Distinguishing Fear From Anxiety

Distinguishing worship From AnxietyIntroductionAnxiety disorders constitute the largest gathering of mental diseases in European countries Andlin-Sobocki et al., 2005, Eur J Neurol, 12 Suppl 1, 1-27. Human solicitude disorders fanny be categorized into generalized anxiety disorders, panic bangs, Posttraumatic mark disorders (PTSD), obsessive-compulsive disorder (OCD) and special phobias, be amongst the most prevalent with a 28% lifetime prevalence and an incidence of 18% Kessler et al., 2005, Arch Gen Psychiatry, 62, 617-27. Pathological normal of twain hero-worship and anxiety argon thought to represent certain aspects of anxiety disorders. detail phobias ar considered, as devotion disorders, whereas generalized anxiety is viewed as an compositors case of anxiety disorders. PTSD patients do not only suffer from conditioned panic symptoms to discrete cues that act as a reminder of a antecedent trauma, but they as well parade persistent symptoms of sustained anxiety. The regulation of timidity and anxiety is the heart of many psycho pathologic disorders also reflected in the extremely spirited comorbidity rate with other mood disorders, such as depression. Up to 90% of individuals expressing an anxiety disorder also develop depression, which could increase suicide rates (Gorman, 1997) and constitutes a significant problem for the community in general.Currently available pharmacotherapies such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have emerged as in force(p) alternatives to the benzodiazepines and have been par aloneeled by a similar growth in effective and available psychological treatments, government agencyicularly cognitive and cognitive-behavioural therapy. A considerable portion of patients, however, requires long-run treatment throughout the whole life or does not respond at all. For coping with these limitations, focusing on a better understanding of these diseases and change treat ment is urgently needed.Distinguishing fear from anxietyFear Vs AnxietyFear- Behavioural manifestation associated with clearly identified imminent threat.Anxiety- Generalized fear without object, an apprehensive hope of future potential threatsThe main function of fear and anxiety is to act as a signal of danger, threat, or motivational conflict, and to trigger appropriate adjustive repartees. For some authors, fear and anxiety argon indistinguishable, whereas others believe that they be searching phenomena. In particular fear is a generalized adaptive state of discretion to an imminent threat (Michael Davis, 2010). It begins rapidly and dissipates rapidly once a threat is removed. Fear is provoked by imminent and real danger, Animals may learn to fear situations in which they have previously been exposed to pain or stress, and subsequently utter neutraliseance behavior when they re-encounter that situation. Young animals may show an innate fear reaction to sudden noise or d isturbances in the environment, but rapidly become habituated to them. When they are utilise to a familiar environment, then a fear of novelty may develop. Ethologists have also made the important observation that fear is often mixed up with other aspects of motivation. Thus, conflict surrounded by fear and approach behavior may results in displacement activities (e.g., self-grooming in rats and mice). Such displacement activities may be the behavioral pattern of an anxious state.In severalise anxiety is often elicited by less specific and less predicable threats (Michael Davis, 2010). Anxiety is a generalized reaction to an unknown threat or inhering conflict, whereas fear is focused on known external danger. It has been suggested, anxiety can only be understood by taking into account some of its cognitive aspects, particularly because a basic aspect of anxiety appears to be uncertain. Originally, anxiety is associated with arousal and vigilance, as a result it can be defined as longer lasting state of apprehension that can become pathological if its become extreme. Defense and coping strategiesFear or anxiety, result in the expression of a range of adaptive or defensive behaviors, which are aimed to escape from the source of danger or motivational conflict. These behaviors depend on the context and the repertory of the species. Fight or f slack, was coined exactly 75 years ago, in 1929, Walter Cannon originally formulated this term for the human response to threat, Fear and anxiety. The phrase press or flight has influenced the understanding and expectations of both clinicians and patients. However, both the order and the completeness of Cannons famous phrase are suspect. Fight or flight mischaracterizes the ordered sequence of responses that mammals exhibit as a threat escalates or approaches. In recent years, ethologists working with nonhuman primates have clearly established distinct fear responses that bear on sequentially in response to increasi ng threat. The order of these responses may have important implications for understanding and treating acute stress in humans. The sequence, originally described by Jeffrey A. Gray, begins with what ethologists call the freeze response or freezing, terms corresponding to what clinicians typically refer to as hypervigilance (being on guard, watchful, or hyper-alert). This initial freeze response is the stop, look, and get a line response associated with fear. The survival advantage of this response is obvious. Specifically, ethological research has demonstrated that prey that remains frozen during a threat are more likely to avoid detection because the visual cortex and the retina of mammalian carnivores primarily detect moving objects rather than color. Immobilization or freezing, are usually elicited when the threat is inescapable, and is characterized by autonomic inhibition (hypotension, bradycardia), and a more pronounced increase in the neuroendocrine response activation of th e hypothalamopituitary-adrenal axis and increased glucocorticoid secretion.This type of resistless response was originally described by Engel Schmale as a conservation-withdrawal strategy. The concept of alternative (active/passive) strategies itself owes much to the work of Henry and coworkers. Specific originator circuits appear to mediate distinct coping reactions to different types of stressors.Psychopathological fear/anxietyAlthough fear acts as a physiological signal of danger, threat, or motivational conflict, it can become pathological and interfere with the ability to survive. Development of specific anxiety disorders, i.e., social phobia, obsessive-compulsive and panic disorders or specific phobias are consequences of pathological fear expression. Anxiety disorders are marked by excessive future fear, often in response to specific objects or situations and in the absence of a true danger. Anxiety disorders are extremely common in the general population. According to a r ecent epidemiological breeding, the lifetime prevalence of any anxiety disorder is 28.8% (Kessler et al, 2005).Increased anxiety in animal models, as a trait, can be attributed to at least two sets of factors (i) a genetic predisposition, essentially linked to the expression of genes that are pertain in the various neurochemical mechanisms underlying fear and anxiety and (ii) the influence of environmental factors. These environmental factors can interact with the expression of the relevant genes during early education and determine the functional properties of the neural and biochemical systems involved in coping with stressful events. They can also modulate the learning processes that occur at a later stage, when the individual is confronted with various life events, and determine the capacity to cope successfully with aversive or threatening situations in adulthood.These predisposing factors, either innate or acquired, determine individual affective styles or coping strategies , which are thought to play an important role in vulnerabilityto psychopathology.Brain structures and functional circuitry involved in fear/anxietyLimbic System Emotional starLimbic areas include the hippocampus (HPC), corpus amygdaloideum, cortex, thalamus, hypothalamus and the bed nucleus of striaterminalis (BNST). Hippocampus and amygdala are considered as a main area involves in perception, but I will mainly focus on the amygdala.HippocampusThe hippocampus is a part of the fore witticism, located in the medial temporal lobe. The hippocampus consists of the dentate gyrus, the Cornu Ammonis fields (CA1-CA3), and the subiculum. The main information commentary to the hippocampus is via the entorhinal cortex and the main information outturn from the hippocampus is via the subiculum. Between entorhinal cortex and subiculum, three major pathways of the hippocampus are described. The perforant pathway from entorhinal cortex forms excitatory connections with the granule cells of the dentate gyrus (Bliss and Lomo, 1973). The mossy fiber pathway, organize by the axons of the granule cells of the dentate gyrus, connects the granule cells with the pyramidal cells in the area CA3 of the hippocampus (Lu et al., 1997). The Schaffer collateral pathway connects the pyramidal cells of the CA3 region with the pyramidal cells in the CA1 region of the hippocampus (Collingridge et al., 1983). amygdaloid nucleusThe amygdala is a limbic system structure and is a key target area implicated in emotional processing. It is composed of several join nuclei located in the medial temporal lobes in mammals and is reciprocally linked to sensory cortices, thalamus, and autonomic control centers (Sah et al., 2003). Its internal and external connections permit the amygdala to label environmental stimuli, attach salience to them, then generate appropriate autonomic, endocrine, and behavioral responses (Adolphs, 1999 Rogan LeDoux, 1996 Walker Davis, 2002). In addition, the amygdala is involved in detecting and evaluating emotional expression (Adolphs, 1999). The lateral nucleus of the amygdala (LA) has been implicated as the critical area where sensory stimuli achieve emotional salience. Consequently, the amygdala is needed for proper emotional processing, as in fear and anxiety, memory board, and attention (Davis, 1997 Keele, Hughes, Blakeley, Herman, 2008 LeDoux, Cicchetti, Xagoraris, Romanski, 1990). Plasticity in neurotransmission is important in maintaining the emotional significance of stimuli we encounter (Ehrlich, 2009). However, if those synapses and circuits become super-sensitized, what was once adaptive emotional behaviors can become psychopathologies, such as anxiety disorders and depression (Keele, 2005 Rosen Shulkin, 1998).Amygdala structureThe amygdaloid complex is comprised of 13 nuclei, which are further divided into 3 groups the basolateral complex, the cortical nuclei, and the centromedial nuclei. The basolateral complex is composed primar ily of the basolateral (BLA) and lateral (LA) amygdala nuclei (Keele et al., 2008 Sah et al., 2003). Neuroanatomical studies reveal that there are broad internuclear and reciprocal intranuclear connections (Pitkanen, Savander, LeDoux, 1997). Physiological studies further suggest that the amygdala nuclei are primarily individual functional units with the flow of information through the amygdala being super organized, as seen in fear learn studies (LeDoux, 2000). receptive afferents (context + tone) terminate in the LA (Romanski, Clugent, Bordi, LeDoux, 1993). The information proceeds in a predominantly unidirectional flow from the lateral to medial at which point the LA sends glutamatergic projections to the central nucleus of the amygdala (CeA), as well the BLA and other nuclei (Sah et al., 2003 Pitkanen et al., 1997 Smith Par eacute, 1994). The CeA, where much of the amygdala nuclei projections converge and insubstantial intra-amygdaloid fibers exit, constitutes the output o f the amygdala (Sah et al., 2003 Pitkanen et al., 1997). deuce main cell types have been described morphologically and physiologically in the BLA (Rainnie, Asprodini, Shinnick-Gallagher, 1993 Sah et al., 2003). The first type is glutamatergic projection neurons that give off collaterals within the nucleus. They account for 70% of the neuronal population (McDonald, 1982). Their secondary and tertiary dendrites appear spiny, distinguishing them from the other neuronal type (Sah et al., 2003). In the LA, pyramidal neurons account for about 95% of the population. Pyramidal neurons show broad action potentials and spike frequency accommodation of varying degrees, and express N-methyl-D-aspartic acid (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors. Main input to these neurons is cortical and thalamic, but they are highly modulated by interneurons and monoaminergic afferents from brain stem nuclei (Marowsky, Yanagawa, Obata, Vogt., 2005 Rainnie , 1999 Sah et al., 2003 Sullivan, Coplan, Kent, Gorman, 1999). The second type of neurons is interneurons, also called stellate cells (Sah et al., 2003). They account for 5-10% of the neurons in the BLA and are local circuit gamma-aminobutyric acid (GABA) purgative cells with short duration action potentials and no spike frequency accommodation. AMPA receptors are expressed but NMDA receptors are informly absent (Sah et al., 2003). Like the projection neurons, input is cortical and thalamic with modulatory input from brainstem nuclei (Lang and Par eacute, 1998).Afferent and Efferent ConnectivityAmygdala botheration consists of sensory input from the thalamus and cerebral cortex and autonomic input from the hypothalamus and brain stem (Keele et al., 2008 Sah et al., 2003). All sensory modalities glutamatergically project to the amygdala via the thalamus, sensory cortices, association cortices, and other polymodal cortical areas (McDonald, 1998 Romanski LeDoux, 1993 Sah et al., 2003). Brain stem projections provide monoaminergic modulation of the amygdala. There is extensive serotonergic innervation from the dorsal raphe nucleus (DRN), dopaminergic innervation from the ventral tegmental area, and noradrenergic innervation from the locus coeruleus (Clayton Williams, 2000Marowsky et al., 2005 McIntyre, Power, Roozendaal, McGaugh, 2003 Rainnie, 1999). Main output of the amygdala is projected from the CeA. Lesion and stimulant studies have shown cortical, hypothalamic, and brain stem regions to be target areas, directly and indirectly through projections to the bed nucleus of the stria terminalis (Iwata, Chida, LeDoux, 1987 LeDoux, Iwata, Cicchetti, Reis, 1988 LeDoux, 2000 Sah et al., 2003 Turner, Mishkin, Knapp, 1980 Walker Davis, 2002). CeA efferents modulate specific behavioral and autonomic responses to fear, anxiety, and stress (Davis, 1997 Rosen Schulken, 1998 Sah et al., 2003). The CeAs connection to the hypothalamus allows activation of the sym pathetic nervous system, such as an increase in heartbeat, galvanic skin response, and pupil dilation in response to fear. For bring forth behavioral responses to fear, there are projections from the CeA to brainstem nuclei. For instance, connections with the periaqueductal gray induce freezing behavior and with the nucleus reticularis pontis caudalis (PnC) increase acoustic startle response (Davis, 1992). The brainstem innervation is so extensive that the amygdala contacts almost every brainstem region involved in autonomic functioning (Keele et al., 2008 LeDoux, 1992 Price, 2003).Behavioral FunctionThe amygdalas contribution to emotion has long been documented. Initially, monkey bilateral temporal lobectomy studies performed by Klver and Bucy (1937 1939), resulted in agnosia, hyperorality, hypersexuality, social withdrawl, difficulty recognizing emotionality of objects, and placidity. This became known as Klver-Bucy syndrome. In following amygdalectomy studies a overtaking of f ear, aggression, and normal social interactions with an increase in exploration was found (Goddard, 1964 Aggleton Young, 2000). Rodent lesion studies further demonstrated decreased active fear avoidance (Poremba Gabriel, 1999) and decreased passive conditioned fear response (Roozendaal, Koolhaas, Bohus, 1993), for instance, amygdala lesioned rats fail to show freezing behavior in the presence of danger, such as a cat (Blanchard Blanchard, 972). Specific lesioning of the lateral nucleus of the amygdala blocked conditioned fear (LeDoux et al., 1990). Amygdalectomized humans also show impairments in fear conditioning (LaBar, LeDoux, Spencer, Phelps, 1995). Additionally, human subjects do not recognize fear from facial expressions, voices, (Adolphs, Tranel, Damasio, Damasio, 1995), or music (Gosselin et al., 2005), and judge deceitful looking individuals as trustworthy (Adolphs, Tranel, Damasio, 1998). Stimulation and activation studies further corroborate amygdala lesion evidenc e. Human amygdala stimulation often produces observable fear responses as well as subjective feelings of fear (for review see Davis, 1992). Functional magnetized resonance imaging (fMRI) further shows activation of the amygdala during viewing of fearful faces (Rosen Donley, 2006) and following fear conditioning when the conditioned stimulus is presented (LaBar, Gatenby, Gore, LeDoux, Phelps, 1998). In animals, amygdala stimulation shows an increase in behaviors, such as, vigilance, attention, and arousal (Rosen Schulkin, 1998) and an increase in autonomic responding such as, respiration, heart rate, and blood pressure (for review see Davis, 1992). Additional emotions reported in humans have been anger and rage (Joseph, 2000). One female subject displayed enraged facial expressions, lips retracted and grimacing, then progressed to aggressive behavior and attack (Mark, Ervin, Sweet, 1972). These are emotional behavior autonomic responses that are often a component of the fear res ponse. Fear Conditioning and Long-Term Potentiation One commonly used technique for studying amygdala function in both animals and humans is conditioned fear learning (Bchel, Morris, Dolan, Friston, 1998 Walker Davis 2002). To accomplish this type of learning a neutral sensory stimulus (conditioned stimulus or CS, often a light or tone) is paired with a noxious stimulus (unconditioned stimulus or US) such as a mild electric shock. Upon repeated US-CS pairing the erudite association between the two stimuli elicits a behavioral response (conditioned response or CR) that can last indefinitely with only a few pairings (Maren, 2005). The convergence of the cortical sensory input and thalamic relays from the spinothalamic tract in the amygdala as well as the abolishment of learned fear response after amygdala lesions implicate it as the site for conditioned fear learning (LeDoux et al., 1990 Ledoux, 2000). The learned association as well as the fear behavioral response is seen across m any species and has been extensively studied in rats, cats, primates, and humans. The neural mechanisms have also been conserved across these animal species and probably humans as well (LeDoux, 1996 Price, 2003). Long-term potentiation (LTP) functions as a mechanism for increasing synaptic strength between two neurons. Experimentally it can be induced by tetanic stimulation of afferent fibers however, naturally occurring similar mechanisms are induced in the LA during conditioned fear learning (McKernan Shinnick-Gallagher, 1997 Rogan LeDoux, 1996 LeDoux, 2000). Support comes from the observation that before conditioning, neurons in the LA respond to CS and US input. After conditioning, the postsynaptic neurons response to the CS is greatly enhanced. This suggests that fear conditioning provides a suitable means for examining amygdala synaptic plasticity and fear circuitry. The proposed LTP molecular mechanism initiating fear conditioning is that the CS induces a release of glutama te, which activates the glutamatergic receptors on postsynaptic LA neurons. The US further depolarizes the neurons causing the release of the Mg2+ block in the NMDA receptors (NMDARs) allowing an influx of Ca2+. The additional Ca2+ initiates second messenger cascades that are responsible for the increased neuronal response to the CS. Blocking NMDARs with the antagonist DL-2-amino-5- phosphonovalerate (APV) prevents the acquisition of fear conditioning. If APV is delivered after training it does not affect the consolidation of the fear memory further supporting the necessary involvement of NMDARs in the LTP mechanism. Ca2+ influx due to L-type voltage-gated calcium channels (L-VGCCs) is also required for the association to occur. The L-VGCCs may be hypothesis in response to the strong depolarization from the US, especially when postsynaptic spiking and back-propagating action potentials occur. How learned fear memories are acquired and the mechanisms involved is essential to underst anding normal amygdala functioning. Fear conditioning provides a means for studying dysfunction of fear circuitry and the resulting abnormal fear behaviors. Fear circuitry receives intense inhibitory modulation. When the inhibition is removed the fear conditioning mechanisms, such as LTP, are unmodulated and the circuitry enters a hyperexcited state. This could potentially lead to abnormally enhanced fear associations resulting in heightened fear responses. Manipulating the fear circuitry by fastener inhibitory modulators and then assessing the fear behavior responses could elucidate the mechanisms leading to fear and anxiety disorders.Neuropeptide Y (NPY) system Involvement in fear and anxietyNPY OverviewNeuropeptide Y(NPY) was stranded from porcine brain more than two decades ago (Tatemoto et al., 1982). This 36-amino-acid residue is one of the most abundant peptides found in the central nervous system (CNS) of all mammals, including humans Chan-Palay et al., 1985 Chan-Palay et a l., 1986. It is one of the most conserved peptides in evolution (Larhammar, 1996 Larhamar and Salaneck, 2004), suggesting an important role in the regulation of basic physiological functions (Larhammar et al., 1993). At present, five NPY receptor subtypes have been cloned and designated-Y1, Y2, Y4, Y5, and y6 (Dumont et al., 1993 Gehlert, 1994 Michel et al., 1998)-all of which couple to Gi/o proteins and inhibit the production of cyclic AMP (Palmiter et al., 1998). NPY has important modulatory functions in the immune and cardiovascular systems (Song et al., 1996 Michalkiewicz et al., 2001), circadian rhythms (Antonijevic et al., 2000 Yannielli and Harrington, 2001), food uptake (Jolicoeur et al., 1995), and seizure (Husum et al., 1998 Colmers and El Bahh, 2003) and the response to pain (Munglani et al., 1996). NPY is involved in anxiety related behaviors (Thorsell and Heilig, 2002), and there is increasing support for the role of NPY in mood disorders such as depression (Redrobe et al., 2002a).It is constantly reported that NPY producing anxiolytic-like effect and can be observed different battery of behavioral tests like elevated plus maze, light dark, open field, and stressed induced hyperthermia. Consistent findings across different rodent modes have been proving the true anxiolytic effect of NPY. The presence of different NPY receptors and the plethora of NPY-induced behavioral effect raise the question as to whether NPY and its receptors have an effect on fear, and extinction of conditioned fear.The NPY Y1 receptors can be found in number of brain regions but prominent in cerebral cortex, amygdala, and hippocampus (Kask et al., 2002). The majority of studies have been proved the involvement of NPY Y1 receptor in the regulation of anxiety. In the present study I am focusing on fear reducing properties of NPY following the hypothesis that anxiolytic-like effect of NPY mediated my Y1 receptors.