\r\n\tThere has been a long debate regarding the superiority of off-pump versus on-pump coronary artery bypass grafting. In addition, there is a debate on ways of treating concomitant carotid and coronary artery disease. In the meantime, robotic coronary artery bypass grafting has emerged as a minimally invasive surgery. This technique provides the new approach to coronary artery disease. A hybrid approach, which is a combination of minimally invasive surgery and percutaneous coronary intervention, could be an alternative treatment option in selected patients. During postoperative recovery, early mobilization of the patients cannot be too stressed. Cardiac rehabilitation and physical therapy would play a big role.
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Dr. Murashita received his MD from Kyoto University, Japan. He has published over 30 peer-reviewed papers as a first author, and 8 book chapters for In-Tech publications. He has a membership for Society of Thoracic Surgeons, and Asian Society for Cardiovascular and Thoracic Surgeons. 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Chan and Manoj Kumar Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/3794.jpg",editedByType:"Edited by",editors:[{id:"252210",title:"Dr.",name:"Felix",surname:"Chan",slug:"felix-chan",fullName:"Felix Chan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41592",title:"The Irritable Bowel Syndrome: How Stress Can Affect the Amygdala Activity and the Brain-Gut Axis",doi:"10.5772/52066",slug:"the-irritable-bowel-syndrome-how-stress-can-affect-the-amygdala-activity-and-the-brain-gut-axis",body:'Irritable bowel syndrome (IBS) is a functional digestive disorder characterized by abdominal pain, bloating and altered bowel habits without any organic cause (Drossman 1999b; Mulak and Bonaz 2004). Patients with IBS exhibit enhanced perception of visceral sensation to colonic distension which is associated with hypervigilance at the origin of visceral hypersensitivity (VHS) (Ritchie 1973; Bradette, et al. 1994; Elsenbruch, et al. 2010). VHS is a clinical marker of IBS considered to play a major role in its pathophysiology. The exact cause of VHS is unknown but a number of mechanisms are evoked as represented by neuroplastic changes in primary afferent terminals (peripheral sensitization) due to peripheral inflammation or infection of the gut (i.e. post-infectious IBS) but also in the spinal cord (central sensitization) and in the brain (supraspinal pain modulation) or in descending pathways that modulate spinal nociceptive transmission (Bonaz 2003; Mulak and Bonaz 2004). In addition, stress is able to increase visceral sensitivity either at the central and/or peripheral level (Mulak and Bonaz 2004; Larauche, et al. 2011).
There is a bidirectional communication between the central nervous system (CNS) and the gastrointestinal (GI) tract, i.e. the brain-gut axis, such as signals from the brain can modify the motor, sensory, secretory, and immune functions of the GI tract and, conversely, visceral messages from the GI tract can influence brain functions in a top-down and bottom-up relation. Numerous data argue for a dysfunction of this brain-gut axis in the pathophysiology of IBS (Mulak and Bonaz 2004; Bonaz and Sabate 2009; Tillisch, et al. 2011).
Stress, through the corticotrophin-releasing factor (CRF) system (CRF, urocortins and their receptors CRF1,2), is a key factor involved in the pathophysiology of IBS. Indeed, stress is able to modify visceral sensitivity as well as GI motility, permeability, intestinal microbiota, and immunity of the GI tract, all mechanisms that are involved in the pathophysiology of IBS. In addition, stress is able to modulate the hypothalamic pituitary adrenal (HPA) axis and the autonomic nervous system (ANS) which is the link between the gut and the CNS and an imbalance of the ANS is observed in IBS patients (Pellissier, et al. 2010a; Mazurak, et al. 2012). The main brain areas involved in stress are the prefrontal cortex, the limbic system (e.g. the hippocampus and the amygdala) and the hypothalamus. Relations between the prefrontal cortex and the limbic system are important in the management of stress response.
The amygdala is a key structure involved in the stress effect on the GI tract. Indeed, the amygdala is involved in brain-gut and gut-brain interactions. i) The amygdala receives informations from the gut through the parabrachial (PB) nucleus, a sensitive nucleus, and the dorsal vagal complex. The latter, composed of the nucleus tractus solitaries (NTS), is the main entrance of the vagus nerve (vagal afferents) and sends projections to the amygdala. The amygdala is therefore a relay of somatic and visceral nociceptive and non-nociceptive afferents through ascending inputs from the spinal cord and the NTS to the insula which is the main cortical area involved in sensitive information processing. ii) The amygdala controls the ANS which is a key element in the neuro-endocrine and autonomic responses to stress of the organism to maintain homeostasis. On the one hand, the amygdala projects to the dorsal motor nucleus of the vagus nerve (DMNV) at the origin of the parasympathetic branch of the vagus nerve (vagal efferents); this makes the amygdala able to modulate the functioning of the parasympathetic system through the vagus nerve. On the other hand, the amygdala projects to the intermediolateral column cells of the spinal cord, at the origin of the sympathetic nerves, and locus coeruleus (LC) in the pons. It makes the amygdala able to modulate the sympathetic nervous system, the other branch of the ANS, and thus to modulate the sympatho-vagal balance, a marker of brain-gut interactions (Mazurak, et al. 2012). iii) The amygdala controls the HPA axis activation either directly or indirectly via the hippocampus (i.e. inhibition), known to inhibit the HPA axis, and thus to decrease stress response. iv) The amygdala is also involved in childhood psycho-traumatic experiences which are key elements in the pathophysiology of IBS. Indeed, early life stress, as represented by sexual abuse in infancy or adolescence, is present in 30 to 50% of IBS patients (Chitkara, et al. 2008; Bradford, et al. 2012). The amygdala is particularly vulnerable to stressors in early life. The amygdala contains all the elements of the CRFergic system (e.g. CRF, Ucns, CRF1,2) and early life stress induces persistent changes of the CRFergic system in the amygdala leading to an increased stress sensitivity in adulthood. This has been well modelled in the maternally separated (MS) rat model where morphological modifications of the amygdala (e.g. enlarged amygdala volumes and increases in CRF-containing neurons) are induced. v) The amygdala (central nucleus; CeA) and the bed nucleus of the stria terminalis (BNST) are highly interconnected with limbic regions (Bienkowski and Rinaman 2012). These two regions are frequently referred as a “central extended amygdala”, which shares similar connectivity with other brain regions (e.g. hypothalamus and brainstem) that coordinate behavioural and physiological responses to interoceptive and exteroceptive stressors. It makes the amygdala able to link pain and emotional processings. Furthermore, the amygdala is sensitive to stress-induced increase in glucocorticoids since the existence of elevated glucocorticoid level in the amygdala is associated with anxiety-like behavior and visceral hypersensitivity (Myers and Greenwood-Van Meerveld 2007b; 2010). The amygdala is therefore at the cross-road of anxiety, stress, and visceral sensitivity. The role of the amygdala in IBS is therefore crucial since IBS patients reported higher score of state and trait anxiety than healthy volunteers or in inflammatory bowel disease (IBD) patients in remission with IBS symptoms (Drossman 1999b; Pellissier, et al. 2010a). vi) The prefrontal cortex (PFC), and particularly its medial part (mPFC), is able to modulate the functioning of the amygdala. Indeed, the mPFC involvement in fear extinction process (Sotres-Bayon, et al. 2004; Quirk, et al. 2006a) has been shown to be indirectly mediated by its inhibitory action on the amygdala output (Vidal-Gonzalez, et al. 2006). vii) Brain imaging techniques (fMRI, PET) have contributed to a better understanding of the pathophysiology of IBS. During rectal distention, an activation of most of the brain structures referenced above, and in particular the amygdala, have been observed in healthy volunteers (Baciu, et al. 1999) while an abnormal brain processing (i.e. abnormal loci of cerebral activation) of pain was observed in IBS patients (Bonaz, et al. 2002; Agostini, et al. 2011). In addition, brain structural changes of the HPA axis and limbic structures have been recently reported in IBS patients (Blankstein, et al. 2010; Seminowicz, et al. 2010).
At the present time, the only medical treatment of IBS is directed at GI motor/sensory or CNS processing. Unfortunately, this treatment is poorly effective and often associated with high placebo effects, thus revealing the importance of the overlap between pain and placebo neurobiological pathways. The therapeutic approach is essentially focused on the symptoms as represented by anti-spasmodics for pain, laxatives or bulking agents, 5-HT4 agonists and guanylate cyclase-C agonist for intestinal transit regulation and anti-depressives/anxiolytics drugs. Placebo has a ≈ 40% efficacy in IBS patients (Patel, et al. 2005) and pronounced placebo analgesia is coupled with prominent changes of brain activity in visceral pain matrix, as represented by the amygdala (Lu, et al. 2010). Non-pharmacological therapies are of special interest. Cognitive behavioral therapy is associated with reduced limbic activity (e.g. reduced neural activity in the amygdala), GI symptoms, and anxiety (Lackner, et al. 2006). Hypnosis has shown efficacy in IBS (Whorwell, et al. 1984) and is known to modify the activity of the amygdala (Drossman 1999b). All methods focused on stress reduction such as mindfulness-based stress reduction should reduce pain perception (Drossman 1999a). Repetitive transcranial magnetic stimulation of the PFC that decreases the activity of the amygdala (Baeken, et al. 2010) would also be of interest in IBS patients. In this context, vagal nerve stimulation, used for the treatment of refractory epilepsy and depression, should be of interest in the treatment of IBS by modulating the amygdala. Indeed, an inhibitory action of vagal nerve stimulation on amygdala-mPFC neurotransmission, probably due to the deactivation of the amygdala, has been described under VNS (Kraus, et al. 2007). Consequently, new methods aimed at modifying the activity of the amygdala represent a therapeutic challenge in the management of IBS patients.
The irritable bowel syndrome (IBS) is the most common disorder encountered by gastroenterologists. IBS is defined as “a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit with features of disordered defecation and distension”(Drossman 1999b). Classically the syndrome is considered as functional since biological as well as morphological (e.g. colonoscopy) investigations are not able to evidence any detectable organic lesions or anatomical abnormalities (colonic polyps or diverticulosis…) relative to symptomatology of the affected patients. The syndrome has been defined according to Rome III criteria (Longstreth, et al. 2006). There is a female predominance in a ratio of 2:1 (Drossman, et al. 1993). IBS affects up to 10–15% of the population with an estimated 1.7 billion dollars in annual direct cost (Talley, et al. 1991). Generally patients suffer from the absence of a real diagnostic and from the consideration that they have a psychosomatic disease. Pain is perceived by patients as the most distressing symptom and constitutes their major reason for consulting a physician (Sandler, et al. 1984). Extra-intestinal manifestations are also frequently described by the patients (e.g. headache, low back pain, chronic fatigue, interstitial cystitis…) (Whitehead, et al. 2002).
The pathophysiology of IBS is multifactorial. Altered bowel motility, sensory disorders, psychosocial factors are evoked (Drossman, et al. 1999c; Gaynes and Drossman 1999; Bonaz and Sabate 2009). Local features have also been considered as important. The role of food is often evoked by patients and a number of them are intolerant to lactose, fructose, gluten, polyols (Dapoigny, et al. 2004; Morcos, et al. 2009) with an enhancement of their symptoms following an eviction of such foods from diet. There is also good evidence for a role of the GI microbiota in its pathogenesis (Parkes, et al. 2008). Neuroimmune interactions are also involved, based on the development of IBS after infectious gastroenteritis (i.e. post-infectious IBS) (Gwee 2001) or in patients with IBD in clinical remission (i.e. post-inflammatory IBS) (Long and Drossman 2010). A low grade inflammation has been observed in IBS patients with a predominance of mastocytes in close contact with neural fibers explaining why IBS is assimilated to an IBD by some authors (Ford and Talley 2011).
Sensory disorders, and especially VHS, have also been evoked in the pathophysiology of IBS. VHS, represented by the increased sensation of pain when the pelvic colon is distended with an inflated rectal balloon, is a clinical marker of IBS which is observed in most of IBS patients. The exact location of the abnormal processing of visceral pain is unknown, and can have a peripheral origin, i.e. in the digestive tract by altered peripheral functioning of visceral afferents (i.e. bottom-up model), a spinal origin, e.g. spinal hyperalgesia by a defect of the gate control, or a defect of descending inhibitory controls or an altered central processing of afferent information from the gut, i.e. top-down model or a combination of all these hypotheses. IBS patients have an alteration in the spinal modulation of nociceptive process by the inhibitory descending pain modulation systems (Wilder-Smith, et al. 2004) in which the amygdala could be involved.
Psychosocial factors are often found in IBS patients. Among 20 to 50% of IBS patients have psychiatric disorders, such as major depression, anxiety, and somatoform disorders (Garakani, et al. 2003). Low dose of tricyclic antidepressants have shown efficacy in ameliorating the symptoms in patients (Rahimi, et al. 2009). IBS is also frequently associated with fibromyalgia in 30% to 70% of the cases. This syndrome is characterized by somatic hyperalgesia, the physiopathology of which is close to IBS (Mathieu 2009). IBS and fibromyalgia are classified by some authors as central sensitization syndromes (Woolf 2011). A majority of IBS patients associate stressful life events with initiation or exacerbation of their symptoms (Whitehead, et al. 1992) and stress is able to act at all levels of the physiopathology of IBS (see below). Globally, a concept has emerged that IBS is the result of a dysfunction of the brain-gut interplay, as conceptualized in the brain-gut axis. The ANS is, with the HPA axis, the link between the CNS and the gut and an autonomic dysfunction is observed in IBS patients which could be of top-down or bottom-up origin, as observed for VHS.
The brain talks to the gut and conversely through a bidirectional communication under normal conditions and especially during perturbations of homeostasis. The CNS and the gut communicate through the ANS and the circumventricular organs and the gut contains a “little brain” as represented by the enteric nervous system which is a target of the ANS.
The enteric nervous system can control functions of the intestine even when it is completely separated from the CNS (Bayliss and Starling 1899). The enteric nervous system contains three categories of neurons, identified as sensory, associative, and motor neurons (both excitatory and inhibitory) which are the final common pathways for the control of signals to the musculature, submucosa, mucosa, and vasculature, both blood and lymphatic. The enteric nervous system contains as many neurons as in the spinal cord (400–600 million) and confers an autonomy to the digestive tract such as the enteric nervous system can function independently of the CNS for the programming of motility and secretion (Furness 2012). Some neuropeptides and receptors are present in both the enteric nervous system and the CNS. The function of the GI tract is modulated by both the enteric nervous system and the ANS.
The ANS is composed of the sympathetic (i.e. the splanchnic nerves) and parasympathetic nervous system (i.e. the vagus nerves and the sacral parasympathetic nucleus represented by the pelvic nerves) which are mixed systems.
The vagus nerve contains essentially 80-90% of afferent fibers vehiculating informations from the abdominal organs to the brain (Altschuler, et al. 1989) with the exception of the pelvic viscera for which informations are vehiculated to S2-S4 levels of the spinal cord by the pelvic nerves with central projections similar to other spinal visceral afferents. The vagus nerve carries mainly mechanoreceptor and chemosensory informations from the gut. If classically vagal afferents do not encode painful stimuli, they are able to modulate nociceptive processing in the spinal cord and the brain (Randich and Gebhart 1992).
The sympathetic nerves contain 50% afferent fibers. Visceral afferents that enter via spinal nerves (i.e; splanchnic and pelvic nerves), at thoracic 5 - lumbar 2 segments of the spinal cord, carry information concerning temperature as well as nociceptive visceral inputs related to mechanical, chemical, or thermal stimulation through C and Aδ fibers, which will reach conscious perception.
The afferent informations of the ANS reach the CNS at the spinal cord level, for the splanchnic nerves, the nucleus tractus solitarius (NTS) level in the dorsal medulla for the vagus nerve, and the sacral parasympathetic (S2-S4) level for the pelvic nerves. At the level of the spinal cord, sympathetic afferents are integrated at the level of laminae I, II outer, V, VII (indirectly) and X. Then the information is sent to the upper level through the spino-thalamic and spino-reticular tracts, the dorsal column with projection to the thalamus (ventral posterolateral nucleus, intralaminar nucleus) and the cerebral cortex (insular, anterior-cingulate, dorsolateral PFC…). Neurons from laminae I, IV, and V responding to visceral stimuli also receive nociceptive cutaneous inputs (Foreman 1999).
At the level of the NTS, vagal afferents are integrated in subnuclei according to visceral somatotopy (e.g. medial, commissural, gelatinosus) (Altschuler, et al. 1993) and then projections to the PB nucleus, in the pons, according to a viscerotopic organization, which in turn projects to numerous structures in the brainstem, hypothalamus, basal forebrain, thalamus, and cerebral cortex (Fulwiler and Saper 1984). In the cerebral cortex, the insular cortex acts as a visceral (e.g. GI) cortex through a NTS-PB-thalamo-cortical pathway according to a viscerotopic map. The insular cortex is connected with the limbic system (bed nucleus of the stria terminalis and CeA) and with the lateral frontal cortical system (Saper 1982). The NTS also sends projections to the ventrolateral medulla, the hypothalamus, and the amygdala/bed nucleus of the stria terminalis contributing to visceral perception. The NTS receives convergent afferents from both the spinal cord (i.e. laminae I, V, VII, and X) and the vagus nerve; some of these afferents probably being at the origin of autonomic reflex responses. This convergence is also observed at the level of the PB and ventrolateral medulla (Saper 2002) thus arguing for a relationship of pain with visceral sensations.
At the forebrain level, the spinal visceral sensory system constitutes a postero-lateral continuation of the cranial nerve to the visceral sensory thalamus and cortex (Saper 2000). There is also a spino-PB pathway since about 80% of lamina I spinothalamic axons send collaterals to the PB (Hylden, et al. 1989) and a spino–parabrachio–amygdaloid pain pathway which implicates the transmission of nociceptive information to the amygdala. Spinal nociceptive neurons in laminae I, IV, V, VII, and X directly innervate the hypothalamus and medial prefrontal cortex (Cliffer, et al. 1991; Burstein 1996). The messages coming from the gut are integrated in the central autonomic network (see below), which, in turn, adapts the response of the digestive tract through the efferent ANS through reflex loops which are essentially unconscious or become conscious in pathological conditions such as VHS observed in IBS. There is also descending pathways that control somatic as well as visceral pain by modulating visceral informations at the spinal cord level. These pathways are both inhibitory, thus producing analgesia as represented by projections from the periaqueductal gray to the rostroventral medulla, and LC descending fibers to the spinal cord as well as facilitatory producing hyperalgesia (rostroventral medulla and OFF and ON cells) (Tsuruoka, et al. 2010).
The circumventricular organs are highly vascularized structures with fenestrated capillaries located around the 3rd and 4th ventricles. They are characterized by the lack of a blood–brain barrier and represent points of communication between the blood, the brain, and the cerebrospinal fluid (Benarroch 2011). They are represented by the subfornical organ, median eminence, pineal gland, area postrema, organum vasculosum of the lamina terminalis. The circumventricular organs are sensitive to the vascular content (e.g. circulating interleukins, electrolytes). They activate dendritic cells releasing prostaglandins acting on PGE2 receptor of neurons located closely to these circumventricular organs. These neurons send projections to the hypothalamus, activating the HPA axis, and to the central autonomic network represented by the DMNV and the sympathetic pre-ganglionar neurons of the intermediolateralis column. The circumventricular organs are consequently involved in the central integration of a peripheral message to maintain homeosthasis. For example, they are involved in sodium and water balance, cardiovascular regulation, metabolic and energetic balance, immune function, regulation of body temperature, vomiting, reproduction. During an immune challenge represented by systemic inflammation, cytokines released in the circulation talk to the brain through two routes i.e. neural (vagal afferents) and humoral (circumventricular organs) to activate the HPA axis.
The central autonomic nervous system integrates and modulates afferent informations from the gut and sends reversible inputs to the gut. In the CNS, visceral informations are integrated in the central autonomic nervous system via brain regions involved in the autonomic, endocrine, motor, and behavioral responses (Saper 2002). The brain network can be roughly divided into executive structures, mainly hypothalamic, coordinating structures, mainly included in the limbic system, and high level control structures, mainly the frontal cortex.
The hypothalamus e.g. paraventricular nucleus (PVN), lateral hypothalamus, arcuate nucleus and adjacent retrochiasmatic area innervate the parasympathetic and sympathetic preganglionic neurons. The principal neuromediators are oxytocin and vasopressin (Hallbeck, et al. 2001). Through the release of CRF, the neuromediator of stress, the PVN is involved in the HPA axis response to stress. The limbic system is represented by the amygdala and its nuclei, the bed nucleus of the stria terminalis, considered as the extended amygdala, the septum and the hippocampus. The limbic system modulates the endocrine system and the ANS, two major components of the brain-gut axis. Classically, the amygdala is involved in the integration of emotions and the emotional conditioning which is represented by the association of a conditioned stimulus (i.e. a sound) with an unconditioned stimulus (the reinforcement) (Henke, et al. 1991; Benarroch 2006; LeDoux 2007). The amygdala receives afferents from the NTS, PB nucleus, frontal cortex, and LC and sends projection to the ANS, the frontal cortex and the hippocampus. The amygdala inhibits the DMNV, stimulates the sympathetic nervous system and the stress response through the HPA axis. The amygdala is a CRF-containing nucleus.
The prefrontal, insular, and anterior cingulate cortices are involved in the integration of visceral informations, attention, emotions and in the regulation of humor. The anterior cingulate cortex is divided in a cognitive dorsal part and an affective ventral part i.e. the perigenual part which has been frequently activated in brain imaging by numerous emotional stimuli. Most of these structures (ANS, HPA axis, limbic system, endogenous pathways that modulate pain and discomfort…) are part of the emotional motor system that mediates the effect of emotional states on the GI function, modulates gut functions and communicates emotional changes via the ANS to the gut. The threshold for visceral perception is dependent on the individual’s emotional and cognitive state (Mayer 2000; Mayer 2011).
Visceral as well as stressful informations activate the LC, a nucleus belonging to central noradrenergic system localized in the pons. The LC is the largest group of noradrenergic neurones. It is involved in emotional arousal, autonomic, and behavioural responses to stress and attention-related processes through its dense projections to most areas of the cerebral cortex and alertness-modulating nuclei (e.g. majority of the cerebral cortex, cholinergic neurones of the basal forebrain, cortically-projecting neurones of the thalamus, serotoninergic neurones of the dorsal raphe and cholinergic neurones of the pedunculopontine and laterodorsal tegmental nucleus). The LC also exerts an indirect action on autonomic activity via projections to the PVN and to the cerebral cortex and amygdala, structures which are known to influence the activity of premotor sympathetic neurones in the PVN. LC activation leads to anxiety through an activation of the amygdala (Tasan, et al. 2010).
Stress is defined as the response of the organism to a solicitation of the challenging environment. The body engages a “fight or flight” response when exposed to an acute challenge with a sympathetic activation leading to an increase of heart rate and respiration, increased arousal, alertness, and inhibition of acutely non adaptive vegetative functions (feeding, digestion, growth and reproduction). The time course of the reaction corresponds to the general syndrome of adaptation defined by Hans Selye in 1950 (Selye 1950). The reaction of stress is physiological but may become pathological following an unbalance between the capacities of adaptation and the requirement of the environment, thus leading to functional, metabolic, and even lesional disorders.
CRF is a 41-amino acid peptide derived from a 191-amino acid preprohormone. CRF is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress (Vale et al. in 1981) as well as its related peptides the urocortines (Ucn) i.e. Ucn 1, Ucn 2 (also known as stresscopin-related peptide), and Ucn 3 (also known as stresscopin). CRF and the Ucns exert their biological actions on target cells through activation of two 7–transmembrane-domain G protein–coupled receptors, known as CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2) which are encoded by 2 distinct genes [for review (Gravanis and Margioris 2005)]. CRF and Ucn 1 have equal affinity for the CRF1 receptor, although Ucn 1 is 40 times more potent than CRF in binding CRF2. In contrast, Ucns 2 and 3 bind selectively to CRF2. The population of CRF synthetizing neurons is predominantly expressed in the parvocellular part of the PVN of the hypothalamus and projects via the external zone of the median eminence to the anterior pituitary. In addition to its role as a hypothalamic hypophysiotropic hormone, CRF acts as a neurotransmitter in several brain areas. CRF has predominantly excitatory actions on neurons in the hippocampus, cortex, LC, and hypothalamic nuclei (Siggins, et al. 1985). CRF1 mediates anxiety-like behaviors whereas CRF2 mediates anxiolytic effects in the defensive withdrawal test (Heinrichs, et al. 1997). Competitive CRF receptor antagonists have been developed to determine the functions of CRF receptors under basal and stress conditions (Bonaz and Tache 1994b). The CRF system plays a critical role in coordinating the autonomic, endocrine, and behavioural responses to stress (Dunn and Berridge 1990).
The effect of stress on the GI tract is now well characterized. Stress induces modifications of motility, secretion, visceral sensitivity, local inflammatory responses (Delvaux 1999; Mawdsley and Rampton 2006; Tache and Bonaz 2007) through a central and/or peripheral action through CRF1,2 related receptors. Alterations of this complex system in humans are linked to a variety of anxiety-related psychiatric disorders and stress-sensitive pain syndromes, including IBS. Dysfunction in the HPA axis regulation attributable to overactivation of CRF/CRF1 signaling in response to chronic stress has been implicated in the pathophysiology of IBS symptoms (Chang, et al. 2009).
Stress is known to decrease gastric emptying, lengthen small bowel motility and increase colonic motility (Tache and Bonaz 2007). The effects of stress on gut function are mediated by the ANS represented by the sympathetic, vagal and pelvic parasympathetic innervation of the enteric nervous system (Grundy 2006). At the central level, stress inhibits the parasympathetic nervous system and activates the sympathetic nervous system through the effect of PVN projections on the DMNV and intermediolateral column cells of the spinal cord.
CRF signaling is a key component in the alterations of gut motor function in response to stress in both the brain and the gut. The CRF/CRF1 signalling pathway is involved in stress-induced anxiety/depression (Holsboer and Ising 2008) and alterations of colonic motor and visceral pain while both central and peripheral CRF2 receptor activation may exert a counteracting influence (Tache, et al. 2005; Million, et al. 2006). At the level of the GI tract, stress delays gastric emptying through CRF2 while increasing colonic motility and secretion through CRF1 (Tache and Bonaz 2007). In the small bowel, CRF-like peptides stimulate the contractile activity of the duodenum through CRF1 receptor while inhibiting phasic contractions of the ileum through CRF2 receptor (Porcher, et al. 2005).
Stress also induces an activation of the sacral parasympathetic nucleus through the projections of the Barrington nucleus through CRF activation thus stimulating recto-colonic motility (Tache and Bonaz 2007). Numerous data have established the involvement of peripheral CRF signalling in the modulation of secretory function under stress conditions via activation of both CRF1 and CRF2 receptors, activation of cholinergic enteric neurons, mast cells and possibly serotonergic pathways (Larauche, et al. 2009).
An increase of intestinal permeability is observed in the colon of IBS patients, associated with visceral or somatic hypersensitivity (Zhou and Verne 2011). Stress is able to disrupt the intestinal epithelial barrier thus increasing the penetration of luminal antigens into the lamina propria, leading to nociceptors sensitization and favoring the development of visceral hypersensitivity (Ait-Belgnaoui, et al. 2005). This increase of intestinal permeability is due to an activation of peripheral CRF signaling involving both CRF2 and CRF1 (Buckinx, et al. 2011) as well as mast cell activation (Santos, et al. 2001).
Stress is able to increase intestinal inflammation by increasing intestinal permeability (see above) thus activating mast cells and visceral afferents in a local loop. Stress favours intestinal inflammation by stimulating the sympathetic nervous system and inhibiting the vagus nerve thus decreasing the cholinergic anti-inflammatory pathway. Stress, through its immune-suppressive function also favours inflammation (Ghia, et al. 2006; Mawdsley, et al. 2006; Bonaz 2010).
Bacteria in the gut (400–1,000 different bacterial species) have an important role in the immune response, including inflammation (Lee and Mazmanian 2010). Stress is able to modify the intestinal microbiota (Bailey, et al. 2010). Alteration of the microbiota favors translocation of bacteria from the intestinal lumen to the interior of the body where they can stimulate the immune system (Clarke, et al. 2010). This can in turn have significant impact on the host and affect behavior, visceral sensitivity and inflammatory susceptibility (Collins and Bercik 2009).
Stress is known to increase visceral sensitivity [(Larauche, et al. 2012) for review]. Either acting at the central and/or peripheral (e.g. digestive) level, stress is able to increase visceral perception and emotional response to visceral events by a disturbance of the brain-gut axis at its different levels, central, gut and the ANS. Genetic model of depression or anxiety, such as the high-anxiety Wistar-Kyoto (WKY) rats or Flinders Sensitive Line rats have shown increased sensitivity to colorectal distension (Overstreet and Djuric 2001). In the same way genetic models deleting CRF1 exhibit a decrease in colonic sensitivity to colonic distension (Trimble, et al. 2007) while models overexpressing CRF1 exhibit enhanced response to colonic distension (Million, et al. 2007). These data argue for the filiation stress-anxiety-inflammation and visceral hypersensitivity.
Again, the CRF signalling, at both the central and peripheral level, is a key element involved in stress-induced visceral hypersensitivity. Recent data argue for an equally important contribution of the peripheral CRF/CRF1 signalling pathway locally expressed in the gut to the GI stress response (Larauche, et al. 2009). At the peripheral level, mast cells degranulation observed in the colon following stress and peripheral administration of CRF (Wallon, et al. 2008) induces visceral hypersensitivity via the release of mediators (histamine, tryptase, prostaglandin E2, nerve growth factor) that can stimulate or sensitize sensory afferents (van den Wijngaard, et al. 2009; 2010). Intravenous administration of CRF increases GI motility and visceral pain sensitivity in IBS patients compared with healthy controls, whereas administration of a non-selective CRF receptor antagonist improved these responses (Million, et al. 2005; Tache, et al. 2005; Tsukamoto, et al. 2006).
The GI tract is a sensitive target to stress. Numerous data argue for a role of stress in the pathophysiology of IBS. Patients with IBS report more stressful life events than medical comparison groups or healthy subjects (Drossman, et al. 1996; 2000; Drossman 2011). Stress is strongly associated with symptom onset and symptom severity in IBS patients. Illness experience, health care-seeking behavior, and treatment outcome are adversely affected by stressful life events, chronic social stress, anxiety disorders, maladaptive coping style. A history of emotional, sexual, or physical abuse is often found in IBS patients [(Chitkara, et al. 2008) for review]. For example, there is a significantly higher prevalence (i.e. 44%) of sexual or physical abuse in patients with functional GI disorders than in controls with organic GI disorders (Drossman, et al. 1990). Psychiatric comorbidity, especially major depression, anxiety, and somatoform disorders, occur in 20 to 50% of IBS patients (Garakani, et al. 2003) and more likely precede the onset of the GI symptoms, thus suggesting a role for psychiatric disorders in functional GI disorder development (Sykes, et al. 2003).
Functional brain imaging studies have shown that there is a major influence of cognitive-affective processes on GI sensations and its CNS correlates in health and functional digestive disorders as IBS (Mayer, et al. 2006; Van Oudenhove, et al. 2007). Cognitive-affective processes including arousal, attention and negative emotions strongly influence visceral pain perception through modulation of its neural correlates (Mayer 2011). Feeling emotions requires the participation of brain regions, such as the somatosensory cortices and the upper brainstem nuclei that are involved in the mapping and/or regulation of internal organism states (Damasio, et al. 2000). This has led to the biopsychosocial concept of IBS (Drossman 1996b). These data are in agreement with the role of hypervigilance in the visceral hypersensitivity observed in IBS patients (Naliboff, et al. 2008). Spence et al. (Spence and Moss-Morris 2007) have characterized predictors of post-infectious IBS such as perceived stress, anxiety, somatisation and negative illness beliefs at the time of infection in favor of a cognitive-behavioural model of IBS. The importance of psychosocial factors and somatisation compared to gastric sensorimotor function is most pronounced in hypersensitive patients with functional dyspepsia, another functional GI disorder (Van Oudenhove, et al. 2008).
Early life trauma (neglect, abuse, loss of caregiver or life threatening situation) increases susceptibility to develop later affective disorders such as depression, anxiety, and is a key factor in the development of IBS (Bradford, et al. 2012). Traumatic events, such as war, environmental disasters, physical abuse or a bad accident in adulthood can induce post-traumatic stress disorder (PTSD) with increased prevalence of GI symptoms, such as IBS (Cohen, et al. 2006).
The role of stress sensitization is also reproduced in preclinical studies. Adults rats previously subjected to neonatal maternal separation (MS) exhibit visceral hypersensitivity to colorectal distension in basal conditions (Ren, et al. 2007). This visceral hypersensitivity is exacerbated in acute stress (e.g. water avoidance stress: WAS; Avoidance to water for 1 h by standing on a small platform; Bonaz & Taché 1994b) conditions (Coutinho, et al. 2002). Chronic exposure to repeated WAS is used to study visceral hypersensitivity and is very close to clinical conditions. However, habituation of the CRFergic system is observed in chronic conditions (Bonaz and Rivest 1998) and may induce analgesia. It seems that these conflicting data are influenced by the basal state conditions of the animals before applying the repeated stressor (surgery and single housing) (Larauche, et al. 2010).
The amygadala is a key element in the pathogeny of IBS.
The amygdala is divided into a primitive group of nuclei associated with the olfactory system (central, medial and cortical nuclei, and nucleus of the lateral olfactory tract), and a phylogenetically new group of nuclei (lateral and basal) (Knapska, et al. 2007). The lateral (LA), basolateral (BLA), and central nuclei (CeA) are important for sensory processing (Neugebauer 2006; LeDoux 2007). The amygdala is part of the central autonomic nervous system that is involved in the brain-gut axis. The amygdala is a key element in emotional/affective behavior (LeDoux 2007), including the emotional responses to pain such as anxiety and fear of pain (Gauriau and Bernard 2002; Neugebauer, et al. 2004; Neugebauer 2006) as well as in the reciprocal relationship between pain and affective state (Meagher, et al. 2001; Rhudy and Meagher 2003). Affective content is attached to sensory information through associative processing in the LA–BLA circuitry and is then transmitted to the CeA which is the output nucleus for major amygdala functions (Maren 2005; Phelps and LeDoux 2005). The CeA serves to attach emotional significance to afferent nociceptive transmission and coordinates appropriate autonomic, affective and motor behavioral responses through its outputs to the hypothalamus, cortex and brainstem (Neugebauer, et al. 2004).
The CeA receives numerous sensory informations from descending cortical, thalamic (perigeniculate, paraventricular) and brainstem inputs (Whalen and Kapp 1991), as well as from the olfactory system, medial PFC, insula, brainstem viscerosensory and nociceptive centers (NTS, PB), and from all parts of the amygdala. The amygdala increases the excitability of CNS sites regulating behavioral, neuroendocrine, and autonomic responses to stress (LeDoux, et al. 1988) and thus is able to modify GI functions. The amygdala is involved in the affective processing of sensory information and in the generation of anxiety and fear (Davis 1997), elements which are involved in the pathogeny of IBS.
The amygdala, and particularly the CeA, is a major site of extrahypothalamic CRF, in cell bodies and terminals as well as CRF1 and, to a lesser extent, CRF2 receptors. The amygdala is a key element of the extrahypothalamic circuits through which CRF contributes to anxiety-like behavior and affective disorders (Aguilera, et al. 1987; Sajdyk, et al. 1999; Reul and Holsboer 2002; Fu and Neugebauer 2008). Excepting the hypothalamus, the amygdala is the major site of urocortin III (the endogenous ligands for CRF2 receptors) expression (Li, et al. 2002). In particular, activation of CRF neurons in the CeA that project to the LC increase its firing thus resulting in a noradrenaline release in the structures it is projecting to (Bouret, et al. 2003). LC activation leads to anxiety through the activation of the amygdala and, conversely, anxiety producing stimuli (stressful and fear-inducing stimuli) that increase the activity of the amygdala lead to LC activation (Samuels and Szabadi 2008).
The CEA is involved in the modulation of the ANS because of its brainstem projections to the DMNV, NTS, PB and the periaqueductal gray (Rizvi, et al. 1991), known to modulate the spinal cord processing of noxious information through descending inhibitory controls (Le Bars, et al. 1992). The CEA innervates hypothalamic nuclei, modulating the HPA axis (Rodrigues, et al. 2009). The CeA also projects to the medial peri-LC dendritic region, resulting in increased norepinephrine release and other monoamine systems in the brainstem and forebrain (Gray 1993; Fudge and Emiliano 2003; Pare 2003) which are involved in arousal and hypervigilance.
The LC has an inhibitory effect on the BLA and the activation of this pathway leads to a disinhibition of the CeA, since the BLA has a predominantly inhibitory influence over the CeA (Rosenkranz, et al. 2006). The LC is involved in the stress response through CRF1 receptors as well as CRF afferent fibers from the Barrington nucleus which is ventro-laterally located to the LC. The Barrington nucleus projects to the sacral parasympathetic nucleus to increase the motility of the distal recto-colon (Valentino, et al. 1993). Colorectal distension increases the firing of the LC through CRF1 through a LC-Barrington nucleus pathway (Rouzade-Dominguez, et al. 2001). In addition, the LC is involved in the brain noradrenergic modulation of the GI tract motility (Bonaz, et al. 1992a; 1992b; 1995). Consequently, the Barrington-LC-amygdalo complex is ideally positioned to bidirectionally coordinate brain-gut interactions.
The use of C-Fos expression as a marker of neuronal activation has shown that somato-visceral (Bonaz and Fournet 2000; Sinniger, et al. 2004; 2005), and visceral (Wang, et al. 2009) pain as well as stress- or abdominal surgery-induced GI disturbances (Bonaz and Tache 1994a; 1994b; 1997; Bonaz and Rivest 1998) and colitis (Porcher, et al. 2004) induced the activation of the amygdala. In addition, the amygdala is one of the central areas from where digestive sensations are elicited in epileptic patients (Mulak, et al. 2008) during intracerebral electrical stimulations. In a model of visceral pain induction such as inflating a balloon into the rectum, an activation of the amygdala is observed in healthy volunteers (Baciu, et al. 1999) while aberrant functional responses (e.g. deactivation of the amygdala) to noxious rectal stimulation was observed in areas of the brain involved in emotional sensory processing, particularly the amygdala, insula, and prefrontal cortex in IBS patients (Bonaz, et al. 2002; Elsenbruch, et al. 2010; Tillisch, et al. 2011) thus arguing for an abnormal brain processing of visceral pain following rectal distension.
Activation of corticosteroid receptor (both glucocorticoid and mineralocorticoid receptors) in the CeA is involved in the induction of anxiety and visceral hypersensitivity (Myers and Greenwood-Van Meerveld 2007b). High levels of glucocorticoids result in CRF mRNA level increases in the amygdala (Makino, et al. 1994). The group of Greenwood-Van Meerveld ) have shown that implants of corticosterone micropellets in the CeA increase anxiety-like behavior as well as visceral hypersensitivity to colonic distension and increased responsiveness of viscera-sensitive lumbosacral spinal neurons that mediate visceromotor reflexes to colo-rectal distension (Greenwood-Van Meerveld, et al. 2001; Myers, et al. 2005; Greenwood-van Meerveld, et al. 2006; Myers and Greenwood-Van Meerveld 2007a). Indeed, exposure of the amygdala to corticosterone-releasing micropellets caused an increase in action potential frequency in the dorsal horn neurons in the L6-S1 spinal segments suggesting that a descending neuronal pathway, originating in the amygdala, could be triggered by continuous activation by corticosterone. The neurons responding with excitation to colorectal distension were short-lasting and long-lasting excitatory neurons based on the duration of the reponse (Venkova et al. 2009). Mineralocorticoid receptors but not glucocorticoid receptors in the amygdala trigger descending pathways facilitating viscero-nociceptive processing in the spinal cord (Venkova, et al. 2009). In addition, a WAS known to activate the amygdala (Bonaz and Tache 1994b), performed during 7 consecutive days induced VHS that was abolished by glucocorticoid receptor and mineralocorticoid receptor antagonists in the amygdala. These results argue for a role of amygdaloid glucocorticoid receptor and mineralocorticoid receptor in IBS.
The CRF signaling is also involved in pain processing. WKY is a rat strain for studying anxiety and IBS. WKY express a greater amount of CRF and CRF1 mRNA in the CeA and the PVN (Bravo, et al. 2011). In this model, it has been shown that colonic hypersensitivity to luminal distension is reversed by peripheral administration of a CRF1 antagonist (O\'Malley, et al. 2011). Infusion of CRF1 antagonist into the CeA attenuates the hypersensitivity to colonic distension in the WKY rats, thus confirming the role of CRF1 receptor in the amygdala in VHS mechanism (Johnson, et al. 2012). The basal expression of CRF in the LC is increased in WKY rats and a selective CRF1 receptor antagonist abolished the activation of LC neurons by colorectal distension and intracisternal CRF in rats (Kosoyan, et al. 2005). These data strengthen the role of the CeA and LC in VHS through CRF1 which is in agreement with the interactions between both nuclei involved in emotional-arousal circuit. Indeed, CRF neurons in the CeA project directly to the LC and increase the firing rate of LC neurons thus increasing noradrenaline release in the vast terminal fields of this ascending noradrenergic system. In humans, oral administration of a selective CRF1 antagonist (GW876008) is followed by a significant BOLD signal reductions within the amygdala during pain expectation in IBS patients (Hubbard, et al. 2011). CRF1 receptors in the amygdala contribute to pain-related sensitization, whereas the normally inhibitory function of CRF2 receptors is suppressed in the arthritis pain model. Thus, due to the opposing effect of CRF1 and CRF2 receptors, CRF can induce a dual effect in the amygdala. The differential effects of CRF1 and CRF2 receptor antagonists on pain-related processing in the amygdala have reciprocal opposing influences on anxiety-like behaviors. CRF1 and CRF2 receptors in the amygdala mediate opposing effects on nociceptive processing (Ji and Neugebauer 2007). Numerous data argue for a role of CRF1 and CRF2 to mediate pro- and anti-nociceptive effects of CRF respectively. It has been shown that low concentrations of CRF facilitate nociceptive processing in the CeA neurons through CRF1 while higher concentrations of CRF have inhibitory effects through CRF2 receptors. This is in agreement with the concept that CRF2 receptors serve to dampen or reverse CRF1-initiated responses (Tache and Bonaz 2007). These results clarify the controversial role of CRF in pain modulation and show that the CRFergic system in the amygdala may be a key link between pain and affective states and disorders.
Systemic cortisol is a classical marker of the HPA axis activation. The amygdala and hippocampus have numerous receptors for cortisol and are consequently highly susceptible to the products of the HPA axis. Glucocorticoid occupation of hippocampal receptors has a suppressive effect on the HPA axis (van Haarst, et al. 1997) whereas glucocorticoid occupation of amygdala receptors have a facilitating effect on the HPA axis, often increasing CRF expression within the amygdala (Makino, et al. 1994). CRF receptors are greatly expressed in the amygdala and hippocampus early in development (Baram and Hatalski 1998), thus explaining why young animals are especially vulnerable to threat. In agreement, early-life stress induces a decrease of hippocampal volume and functional alterations when measured in adulthood (Nemeroff, et al. 2006). Structural changes have also been observed in IBS patients using brain imaging (Blankstein, et al. 2010; Seminowicz, et al. 2010). Also, circulating glucocorticoids can have contrasting effects in the amygdala and hippocampus, and these two structures can play contrasting roles in the activity of the HPA axis. In the context of an overactivity of the HPA axis due to an enhanced stress responsiveness, greater basal levels of systemic cortisol have been reported in IBS patients (Chang, et al. 2009). Circulating cortisol regulates the HPA axis and is also able to act within the amygdala by binding to selective glucocorticoid and mineralocorticoid receptors, highly expressed in the amygdala (Sapolsky, et al. 1983) to facilitate behavioral and psychological stress responses including GI motility.
Functional imaging studies indicate that the mPFC is engaged in fear extinction process in relation with the amygdala (Phelps, et al. 2004). The amygdala is an important region involved in the acquisition of fear conditioning, a learning that corresponds to the association between a conditioned stimulus andan unconditioned stimulus. The infralimbic region of the mPFC participates in the mechanism of fear extinction (Rosenkranz, et al. 2003; Quirk and Vidal-Gonzalez 2006b) and also in the recall of fear extinction with an active inhibition of the previous fear condition responses. This is mediated by a down regulation of amygdala outputs with mPFC neurons exciting (glutamate) inhibitory neurons (GABA) within the BLA or in the intercalated region inhibiting in turn amygdala outputs from the CeA (Vidal-Gonzalez, et al. 2006). The activity of intentional regulation of treat related-cues by the PFC is decreased in anxious patients and the conditioned fear extinction is also less active, in PTSD-anxious patients and this is associated with symptoms provocations (Bradette, et al. 1994). The amygdala is also activated by uncertainty and the capacity of the PFC to regulate attention, (re) interpretation of the situation will modulate the level of the response of amygdala to uncertainty. In IBS, uncertainty plays an important role in the perception of pain. Therefore it seems important to study the fronto-amygdalar relations in IBS patients. The inhibitory control of the mPFC on CeA would maintain an homeostatic state with an equilibrated sympatho-vagal balance and low glucocorticoids circulating levels. In the case of a deficit in PFC activity with a lack of inhibitory regulatory communications with the amygdala, a chronic imbalance of the ANS with an increase sympathetic activity should appear as we have observed in IBS patients exhibiting a low heart rate variability and a high score of anxiety (Pellissier, et al. 2010a). Moreover, there is a strong relation between the activity of the ANS and the immune system as recently shown by the cholinergic anti-inflammatory pathway (Huston and Tracey 2011). Hence, when the parasympathetic system is hypoactive as a consequence of anxiety for instance, it could facilitate inflammation which could be deleterious for health and well-being (Bonaz 2003). The hypoactivity of the PFC and the enhancement of amygdala (re)-activity are strongly influenced by stress as demonstrated by a number of studies. It has recently been shown an increase in the dendritic arborization, and synaptic connectivity in the LA/B neurons under chronic stress conditions (Vyas, et al. 2002; Vyas, et al. 2006). LA/B neurons from stressed animals display increased firing rates and greater responsiveness (Kavushansky and Richter-Levin 2006) since the mediators of stress i.e. norepinephrine, and glucocorticoids decrease GABA inhibition (Rodriguez Manzanares, et al. 2005), thereby allowing for increased excitability in LA/B. In the meantime, an atrophy and spine loss of neurons in the mPFC following stress and glucocorticoid exposition is observed (Czeh, et al. 2008) allowing an over-activation of amygdala under chronic stress exposition.
Environmental events during early postnatal life can influence the formation of neural circuits that provide limbic and cortical control over autonomic emotional motor output since a differential timing of hypothalamic and limbic forebrain synaptic inputs to autonomic neurons has been observed during the first 1–2 weeks postnatal (Rinaman, et al. 2011). This provides a potential structural correlate for early experience-dependent effects on later responsiveness to emotionally evocative stimuli and an enhanced risk for the development of psychopathologies such as mood and aggressive disorders. MS is classically used as a model of brain-gut axis dysfunction (O\'Mahony, et al. 2011) and early life trauma are often observed in IBS patients (Bradford, et al. 2012). The amygdala is functionally active early in life and demonstrates continued refinement, through increased cortical connections, throughout childhood and adolescence. The amygdala is particularly vulnerable to stressors early in life. Reduced hippocampal volumes (Woon, et al. 2010) and increased amygdala volumes (Tottenham, et al. 2010) have been associated with early life stress.
Numerous studies have shown that the HPA axis of MS rodents shows hyperactivity in the PVN and amygdala (Plotsky and Meaney 1993; Coutinho, et al. 2002; Plotsky, et al. 2005; Schwetz, et al. 2005). Offspring of mothers that exhibit more licking and grooming of pups show reduced plasma ACTH and corticosterone responses to acute stress and decreased levels of hypothalamic CRF mRNA in correlation with the frequency of maternal licking and grooming during the first 10 days of life (Plotsky, et al. 2005). Thus, it is likely that a major part of the alterations associated with early life stress are related to CRF hyperproduction that account for amygdala hyperactivity. Maternal care during the first week of life is associated with increased GABAergic inhibition of amygdala activity (Diorio and Meaney 2007). These data reflect the importance of early environmental factors in regulating the development of the hypothalamic CRF system in relation with amygdala activity and the vulnerability to stress. Moreover, there is a sex-specific difference in the effects of early life stress on HPA axis activity consistent with the higher prevalence of major depression with hypercortisolism in women than in men. Moreover, women who experienced early life stress are more likely to develop depression as well as IBS (Bradford, et al. 2012). Sex-hormones influence amygdala development in human populations (Rose, et al. 2004). An alteration in the central CRF system has been evidenced in two different rat models of comorbid depression and functional GI disorders (e.g. IBS) represented by neonatal MS and the WKY rat, a genetically stress-sensitive rat strain, that display increased visceral hypersensitivity and alterations in the HPA axis. These rat strains express a greater amount of CRF and CRF1 mRNA in the amygdala (CeA) as well as in the PVN (Bravo, et al. 2011). They also present a positive correlation between increased central CRF and CRF1 receptor expression, with elevated anxiety-like behavior and colonic hypersensitivity (Gunter, et al. 2000; Shepard and Myers 2008). An increase of CRF1 mRNA was observed in the PVN and amygdala while CRF2 mRNA, classically counteracting CRF1 in the CNS, was lower in the amygdala of MS rats. Such modifications, by affecting the HPA axis regulation, may contribute to behavioral changes associated with stress-related disorders, and alter the affective component of visceral pain modulation, which is enhanced in IBS patients (Bravo, et al. 2011).
The amygdala has interconnections with the anterior cingulate cortex, the PFC, the hippocampus, the hypothalamus (e.g. PVN), the bed nucleus of the stria terminalis, the lateral septum, the thalamus, the periacqueductal gray, the PB, the LC, the raphe nuclei, and the dorsal vagal complex (area postrema, nucleus tractus solitarius and DMNV) (Knapska, et al. 2007). All these regions have been shown to be activated in experimental models of stress, inflammation, and pain as represented by c-fos expression and/or CRF receptor mRNA induction (Bonaz and Tache 1994a; Bonaz and Rivest 1998; Bonaz, et al. 2000; Porcher, et al. 2004; Sinniger, et al. 2004; 2005) or electrical stimulations (Mulak, et al. 2008). In addition, brain imaging techniques (fMRI, PET), have contributed to the better understanding of IBS. An activation of most of the brain structures referenced above, and particularly the amygdala, has been observed in healthy volunteers following rectal pain while an abnormal brain processing of pain was observed in IBS and IBD patients (Baciu, et al. 1999; Bonaz, et al. 2002; Agostini, et al. 2011). In addition, brain structural changes of the HPA axis and limbic structures have been recently reported in IBS patients (Blankstein, et al. 2010; Seminowicz, et al. 2010). Because psycho- or pharmacotherapy tends to result in normalization of activity of key structures such as the PFC including anterior cingulate cortex, hippocampus, or amygdala, either through a top-down or bottom-up effect (Quide, et al. 2012), the determination of psycho-physiological vulnerability in IBS patients should be a flag to consider the psychological needs in the follow-up of such patients in the prevention of relapses of such diseases (Pellissier, et al. 2010b).
The effect of stress on amygdala functioning has therapeutic implications both with non-pharmacological and pharmacological treatment to reduce stress perception. Psychological mind-body interventions including psychotherapy, cognitive behavioral therapy, hypnotherapy, relaxation exercises or mindfulness mediation have been shown to improve symptoms of IBS patients (Kearney and Brown-Chang 2008; Ford 2009; Whorwell 2009). Repetitive transcranial magnetic stimulation of the PFC, based on the central role of the mPFC in cognitive theory of mind, can cause changes in acute pain perception and has been used in a model of central sensitization syndrome such as fibromyalgia (Mhalla, et al. 2011; Short, et al. 2011) but no data have been currently published in IBS patients. Modulation of the ANS by restoring the sympatho-vagal balance (DeBenedittis, et al. 1994; Nishith, et al. 2003; Gemignani, et al. 2006) as well as modifying coping strategies vigilance state and globally the restoration of a functional brain-gut axis, are at the origin of the efficacy of these treatments. Brain imaging techniques have shown modulation of brain activation, as for example in the amygdala, by such treatments (Goldin and Gross 2010; Lawrence, et al. 2011). Conventional treatment as represented by anti-depressives, anxiolytics, drug targeting the central sensitization syndrome [α2δ ligand (pregabalin, gabapentin); tachykinin receptor antagonists] either directly and/or indirectly are supposed to target the hyperfunctioning of the amygdala (Ghaith, et al. 2010; Gale and Houghton 2011; Trinkley and Nahata 2011; Larauche, et al. 2012). In the context of the microbiota-brain-gut axis, probiotics, prebiotics, antibiotics such as rifaximin, an antibacterial agent that is virtually unabsorbed after oral administration and is devoid of systemic side effects, are of interest (Bercik, et al. 2011; Fukudo, et al. 2011; Fukudo and Kanazawa 2011). If targeting CRF signaling with CRF1 receptor antagonists, based on pre-clinical and/or clinical data (brain imaging) has been used successfully in humans to treat depression and anxiety (Kunzel, et al. 2003) their efficacy is still matter of debate in the treatment of IBS patients (Sweetser, et al. 2009).
A growing body of evidence argues for an important role of stress, through the HPA axis, limbic system activity (e.g. the amygdala), and the ANS, i.e. the sympathetic and the parasympathetic (e.g. the vagus nerve) nervous system, in the initiation and perpetuation of IBS. Stress, pain, and immune activation are common risk factors involved in the pathogenesis of IBS which are able to act through this neuro-endocrine-immune axis. The amygdala, through its connections with the PFC, LC, hippocampus, HPA axis, and ANS is a key structure involved in the pathogeny of IBS. Animal models of activation of the CRFergic system in the amygdala, as represented by maternal separation stress or WKY rats, developed VHS as observed in most of IBS patients. Thereofore, a therapeutic targeting of the amygdala either through pharmacological or non-pharmacological approach should be of interest for the treatment of IBS.
Gender is a set of morphological and physiological characteristics of the organism, providing reproduction, the essence of which is to fertilization, i.e. the fusion of male and female germ cells (gametes) in zygote, which develops into a new organism. Differentiation of sex (its phenotypic manifestation) includes two successive stages: the primary determination of sex and the appearance of secondary (external) sexual characteristics (actual differentiation). It is believed that the concept of this process is conservative. Sex determination is both a genetic and ecological process, with the sex of the individual being determined by an alternative physiological solution. It is assumed that there are two main mechanisms for determining sex: genetic (GSD—genetic sex determination) and environmental (ESD—environmental sex determination). Genetic sex is determined at the time of conception and depends on genetic differences between males and females, and ecological sex depends on external conditions in the absence of significant genetic differences and is determined after fertilization in response to environmental conditions. For birds and mammals, only the GSD is characteristic, and for crocodiles—TSD (one of the forms of ESD). In addition, there are two varieties of the genetic sex determination system: with heterogametic males (XY, mammals) and heterogametic females (ZW, birds). It should be noted that amphibians have both genetic systems, and for lizards, snakes, turtles, and bony fish, all possible variants of sex determination are described [1, 2, 3].
\nSex steroid hormones including androgens, estrogens, and progesterone are present in all vertebrates which play essential roles in modulating a variety of behavior and processes, such as embryonic development, sexual differentiation, growth, aggression, reproduction, learning, memory, social communication, and so on. Many signaling actions of these sex steroid hormones are mediated by their receptors that belong to the superfamily of steroid nuclear receptors. Once a sex steroid hormone ligand binds to its receptor, the receptor becomes phosphorylated and is translocated into the nucleus, where it binds to specific DNA sequences and activates gene transcription. Androgens have a critical physiological role in reproductive biology and sexual differentiation, particularly in the development of male secondary sex characteristics [4, 5].
\nIt is assumed that sex determination is a combination of hormonal and genetic factors and is divided conditionally into appropriate stages. This phenomenon is reflected in the possibility of sex inversion—the possibility of its complete or partial hormonal alteration. For fishes and amphibians, there is the sensitivity of normal development of the gonads to androgens and estrogens. In reptiles, birds and marsupials, only estrogens are effective. The appearance of the gonads of placental mammals does not depend on sex hormones. This trend is associated with the stability of growing offspring or incubation of eggs [6].
\nThe proposed chapter will consider the system of sex determination in fish, amphibians, reptiles, and birds in comparing the role of hormonal and genetic mechanisms, possibilities, and mechanisms of sex inversion.
\nFishes are perhaps the most complex group of animals in the mechanism of sex determination. Only bony fish include over 30,000 species. It is the largest group of vertebrates. They are divided into three groups in accordance with the laws of sex determination: (1) gonochoristic species whose sex is determined genetically or through environmental factors; (2) sequential hermaphrodites (about 2% of all existing species), changing the sex of males to females (protandrous), the sex of females to males (protogynous), or in both directions (serial) in the process of ontogenesis; (3) unisexual type of sex determination (characteristic only for Amazon mollies (Poecilia formosa)). Gonochoristic genetics of sex in fish is largely unclear. Functional hermaphroditism occurs in many different species of animals such as echinoderms, crustaceans, molluscs, and fish; however, it is lost in vertebrates during the transition from amphibians to mammals. From here, fishes provide a unique model for studying the mechanism of hermaphroditism in vertebrates. Unfortunately, only one species of fish (Japanese medaka—Oryzias latipes) was identified by a primary system of sex determination [7, 8].
\nThe Japanese medaka (Oryzias latipes) and Maebashi medaka (Oryzias curvinotus)—species with heterogametic male sex with homomorphic sex chromosomes that are a very early stage of evolution, the recently described Y-chromosome plot, containing hypothetical gene dmy. This gene is specifically expressed in the gonads and is essential for embryo development in male type. Gene dmrt1bY (dmy) homologous (about 80%) of the dmrt1 gene in other species of vertebrates represents the equivalent of sry gene in mammals. It is important that medaka dmy/dmrt1bY is a unique system. This species is described as ontology mammalian sox9 gene, but in contrast to amniotes and amphibians, this does not play a role in determining the testes. Sex determination system of medaka is unstable. Medaka has interesting significant genetic divergence: dmy gene is absent in some lines of the Japanese medaka (over 10%) and other types of fish of the genus Oryzias. In some laboratory lines, the proportion of homogametic males (XX) exceeds 20%. It is believed that gene dmy has occurred as a result of the dmrt1 gene duplication and transposition of part of its copy size to 280 kbp about 10 million years ago. The products of these genes differ only in one amino acid replacement (Ser26/Thr), which may have led to such differences by gender. It has been shown that the rate of synonymous substitutions in the dmy is 1.78 times greater than that of dmrt1 and this is consistent with the hypothesis of evolution through males (male-driven evolution hypothesis). In birds and salmon, it has the same orientation. The speed ratio of nonsynonymous substitutions (dN) to synonymous (dS) is also higher in comparison with dmy/dmrt1.
\nOnly two sex determining genes in vertebrates were described: sry and dmy. It is believed that the protein DMY performs two different functions in germ and somatic cells. In somatic cells surrounding germ ones, it affects the proliferation of the latter (for example, influencing a cascade of genes involved in the transmission of the estrogen signal). Another feature is the induction of development of pre-Sertoli cells (cells surrounding the primary germ cells (PGCs)) in the gonad heterogametic XY sex. In this case, there is an analogy with sry, which is involved in the activation of other genes that support the development of Sertoli cells. In medaka, there are other female-specific genes and male-specific genes (Figure 1). Moreover, the latter gene is located in autosomes. Some ideas of the diversity of sex determining genes among medaka given.
\nA schematic diagram of sex determination and gonad (testis or ovary) differentiation in fish with XX/XY sex determination system (adоpted from Mei and Gui [10]).
In this species, the sex determined region of the Y chromosome is only 260 kb (1% of the total length of the Y chromosome (59 Mbps)). In this area, there is suppression of recombination. In medaka, all XY individuals carry mutations in the gene dmy form ovaries. In individuals with altered gsdf-gene, sex inversion is also observed. It is believed that for medaka, the normal gene dmrt1 (dmy) initiates the formation of the testes and controls their maintenance with gsdf. The study of sex chromosomes in six species of medaka from the group celebensis with XX/XY-sex determination showed that O. marmoratus and O. profundicola sex chromosomes homologous sex chromosomes of O. latipes from the LG10 linkage group. Four species O. celebensis, O. matanensis, O. wolasi and O. woworae marked homology with the chromosomes of LG 24, which involves the transformation of chromosomes from O. latipes LG to 24 LG10 within this group. All six studied species share a common sex determined gene (SD). It is shown that genomiс predecessor is the Y-chromosomal gene sox3 and this process involves specific insertion (430 bp).
\nThe zebrafish testes derived from dmrt1 mutant fish fail to express the anti-Müllerian hormone (amh) gene, a key testis-expressed gene, and over-express the ovary-associated gene foxl2. Therefore, zebrafish dmrt1 shares similar roles in male sexual development as other organisms in regulating sex determination and testis differentiation.
\nIn other fishes, e.g., salmonids, there appear to be an early stage of differentiation of sex chromosomes. In rainbow trout (Oncorhynchus mykiss) with monofactorial XX/XY system of sex determination, a new gene sdY responsible for the development of testes is described. This gene is partially similar to the gene regulator of interferon 9. It has been found that highly conserved in sdY salmon is male Y-chromosomal gene for the majority of these species. It is assumed that it is the main testis determining gene for this group of fishes. For the two species of whitefish (subfamily Coregoninae), the sdY gene is found in both males and females. This implies that there is an alternative system of sex determination in this family. Among other candidate genes for sex determination, gene antimullerian hormone (amh) tilapia is discussed. Fishes with hermaphrodite sex determination (Labridae, fish-clowns—amphiprion (Amphiprion), and gobies—Trimma okinawae) have got bisexual gonads capable of restructuring with the participation of aromatase and gonadotropin receptors. For some species, such as blue tilapia (Oreochromis aureus), sex determined putative gene is located on the genetic map of a sex determining region consisting of more than 550 minisatellite markers [7, 9].
\nIn vertebrates, until recently, only four sex determining genes were discovered: sry (in mammals), dmrt1 (in domestic chicken), dmy (the Japanese medaka), and dm-w (the frog). Recently, four candidate genes were found for this role (and all fish): Patagonian aterin have amhy, Luzon ricefish (Oryzias luzonensis) have gsdf, and puffer (Takifugu or Fugu)—amhr2 and rainbow trout—sdy. In the Nile tilapia (Oreochromis niloticus) gene gdf, (gonadal soma derived factor (gsdf)) also induces the development of the testes. Assume that the Atlantic salmon sdY gene product activates genes gsdf and amh/mi, thereby reducing the activity of aromatase (cyp19a gene), leading to the appearance of males. Where sdY is missing, aromatase is synthesized in quantities sufficient for the emergence of the females [8, 10].
\nSex determining genes in fish are not conservative. It is believed that the reason for this is the more frequent variation of sex chromosomes in fish than other cold-blooded animals and mammals (Figure 1).
\nThese objects sex determination has a high plasticity and is, therefore, possible sex reversal, even in species with established regulatory genes. Striped Danio (Danio rerio) experimental data are in good agreement with polygenic sex determination (PSD) when the sex is determined by allelic combinations of several loci. Typically, these loci are dispersed throughout the genome, but some species of bony fish are placed in special sex chromosomes. In hermaphroditic fish, ovotestis develops first, and then secondary sex determination occurs. So, the black bass individuals (genus Micropterus) in the first 2 years of life are males, but in the third year, 50% of them are transformed into females. Sex determining male genes such as dmrt1, amh, and amhr2 are activated during differentiation of the testis, and their expression is maintained at high level during the period of functioning as males. High dose estrogen E2 induces the development of ovarian and testicular tissue degradation [11, 12].
\nIn fish, there are two systems of sex determination: XX/XY and ZW/ZZ. The most common one is the last. Exploring the flatfish Cynoglossus semilaevis as a model species with genetic sex determination system of ZW-type and the simultaneous presence of ESD, it was found that about 14% of females at a temperature of 22°C become males (pseudomales). It is believed that there is dmrt1 gene (double sex and mab-3 related transcription factor 1) which is the sex determining gene in this species. It was also shown that pseudomales change the level of methylation of a certain portion of the Z chromosome, resulting in the intensity of transcription in this area as in normal males. In females, on the contrary, the activity of the corresponding plot of W chromosome by methylation is suppressed. Unusual WXZ-system is described for the swordtail (Xiphophorus helleri). Not so many fish species had morphologically different sex chromosomes (about 10%) and in most species they are in the early stages of their differentiation. For many members of this class, sex is determined by the environment, and even changes under the influence of behavioral factors. There are species with heterogametic male and female [13].
\nFish is characterized by plasticity of germ and somatic cells. This plasticity is maintained throughout the life cycle. Furthermore, they have described the influence of factors on this process such as temperature, pH, density of population, etc. It should be noted that the temperature sensitivity of fish is different from that of reptiles, especially because these types of monosexual populations are rare, even under extreme conditions. TSD in fish is less common than previously thought. The effect of estrogens, acting via estrogen receptors (ER) and directly or indirectly regulating P450arom and AMH, is particularly noticeable. It is noted that the analysis of the differences between gonochoristic and hermaphroditic fish species will help to understand the mechanism of plasticity of sex determination in vertebrates. In addition, there is the idea that gender in fish depending on species is a complex trait under the control of one or many genetic factors in addition to environmental effects [9, 14]. In the Chinese tongue sole (Cynoglossus semilaevis), genetic ZZ females may change into pseudomales, thereby increasing aquaculture costs because of the lower growth rate of the males than that of the females. A new locus was identified to regulate sex reversal interactively with the SNPCyn_Z_6676874; the linkage between these two loci and the absence of W sperm for pseudomales clearly elucidate the genetic architecture of sex reversal in the tongue sole [15]. Sexual determination in zebrafish is unique in that laboratory strains lack a sex chromosome, and no sex determining gene has been identified. GPER (estrogen receptor) is not required for normal sex differentiation, gonad development, or gonad function in zebrafish [16]. Genetic studies suggest that gonadal sexual fate is not only established by competition for primacy between two sexes via antagonistic signaling pathways during embryonic development but also requires active maintenance to suppress the opposite sex during adulthood. Documented in about 2% of teleost species spanning over 20 families, functional sex change generally occurs in three ways: protogynous (female-to-male), protandrous (male-to-female), and sequentially bi-directional. Most sequentially hermaphroditic fish are protogynous. Sex change in all hermaphroditic species involves radical gonadal transformation, and follows diverse ontogenetic pathways in different lineages particularly where sequential hermaphroditism has independently evolved. Gonadal transition in sex-changing fish is accompanied by changes in plasma concentrations of gonadal steroids. These steroids control gonad differentiation and maintain sexual phenotypes in teleost fish, wherein 17β-estradiol (E2) and 11-ketotestosterone (11-KT) function as the major estrogen and androgen, respectively. The balance between estrogen and androgen production is expected to control sexual fate of the gonads during sex change. For example, factors regulating cyp19a1a expression are strong candidates for the trigger that initiates gonadal sex change; cyp19a1a promoter regions contain binding motifs for numerous factors that potentially regulate its expression [15].
\nHowever, hermaphroditic fishes have a plastic sex, and a stable sex is difficult to maintain with sex steroids. The black porgy regulated the dynamic development of both sexes; only one sex can grow while the other sex exists in a rudimentary stage (Figure 2). The sexual fate of the digonic gonad is determined by the male fate maintenance and through the Gnrh—Gth—Dmrt1 signaling. Altogether, testicular dmrt1 and ovarian cyp19a1a expression are critical to the sexual fate of a male phase and female phase, respectively (Figure 3).
\nThe profiles of gonadal development in three different sexual phases in hermaphroditic Japanese black porgy, Acanthopagrus schlegelii. Maleness: the fishes are functional males in the first two spawning seasons. The testis exists at all stages of the reproductive cycles in maleness. Active femaleness: the fishes are functional females following the natural sex change that occurs in fish older than 2 years or when induced by the removal of the testis of the digonic gonad. The ovary could reach to the stage of vitellogenesis, vitellogenic, and mature oocytes. Passive femaleness: Long-term E2 (4–6 mg/kg feed) administration for 2–3 months results in the appearance of a dominant ovary (with the primary oocytes) with a regressed testis in fish younger than 2 years old, and no vitellogenic oocytes are observed in E2-induced sex-changing fish. A reversible sex change (from passive femaleness to maleness) exists after E2 administration has been withdrawn. Undiff. gonad, undifferentiated gonad; E2, estradiol-17β; PO, primary oocyte stage; and VO, vitellogenic oocyte stage (adopted from Wu and Chang [16]).
The potential mechanism for sexual fate decision through the Gnrhs—Gths—Dmrt1 axis (brain-pituitary-testis axis). The model shows that the male fate decision is controlled by gonadotropins through the Gnrhs—Gths—Dmrt1 axis. The testis may stimulate the epigenetic modification of the ovary by DNA methylation of the cyp19a1a promoter to suppress the cyp19a1a expression. Gnrhs, gonadotropin-releasing hormones; Gths, gonadotropins; and Gthrs, gonadotropin receptors (adopted from Wu and Chang [16]).
Amphibians have two sex determined systems: XX/XY and ZZ/ZW. Most tailed amphibians (order Caudata) have XX/XY-system. For 63 species of 1500, sex was determined and only 20 species have differing sex chromosomes. Males of some New Zealand frogs (Leiopelma hamiltoni and L. hochstetteri) have heterogametic sex. In most amphibians, sex chromosomes are homomorphic (undifferentiated) in both sexes and are characterized by frequent turnover. This is in sharp contrast to sex chromosomes in two major vertebrate groups, the mammals and birds, where they are heteromorphic in one sex and are highly conserved. Thus, amphibians are excellent research materials on the turnover of sex sensitive to a resistant state, indicating the relationship between sex chromosome turnover and sex ratio control.
\nModels of sex differentiation in amphibians can be divided into three types: (1) a direct development of the undifferentiated gonads into testes or ovaries, (2) the development of the undifferentiated gonad into the ovary and subsequent development of the testis through the ovary, and (3) the development of the testes through the intersex phase (prodifferentiating type) [17]. For a long time, genes that determine sex could not be found in amphibians. Recently, for smooth clawed frog (Xenopus laevis), the candidate gene has been found suitable for such a role. It is believed that it is involved in the development of the ovary. African clawed frog has a ZZ/ZW system of sex determination. Its dm-w gene was described. It is localized in the X chromosome and possessed a DM-domain. The nucleotide sequence of gene encoding a DNA-binding domain has 89% identity with dmrt1, but there is not similarity in transactivational region dm-w and dmrt1: genes are expressed exclusively in the primordial gonads, and dm-w is expressed more actively than in the gonads of ZW-larvae. The gene dmrt1 (dmrt1α and dmrt1β) is located in autosome and there are no differences in its expression in males and females. The product of this gene enhances the expression of cyp19 and foxl2 ones. A similar gene was not detected in other species of amphibians. It is assumed that in these frogs, homo- and heterodimer products of dmrt1 and dm-w participate in the sex determination [18, 19] (Figure 4).
\nModel of ZZ/ZW-sex determined system and the formation of the ovary from Xenopus laevis (adopted from Liu et al. [18]).
In the northern crested newt (Triturus cristatus), the proportion of males increases when the ambient temperature increases, and a decrease of temperature leads to an excess of females. Thus, in amphibians, an increase or decrease of the ambient temperature leads to a modification of the normal development of the gonads and sex determination. Here, sex-determining genes are not the decisive factor in determining sex. A number of experiments have shown that atrazine and some other pesticides that affect the endocrine system affect the formation of sex in frogs. As a result, males are changed to females. Exogenous steroids (introduced from the outside) are also changing the sex in amphibians [20]. The unexplainable mechanism of sex determination in the rice frog species was introduced. Amphibians bearing a novel sex determining mechanism are yet to be identified [17].
\nThe dominant hypothesis of sex determination for amphibians is proposed in relation to the Rana rugosa. In the Japanese wrinkled frog (Rana rugosa), four populations are described, in one of which (the northern population) females are heterogametic. Assume that sex determining genes really do not need to determine the sex of amphibians, as well as the presence of the transcription factor, localized in the X or W chromosomes, influencing the feminization of vertebrates with TSD or GSD systems of sex determination. In males, if there is a specific mechanism of sex determination, it is likely that it supports the regulation of steroid hormones in undifferentiated gonads through the inhibition of cyp19 gene transcription for the formation of the ovaries. In the scheme of Figure 5, a possible role of steroid hormones in sex determination is shown for Rana rugosa [21]. According to the next experimental data, complete female-to-male sex reversal occurred in the AR-Tg-transgenic ZW female frogs when a low dosage of T was supplied in the rearing water of tadpoles. In the sex reversed testes, the expression of dmrt1, ar, and cyp17 genes required for masculinization was significantly upregulated. Next, AR-knockdown (KD) ZW female frogs were produced by the CRISPR/Cas9 system. Interestingly, no sex-reversal was observed in AR-KD ZW female frogs when the gonads were treated with dosages of T high enough to induce complete female-to-male sex-reversal, even in wild type frogs. In the AR-KD ZW female gonads, the expression of genes required for masculinization was not up-regulated. These results indicate that AR together with androgens can be a male sex-determinant in an amphibian species [22, 23].
\nThe role of steroid hormones in sex determination from Rana rugosa. At the stage of sex determination in the undifferentiated gonads of males, testosterone is synthesized at the same time females synthesize estradiol-17β. Letters ZZ, ZW indicate sex chromosomes. AR-T and ER-E2 represent complex androgen receptor (AR) to testosterone, and respectively, estrogen receptor and estradiol-17β (adopted from Nakamura [23]).
Sex determination by environmental factors is mainly known in reptiles. The most well studied temperature sex determination (TSD) is occurring in three of the five main taxonomic groups of reptiles: turtles, crocodiles, and lizards, but it is not found in snakes. The adaptive significance of such sex determination mechanism is shown. During early embryonic development of gonad, epithelial cells are divided and unite in the epidermal strip of mesonephros mesenchyme. Further, during the so-called temperature-dependent period under the level of endogenous estrogen, such strip forms seminiferous tubules with Sertoli cell epithelium or gaps with squamous epithelium. The mechanism of this sex determination is poorly understood. Obviously, it is found in species with undifferentiated Y chromosome. The transition from the female promoting temperature (FPT) to male promoting temperature (MPT) is carried out in a temperature-period (TSP), during the so-called “window” of vulnerability [24].
\nIn some species of reptiles, GSD is not fixed for life, and the original gender may change during development without changing the genotype. This phenomenon is known as environmental sex reversal (ESR) and observed also in insects, fish, and amphibians [25] (Figure 6).
\nThe continuum of sex determination. Distribution mechanisms from GSD to ESD, including intermediate system to overcome genetic sex determination with environmental factors (GSD + EE) (adopted from Valenzuela et al. [26]).
In reptiles, there is an “open” sex determination program that is different from a “closed” program, characteristic of birds and mammals. It is believed that in this case, the gender depends on the ratio of estrogens and androgens during sexual differentiation of the gonads. The temperature of incubation may change the activity of genes encoding aromatase, estrogen receptor, and reductase. It is not excluded that different taxonomic groups of animals with TSD have different mechanisms of regulation of sex. There may be temperature-sensitive genes sox9 and dax1 (freshwater turtles—Emydidae) and genes sox9, sf1, and wt1 (Testudinidae). In mammals, this mechanism is not valid, because the Y chromosome has genes that inhibit the aromatase enzyme.
\nFor Mississippi alligator (Alligator mississippiensis), pond slider turtle (Trachemys scripta), and olive ridley (Lepidochelys olivacea, from the family of sea turtles), the expression level of the gene dmrt1 was higher during the incubation of embryos at a temperature that contributed to the emergence of males. In reptiles and in particular Trachemys scripta elegans, a large amount of the KDM6B product is observed at a temperature favorable for males (MPT) and activates the expression of the dmrt1 gene, and its reduction represses the expression of dmrt1 and promotes the appearance of females. The latter is associated with H3K27 trimethylation. KDM6B is a member of the Jumonji gene family. It is believed that such genes are somehow regulated. One such regulator—cirbp (cold-inducible RNA binding protein)—has recently been described in the turtle Chelydra serpentina [27]. It managed to detect differences in the structure of dmrt1-gene in 34 species of reptiles with temperature and genetic mechanisms of sex determination, affecting sequence in exon 2 near DM-binding domain. In species with TSD, threonine occurs at position 54 (T54) and serine at position 57 (S57), while in species with a genetic sex determination mechanism, serine is observed in the S54-S57 position. This is obviously only the discovery of the molecular differences in sex determining gene when changing the mechanism of sex determination [28]. The discovery of the triploid male (ZZW) in the colubrid snake testifies to the absence of a particular role of the B chromosome in the determination of sex in this species [29].
\nSex reversal has not yet been demonstrated in nature for any amniote, although it occurs in fish and rarely in amphibians. There is only one report about sex change in reptiles in the wild (Australian bearded dragon (Pogona vitticeps)) and the use of animals with inverse sex in order to experimentally induce a rapid transition from GSD to ESD. Controlled mating of normal males to sex-reversed females produces a viable and fertile offspring whose phenotypic sex is determined solely by temperature (temperature-dependent sex determination). The W sex chromosome is eliminated from this lineage in the first generation which indicates its specific role in genetic sex [30].
\nIn birds, estrogens play an important role in sex determination. They regulate expression of key sex determining genes during the first 3 days of embryonic development and further. At the same time, the set of sex chromosomes is equally important. Embryos with two Z chromosomes in birds develop as males, and those with ZW chromosomes develop as females. At present, two hypotheses on sex determination in birds compete. One of these hypotheses considers the number of Z chromosomes as a key sex determining factor, while the other hypothesis supposes the presence in W chromosome of the key gene controlling ovarian development or suppressing the appearance of testes. The presence in Z chromosome of a strong candidate gene for sex determination (DMRT1 gene) supports the dose scheme. Figure 7 presents a hypothetical scheme of genetic control of primary sex differentiation in Gallus gallus. The gonad appears on the 3.5th day (stage 22) as thickening on the surface of mesonephros. It consists of the epithelial layer of somatic and germ cells and medullary cordate layer (epithelial cords), which is mixed with mesenchymal cells. On the 6.5th day (30th stage), the first sex determining genes are activated. In the modern scheme of the genetic control of sex determination in birds (practically within the dose scheme), an epigenetic mechanism for switching off the single allele of avian key sex determining dmrt1 gene in females through hypermethylation and using noncoding MHM RNA came into sharp focus (Figure 8) [30, 31, 32, 33, 34]. Synthetic aromatase inhibitors (an enzyme catalyzing the synthesis of estrogens) can induce steady female → male sex inversion. In this case, the left gonad becomes an ovotestis, or a testis, and the right gonad becomes a testis. Injection of aromatase inhibitors in ovo in most experiments was carried out on the third or fourth day of incubation. At the same time, in experimental males, injection of estradiol results in reversible feminization of the gonads [35, 36]. Unfortunately, the genetic and hormonal status of individuals with sex inversion was not investigated. The two enzymes required for the synthesis of estrogen, aromatase, and 17-beta-hydroxysteroid dehydrogenase (17β-HSD) are synthesized only in ovarian medullary cords at the onset of morphological differentiation. It is suggested that the earliest expression of aromatase in birds is detected only on the fifth day of embryonic development. It is worth mentioning that the appearance of aromatase was recently demonstrated as early as in the maternal body, upon oogenesis in the theca layer of early follicles [37]. The data obtained make it possible to suggest earlier appearance of aromatase and estrogens in female gonadogenesis than that follows from the classical scheme of primary sex determination in Gallus gallus [38].
\nPossible models of primary sex determination in birds by the example of Gallus gallus (adopted from Kuroiwa [33]).
The large Z chromosome (82.3 Mb) is drawn to scale next to the degenerate W chromosome (7 Mb). (A) Male (ZZ) have two copies of DMRT1 and HEMGN, while the female (ZW) only has one. The MHM locus is transcribed from the single Z in the female and may play a role in local dosage and epigenetic regulation of DMRT1 in the female. (B) Location and orientation of the 28 protein coding genes that are located on the W chromosome (adopted from Hirst et al. [34]).
In birds, sex determination depends on sex hormones and sex-hormone-specific receptors. Estrogen receptors are also important in this process. In a recent study, the gonads and endocrine profile of a gynadromorphic chicken were described. It had male features on the right and female features on the left. At sexual maturity, the gonads of this bird were largely testicular. The right gonad was a testis, with SOX9+Sertoli cells, DMRT1+germ cells, and active spermatogenesis. According to histology, the left gonad was primarily testicular, but with a few number of peripheral aromatase follicles. The gynandromorph had low levels of serum 17β-estradiol (39 pmol/L). In contrast, the gynandromorph had very elevated levels of serum testosterone (41.3 nmol/L). Despite the elevated testosterone, the bird was female on one side of the body. The right male side was almost entirely ZZ (96%), whereas those from the left female side were a mixture of male (77% ZZ) and female (23% ZW) cells. It had a low percentage of ZW cells on the female side, but still had female sex-linked feathering, smaller muscle mass, smaller leg and spur, and smaller wattle. This indicates that sexually dimorphic structures such as the wattle, spur, and feathering must be at least partly independent of sex steroid effects. Even a small percentage of ZW cells appear sufficient to support female-type sexual differentiation [39, 40, 41]. Studies of chimeric embryos also support the hypothesis that avian sexual differentiation is largely, or partly, cell autonomous, involving direct genetic factors and steroid hormones.
\nSo, estrogens and androgens play important roles in sexual differentiation and reproduction, particularly in the development and expression of male and female sexual characteristics. These effects are principally mediated by the estrogen and androgen receptors (ESRs and ARs), which belong to superfamily of the nuclear receptors [42]. The nature of the relationship between sex hormones and gender determining genes and the patterns of their interaction remains unclear. For some amphibians, the absence of appropriate genes and the replacement by control factors of steroid hormones and receptors are postulated. For birds, we can assume a special role of heteromorphism of sex chromosome and the presence of a specific interaction of the W and Z chromosomes. In this regard, we should mention the phenomenon of detection of specific chromosomes (germ line restricted chromosomes, GRS) found only in the germ cells of songbirds.
\nIn mammals, aromatase is expressed later in embryonic development and the gonadal sex is formed independently of sex hormones and differentiation can occur in the absence of steroidogenesis. For mammals, two-step primary sex determination is typical. At the first stage, its determination is carried out by the sry gene. At the second one, sex hormones are synthesized in gonads and genetic endocrine regulation of sex development is maintained. It raises questions about the sensitivity to androgens and estrogens of sex determination in fish, amphibians, reptiles, and birds. The functional role of the emerging chromosome heteromorphism is not clear. It is believed that the realization of the phenomenon of sex reversal is different in nonmammal vertebrates and mammals. It is intended to introduce a special term for nonmammal’s sex change [43].
\nSo, determination of gonadal development in vertebrates like testis or ovary was initially controlled mainly by sex hormones (fish and amphibians). Later, various sex determining genes were involved in this process. The system was quite plastic and was able to respond to changes in external conditions (reptiles). The appearance of heteromorphic sex chromosomes (birds) has led to the emergence of some specific W chromosomal signal, which provides estrogen control of the development of a heterogametic sex. In mammals, the control of the primary determination of sex (the appearance of the gonad) becomes purely genetic, and the role of sex hormones is reduced to the differentiation of testis or ovaries.
\nThis research was supported by a grant 17-04-01321A Russian Foundation for Basic Research (RFBR). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest.
\nThis is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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\\n\\n5. LANGUAGE COPYEDITING, TECHNICAL EDITING AND TYPESET PROOF
\\n\\nYour manuscript will be sent to SPi Global, a leader in content solution services, for language copyediting. You will then receive a typeset proof formatted in XML and available online in HTML and PDF to proofread and check for completeness. The first typeset proof of your manuscript is usually available 10 days after its original submission.
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\\n\\nIntechOpen will help you complete your payment safely and securely, keeping your personal, professional and financial information safe.
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\n\nAfter approval, you will proceed in submitting your full-length manuscript. 50-130 pages for compacts, 130-500 for Monographs & Edited Books.Your full-length manuscript must follow IntechOpen's Author Guidelines and comply with our publishing rules. Once the manuscript is submitted, but before it is forwarded for peer review, it will be screened for plagiarism.
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