Mesolimbic dopaminergic pathways in fear conditioning

Laboratory of Behavioral Neurobiology, The Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, CH 8603 Schwerzenbach, Switzerland.
Progress in Neurobiology (Impact Factor: 9.99). 01/2005; 74(5):301-20. DOI: 10.1016/j.pneurobio.2004.09.004
Source: PubMed


One of the most common paradigms used to study the biological basis of emotion, as well as of learning and memory, is Pavlovian fear conditioning. In the acquisition phase of a fear conditioning experiment, an emotionally neutral conditioned stimulus (CS)--which can either be a discrete stimulus, such as a tone, or a contextual stimulus, such as a specific environment--is paired with an aversive unconditioned stimulus (US), for example a foot shock. As a result, the CS elicits conditioned fear responses when subsequently presented alone during the expression phase of the experiment. While considerable work has been done in relating specific circuits of the brain to fear conditioning, less is known about its regulation by neuromodulators; the understanding of which would be of therapeutic relevance for fear related diseases such as phobia, panic attacks, post traumatic stress disorder, obsessive compulsive disorder, or generalized anxiety disorder. Dopamine is one of the neuromodulators most potently acting on the mechanisms underlying states of fear and anxiety. Recently, a growing body of evidence has suggested that dopaminergic mechanisms are significant for different aspects of affective memory, namely its formation, expression, retrieval, and extinction. The aim of this review is to clarify the complex actions of dopamine in fear conditioning with respect to the wide-spread distribution of dopaminergic innervation over structures constituting the fear related circuitry. A particular effort is made to understand how dopamine in the amygdala, medial prefrontal cortex and nucleus accumbens--target structures of the mesolimbic dopamine system originating from the ventral tegmental area--could relate to different aspects of fear conditioning.

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    • "The neurotransmitter dopamine plays a crucial role in memory processing. Although well known for its involvement in appetitive learning and memory (Schultz 2013), dopamine also mediates certain aversive memory processes (Pezze and Feldon 2004; Iordanova 2009; Volman et al. 2013). During "
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    ABSTRACT: Dopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear. The objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA). Rats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK-801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined. Systemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity. These findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory.
    Psychopharmacology 03/2015; 232(14). DOI:10.1007/s00213-015-3897-y · 3.88 Impact Factor
    • "This is in agreement with previous studies (Galvez et al. 1996; Inglis and Moghaddam 1999; Bouchez et al. 2012) and suggests that stress activates dopaminergic and noradrenergic projections to the amygdala in addition to the HPA axis. Dopamine, noradrenaline and corticosterone in amygdala contribute to emotional processing and the ability to cope with stressors (Morilak et al. 2005; Pezze and Feldon 2004; Roozendaal et al. 2009b). PFC exerts a top-down regulation in response to stress (Ulrich-Lai and Herman 2009; Amat et al. 2005). "
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    ABSTRACT: A dysfunction of prefrontal cortex has been associated with the exacerbated response to stress observed in schizophrenic patients and high-risk individuals to develop psychosis. The hypofunction of NMDA glutamatergic receptors induced by NMDA antagonists produces cortico-limbic hyperactivity, and this is used as an experimental model to resemble behavioural abnormalities observed in schizophrenia. The aim of the present study was to investigate whether injections of NMDA antagonists into the medial prefrontal cortex of the rat change (1) the increases of dopamine, noradrenaline and corticosterone concentrations produced by acute stress in amygdala, and (2) the acquisition of aversive memory related to a stressful event. Male Wistar rats were implanted with guide cannulae to perform microdialysis and bilateral microinjections (0.5 μl/side) of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) (25 and 100 ng). Prefrontal injections were performed 60 min before restraint stress in microdialysis experiments, or training (footshock; 0.6 mA, 2 s) in inhibitory avoidance test. Retention latency was evaluated 24 h after training as an index of aversive memory. Acute stress increased amygdala dialysate concentrations of dopamine (160 % of baseline), noradrenaline (145 % of baseline) and corticosterone (170 % of baseline). Prefrontal injections of CPP did not change the increases of dopamine, noradrenaline or corticosterone produced by stress. In contrast, CPP significantly reduced the retention latency in the inhibitory avoidance test. These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory.
    Psychopharmacology 03/2015; 232(14). DOI:10.1007/s00213-015-3894-1 · 3.88 Impact Factor
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    • "On the other hand, Hikida et al. (2013) suggested that reward and aversive learning are regulated by pathway-specific neural plasticity in the NAcc. This is in line with other studies that pointed on the NAcc role in various tasks involving aversive motivation (for reviews, see: Salamone, 1994; Pezze and Feldon, 2004). Indeed, it was shown that amygdala–striatal interactions are critical for processing of information about learned motivational value (Setlow et al., 2002). "
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    ABSTRACT: The ventral subiculum of the hippocampus projects both to the basolateral amygdala (BLA), which is typically, associated with a response to aversive stimuli, as well as to the nucleus accumbens (NAcc), which is typically associated with a response to appetitive stimuli. Traditionally, studies of the responses to emotional events focus on either negative or positive affect-related processes, however, emotional experiences often affect both. The ability of high-level processing brain regions (e.g., medial prefrontal cortex) to modulate the balance between negative and positive affect-related regions was examined extensively. In contrast, the ability of low-level processing areas (e.g., periaqueductal gray—PAG) to do so, has not been sufficiently studied. To address whether midbrain structures have the ability to modulate limbic regions, we first examined the ventral subiculum stimulation's (vSub) ability to induce plasticity in the BLA and NAcc simultaneously in rats. Further, dorsal PAG (dPAG) priming ability to differentially modulate vSub stimulation induced plasticity in the BLA and the NAcc was subsequently examined. vSub stimulation resulted in plasticity in both the BLA and the NAcc simultaneously. Moreover, depending on stimulus intensity, differential dPAG priming effects on LTP in these two regions were observed. The results demonstrate that negative and positive affect-related processes may be simultaneously modulated. Furthermore, under some conditions lower-level processing areas, such as the dPAG, may differentially modulate plasticity in these regions and thus affect the long-term emotional outcome of the experience.
    Frontiers in Behavioral Neuroscience 03/2015; 9(53). DOI:10.3389/fnbeh.2015.00053 · 3.27 Impact Factor
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