behind mental disorders such as depression and schizophrenia, according to new research by a Portuguese team from the ICVS at the University of Minho. The study, in Molecular Psychiatry, shows how a simple reduction of astrocytes in the prefrontal cortex (which is linked to cognition) can kill its neurons and lead to the cognitive deficits that characterise several mental diseases. Although malfunctioning astrocytes have been found in psychiatric patients before, it was not clear if they were a cause or a consequence of the disease.

"This is the first time that cognitive deficits of a psychiatric illness can be mimicked by solely affecting astrocytes" - says the team leader, João Filipe Oliveira - "opening a whole new range of possibilities, both on the causes and potential treatments for these disorders." The research by Ana Raquel Lima, João Filipe Oliveira and colleagues is particularly significant when we look at the heavy burden in human suffering and financial cost of mental diseases. In the US and Europe about 1 in 4 adults are affected in every given year (this is about 26% of the populations), while depression alone uses almost 5% of the total world health budget. And a new player behind a disease offers also potential new and maybe more effective treatments.

So what are astrocytes? These star-shaped cells are part of the so called "glial population" - non-neuron cells that form the brain background and that for a long time were considered mere "housekeepers" of the real players - the neurons. In fact, traditionally, brain function is the result of electrical impulses passing between neurons, transmitting the information necessary for all those extraordinary abilities of this brains ours, from memory storage and motor control to personality quirks.

But astrocytes, even if believed to be "the help", have always been the subject of much curiosity since it was claimed by some (and denied by others) that one of the few uniqueness of Einstein's brain was larger and more complex astrocytes within its cerebral cortex than "normal" individuals. Equally curious, was the fact that these are the most numerous cells in the mammalian brain, because keeping cells alive costs energy, which is always in short supply, and astrocytes were not even part of the of main action/brain activity. Or so it was thought.

In fact, the last decade has seen our ideas on astrocytes (and glial cells in general) change radically; we now known they perform highly complex jobs, including several previously associated with neurons. They are, for example, important for synapses (the specialised structures that do the contact between different neurons and through which the electrical signal is transmitted), where astrocytes detect and modulate activity, so effectively controlling the transmission of information in the brain.

Supporting their importance in the brain several studies have shown that patients with mental diseases - such as depression, bipolar disorder and schizophrenia - have lower than normal astrocyte density in the brain, especially in the prefrontal cortex. This can be improved, though, with anti-psychotic drugs.

This not only supports the importance of astrocytes in normal brain function, but also suggests they could play a role in mental disorders. And in fact, in one study killing astrocytes in the prefrontal cortex of rats seemed to cause a depression-like behaviour. But even if faulty astrocytes and mental diseases were often seen together, it was not possible to be sure, at least in psychiatric patients, that these cells were behind the disorder.

It is in this state of affairs that Lima and colleagues, in the work now published, decided to design a simple but very effective experiment to understand what was happening.

They start by injecting rats in the prefrontal cortex with a toxin that specifically kills astrocytes in a very localized way, and then tested the animals' cognitive abilities correlating these with the animals' (changed?) brain structure. The prefrontal cortex was chosen because it controls cognitive abilities such as planning, reasoning and problem solving, which are affected not only in the most common mental diseases, but also on age-related neurodegenerative illnesses like Alzheimer's.

As expected toxin-injected animals developed the cognitive deficits typical of mental disorders where the prefrontal cortex is affected. But what was really interesting, were the brain changes found - not only the prefrontal cortex's astrocytes had died with the toxin (as expected) but, as time passed, also did its neurons. Control animals injected with a solution free of toxin had no changes, either in behaviour or brain structure.

So even if faulty astrocytes have been found before in mental patients, the Portuguese researchers' results give robust support to the idea that astrocyte breakdown can be a primordial cause for these disorders (and not a result of them), and also suggests how it occurs. "Until now, we have blamed the poorer performance of the prefrontal cortex in these diseases on the surrounding astrocyte pathology" - says Oliveira - "but this study now supports the view that astrocytes, targeted in a pathological process, may actually lead to neurodegeneration in a specific brain region. Psychiatric disease can be mimicked by simply affecting astrocytes!"

This is a totally new perspective on how these diseases can develop, and consequently on how to treat them. For now, while we do not test other brain areas, Oliveira's results are specially relevant for mood disorders diseases - depression, schizophrenia and bipolarity - which we know to have both loss of cognitive functions, and abnormalities in the astrocytes of the prefrontal cortex.

But Oliveira and his team's findings are also important challenging the still too present view of the brain as a simple network of neurons, clearly showing that we need to see it instead as an interdependent circuit of neural and glial cells (in particular astrocytes) both in health and disease.

The new work also makes us also wonder if the claims on the importance of the astrocytes in Einstein's brain were that crazy after all...

* * * * *

Full Citation:

Lima, A, Sardinha, VM, Oliveira, AF, Reis, M, Mota, C, Silva, MA, Marques, F, Cerqueira, JJ, Pinto, L, Sousa, N and Oliveira, JF. (2014, Jul). Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats. Molecular Psychiatry; 19, 834-841. doi:10.1038/mp.2013.182

Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats

A Lima, V M Sardinha, A F Oliveira, M Reis, C Mota, M A Silva, F Marques, J J Cerqueira, L Pinto, N Sousa and J F Oliveira

Abstract

Interest in astroglial cells is rising due to recent findings supporting dynamic neuron–astrocyte interactions. There is increasing evidence of astrocytic dysfunction in several brain disorders such as depression, schizophrenia or bipolar disorder; importantly these pathologies are characterized by the involvement of the prefrontal cortex and by significant cognitive impairments. Here, to model astrocyte pathology, we injected animals with the astrocyte specific toxin L-α-aminoadipate (L-AA) in the medial prefrontal cortex (mPFC); a behavioral and structural characterization two and six days after the injection was performed. Behavioral data shows that the astrocyte pathology in the mPFC affects the attentional set-shifting, the working memory and the reversal learning functions. Histological analysis of brain sections of the L-AA-injected animals revealed a pronounced loss of astrocytes in the targeted region. Interestingly, analysis of neurons in the lesion sites showed a progressive neuronal loss that was accompanied with dendritic atrophy in the surviving neurons. These results suggest that the L-AA-induced astrocytic loss in the mPFC triggers subsequent neuronal damage leading to cognitive impairment in tasks depending on the integrity of this brain region. These findings are of relevance to better understand the pathophysiological mechanisms underlying disorders that involve astrocytic loss/dysfunction in the PFC.

Neuron-Glia Interaction as a Possible Glue to Translate the Mind-Brain Gap

Hmmmm . . . . I'm not sure what I think of this article. The mere fact that they use the terms Id, Ego, and Super Ego lead me to suspect that the authors are very poorly trained in contemporary psychology models, especially post-Freudian psychoanalysis.

Still, looking at the interactions between glia and neurons may be a worthy path to a better understanding of how the body-brain generates the emergence of mind.

Neuron-glia interaction as a possible glue to translate the mind-brain gap: a novel multi-dimensional approach toward psychology and psychiatry

Takahiro A. Kato [1,2], Motoki Watabe [3] and Shigenobu Kanba [1]

1. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2. Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan
3. Department of Management, School of Business, Monash University, Sunway, Malaysia

Neurons and synapses have long been the dominant focus of neuroscience, thus the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine. However, the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes, and microglia. Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored. Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. We briefly review the current situation of glial research in the field, and propose a novel translational research with a multi-dimensional model, combining various experimental approaches such as animal studies, in vitro & in vivo neuron-glia studies, a variety of human brain imaging investigations, and psychometric assessments.

Full Citation: 
Kato TA, Watabe M and Kanba S (2013) Neuron-glia interaction as a possible glue to translate the mind-brain gap: a novel multi-dimensional approach toward psychology and psychiatry. Frontiers in Psychiatry: Neuropsychiatric Imaging and Stimulation; 4:139. doi: 10.3389/fpsyt.2013.00139

Introduction

Neurons and synapses have long been the dominant focus of neuroscience, thus the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine. However, the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes, and microglia. Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored (1). Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. In addition, glial pathophysiology may explain the possible implications for the pathogenesis of major psychiatric disorders. The complexity of these aspects has yet to be well investigated. To explore these physiological and pathological aspects, novel translational methods should be applied with a multi-dimensional approach. Herein, we will briefly review the current situation of glial research in the field, and propose a novel translational research with a multi-dimensional model, combining various experimental approaches such as animal studies, in vitro & in vivo neuron-glia studies, a variety of human brain imaging investigations, and psychological/psychiatric assessments.

Glial Roles and Pathology in Psychiatric Disorders

Recent biological studies have been revealing the important roles of glial cells in the process of neuropsychiatric disorders. 

Astrocytes

Astrocytes are the most prevalent cell type in human brain and contribute to the homeostasis of the brain by regulation of neuronal metabolism, modulation of CNS inflammation, and direct/indirect synaptic transmission such as MNDA receptors (2, 3). Astrocyte dysfunction has been critical for various neurological disorders (4). Recent studies have shown abnormal expression of glial fibrillary acid protein (GFAP) – a prototypical marker of astrocyte – in postmortem brain of patients with schizophrenia and major affective disorders (5–7). In addition, recent rodent studies have suggested that astrocytes modulate anxious and depressive behaviors (8, 9). On the other hand, direct modulating effects of antidepressants have also been revealed (10–13). Thus, astrocytes have been supposed to be a novel therapeutic target against various psychiatric disorders such as major affective disorders and bipolar disorders (14, 15).

Oligodendrocytes

Oligodendrocytes contribute to brain development and homeostasis in the brain by formulating myelin around axons, supporting neuronal networks in the brain. Recently, novel oligodendrocyte functions have been revealed such as monitoring neuronal activities via myelin-forming oligodendrocytes (16) and modulating the conduction velocity of action potentials along axons in the rat hippocampus (17). Dysfunctions of oligodendrocytes have been indicated in psychiatric disorders, especially schizophrenia and major affective disorders, from a series of genetic studies (18, 19), postmortem studies (20–22), and diffusion tensor imaging (DTI) studies (23–27). A novel animal model of schizophrenia has been developed by treating a copper chelator, which induces oligodendrocyte dysfunction and white matter abnormality as demyelination and schizophrenia-related behaviors (28, 29). Cuprizone caused marked behavioral changes (working memory deficit) indicated by the results of Y-maze task, which showed an increase in the number of arm entries and a decrease in alternation behavior. These cuprizone-induced behavioral changes were effectively prevented by chronic administration of quetiapine, an atypical antipsychotic, which also diminished demyelination (28). On the other hand, recent rodent studies have revealed the interaction between oligodendrocyte dysfunction and social behaviors. Makinodan et al. reported that oligodendrocyte dysfunction is formed by early-period social isolation and this maladaptive environment induces working memory deficit associated with prefrontal cortex (PFC) function in later life (30). Liu et al. reported that protracted social isolation of adult mice induces behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the PFC and impairs adult myelination (31).

Microglia

Microglia are unique glial cells of mesodermal origin in the brain that act as “brain macrophage”; immunological/inflammatory players by moving around and releasing cytokines and free radicals (32, 33). Thus, microglia have proved to play important roles in various brain pathologies such as neurodegenerative diseases and neuropathic pain via inducing inflammation and oxidative stress (34–36). Recently, microglia have been revealed to have direct contact with synapses and have proved to play crucial roles in neuronal development through synaptic pruning (37–39). Postmortem studies have shown microglial activation in the brain of patients with schizophrenia and major affective disorders, especially suicide victims (40–42). In addition, positron emission tomography (PET) imaging studies using the peripheral benzodiazepine receptor bindings has shown that microglia are activated in patients with schizophrenia (43–45) and autism (46). On the other hand, minocycline, an antibiotic with inhibitory effects on microglial cells, has been reported to have therapeutic effects on schizophrenia and unipolar psychotic depression (47–49). In addition, rodent in vitro studies have proved the novel effect of psychotropic drugs (atypical antipsychotics such as risperidone and aripiprazole, and antidepressants such as paroxetine and sertraline, both selective serotonin reuptake inhibitors) directly on microglia by suppressing release of inflammatory cytokines and free radicals (50–54). Thus, microglia are suggested to play key roles in psychiatric disorders (53, 55, 56).

In the brain, neurons, astrocytes, oligodendrocytes, and microglia are mutually communicating with each other, by direct-contacting or via neurotransmitters and other various small molecules (57), and dysfunction of neuron-glia communication may induce pathological conditions not only in neurodegenerative diseases (58) but also in psychiatric conditions such as psychosis, depression, and anxiety. The above-mentioned recent findings strongly suggest that glial cells contribute to psychiatric disorders, while the underlying mechanisms have not been clarified.

Possible Glial Roles in Human Mental Functions

Until recently, the actual roles of glia in mental activities, especially for healthy humans, have not been investigated. As the first step to clarify this unexplored field, we have started to conduct a series of social decision-making experiments with healthy human subjects using minocycline, a microglial inhibitor (59–61). Healthy Japanese adult males made a monetary decision about whether or not to trust an anonymous partner after a 4-day oral administration of minocycline. Our first trial revealed that the minocycline group showed a positive correlation between their monetary score in trust game and their evaluation scores of others’ trustworthiness in a questionnaire (Yamagishi’s General Trust Scale), but surprisingly the placebo group did not (60). It would be rational to consider the monetary and questionnaire score to be positively correlated because both scores measure the other’s trustworthiness, but there was no positive correlation with the placebo group. The questionnaire is measuring only conscious-level decision-making, on the other hand the monetary score is measuring the final decision-making affected by not only the conscious but also the unconscious; suggesting that some unconscious noisy factors seem to be affecting the placebo group. Treatment with minocycline, a microglial inhibitor, has shown the positive correlation. Therefore, this first trial has indicated that microglial activation may cause “unconscious noises” against appropriate social decision-making, and inhibiting microglial activity may reduce such noise (60). In a next trial with larger samples, we additionally measured the effects of anxiety and personality as candidates for “noise” factors, by using Temperament and Character Inventory (TCI) and State-Trait Anxiety Inventory (STAI) (59). The monetary score in trust game was significantly lower in the minocycline group. Interestingly, participants’ ways of decision-making were significantly shifted; certain personality traits (cooperativeness, reward dependence, and self-directedness) proved to be the main modulating factors of decision-making in the placebo group, on the other hand the minocycline group was mainly modulated by state anxiety and trustworthiness. Our results of the second trial suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Interestingly, cooperativeness has proved to be the most influential factor in the process of decision-making in the placebo group of Japanese participants (59). It is widely known that cooperativeness and cooperative behaviors have been highly respected and emphasized aspects in Japanese society. Thus, of course, these aspects are ingrained during childhood by various sociocultural experiences within family relationships, schools, and other areas of society in Japan. Early-life events may activate human microglia, establish a certain neurosynaptic connection, and this formation may determine personality and personality-oriented social behaviors in later life (59, 62). If these experiments are conducted in other countries with different sociocultural backgrounds, other personality traits may be identified.

In addition, we have recently reported a possible outcome that minocycline, a microglial inhibitor, also reduces the risk of the “honey trap” during economic exchanges between males × females (61). Males tend to cooperate with physically attractive females without careful evaluation of their trustworthiness. In our experiment, young healthy male participants made risky choices (whether or not to trust female partners, identified only by photograph, who had decided in advance to exploit the male participants). The results show that trusting behavior in male participants significantly increased in relation to the perceived attractiveness of the female partner, but attractiveness did not impact trusting behavior in the minocycline group (61). These novel effects of minocycline may highlight the unknown roles microglia play in deeper human mental activities; microglia may modulate our unconscious drives in various social settings. The above-mentioned findings shed new light on the dark side of microglial social/mental functions in humans, especially highlighting the role of microglia for the unconscious. In the same way that Sigmund Freud, the founder of psychoanalysis, proposed that our behaviors must be controlled by the unconscious world, microglia may unconsciously control our behaviors. How do microglia act as fundamental mediators between the conscious and the unconscious world? What do neurobiological mechanisms justify their eventual role in bridging the gap between neuroscience and psychoanalysis? Answers to the above questions are not yet clear, but we have recently proposed a hypothesis creating a link between Freud’s unconscious drives such as the death drive and microglial activation (62). For example, microglial maladaptive over-activation in a certain brain region may activate human aggressive behaviors as a result of destructive drives [For the details, please see our recent article; Ref. (62)]. In the brain, not only microglia but also other glia such as astrocytes and oligodendrocytes exist, thus complicated neuron-glia interactions may modulate our mental activities including the unconscious (Figure 1). Further research should be applied to clarify these unresolved questions.

FIGURE 1  

Figure 1. The mind-brain gap from a novel glial neuropsychoanalytic perspective. The interaction between the mind and the brain has not been well understood. Freud, the founder of psychoanalysis, proposed the conception of mind structure models consisting of the following three components: the ID (unconscious/instinctual drives), the EGO (the exclusive apparatus of the conscious mind), and the SUPER-EGO (which represses the id in order to avoid any disruptions of rational thought). The existence and the significances of these mental components may be explained by future understandings of the neuron-glia interactions. The hypothetical interaction between the ID (unconscious drives) and microglia has already been proposed in our recent theoretical paper (62).

After Freud’s theory of unconscious roles in behaviors which was initially identified in the 1980s (63), Pribram and his colleagues have developed this theory in terms of a better articulated model of neural computation (64, 65). In addition, recent neuropsychoanalytic movements have been updating Freud’s theory with modern sophisticated methods of cognitive neuroscience (66–72). Thus, these recent approaches have been revealing the underlying mechanisms of implicit processing in a variety of information-processes including the social processes using rodent experiments. At present, the link underlying mechanisms between neuron-glia interactions and the conscious-unconscious relationship is largely unsolved, and few experimental methods have been developed to test these unknown brain mechanisms at either the microscopic or macroscopic level. Unconscious processing needs to be given a greater focus in terms of brain mechanisms. One possible solution is the novel ontogenetic approach; called “optogenetics” (73–76). Optogenetics is a revolutionary technique involving taking a light-activated gene (called a channel rhodopsin) targeted into a single neuron type. This technique enables to clarify direct interaction between activation of specific neuron in specific region by light and the resulting outcomes such as behaviors and emotional reactions at rodent level. A recent study has interestingly shown that activation of specific neurons in hippocampus produce a false memory in mice (77). Further technological developments in modulating glial cells by light and in activating both neurons and glial cells at the same time, by multiple fluorescent lights, may shed new light on resolving unknown roles of glia and neuron-glia interaction in behaviors and the conscious-unconscious. Functional roles and pathological contributions of astrocyte, oligodendrocyte, and/or microglia in conscious or unconscious processes have not been well understood, and we hypothesize that each cell may differently contribute to these physical and/or pathological processes in different brain regions such at the brainstem, limbic, or thalamocortical region, respectively. Future developments in optogenetics may clarify these unknown aspects.

Limitation and Future Perspectives of Neuro-Glia Research on Psychology and Psychiatry

To explore the above-mentioned hypothesis, further translational research is needed. Several limitations should be made note of at the present stage. At first, rodent studies focusing on the unconscious are limiting. Even if the unconscious exists in rodents, it seems to be impossible to measure the unconscious in rodents devoid of human language capabilities. Therefore, to uncover the unconscious mechanisms, we have no alternative method except examining actual human subjects. We have no specific drugs to modulate glial cells utilized in human, and minocycline is reported to have other brain functions in addition to microglial inhibition (78, 79). On the other hand, some brain imaging techniques enable us to explore the unknown roles of glial cells such as DTI technique and PET imaging using the peripheral benzodiazepine receptor bindings, while the specificities of these imaging methods are not at satisfactory levels (80). On the other hand, we can reconsider previous findings of brain imaging experiments. Functional MRI (fMRI) is a brain imaging procedure measuring brain activity by detecting associated changes in blood flow (81, 82). Outcomes of fMRI have long been believed to monitor solely neuronal activities, because cerebral blood flow and neuronal activation have been thought to be almost equivalent. However, not only neuronal activities but also glial activities, especially astrocyte activities, rely on cerebral blood flow. Therefore, at least to some extent, brain activities expressed by fMRI may be showing a part of glial activation. In addition, MR spectroscopy (MRS) is one of the novel imaging approaches to measure dynamic brain functions focusing on metabolomics including glia-related molecules. For example, myo-inositol, which can be measured by MRS, is regarded as a marker of astrocyte activity (83). These imaging methods and combination of these imaging techniques may shed new light on clarifying unknown roles of glia in psychiatric disorders (84, 85). For example, activated microglia-derived myelin damage has been indicated in the pathophysiology of schizophrenia by rodent experimental models (28, 29, 86, 87), while it is not confirmed in human subjects. Combination of human DTI and PET may clarify the mutual interaction between microglial activation and myelin damage in schizophrenia patients. On the other hand, connectivity of each brain region has been important in the understanding of the roles of brain functions from the era of Hughlings Jackson. fMRI studies have revealed the importance of these aspects (88, 89), and the recent development of DTI is showing us the significance of more complicated brain networks focusing on not only neurons but also glial cells such as oligodendrocytes (90, 91).

Finally, we propose the multi-dimensional approach to clarify the underlying brain mechanisms of mental functions including the unconscious (Figure 2). Based on our discussion, we believe that not only neurons but also glial cells have a vital role in the process of mental activities, a novel approach focusing on neuron-glia interactions should be applied. Combination of brain imaging techniques focusing on both neurons and glial cells should be applied (24, 26, 27, 43–46, 92–94). The most significant limitation in human brain research is that we cannot obtain living brain cells, including glial cells, from living human subjects from an ethical perspective. Presently, we can apply an alternative method; human brain cells such as neuronal cells can be established from somatic cells (not from the brain) such as skin fibroblasts by utilizing the gene-modification technique of induced pluripotent stem (iPS) cells. In addition, recently, neuronal cells are more easily established from directly conversion of human skin fibroblasts, called induced neuronal (iN) cells (95–99). Novel methods of establishing glial cells are strongly warranted based on iPS or direct conversion techniques in the near future. Multi-dimensional aspects of same human subjects, from genes, blood, brain imaging, psychometrics, social function, unconscious functions, psychodynamic assessments to molecular functions of somatic tissue-derived neuronal and glial cells, should be investigated and analyzed together (Figure 2). This approach may explore the novel roles of glial cells in various human mental activities including the unconscious. The application of this method for psychiatric patients should also be encouraged in the establishment of novel diagnostic methods and novel therapies.

FIGURE 2

Figure 2. A novel multi-dimensional approach toward psychology & psychiatry.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research on (1) Innovative Areas “Glia Assembly” (No. 25117011) of The Ministry of Education, Culture, Sports, Science, and Technology, Japan, (2) the Japan Society for the Promotion of Science (No. 24650227), and (3) the Health and Labor Sciences Research Grant No. [H 24-Seishin-Jitsuyouka (Seishin)-Ippan-001].

References available at the Frontiers site.

TEDxHendrixCollege (2011) - What Can Your Mind Do for You?

The TEDx event at Hendrix College (Arkansas) was focused on the topic, What Can Your Mind Do for You? There are five good videos here on topics ranging from connectome, glial cells, functionalism, and the impact of modern technology on the brain. Good stuff.

Below are the talks from TEDxHendrixCollege 2011: What Can Your Mind Do for You?




Dr. Doug Fields: The Other Brain

In this talk, Dr. Doug Fields discusses glia, or "glue," which make up 85% of the cells in the human brain. New discoveries about these glial cells are revolutionizing the way that scientists view the brain, and Dr. Fields gives us a glimpse into this burgeoning area of neuroscience.

R. Douglas Fields, Ph.D., is the Chief of the Section on Nervous System Development and Plasticity at the National Institute of Child Health and Human Development, a part of the National Institutes of Health (NIH), and Adjunct Professor in the Neuroscience and Cognitive Science Program at the University of Maryland, College Park. He is author of the new book The Other Brain, which gives readers an eyewitness view of the discovery of brain cells, called glia, that communicate without using electricity. He is an internationally recognized authority on neuron-glia interactions, brain development, and the cellular mechanisms of memory. In 2004 Dr. Fields founded the scientific journal Neuron Glia Biology, where he is the Editor-in-Chief, and he serves on the editorial board of several other neuroscience journals. The author of over 150 articles in scientific journals, Dr. Fields also enjoys writing about science for the general public. He is a scientific advisor to Scientific American Mind and Odyssey magazines. He has written articles for Outside Magazine, the Washington Post and other, and he writes on-line columns for the Huffington Post, Psychology Today and Scientific American. Dr. Fields received advanced degrees at UC Berkeley (B.A.), San Jose State University (M.A.), and in 1985 he received the Ph.D. degree from the University of California, San Diego, jointly from the Neuroscience Department, in the Medical School and the Neuroscience Group, at the Scripps Institute of Oceanography. He held postdoctoral fellowships at Stanford University, Yale University, and the National Institutes of Health before starting his research laboratory at the NIH in 1994. In addition to science he enjoys building guitars, rock-climbing, and scuba diving.

Dr. Andy James: The Cognitive Connetome

Dr. Andy James is exploring individual differences in cognition using fMRI. By developing a cognitive connectome, or a map of connections in the brain that are involved in cognition, Dr. James hopes to identify the cognitive differences between healthy individuals to help understand cognition in both healthy and clinical populations.

Dr. Andrew James is an assistant professor in the Brain Imaging Research Center of the Psychiatric Research Institute at the University of Arkansas for Medical Sciences.  After receiving bachelor degrees in Chemistry and Applied Psychology at the Georgia Institute of Technology in 1999, he pursued graduate studies in neuroscience at the University of Florida. There he was introduced to functional magnetic resonance imaging, which combined his passions for analytic instrumentation and cognition. After receiving his Neuroscience Ph.D. in 2005, he spent four years as a postdoctoral fellow at Emory University and the Georgia Institute of Technology before accepting a professorship at the University of Arkansas for Medical Sciences.

Dr. James's research focuses upon developing novel experimental designs and statistical analyses to push the methodological boundaries of functional neuroimaging. His past research has encompassed a broad range of topics including age-related changes in neural networks mediating motor learning, the neural encoding of aftertaste perception, the reorganization of motor networks following stroke, and modeling inter- and intra-subject variability in emotion-regulating networks with major depressive disorder.  His recent work focuses on how the brain encodes individual differences in reasoning and personality, where he seeks to bridge the gap between well-validated neuropsychological measures of cognition and the brain's functional networks.

Dr. Jack Lyons: Why You Need a Brain (and Why You Don’t)

In this entertaining talk, philosopher Dr. Jack Lyons outlines his version of functionalism and asks the audience if they really do need a brain.

Dr. Jack Lyons is Associate Professor of Philosophy at the University of Arkansas in Fayetteville. He got his bachelor's degree from Valparaiso University in Indiana and his PhD in philosophy with a minor in cognitive science from the University of Arizona. He taught at Florida State University for two years before coming to Arkansas. He works mainly in epistemology, cognitive science, and philosophy of mind. Recent projects concern various issues in the foundations of cognitive science, including modularity, the nature of representation, multiple realizability, and the recent neoreductionist movement in the philosophy of mind. Most of his current work has involved the epistemology of perception. He has published several journal articles on epistemology and philosophy of psychology/cognitive science and has a recent book on Oxford University Press, entitled Perception and Basic Beliefs. He is an associate editor for the journal Episteme: A Journal of Individual and Social Epistemology.

Carl Schoonover: Portraits of the Mind

Carl Schoonover's talk at TEDxHendrixCollege took the audience on a visually stunning journey through the history of neuroscience, showcasing the gorgeous results of the various methods that have been used to study the brain from antiquity through the 21st century.

Carl Schoonover is a neuroscience PhD candidate and National Science Foundation graduate fellow at Columbia University, and the author of Portraits of the Mind. He has written for The Huffington Post, Scientific American, Design Observer, Science Magazine, Le Figaro, Commentaire, Boing Boing and LiveScience, and cofounded NeuWrite, a collaborative working group for scientists, writers, and those in between. He hosts a radio show on WKCR 89.9FM, which focuses on opera, classical music, and their relationship to the brain.

Dr. Sandra Aamodt: The Wired Brain: How Modern Life Is Changing Your Mind

Sandra Aamodt reveals how technology is changing the development of the next generation in our increasingly modernizing world, both for the better and the worse.

Sandra Aamodt is a former editor in chief of Nature Neuroscience, the leading scientific journal in the field of brain research. She received her undergraduate degree in biophysics from the Johns Hopkins University, and her doctorate in neuroscience from the University of Rochester. After four years of postdoctoral research at Yale University, she joined Nature Neuroscience at its founding in 1998 and was editor in chief from 2003 to 2008, when she left to spend a year sailing across the Pacific Ocean. She lives in Northern California with her husband, one cat, and three chickens.

During her editorial career, she read over three thousand neuroscience papers and wrote dozens of editorials on neuroscience and science policy. She also gave lectures at twenty universities, and attended forty-five scientific meetings in ten countries. Her science writing has been published in The New York Times, the Washington Post, El Mundo and the Times of London. Her first book, Welcome to Your Brain: Why You Lose Your Car Keys But Never Forget How to Drive and Other Puzzles of Everyday Life (coauthored with Sam Wang), won the 2009 American Association for the Advancement of Science/Subaru SB&F Prize for Excellence in Science Books. Welcome to Your Child's Brain: How the Mind Grows from Conception to College, by the same authors, will be published in September 2011.