Genes, Memes, Culture, and Mental Illness: Toward an Integrative Model

Part 1

What Is Mental Illness? An Epigenetic Model

Hoyle Leigh and Hoyle LeighGenes, Memes, Culture, and Mental IllnessToward an Integrative Model10.1007/978-1-4419-5671-2_1© Springer-Verlag New York 2010

1. Genes and Mental Illness

Hoyle Leigh¹  

(1)

University of California, San Francisco, California, USA

Hoyle Leigh

Email: [email protected]

Abstract

The concept of mental illness evolved from possession by gods and an imbalance of body fluids (including the modern version of neurotransmitter imbalance) to a model that posits an interaction between genes and the environment. Environmental stress is known to play an important role – both by altering the genes early in development and as a precipitating factor for illness in later life. Recent evidence suggests that the interaction between the genes and the environment is mediated by memes – information encoded in neural connections which may be endogenous or exogenous.A gene × meme interaction model of mental illness is proposed.

1.1 The Evolution of the Concept of Mental Illness

Alienist s used to treat mental illness and those afflicted were considered alienated or strange. There have been essentially two lines of thought concerning the causes of mental illness: alien and endogenou s. The alien causes may be a possessio n of the gods or the devil, or, more recently, microorganisms such as bacteria and virus. The endogenous causes may be an imbalance of the body flu ids – the Hippocr atic blood, phlegm, yellow bile, and black bi le (thence the term, melancholia) or the modern version of an imbalance among seroto nin, norepinep hrine, and do pamine. It is also generally accepted that severe environmental factors such as extreme heat or cold can cause mental aberrations such as del irium.

Certain types of mental dysfunction, such as maladaptive patterns of behavior and neur osis, have been also attributed to faulty learn ing or bad mode ling. Experimenta l neuroses and lea rned helplessness have been produced in animals by confusing re wards or inescapable punishm ent (Saunders et al., 1995; Seligman, 1972).

Mental illness is known to run in families. With the advent of biological psychiatry, it was hoped, in the latter part of the twentieth century, that the etiologic genes of mental illness would be discovered. In fact, the diagnostic and statistical manual for mental illness adopted by the American Psychiatric Association in 1980 (D SM III) was based on the resear ch diagnostic criteria (Feighner et al., 1972) that were designed to isolate pure cultures of psychiatric illness for biological research.

At the time DSM III was introduced, the catechola mine theory of affective disorders (Schildkraut, 1965) was the prevailing theory of mood disorders, chlorproma zine the most commonly used antipsychotic, and the Human G enome Project was yet not even a gleam in anyone’s eyes. Exciting developments have since occurred in molecular biology and genetics and the Human Genome Project has been completed ahead of schedule (2003). Psychiatric research, at least in part fostered by the rigorous diagnostic criteria of DSM III and its slight modification, DSM IV (1994), has made breathtaking advances, taking full advantage of these and other developments during the Dec ade of the Brain, including neuroimag ing techniques. On the strength of these developments, a new theoretical model of psychiatric illness has emerged that is open and evidence based.

Many putative genes that code for vulnerability for psychiatric syndromes are evolutionarily conserved. This explains why schi zophrenia which is associated with low fertility rates in the afflicted has not become extinct. Crow (1997a, b, 2000, 2007) and Mitchell and Crow (2005) postulate that vulnerability to schizophrenia may be the price that Homo sapiens had to pay for the development of lang uage, i.e., the speciat ion of humans from their ancestral apes involves the same genes that caused the left hemisph eric dominance and language. Crow proposes that there are gradations in the genetic predisposition to psychosis, across diagnostic categories of schizoph renia and bip olar disorder.

Certain genes that endow vulnerability to anxiety, for example, the short allele of the serotonin transporter promo ter gene (more of this below), may confer sensitivity to the smoke de tector of anxiety activation (Nesse, 2001) and be evoluti onarily adaptive when humans dwelled in caves in fear of predator animals. In the modern world, however, such sensitivity to anxiety would be dysfunctional for the individual and thus be considered a psychiatric syndrome.

1.2 Gene-Environment Interaction and Brain Morphology and Function

The genes coding for predisposition to various psychiatric syndromes are currently being defined using various techniques including linka ge studies and gen ome scan. As far as psychiatric diagnosis goes, current state of affairs can be summarized as follows: For each diagnostic category, there are many susce ptibility genes, and a single gene or a few genes may code for the susceptibility for many different disorders. On the basis of genetic studies, Kendler et al. (1998) proposed that psychosis be reclassified as: (1) classic schiz ophrenia, (2) major depressio n, (3) schiz ophreniform disorder, (4) bipolar-schizom a ni a, (5) schizo depression, and (6) he bephrenia.

What seems clear is that psychiatric disorders are syndromes, pheno menological convergence of a number of different genetic-pathophysiologic pathways. An analogy might be hypertension. Hyper tension is a syndrome that has definable signs and complications that can be treated with antihypertensive drugs. Hypertension, however, is pathophysiologically heterogeneous – it may be nephrogenic, cardiogenic, neurogenic, endocrine, secondary to familial hyperlipidemia, stress-induced, etc.

1.3 Gene–Environment Interaction: Serotonin Transporter Gene as an Exemplar

A single gene that codes for the vulnerability to multiple psychiatric (and medical) conditions is the serotonin transport er gene (SERT) and its promoter region polymorphism (5-HTTLPR). SERT is highly evolutionarily conserved and regulates the entire seroto ninergic system and its receptors via modulation of extracellular fluid serotonin concentrations. D NA screens of patients with autism, ADH D, bipolar disorder, and Tourette’s syndrome have detected signals in the chromoso me 17q region where SE RT is located (Murphy et al., 2004). 5-HTTLP R polymorphism consists of short (s) and long (l) alleles, and the presence of the short allele tends to reduce the effectiveness and efficiency of SERT. The short allele has been identified as the underlying variation for the risk for the above disorders as well as anxiety, increased neuroticism scales, smoking oticism, smoking behavior, negative mood, social behavior, especially to reduce negative mood and feel stimulated, difficulty in quitting smoking, social phobia, major depression, and irritable bowel syndrome (Hu et al., 2000; Lerman et al., 2000; Lotrich and Pollock, 2004; Yeo et al., 2004).

Why does a single gene code for so many vulnerabilities? One simple answer may be that the gene codes for one or more basic evolutionarily adaptive predispositions that, in combination with other factors, may determine the development and severity of a psychiatric syndrome. When we look at the list of vulnerabilities above, it seems clear that there is a continuum, from anxiety to adaptive/maladaptive behavior to phobia to major depression, and/or to physical symptoms. The concept of endophen otype is useful in understanding traits associated with syndromes (e.g., eye-tracking abnormality in schizophrenics and relatives) (Gottesman and Gould, 2003) and might provide clues to a genotypic diagnosis.

Pezawas et al. (2005) showed that the short allele carriers show reduced gray matter in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional MRI studies of fearful stimuli show a tightly coupled feedback circuit between the amygdala and the cingulate, implicated in the extinction of negative affect. Short allele carriers showed relative uncoupling of this circuit and the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. They also show increased amygdala activation to fearful stimuli (Bertolino et al., 2005; Hariri et al., 2002). Thus, this gene seems to increase the affected individual’s brain’s sensitivity to negative affect and anxiety (Gross and Hen, 2004). What other factors, then, may further predispose the individual for a major depression?

Fig.a

Differences in processing of emotional stimuli between s allele carriers (darker arrows) and homozygous l allele carriers (lighter arrows). Negative emotional stimuli are evaluated by the amygdale after preliminary analysis in the ventral visual pathway (not shown). Carriers of the s allele have markedly reduced positive functional coupling between the rostral anterior cingulate (rACC) and the amygdala, which results in a net decrease in inhibitory feedback from the caudal anterior cingulate (cACC), via connections between rACC and cACC (short upward arrows). Brain volume was also substantially reduced in s allele carriers in the rACC and, to a lesser extent, the cACC and amygdala. The consequence of these genotype-based alterations is an emotional hyperresponsivity to negative affective stimuli in s allele carriers (large dark cloud) compared with individuals lacking this allele (small light cloud), which may be related to an increased risk of developing depression. As found in a previous study, functional coupling between the vmPFC (light circle on left) and the amygdala was also increased in s allele carriers. (From Hamann, 2005, reprinted with permission)

Ca spi et al. (2002, 2003) have shown, in an elegant longitudinal study, that stress during the most recent 2 years in adulthood and maltre atment in childhood interacted with the 5-HTTLPR status. Individuals with two copies of the short allele who also had the stressors had greatest amount of de pressive symptoms and suicidality than heterozygous individuals, and those with only the long alleles had the least amount of depression. The short allele carriers have been shown to have more neuroticism scores on Eysenck personality inventory, and those with both short allele and high neuroticism were at higher risk of developing lifetime depression (Munaro et al., 2005).

Studies in monkeys have shown that the anxiety-enhancing effect of the short allele is mitigated with good mothering i n infancy (Barr et al., 2004; Suomi, 2003, 2005).

5-HTTLPR may also determine resp onse to drugs. Depressed individuals with the short allele were found to respond better to antidepressants that are both serotonergic and noradrenergic (i.e., mirtazapine) rather than serotonin-specific reuptake blockers. On the other hand, individuals with the long allele may have more side effects with exactly those drugs that are more effective for those with the short allele (Murphy et al., 2004). Diet deficient in the serotonin precursor, tryptophan, has been shown to induce depression in healthy women with the 5-HTTLPR s/s regardless of family history of depression, while those l/l were resistant to depression regardless of family history of depression. Those with l/s without family history of depression were intermediate between l/l and s/s in depressive mood with tryptophan depletion, while l/s with family history of depression showed depressive response like the s/s (Neumeister, 2003; Neumeister et al., 2006, 2002, 2004a, b).

Thus, 5-HTTLPR short allele, in conjunction with childhood stress, confers an individual with the trait to respond to later stress with increased anxiety and neuroticism, which, in turn, predisposes the individual for later major depression, suicida lity, and psychophysiolo gic disorders. Other gene–environment interactions predisposing to trait and disorder have been reported, including type 4 dopamine receptor gen e (D4DR) and novelty seeking and AD HD (Ebstein et al., 1997; Keltikangas-Jarvinen et al., 2003), monoamine oxidas e A (MAOA) and antisocial personality (Caspi et al., 2002; Craig, 2005), and dopamine transporter gene (DAT1) and ADHD (Brookes et al., 2006). The Val66Met allele of the brain-derived neurotrophic factor (BDNF) gene causes reduced dendritic branching in hippocampus, impaired contextual fear conditioning, and increased anxiety that is less sensitive to antidepressant treatment. There are alleles of the glucocorti coid receptor gene found in the normal population, which confer a higher sensitivity to glucocorticoids for both negative feedback and insulin reponsiveness or glucocorticoid resistance and an association with an increased likelihood of depression in several alleles and increased response to antidepressants in one of them (McEwen, 2007).

FKBP5 polymorphism (a glucocorticoid receptor-regulating gene) has also been shown to interact with childhood abuse in increasing the risk of PTSD in an urban general hospital population (Binder et al., 2008).

1.4 Emerging Model of Mental Illness: Gene × Meme Interaction

It seems clear, then, that modern model of psychiatric and medical illness must be based on gene × environment inte raction. This model posits that the vulnerability gene has evolutionarily adaptive function as evidenced by its very conservation. It holds that there are critical interactions between the genotype and early environment in forming a personality trait which may in turn be adaptive or maladaptive at the individual level, e.g., anxiety-prone, exploratory, attention fluctuating, hypervigilant, etc. Kandel showed how environment (and learning) modifies gene expression (Kandel, 1979, 1998).

Recent and current stress may play the role of tipping the balance from a trait to a syndrome that has a course of its own.

How do environment and stress affect the genes exactly? To be precise, except in a few extreme cases of physical stress, environment and stress affect human beings only when they are perceived. As we have seen, the serotonin transporter promoter gene polymorphism may affect how the same stimulus may be perceived – as threatening or non-threatening – and may in turn result in activation or deactivation of genes. The fact that a recent meta-analysis failed to show a significant interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and stress in the risk of depression (Risch et al., 2009) highlights that the interaction is not a simple gene × stress, but rather mediated by the individual traits and percepts.

When a sensation from a sensory organ reaches the brain, it is processed against existing templates formed by both genetic predisposition and memory, the output of this process constitutes perception. The templates and the percept are memes as we will discuss in the next chapter. In sum, environment affects and interacts with genes through memes in the course of development, and mental health and mental illness are the outcomes of this interaction.

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Hoyle Leigh and Hoyle LeighGenes, Memes, Culture, and Mental IllnessToward an Integrative Model10.1007/978-1-4419-5671-2_2© Springer-Verlag New York 2010

2. How Does Stress Work? The Role of Memes in Epigenesis

Hoyle Leigh¹  

(1)

University of California, San Francisco, California, USA

Hoyle Leigh

Email: [email protected]

Abstract

Stress responsiveness is affected by early experience. For example, in rats, high grooming and licking by mother in early life results in decreased reactivity to later stress by increasing the expression of glucocorticoid receptor genes in the brain. Memories of early experience and resulting changes in genes (epigenesis) determine stress sensitivity in later life. Epigenesis may result in increased or decreased susceptibility to influx of stress memes.

Since Selye’s work on the role of stress on the activation of the adrenal cortex and the general adaptation syndrome (Selye, 1956), there has been an explosion of knowledge concerning the effects of stress on the organism in such fields as neuropsychoendocrinology and neuropsychoimmunology.

2.1 Stress, Aging, and Disease

Classically, stress response is the fight–flight reaction to a threatening stimulus such as a dangerous animal, mugger, or approaching fire. It is accompanied with the activation of the autonomic nervous system and hypothalamo-pituitary-adrenal (HPA) axis. The organism needs the normal stress response to survive such danger situations, and inadequate or excessive adrenocortical and autonomic response is deleterious for health and survival. The active process by which the body responds to stresses and maintains homeostasis has been termed allostasis (achieving stability through change) (Sterling and Eyer, 1988). The term allostatic load or overload has been introduced by McEwen to denote the wear and tear and resulting pathophysiology from insufficient management of allostasis either due to too much stress or inappropriate stress response (McEwen, 1998).

When the stress is of short duration, and the behavioral, endocrine, and autonomic responses have been successful in warding off the danger situation, the organism may be strengthened by the stress experience. On the other hand, if the stress is prolonged and/or the organism is unable to master it (allostatic overload), there may be serious health consequences.

Sapolsky et al. proposed the glucocorticoid cascade hypothesis of stress and aging (Sapolsky et al., 1986). Aging animals have impaired ability to terminate the secretion of adrenocortical stress hormones at the end of stress, which may be due to the degeneration of negative feedback neurons. These neurons may further degenerate due to the toxic effects of excessive glucocorticoids, resulting in a feed-forward cascade with potentially serious pathophysiological consequences in the aged subject.

Epel and her colleagues found that perceived stress and chronicity of stress in healthy premenopausal women were significantly associated with higher oxidative stress, lower telomerase activity and shorter telomere length, which are known determinants of cell senescence and longevity in peripheral blood mononuclear cells. They found that women with the highest levels of perceived stress had shorter telomeres on average by the equivalent of at least one decade of additional aging (Epel et al., 2004).

The role of stress in various disease conditions from cancer to cardiac disease has been elucidated in numerous publications – as of this writing, there were more than 18,000 PubMed publications for stress and cancer, and more than 32,000 publications on stress and heart disease. As for the stress and the brain, there were more than 30,000 PubMed publications.

Posttraumatic stress disorder and acute stress disorder are results of massive identifiable stress and are manifested by emotional and behavioral symptoms. As we have seen, however, stress plays a prominent role in depression and anxiety, and, in fact, most psychiatric conditions are either precipitated by or contributed by stress. Even exacerbations of schizophrenia, often thought to be primarily biological, are induced by emotional stress (Marom et al., 2005).

2.2 Stress, Memes, and the Brain

Stress has been shown to change both the structure and function of the brain.

When a stimulus arrives at a sensory cortical area such as the visual cortex, auditory cortex (Wernicke’s area), and/or the somatosensory postcentral gyrus and the thalamus, the neural impulses are projected to the association cortices resulting in a perception. Perception is determined by both genetically determined circuitry and neural projections determined by learning and memory formation, i.e., memes (see Section 2.5 and Chapter 8).

Then the cortical impulses constituting the percepts are projected to the amygdala, the hippocampus, and other limbic structures, all of which are interconnected with each other. Amygdala has a very tight feedback loop with the anterior cingulate gyrus which is connected with the thalamus, neocortex, and the entorhinal cortex. The negative feedback from the anterior cingulate reduces amygdalar activation. Stressful perceptions stimulate amygdala and result in the autonomic and HPA activation. In memetic terms, the perceived human face (meme) arising in the primary visual cortex and arriving at amygdala may be elaborated into a smiling human face, the attribute meme of smiling coming from the anterior cingulate gyrus after processing of the original stimulus.

Hippocampus plays an important role in shutting off the HPA activation – any damage or atrophy of the hippocampus attenuates this resulting in a prolonged HPA activation to stress (McEwen, 2007). Longitudinal studies on aging in human subjects revealed that progressive increases in salivary cortisol during a yearly exam over a 5-year period predicted reduced hippocampal volume and reduced performance on hippocampal-dependent memory tasks (Lupien et al., 1998). Initially, it was thought that aging in hippocampus was associated with a loss of neurons, but subsequent studies on animal models of aging confer greater importance to a loss of synaptic connectivity or impairment of synaptic function (McEwen, 2007).

Neural regeneration is now known to occur in the brain, particularly in hippocampus. Certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the dentate gyrus of the hippocampus. Glucocorticoids, excitatory amino acids acting on NMDA receptors, and endogenous opioids mediate the suppression (Gould et al., 1997). Stress also affects the shape and abundance of dendrites in the hippocampus, amygdala, and prefrontal cortex. Generally, stress results in retraction and simplification of dendrites. In memetic terms, stress memes tend to disconnect incoming memes from existing memes (memories).

Puberty seems to be a particularly vulnerable period for the effect of stress on the brain. Stress in peripubertal rats resulted in a stunting of growth in parts of the hippocampus and a sustained down-regulation of the hippocampal glucocorticoid receptor (GR) gene expression, resulting in deficits in the shut-off of the HPA activation. Daily infusions of corticosterone during puberty resulted in a reduction of both hippocampal volume and the number of neurons in parts of the hippocampus, while it produced only reduction in volume but not in the number of neurons in adults (McEwen, 2007).

Corticosteroids released by HPA activation interact with many chemicals and neurotransmitters in the hippocampus, including serotonin, endorphins, GABA-benzodiazepine receptors, and glutamate and other excitatory amino acids. Chronic stress in rats releases glutamate and affects the neural cell adhesion molecule (NCAM, PSA-NCAM). Chronic stress also releases the tissue plasminogen activator (tPA), an extracellular protease and signaling molecule, that is involved in the loss of spines and NMDA receptor subunits in the hippocampus (McEwen, 2007).

Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) play a role in dendritic proliferation. BDNF knockout mice exhibit a paucity in dendrites and no further reduction in hippocampal dendritic length with chronic stress, while wild-type mice show reduced dendritic length with chronic stress. On the other hand, overexpression of BDNF prevents stress-induced dendritic reductions and an antidepressant-like action on forced swimming test in mice (Govindarajan et al., 2006). Both stress-induced increases and decreases of BDNF expression have been reported, which may reflect that BDNF synthesis may be triggered by stress to offset the depletion of BDNF caused by stress. BDNF and corticosteroids may oppose each other, with BDNF reversing the corticosteroid-induced reduction in hippocampal neuronal sensitivity. BDNF may facilitate meme introduction, replication, and synthesis.

Corticotropin-releasing factor (CRF) plays an important role in mediating stress in the brain. It regulates the ACTH release in the pituitary and also acts on the amygdala that controls the behavioral and autonomic responses to stress including the release of tPA that plays an important part in anxiety. When CRF is injected into the brain, it produces arousal and increased responsiveness to stressful stimuli that seem to be independent of the pituitary adrenal axis and can be reversed by specific and selective CRF antagonists. Such antagonists also reverse behavioral responses to stressors. An interaction between the norepinephrine and the CRF systems seems to occur both at the locus ceruleus and the amygdala. Noradrenergic neurons arising from the locus ceruleus are concerned with behavioral arousal and anxiety. CRF neurons seem to activate locus ceruleus. Norepinephrine, in turn, may stimulate CRF release in the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala. Such a feed-forward system was hypothesized to be particularly important in stress situations where an organism must mobilize not only the HPA but also the central nervous system. Such a positive feedback system that accelerates anxiety response, however, might be particularly vulnerable to dysfunction (Koob, 1999).

Prefrontal cortex and amygdala are also affected by stress. Chronic stress in rats causes dendritic shortening in the medial prefrontal cortex but dendritic growth in the neurons in amygdala and in the orbitofrontal cortex. Glucocorticoids have been shown to produce retraction of dendrites in medial prefrontal cortex. Behaviorally, chronic stress remodeling of the prefrontal cortex impairs attention set shifting (McEwen, 2007). Chronic stress enhances amygdala-dependent unlearned fear and fear conditioning (Conrad et al., 1999). Chronic stress also increases aggression through hyperactivity of amygdala.

The amygdala exerts a regulatory influence on the stress response and is itself affected by stress. The serine protease tissue plasminogen activator (tPA), a key mediator of dendritic spine plasticity, is required for stress-induced facilitation of anxiety-like behavior. In the tPA knockout mice, repeated stress did not cause a reduction in the spine density (Bennur et al., 2007). BDNF may also play a role in amygdala in enhancing anxiety and increasing dendritic density.

All the brain structures mentioned, the prefrontal cortex, amygdala, and hippocampus, are closely interconnected and influence each other. Inactivation of amygdala blocks stress-induced impairment of hippocampal memory long-term potentiation (LTP) and spatial memory (Kim et al., 2005). Stimulation of medial prefrontal cortex reduces responsiveness of central amygdala output neurons and thus the prefrontal cortex plays an important role in fear extinction. Amygdala–hippocampus connections are required for the processing of emotional memories with contextual information (McEwen, 2007).

2.3 Role of Stress and Nurturing in Development: Epigenesis

Development is considered to be epigenetic, i.e., it occurs as an interaction between genes and environment. The phenotypic expression of a gene, i.e., whether it will be turned on or off in the life of an organism, depends on the organism’s interaction with the environment. Stress figures in prominently in this epigenetic model of development. As I discussed in the previous chapter, the effect of childhood stress on the serotonin transporter promoter gene (5-HTTLPR) has been demonstrated and that noxious effects may be mitigated by good mothering in childhood at least in monkeys. But how exactly does stress affect the genes?

In a series of experiments, Szyf et al. (2007), Unterberger et al. (2006), Weaver (2007), and Weaver et al. (2007) studied the effects of different maternal behavior in rats. Maternal behavior in rats affects the neural systems that tonically inhibit corticotrophin-releasing factor (CRF) synthesis and release in the hypothalamus and amygdala, which in turn activate central norepinephrine in response to stress. Glucocorticoids initiate tonic negative feedback inhibition over CRF synthesis and release and thus dampen HPA responses to stress. This glucocorticoid negative feedback is, in part, mediated by glucocorticoid receptors (GR) which are found in many brain areas including hippocampus.

As adults, the offspring of high licking and grooming (LG) mothers show increased hippocampal GR expression and enhanced glucocorticoid feedback sensitivity by comparison to adult animals reared by low-LG mothers. Thus, adult offspring of high-LG mothers show decreased hypothalamic CRF expression and more modest HPA responses to stress. Eliminating the difference in hippocampal GR levels abolishes the effects of early-life experience on HPA.

In essence, the experience of high licking by the rat pup is a meme that forms neural connections as perception that in turn activates existing memes and the ensemble of memes increases hippocampal GR expression.

In addition to alterations in hippocampal GR expression, enhanced maternal LG behavior over the first week of life is associated with increased hippocampal neuronal survival, synaptogenesis, and improved cognitive performance