Distinguishing Fear From Anxiety

Introduction

Anxiety disorders constitute the largest group of mental diseases in European countries {Andlin-Sobocki et al., 2005, Eur J Neurol, 12 Suppl 1, 1-27}. Human anxiety disorders can be categorized into generalized anxiety disorders, panic attacks, Posttraumatic stress disorders (PTSD), Obsessive-compulsive disorder (OCD) and special phobias, are 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 expression of both fear and anxiety are thought to represent certain aspects of anxiety disorders. Specific phobias are considered, as fear disorders, whereas generalized anxiety is viewed as an example of anxiety disorders.  PTSD patients do not only suffer from conditioned fear symptoms to discrete cues that act as a reminder of a previous trauma, but they also exhibit persistent symptoms of sustained anxiety. The regulation of fear and anxiety is the heart of many psychopathological disorders also reflected in the extremely high 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 effective alternatives to the benzodiazepines and have been paralleled by a similar growth in effective and available psychological treatments, particularly cognitive and cognitive-behavioural therapy. A considerable portion of patients, however, requires long-term 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 improved treatment is urgently needed.

Distinguishing fear from anxiety

Fear Vs Anxiety

“Fear- Behavioural manifestation associated with clearly identified imminent threat.

Anxiety- Generalized fear without object, an apprehensive anticipation of future potential threats”

The main function of fear and anxiety is to act as a signal of danger, threat, or motivational conflict, and to trigger appropriate adaptive responses. For some authors, fear and anxiety are indistinguishable, whereas others believe that they are distinct phenomena. In particular fear is a generalized adaptive state of apprehension 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 show avoidance behavior when they re-encounter that situation. Young animals may show an innate fear reaction to sudden noise or disturbances in the environment, but rapidly become habituated to them. When they are used 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 between fear and approach behavior may results in displacement activities (e.g., self-grooming in rats and mice). Such displacement activities may be the behavioral expression of an anxious state.

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In contrast anxiety is often elicited by less specific and less predicable threats (Michael Davis, 2010). Anxiety is a generalized response to an unknown threat or internal 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 it’s become extreme.  

Defense and coping strategies

Fear 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 repertoire of the species. “Fight or flight,” 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 “fight or flight” has influenced the understanding and expectations of both clinicians and patients. However, both the order and the completeness of Cannon’s 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 proceed sequentially in response to increasing 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 listen” 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 the hypothalamopituitary-adrenal axis and increased glucocorticoid secretion.

This type of passive 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 brain circuits appear to mediate distinct coping reactions to different types of stressors.

Psychopathological fear/anxiety

Although 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 recent epidemiological study, 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 involved 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 development 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 vulnerability

to psychopathology.

Brain structures and functional circuitry involved in fear/anxiety

Limbic System: Emotional brain

Limbic areas include the hippocampus (HPC), amygdala, cortex, thalamus, hypothalamus and the bed nucleus of striaterminalis (BNST). Hippocampus and amygdala are considered as a main area involves in emotion, but I will mainly focus on the amygdala.

Hippocampus

The hippocampus is a part of the forebrain, 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 input to the hippocampus is via the entorhinal cortex and the main information output 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, formed 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).

Amygdala

The amygdala is a limbic system structure and is a key target area implicated in emotional processing. It is composed of several interconnected 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 evaluate 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, 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 structure

The 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 primarily of the basolateral (BLA) and lateral (LA) amygdala nuclei (Keele et al., 2008; Sah et al., 2003). Neuroanatomical studies reveal that there are extensive 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 highly organized, as seen in fear conditioning studies (LeDoux, 2000). Sensory 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 of the amygdala (Sah et al., 2003; Pitkanen et al., 1997). Two 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) releasing cells with short duration action potentials and no spike frequency accommodation. AMPA receptors are expressed but NMDA receptors are reportedly 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 Connectivity

Amygdala innervation 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, 2000;Marowsky et al., 2005; McIntyre, Power, Roozendaal, & McGaugh, 2003; Rainnie, 1999). Main output of the amygdala is projected from the CeA. Lesion and stimulation 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 CeA’s connection to the hypothalamus allows activation of the sympathetic nervous system, such as an increase in heartbeat, galvanic skin response, and pupil dilation in response to fear. For inducing 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 Function

The amygdala’s contribution to emotion has long been documented. Initially, monkey bilateral temporal lobectomy studies performed by Klüver and Bucy (1937 & 1939), resulted in agnosia, hyperorality, hypersexuality, social withdrawl, difficulty recognizing emotionality of objects, and placidity. This became known as Klüver-Bucy syndrome. In following amygdalectomy studies a loss of fear, 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 evidence. Human amygdala stimulation often produces observable fear responses as well as subjective feelings of fear (for review see Davis, 1992). Functional magnetic 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 response. Fear Conditioning and Long-Term Potentiation One commonly used technique for studying amygdala function in both animals and humans is conditioned fear learning (Büchel, 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 learned 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 many 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 glutamate, 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 opening 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 understanding 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 altering 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 anxiety

NPY: Overview

Neuropeptide Y(NPY) was isolated 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 al., 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 intake (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.