Data will be reviewed using the acoustic startle reflex in rats and humans based on our attempts to operationally define fear vs anxiety. Although the symptoms of fear and anxiety are very similar, they also differ. Fear is a generally adaptive state of apprehension that begins rapidly and dissipates quickly once the threat is removed (phasic fear). Anxiety is elicited by less specific and less predictable threats, or by those that are physically or psychologically more distant. Thus, anxiety is a more long-lasting state of apprehension (sustained fear). Rodent studies suggest that phasic fear is mediated by the amygdala, which sends outputs to the hypothalamus and brainstem to produce symptoms of fear. Sustained fear is also mediated by the amygdala, which releases corticotropin-releasing factor, a stress hormone that acts on receptors in the bed nucleus of the stria terminalis (BNST), a part of the so-called ‘extended amygdala.’ The amygdala and BNST send outputs to the same hypothalamic and brainstem targets to produce phasic and sustained fear, respectively. In rats, sustained fear is more sensitive to anxiolytic drugs. In humans, symptoms of clinical anxiety are better detected in sustained rather than phasic fear paradigms.

NMDA receptor antagonists block conditioned fear extinction when injected systemically and also when infused directly into the amygdala. Here we evaluate the ability of D-cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine-recognition site on the NMDA receptor complex, to facilitate conditioned fear extinction after systemic administration or intra-amygdala infusions. Rats received 10 pairings of a 3.7 sec light and a 0.4 mA footshock (fear conditioning). Fear-potentiated startle (increased startle in the presence vs the absence of the light) was subsequently measured before and after 30, 60, or 90 presentations of the light without shock (extinction training). Thirty non-reinforced light presentations produced modest extinction, and 60 or 90 presentations produced nearly complete extinction (experiment 1). DCS injections (3.25, 15, or 30 mg/kg) before 30 non-reinforced light exposures dose-dependently enhanced extinction (experiment 2) but did not influence fear-potentiated startle in rats that did not receive extinction training (experiment 3). These effects were blocked by HA-966, an antagonist at the glycine-recognition site (experiment 4). Neither DCS nor HA-966 altered fear-potentiated startle when injected before testing (experiment 5). The effect of systemic administration was mimicked by intra-amygdala DCS (10 microg/side) infusions (experiment 6). These results indicate that treatments that promote NMDA receptor activity after either systemic or intra-amygdala administration promote the extinction of conditioned fear.

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The amplitude of the acoustic startle response is reliably enhanced when elicited in the presence of bright light (light-enhanced startle) or in the presence of cues previously paired with shock (fear-potentiated startle). Light-enhanced startle appears to reflect an unconditioned response to an anxiogenic stimulus, whereas fear-potentiated startle reflects a conditioned response to a fear-eliciting stimulus. We examine the involvement of the basolateral nucleus of the amygdala, the central nucleus of the amygdala, and the bed nucleus of the stria terminalis in both phenomena. Immediately before light-enhanced or fear-potentiated startle testing, rats received intracranial infusions of the AMPA receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)-quinoxaline (3 microg) or PBS. Infusions into the central nucleus of the amygdala blocked fear-potentiated but not light-enhanced startle, and infusions into the bed nucleus of the stria terminalis blocked light-enhanced but not fear-potentiated startle. Infusions into the basolateral amygdala disrupted both phenomena. These findings indicate that the neuroanatomical substrates of fear-potentiated and light-enhanced startle, and perhaps more generally of conditioned and unconditioned fear, may be anatomically dissociated.

There are at least five lipoxygenases (TomloxA, TomloxB, TomloxC, TomloxD, and TomloxE) present in tomato (Lycopersicon esculentum Mill.) fruit, but their role in generation of fruit flavor volatiles has been unclear. To assess the physiological role of TomloxC in the generation of volatile C6 aldehyde and alcohol flavor compounds, we produced transgenic tomato plants with greatly reduced TomloxC using sense and antisense constructs under control of the cauliflower mosaic virus 35S promoter. The expression level of the TomloxC mRNA in some transgenic plants was selectively reduced by gene silencing or antisense inhibition to between 1% and 5% of the wild-type controls, but the expression levels of mRNAs for the four other isoforms were unaffected. The specific depletion of TomloxC in transgenic tomatoes led to a marked reduction in the levels of known flavor volatiles, including hexanal, hexenal, and hexenol, to as little as 1.5% of those of wild-type controls following maceration of ripening fruit. Addition of linoleic or linolenic acid to fruit homogenates significantly increased the levels of flavor volatiles, but the increase with the TomloxC-depleted transgenic fruit extracts was much lower than with the wild-type control. Confocal imaging of tobacco (Nicotiana tabacum) leaf cells expressing a TomloxC-GFP fusion confirmed a chloroplast localization of the protein. Together, these results suggest that TomloxC is a chloroplast-targeted lipoxygenase isoform that can use both linoleic and linolenic acids as substrates to generate volatile C6 flavor compounds. The roles of the other lipoxygenase isoforms are discussed.Lipoxygenases (LOX; EC1.13.11.12) are nonheme iron-containing dioxygenases that catalyze the incorporation of molecular oxygen into polyunsaturated fatty acids containing a cis, cis-1.4-pentadiene moiety, such as linoleic and linolenic acids, converting them into fatty acid hydroperoxides (HPOs). Multiple isoforms of LOX have been detected in a wide range of plants, animals, and microorganisms (Zimmerman and Vick, 1973;Eskin et al., 1977;Shechter and Grossman, 1983;Hamberg, 1986;Samuelsson et al., 1987;Vick and Zimmerman, 1987). The LOX isoforms are distinguished by differences in reaction pH optimum, pI, substrate and product specificity, tissue-specific or subcellular localization, and synthesis at particular developmental stages (Axelrod, 1974;Bild et al., 1977;Axelrod et al., 1981;Ferrie et al., 1994;Royo et al., 1996;Heitz et al., 1997).In animals, it is well established that HPOs are the primary metabolites of the pathways that lead to the formation of important regulatory molecules in inflammatory responses such as leukotrienes and lipoxins (Yamamoto, 1991). In higher plants, on the other hand, the physiological role of HPOs generated by individual LOX isoforms is still uncertain. It has been postulated that plant lipoxygenases may be involved in plant growth and development; biosynthesis of regulatory molecules, such as jasmonic acid (JA) and traumatin; biosynthesis of volatile compounds, s...

The medial division of the central nucleus of the amygdala (CeA M ) and the lateral division of the bed nucleus of the stria terminalis (BNST L ) are closely related. Both receive projections from the basolateral amygdala (BLA) and both project to brain areas that mediate fear-influenced behaviors. In contrast to CeA M however, initial attempts to implicate the BNST in conditioned fear responses were largely unsuccessful. More recent studies have shown that the BNST does participate in some types of anxiety and stress responses. Here, we review evidence suggesting that the CeA M and BNST L are functionally complementary, with CeA M mediating short-but not long-duration threat responses (i.e., phasic fear) and BNST L mediating long-but not short-duration responses (sustained fear or 'anxiety'). We also review findings implicating the stress-related peptide corticotropin-releasing factor (CRF) in sustained but not phasic threat responses, and attempt to integrate these findings into a neural circuit model which accounts for these and related observations. Keywords anxiety; startle; amygdala; bed nucleus of the stria terminalis; corticotropin releasing factor A now-familiar and widely-adopted neural circuit model of fear places the amygdala in center stage and assigns different functions to different amygdala subdivisions (Fig. 1). Thus, the basolateral group (BLA) screens incoming sensory information for threat cues and, if such cues are detected, passes this information on to the central nucleus of the amygdala's medial subdivision (CeA M ), which mediates threat responses by way of its many projections to areas that mediate specific fear-influenced behaviors (c.f., Davis, 1992;Fanselow and LeDoux, 1999;Maren, 2001;Pare et al., 2004).In the following pages, we review evidence suggesting that this model is incomplete, and should be expanded to include the bed nucleus of the stria terminalis (specifically, it's lateral subdivision -BNST L ). In fact, by many criteria, the CeA and BNST are closely related (Alheid © 2009 Elsevier Inc. All rights reserved.Correspondence should be addressed to: David L. Walker, Emory University School of Medicine, 954 Gatewood Road NE, Yerkes Neurosci Bldg -Rm 5214, Atlanta, GA 30329, Ph: (404) Fax: (404) 727-8070, dlwalke@emory.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptProg Neuropsychopharmacol Biol Psychiatry. Author manuscript; available in PMC 2010 November 13. Published in final edited form as:Prog Neuropsychopharmacol Biol Psychiatry. Alheid and Heimer, 1988;Johnston, 1923). Of par...

The concept of the "extended amygdala", developed and explored by Lennart Heimer, Jose de Olmos, George Alheid, and their collaborators, has had an enormous impact on the field of neuroscience and on our own work. Measuring fear-potentiated startle test using conditioned stimuli that vary in length we suggest that the central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNST(L)) are involved in short-term versus long-term fear responses we call phasic versus sustained fear, respectively. Outputs from the basolateral amygdala (BLA) activate the medial division of the CeA (CeA(M)) to very rapidly elicit phasic fear responses via CeA(M) projections to the hypothalamus and brainstem. The BLA also projects to the BNST(L), which together with other BNST(L) inputs from the lateral CeA (CeA(L)) initiate a slower developing, but sustained fear response, akin to anxiety. We hypothesize this occurs because the CeA(L) releases the peptide corticotropin releasing hormone (CRF) into the BNST(L) which facilitates the release of glutamate from BLA terminals. This activates the BNST(L) which projects to hypothalamic and brainstem areas similar to those innervated by the CeA(M) that mediate the specific signs of fear and anxiety. The generality of this idea is illustrated by selective studies looking at context conditioning, social defeat, drug withdrawal and stress induced reinstatement.

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