Generalized vs. stimulus-specific learned fear differentially modifies stimulus encoding in primary sensory cortex of awake rats

Chen, Chien-Fu Fred; Barnes, Dylan C.; Wilson, Donald A.

doi:10.1152/jn.00721.2011

Cited by 82 publications

(105 citation statements)

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“…One potential issue with these results lies in the fact that higher doses of oxotremorine have been shown to have analgesic effects in mice (Wess et al 2003), making them less sensitive to the shock. However, this is likely not an issue here as our dose of oxotremorine was lower than the effective doses for inducing analgesia in the above study.While these results demonstrate that olfactory generalization can be modulated by mAChRs during olfactory aversive learning, generalization can also be affected by other factors such as CS intensity, US intensity, and training conditions (Baldi et al 2004;Cleland et al 2009;Chen et al 2011). While our paradigm serves as the starting point for investigations into cholinergic influence on olfactory generalization, future experiments manipulating these factors are needed to fully characterize generalization of olfactory fear learning.…”

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confidence: 88%

“…While these results demonstrate that olfactory generalization can be modulated by mAChRs during olfactory aversive learning, generalization can also be affected by other factors such as CS intensity, US intensity, and training conditions (Baldi et al 2004;Cleland et al 2009;Chen et al 2011). While our paradigm serves as the starting point for investigations into cholinergic influence on olfactory generalization, future experiments manipulating these factors are needed to fully characterize generalization of olfactory fear learning.…”

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Cholinergic modulation during acquisition of olfactory fear conditioning alters learning and stimulus generalization in mice

et al. 2012

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We investigated the role of cholinergic neurotransmission in olfactory fear learning. Mice receiving pairings of odor and foot shock displayed fear to the trained odor the following day. Pretraining injections of the nicotinic antagonist mecamylamine had no effect on subsequent freezing, while the muscarinic antagonist scopolamine significantly reduced freezing. To test whether cholinergic manipulation affected fear generalization, mice were presented with odors similar to the trained odor. Generalization was increased following pretraining scopolamine, while the muscarinic agonist oxotremorine decreased generalization. These results suggest that muscarinic neurotransmission during the acquisition of olfactory association modulates both the strength and specificity of learning.The olfactory system receives cholinergic input from the horizontal limb of the diagonal band of Broca (HDB) (Zaborszky et al. 1986). Blocking olfactory system cholinergic receptors disrupts several aspects of olfactory processing including olfactory shortterm memory (Hunter and Murray 1989;Paolini and McKenzie 1993;Miranda et al. 2009), perceptual learning, and discrimination (Ravel et al. 1992;Fletcher and Wilson 2002;Linster and Cleland 2002;Mandairon et al. 2006). Despite this, relatively little is known about the role of cholinergic activation during acquisition of olfactory aversive learning. While a recent study has demonstrated that cholinergic blockade during acquisition reduces odor-evoked displays of defensive responses to the learned odor (Kroon and Carobrez 2009), the cholinergic contribution to the magnitude and specificity of olfactory fear learning is currently unknown.Sensory cue-evoked fear conditioning has long been used in the study of the neural mechanisms underlying associative memory. In the standard fear-conditioning paradigm, a neutral stimulus is associated with an aversive foot shock, allowing the conditioned stimulus to acquire an aversive valence and induce fear responses, such as freezing (LeDoux 2003). Olfactory cues have been used as an effective conditioned stimulus in promoting fear-conditioned responses (Otto et al. 2000;Jones et al. 2005;Kroon and Carobrez 2009) and studies in other sensory systems have shown that cholinergic neurotransmission is involved in fear learning (Tinsley et al. 2004). For example, in auditory-cued fear conditioning, blockade of muscarinic receptors disrupts the acquisition of the tone-fear conditioning (Young et al. 1995;Anagnostaras et al. 1999;Feiro and Gould 2005), while blocking nicotinic activation does not affect this learning (Feiro and Gould 2005). Despite this, it remains to be seen whether nicotinic and muscarinic receptors can also mediate conditioned freezing responses to olfactory stimuli.In this study, we found that pretraining injections of the nicotinic receptor antagonist (nAChR) mecamylamine had no effect on olfactory fear learning. However, pretraining injections of the muscarinic antagonist scopolamine (mAChR) significantly reduced freezing to the trained od...

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Cholinergic modulation during acquisition of olfactory fear conditioning alters learning and stimulus generalization in mice

et al. 2012

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“…Recently, Luna and Morozov (2012) reported that the pPC differentially responds to amygdaloid versus cortical inputs by utilizing distinct local microcircuits. The pPC is thus an ideal locus to combine the sensory characteristics of the stimulus with its affective learned value transmitted by the BLA to keep the trace of this emotional olfactory memory as suggested by previous studies (Sevelinges et al 2004(Sevelinges et al , 2008(Sevelinges et al , 2011Barnes et al 2011;Chen et al 2011).Most studies questioning the role of sensory cortices in fear conditioning have used auditory stimuli. These studies revealed that the lesion of auditory sensory cortices do not prevent the acquisition of auditory fear conditioning, thus arguing against their involvement in the learning (Campeau and Davis 1995; Armony et al 1997).…”

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Differential involvement of amygdala and cortical NMDA receptors activation upon encoding in odor fear memory

Hegoburu¹,

Parrot²,

Mouly³

2014

Learn. Mem.

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Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the BLA and olfactory cortex at discrete moments of an odor fear conditioning session. We showed that NMDA receptors in BLA are critically involved in odor fear acquisition during the first association but not during the next ones. In the cortex, NMDA receptor activation at encoding is not necessary for recent odor fear memory while its role in remote memory storage needs further investigation.Although the amygdala plays a crucial role for the acquisition and storage of fear memories (for review, see LeDoux 2000;Maren 2001;Gale et al. 2004), sensory cortices were also shown to be involved in the long-term storage of the sensory attributes of remote fear memories in rats (Sacco and Sacchetti 2010). However, the precise time course of amygdala and sensory cortices involvement in fear conditioning remains to be clearly identified. In a recent study investigating hippocampal -cortical interactions, Lesburguères et al. (2011) showed that neurons in the rat cortex undergo a "tagging process" upon encoding to ensure the progressive rewiring of cortical networks that support remote memory storage. We reasoned that the same phenomenon might occur in amygdala-dependent memories and that the amygdala and cortical networks might be involved together at the time of encoding in order for fear memories to be stored in the long term.In a previous study using odor fear conditioning, we compared the dynamics of glutamate fluctuations between basolateral amygdala (BLA) and olfactory cortex (posterior piriform cortex: pPC) during the acquisition session (Hegoburu et al. 2009). In the BLA, we observed a transient increase in glutamate in response to the first odor-shock pairing only, whereas in the pPC increases in glutamate were seen after each pairing of the acquisition session. This led us to hypothesize that two parallel processes take place at encoding: the BLA might be critically involved early and transiently to encode unexpected stimulus-danger association; in parallel via a glutamatergic projection pathway, the BLA would trigger the involvement of the pPC which might be engaged regularly throughout the session to progressively build up the long-term engram as suggested by the literature (Sacco and Sacchetti 2010;Lesburguères et al. 2011). Because N-methyl-D-aspartate (NMDA) receptors play a major role in memory processes (for review, see Riedel et al. 2003), in this study we manipulated NMDA receptors in either the BLA or the pPC, at discrete moments of the acquisition session. We predicted that blocking NMDA receptors in the BLA before odor-shock training would prevent learning, while delaying the blockade to after the first pairing would not. In contrast, blocking NMDA receptors in t...

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“…Recent studies have shown that olfactory fear conditioning leads to generalized fear of similar odors (Chen et al 2011;Pavesi et al 2012). Additionally, it has been shown that this generalization is related to impairments in olfactory cortical odor discrimination (Chen et al 2011). Animals submitted to our generalization paradigm received pairings of E5 odor and foot shock, and were then tested with the trained and similar odors randomly in the same session.…”

Section: Odor Discrimination and Olfactory Memory Generalizationmentioning

confidence: 99%

Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization

2013

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Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice lacking nNOS received six training trials, each consisting of an odor-CS co-terminating with a foot shock-US. Mice showed reduced freezing responses to the trained odor 24 h and 7 d after training, compared to wild-type mice. Pretraining systemic injections of the NO donor, molsidomine, rescued fear retention in nNOS knockout mice. In wildtype mice, pretraining systemic injections of L-NAME, a nonspecific nNOS blocker, disrupted odor-CS fear retention in a dose-dependent manner. To evaluate whether NO signaling is involved in generalization of fear memories, nNOS knockout mice and wild-type mice receiving L-NAME were trained to one odor and tested with a series of similar odors. In both cases, we found increased generalization, as measured by increased freezing to similar, unpaired odors. Despite the impairment in fear memory retention and generalization, neither mice receiving injections of L-NAME nor nNOS knockout mice showed any deficits in either novel odor investigation time or odor habituation, suggesting intact olfactory perception and short-term memory olfactory learning. These results support a necessary role for neuronal NO signaling in the normal expression and generalization of olfactory conditioned fear.The ability to learn and retain memories is dependent on several transmitters. Currently, there is much interest in the involvement of nitric oxide (NO) signaling in long-term memory formation (Bredt and Snyder 1992;Hawkins et al. 1994;Garthwaite 2008;Kelley et al. 2011). NO is generated from the amino acid L-arginine by the enzyme NO synthase (NOS) and functions as a retrograde neurotransmitter. Due to the diffusible nature of NO and its relationship with NMDA receptor activation, neurons containing the neuronal isoform of NOS (nNOS) could be involved in driving synaptic strength changes during learning processes such as longterm memory Zhuo et al. 1994;Garthwaite 2008).Fear conditioning is a useful tool in studying the neuronal mechanisms involved in the formation of long-term memory and fear-related systems. Rodents can quickly and reliably learn a fear association between a conditioned stimulus (CS) and an aversive stimulus (US), such as a foot shock (Young and Fanselow 1992). The role nNOS plays in fear learning has been investigated using contextual fear conditioning, as well as visual and auditory cues as the CS (Schafe et al. 2005;Kelley et al. 2010Kelley et al. , 2011Overeem et al. 2010). And although the nNOS inhibitor 7-nitroindazole showed no disruption in the acquisition and expression of the contextual fear conditioning (Maren 1998), it was demonstrated that animals lacking the nNOS gene (Nos1or nNOS knockout) have shown deficits in fear condit...

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Generalized vs. stimulus-specific learned fear differentially modifies stimulus encoding in primary sensory cortex of awake rats

Cited by 82 publications

References 50 publications

Cholinergic modulation during acquisition of olfactory fear conditioning alters learning and stimulus generalization in mice

Cholinergic modulation during acquisition of olfactory fear conditioning alters learning and stimulus generalization in mice

Differential involvement of amygdala and cortical NMDA receptors activation upon encoding in odor fear memory

Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization

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