Contributions of postrhinal and perirhinal cortex to contextual information processing.

The role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information was examined with Pavlovian fear conditioning. Rats with electrolytic or neurotoxic lesions of the POR or PER were tested in 2 contextual fear conditioning paradigms. In Experiment 1, electrolytic lesions of the POR or PER produced impairments in contextual fear conditioning but not in conditioning to a phasic auditory conditioned stimulus. Neurotoxic lesions of the POR or PER likewise resulted in anterograde (Experiment 2) and retrograde (Experiment 3) deficits in fear conditioning to the training context in an unsignaled shock paradigm. The results suggest that operations performed on sensory information by the POR and PER are necessary to support contextual learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurotoxic lesions of retrosplenial cortex disrupt signaled and unsignaled contextual fear conditioning.

The majority of research regarding contextual learning and memory has focused on the contributions of the hippocampus and related medial temporal lobe structures. However, little is known about other possible cortical contributions to these processes. Our laboratory recently demonstrated that electrolytic lesions of the retrosplenial cortex (RSP), a posterior region of cingulate cortex, impaired contextual but not cue-specific fear conditioning. The present experiments further examined the role of RSP in contextual fear memory using fiber-sparing neurotoxic lesions and both signaled and unsignaled fear conditioning paradigms. Despite comparable acquisition of the conditioned fear response, rats with neurotoxic lesions of RSP exhibited impaired contextual memory relative to control animals in both the signaled and unsignaled paradigms. These results further suggest an important role for RSP in contextual learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contextual fear discrimination is impaired by damage to the postrhinal or perirhinal cortex.

Postrhinal (POR) or perirhinal (PER) cortex damage impairs acquisition and expression of contextual fear, but the nature of the impairment remains unclear. This study used a contextual fear discrimination paradigm that biased subjects toward using a configural, rather than an elemental, strategy to distinguish between 2 contexts, 1 of which was paired with a mild footshock. Control rats discriminated between 2 contexts when a combination of several cues could be used (Exp 1), but not when individual sensory cues were manipulated (Exp 2). Rats with POR or PER lesions could not discriminate between the shock and no-shock contexts when multiple cues differentiated the contexts (Exp 3). The results indicate that both the POR and PER have a role in configural learning of contextual fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of the retrosplenial cortex in processing multiple conditioned stimuli.

Lesions of retrosplenial cortex (RSP) disrupt spatial and contextual learning, suggesting that RSP may have a fundamental role in processing overlapping, or simultaneously presented stimuli. If so, then RSP lesions might also be expected to disrupt learning that requires the concurrent processing of phasic conditioned stimuli. In Experiment 1, rats were trained in a compound feature negative discrimination task in which a tone was presented and immediately followed by food on some trials, while on other trials a visual stimulus was simultaneously presented along with the tone and not reinforced. Normal rats learned to discriminate between the trials but RSP-lesioned rats exhibited low levels of conditioning on both types of trials. Experiment 2 demonstrated that this effect was not simply due to a general inability to form associations, since RSP-lesioned rats exhibited normal responding when the visual stimulus was presented alone and paired with food. These findings support the view that RSP has an important role in learning that involves the processing of simultaneously presented stimuli and have implications for understanding the functional relationship between the hippocampus and RSP. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain difference in the effect of infralimbic cortex lesions on fear extinction in rats.

The infralimbic division of the medial prefrontal cortex (IL) has been implicated in the consolidation and retention of extinction memories. However, the effects of IL lesions on the retention of extinction memory are inconsistent. In the present experiments, we examined whether rat strain influences the effects of IL lesions on extinction. In Experiment 1, Sprague-Dawley (SD) or Long-Evans (LE) rats received a standard auditory fear conditioning procedure, which was followed by an extinction session; freezing served as the index of conditional fear. Our results reveal that focal IL lesions impair the retention of extinction in SD, but not LE rats. In addition to the strain difference in sensitivity to IL lesions, LE rats exhibited significantly higher levels of contextual fear before the outset of extinction training than SD rats. In a second experiment we thus examined whether contextual fear influenced the sensitivity of extinction to IL lesions in LE rats. LE rats received the same conditioning as in Experiment 1, and then were either merely exposed to a novel context or administered unsignaled shocks in that context, followed by extinction and test sessions. Our results reveal that LE rats with IL lesions showed normal extinction regardless of the levels of contextual fear manifest before extinction. Thus, we conclude that rat strain is an important variable that influences the role of infralimbic cortex in fear extinction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation of human neutrophil procollagenase by nitrogen dioxide and peroxynitrite: a novel mechanism for procollagenase activation involving nitric oxide

Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.     

Involvement of retrosplenial cortex in forming associations between multiple sensory stimuli.

The retrosplenial cortex (RSP) is highly interconnected with medial temporal lobe structures, yet relatively little is known about its specific contributions to learning and memory. One possibility is that RSP is involved in forming associations between multiple sensory stimuli. Indeed, damage to RSP disrupts learning about spatial or contextual cues and also impairs learning about co-occurring conditioned stimuli (CSs). Two experiments were conducted to test this notion more rigorously. In Experiment 1, rats were trained in a serial feature negative discrimination task consisting of reinforced presentations of a tone alone and nonreinforced serial presentations of a light followed by the tone. Thus, in contrast to prior studies, this paradigm involved serial presentation of conditioned stimuli (CS), rather than simultaneous presentation. Rats with damage to RSP failed to acquire the discrimination, indicating that RSP is required for forming associations between sensory stimuli regardless of whether they occur serially or simultaneously. In Experiment 2, a sensory preconditioning task was used to determine if RSP was necessary for forming associations between stimuli even in the absence of reinforcement. During the first phase of this procedure, one auditory stimulus was paired with a light while a second auditory stimulus was presented alone. In the next phase of training, the same light was paired with food. During the final phase of the procedure both auditory stimuli were presented alone during a single session. Control, but not RSP-lesioned rats, exhibited more food cup behavior following presentation of the auditory cue that was previously paired with light compared with the unpaired auditory stimulus, indicating that a stimulus-stimulus association was formed during the first phase of training. These results support the idea that RSP has a fundamental role in forming associations between environmental stimuli. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Intrahippocampal infusions of a metabotropic glutamate receptor antagonist block the memory of context-specific but not tone-specific conditioned fear.

The role of metabotropic glutamate receptors (mGluRs) in the acquisition of learning and memory using fear conditioning as a behavioral model was examined. The mGluR antagonist (R,S)-α-methyl-4-carboxyphenylglycine (MCPG) was infused into the hippocampus 30 min before fear conditioning, and freezing was measured during both acquisition and retention tests. The results show that pretraining antagonism of MCPG-sensitive mGluRs in the hippocampus impaired context-specific memory for an aversive event during testing. The memory for tone-specific fear, however, remained intact despite pretraining infusion of MCPG. Treating rats with MCPG did not affect context- or tone-specific fear during acquisition. Results suggest that mGluR activation may play an important role in hippocampally mediated memory consolidation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Specific changes in conditioned responding following neurotoxic damage to the posterior parietal cortex.

The central nucleus (CN) of the amygdala and basal forebrain cholinergic projections to the posterior parietal cortex (PPC) are involved in regulating changes in attentional processing of conditioned stimuli. In a previous study, lesions of the CN produced a deficit in conditioned orienting behavior (rearing on the hind legs) when a visual stimulus was paired with food. Unconditioned orienting (rearing to nonreinforced presentations of the stimulus) and conditioned food cup behavior were unaffected. The present study examined the contribution of the PPC to attentional orienting behavior. Damage to the PPC did not affect orienting behavior but produced deficits in food cup behavior. These findings help define the specific contributions of the PPC to attentional processing and associative learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early-life exposure to fibroblast growth factor-2 facilitates context-dependent long-term memory in developing rats.

Fibroblast growth factor-2 (FGF2) is a potent neurotrophic factor that is involved in brain development and the formation of long-term memory. It has recently been shown that acute FGF2, administered at the time of learning, enhances long-term memory for contextual fear conditioning as well as extinction of conditioned fear in developing rats. As other research has shown that administering FGF2 on the first day of life leads to long-term morphological changes in the hippocampus, in the present study we investigated whether early life exposure to FGF2 affects contextual fear conditioning, and renewal following extinction, later in life. Experiment 1 demonstrated that a single injection of FGF2 on Postnatal Day (PND) 1 did not lead to any detectable changes in contextual fear conditioning in PND 16 or PND 23 rats. Experiments 2 and 3 demonstrated that 5 days of injections of FGF2 (from PND 1–5) facilitated contextual fear conditioning in PND 16 and PND 23 rats. Experiment 4 demonstrated that the observed facilitation of memory was not due to FGF2 increasing rats' sensitivity to foot shock. Experiment 5 showed that early life exposure to FGF2 did not affect learning about a discrete conditioned stimulus, but did allow PND 16 rats to use contextual information in more complex ways, leading to context-dependent extinction of conditioned fear. These results further implicate FGF2 as a critical signal involved in the development of learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Normal conditioning inhibition and extinction of freezing and fear-potentiated startle following electrolytic lesions of medial prefrontal cortex in rats.

The authors investigated the role of medial prefrontal cortex (mPFC) in the inhibition of conditioned fear in rats using both Pavlovian extinction and conditioned inhibition paradigms. In Experiment 1, lesions of ventral mPFC did not interfere with conditioned inhibition of the fear-potentiated startle response. In Experiment 2, lesions made after acquisition of fear conditioning did not retard extinction of fear to a visual conditioned stimulus (CS) and did not impair "reinstatement" of fear after unsignaled presentations of the unconditioned stimulus. In Experiment 3, lesions made before fear conditioning did not retard extinction of fear-potentiated startle or freezing to an auditory CS. In both Experiments 2 and 3, extinction of fear to contextual cues was also unaffected by the lesions. These results indicate that ventral mPFC is not essential for the inhibition of fear under a variety of circumstances. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of prefrontal cortex in predictive fear learning.

Pavlovian fear conditioning depends on prediction error, or the discrepancy between actual and expected outcomes. We used immunohistochemistry, neuronal tract tracing, and reversible inactivation to study the role of prefrontal cortex and thalamocortical pathways in predictive fear learning. Unexpected, but not expected, conditioned stimulus (CS)–unconditioned stimulus (US) presentations caused increased c-Fos expression in the prefrontal cortex (PFC), midline thalamus, lateral amygdala, as well as retrograde labeled midline thalamic afferents to PFC. Reversible inactivation of dorsomedial PFC, but not infralimbic PFC, prevented the associative blocking of fear learning. These results suggest a role for dorsomedial PFC (dmPFC), and a thalamic → dmPFC pathway, in signaling whether or not aversive events are expected or unexpected and so whether they are to be learned about. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gustatory thalamus lesions in the rat: II. Aversive and appetitive taste conditioning.

The learning capacities of rats with electrolytic lesions of the gustatory thalamus (GT) were investigated in 3 experiments. In Experiment 1, the presence of a taste cue failed to overshadow odor aversion learning in the lesioned rats, yet these same animals acquired normal taste and odor aversions. Thalamic lesions had no discernible effect on the acquisition of a conditioned flavor preference in Experiment 2. Finally, GT lesions completely reversed the anticipatory contrast effect shown by control subjects in Experiment 3. These results suggest that damage to the GT spares taste detection and recognition and simple associative learning but interferes with learning that involves more complex gustatory information processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats.

Three experiments examined the effects of intra-amygdaloid infusions of an N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonovalerate (APV), on contextual fear conditioning in rats. In Experiment 1, APV infusion into the basolateral amygdala (BLA), before training, disrupted the acquisition of contextual fear. In Experiment 2, APV produced a disruption of both the acquisition and expression of contextual fear. This blockade of contextual fear was not state dependent, not due to a shift in footshock sensitivity, and not the result of increased motor activity in APV-treated rats. In Experiment 3, fear conditioning was not affected by a posttraining APV infusion into the BLA. These results indicate that NMDA receptors in the BLA are necessary for both the acquisition and expression of Pavlovian fear conditioning to contextual cues in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporal processing of information: The role of the medial prefrontal cortex and hippocampus: Theoretical comment on gilmartin and mcechron (2005).

M. R. Gilmartin and M. D. McEchron (2005) reported that single cells recorded in the prelimbic cortex of rats during the acquisition of trace fear conditioning display multiple patterns of neuronal firing during the trace. These finding are discussed in the context of the role of the prelimbic cortex in processing temporal information during trace conditioning and delayed matching- or nonmatching-to-sample paradigms based on both electrophysiology and lesion evidence. In addition, evidence is provided for a role of the hippocampus in supporting temporal processing of information and its potential interaction with the prelimbic cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine enhances context learning but not context-shock associative learning.

Nicotine has been found to enhance learning in a variety of tasks, including contextual fear conditioning. During contextual fear conditioning animals have to learn the context and associate the context with an unconditioned stimulus (footshock). As both of these types of learning co-occur during fear conditioning, it is not clear whether nicotine enhances one or both of these types of learning. To tease these two forms of learning apart, the authors made use of the context preexposure facilitation effect (CPFE). Acquisition of the CPFE requires that contextual and context-shock learning occurs on separate days, allowing for their individual manipulation. Nicotine (0.09 mg/kg) administered prior to contextual learning and retrieval enhanced the CPFE whereas administration prior to context-shock learning and retrieval had no effect. Thus, nicotine enhances contextual learning but not context-shock associative learning. Finally, the results are discussed in terms of a theory of how nicotine could alter hippocampal-cortical-amygdala interactions to facilitate contextual learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deficits in Attentional Orienting Following Damage to the Perirhinal or Postrhinal Cortices.

The authors used an associative learning paradigm to assess the effects of perirhinal or postrhinal damage on attentional orienting. Control rats and rats with lesions of either the perirhinal or postrhinal cortex initially displayed high levels of orienting behavior (rearing) to presentations of a light cue. Continued nonreinforced presentations resulted in normal habituation of the response. In addition, orienting reemerged in control rats, indicating increased attentional processing of the cue. This conditioned orienting did not reemerge in rats with either perirhinal or postrhinal lesions, providing direct evidence that the rat perirhinal and postrhinal cortices each play a role in attention. These results are consistent with an emerging view that some structures within the medial temporal lobe have nonmnemonic functions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factors governing single-trial contextual fear conditioning in the weanling rat.

Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The authors adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that N-methyl-D-aspartate (NMDA) receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adenosine A? receptor activation selectively impairs the acquisition of contextual fear conditioning in rats.

Three experiments were conducted to examine the importance of adenosine A? receptors for the acquisition and expression of hippocampal-dependent and hippocampal-independent forms of conditioned fear. In Experiment 1, the selective adenosine A? receptor agonist, N?-cyclopentyladenosine (CPA), or saline was administered intraperitoneally to male rats 30 min prior to Pavlovian fear conditioning, which consisted of 7 tone–shock pairings. Adenosine A? receptor activation dose-dependently and selectively disrupted the acquisition of contextual fear conditioning while sparing tone–shock associations. Experiments 2 and 3 demonstrated that CPA's selective disruption of contextual learning could not be attributed to context being weaker than tone conditioning or to state-dependent learning. Adenosine A? receptor activation also impaired the expression of both context- and tone-elicited fear. These results suggest that endogenous adenosine modulates the acquisition and expression of emotional (fear) memories by acting on A? receptors in brain regions underlying fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disruption of contextual freezing, but not contextual blocking of fear-potentiated startle, after lesions of the dorsal hippocampus.

[Correction Notice: An erratum for this article was reported in Vol 114(2) of Behavioral Neuroscience (see record 2007-17251-001). The captions for Figure 4 (p. 70) and Figure 5 (p. 72) were printed incorrectly. The caption used for Figure 4 should appear under Figure 5, and the caption used for Figure 5 should appear under Figure 4.] The role of the dorsal hippocampus in contextual fear conditioning was investigated with a contextual blocking paradigm. In Experiment 1, rats were given pairings of a light conditioned stimulus (CS) and footshock after preexposure either to footshock or to the context alone. The group preexposed to footshock showed poorer fear conditioning to the light CS, as measured by the fear-potentiated startle reflex. In Experiment 2, a group preexposed to footshock in the same context showed poorer fear conditioning to the light CS than did a group preexposed to footshock in a different context, indicating contextual blocking of fear-potentiated startle. In Experiment 3, lesions of the dorsal hippocampus had no effect on contextual blocking, even though contextual freezing was disrupted. The sparing of contextual blocking indicated that contextual memory was intact following hippocampal lesions, despite the disruption of contextual freezing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)