Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex

Extinction of auditory fear conditioning is thought to form a new memory. We previously found that rats with vmPFC lesions could extinguish fear to the tone within a session, but showed no recall of extinction 24 h later. One interpretation is that the vmPFC is the sole storage site of extinction memory. However, it is also possible that lesioned rats were unable to retrieve extinction memory stored in other structures. To determine if a latent extinction memory could be retrieved with additional training, we repeated the experiment but added an additional 5 d of extinction reminder trials. Replicating our previous findings, vmPFC-lesioned rats extinguished normally on day 1, but showed no recall of extinction on day 2. Over the next 5 d, however, lesioned rats showed significant savings in their rate of re-extinction. Thus, the vmPFC is not the only site where extinction memory is stored. Nevertheless, lesioned rats receiving only two extinction trials per day required twice as many days to initiate extinction as controls. Although recall of extinction is possible without the vmPFC, it is significantly delayed. We suggest that the vmPFC accelerates extinction by permitting access to recently learned extinction trials, thereby maximizing behavioral flexibility.     

Electrolytic lesions of the medial prefrontal cortex do not interfere with long-term memory of extinction of conditioned fear

Lesion studies indicate that rats without the medial prefrontal cortex (mPFC) have difficulty recalling fear extinction acquired the previous day. Several electrophysiological studies have also supported this observation by demonstrating that extinction-related increases in neuronal activity in the mPFC participate in expression of fear extinction. However, a more recent study has shown that fear extinction can be recalled, in certain circumstances, without mPFC potentiation, suggesting contribution of other circuits. Here, we examined this possibility in rats that were subjected to auditory fear conditioning, extinction training, and extinction retention test 7 d later. Electrolytic lesions were made in the mPFC, the motor cortex (MO), the dorsal septum (SEP), or the mediodorsal thalamus (MD), because of their potential participation in conditioned fear inhibition; combined lesions including the mPFC with the MO, SEP, or MD were also made. The lesions were made either 1 wk before conditioning or 1 d after extinction training. All rats normally extinguished their conditioned freezing behavior during extinction training and did not display any return of this behavior during the retention test. These data reveal that the mPFC is not required for the acquisition, the expression, or the retrieval of extinction memories but do not exclude the possibility that the mPFC normally participates in these processes.     

Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear

After extinction of conditioned fear, memory for the conditioning and extinction experiences becomes context dependent. Fear is suppressed in the extinction context, but renews in other contexts. This study characterizes the neural circuitry underlying the context-dependent retrieval of extinguished fear memories using c-Fos immunohistochemistry. After fear conditioning and extinction to an auditory conditioned stimulus (CS), rats were presented with the extinguished CS in either the extinction context or a second context, and then sacrificed. Presentation of the CS in the extinction context yielded low levels of conditioned freezing and induced c-Fos expression in the infralimbic division of the medial prefrontal cortex, the intercalated nuclei of the amygdala, and the dentate gyrus (DG). In contrast, presentation of the CS outside of the extinction context yielded high levels of conditioned freezing and induced c-Fos expression in the prelimbic division of the medial prefrontal cortex, the lateral and basolateral nuclei of the amygdala, and the medial division of the central nucleus of the amygdala. Hippocampal areas CA1 and CA3 exhibited c-Fos expression when the CS was presented in either context. These data suggest that the context specificity of extinction is mediated by prefrontal modulation of amygdala activity, and that the hippocampus has a fundamental role in contextual memory retrieval.Considerable interest has emerged in recent years in the neural mechanisms underlying the associative extinction of learned fear (Maren and Quirk 2004; Myers et al. 2006; Quirk and Mueller 2008). Notably, extinction is a useful model for important aspects of exposure-based therapies for the treatment of human anxiety disorders such as panic disorder and post-traumatic stress disorder (PTSD) (Bouton et al. 2001, 2006). During extinction, a conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US), a procedure that greatly reduces the magnitude and probability of the conditioned response (CR). After the extinction of fear, there is substantial evidence that extinction does not erase the original fear memory, but results in a transient inhibition of fear. For example, extinguished fear responses return after the mere passage of time (i.e., spontaneous recovery) or after a change in context (i.e., renewal) (Bouton et al. 2006; Ji and Maren 2007). In other words, extinguished fear is context specific. The return of fear after extinction is a considerable challenge for maintaining long-lasting fear suppression after exposure-based therapies (Rodriguez et al. 1999; Hermans et al. 2006; Effting and Kindt 2007; Quirk and Mueller 2008).In the last several years, considerable progress has been made in understanding the neural mechanisms underlying the context specificity of fear extinction. For example, lesions or inactivation of the hippocampus prevent the renewal of fear when an extinguished CS is presented outside of the extinction context (Corcoran and Maren 2001, 2004; Corcoran et al. 2005; Ji and Maren 2005, 2008; Hobin et al. 2006). In addition, neurons in the basolateral complex of the amygdala exhibit context-specific spike firing to extinguished CSs (Hobin et al. 2003; Herry et al. 2008), and this requires hippocampal input (Maren and Hobin 2007). Indeed, amygdala neurons that fire more to extinguished CSs outside of the extinction context are monosynaptically excited by hippocampal stimulation (Herry et al. 2008). In contrast, neurons that responded preferentially to extinguished CSs in the extinction context receive synaptic input from the medial prefrontal cortex (Herry et al. 2008).The prevalent theory of the interactions between the prefrontal cortex, hippocampus, and amygdala that lead to regulation of fear by context assumes that when animals experience an extinguished CS in the extinction context, the hippocampus drives prefrontal cortex inhibition of the amygdala to suppress fear (Hobin et al. 2003; Maren and Quirk 2004; Maren 2005). When animals encounter an extinguished CS outside of the extinction context, the hippocampus is posited to inhibit the prefrontal cortex and thereby promote amygdala activity required to renew fear. The hippocampus may also drive fear renewal through its direct projections to the basolateral amygdala (Herry et al. 2008). Although this model accounts for much of the extant literature on the context specificity of extinction, it is not known whether the nodes of this hypothesized neural network are coactive during the retrieval of fear and extinction memories. As a first step in addressing this issue, we used ex vivo c-Fos immunohistochemistry (e.g., Knapska et al. 2007) to generate a functional map of the neural circuits involved in the contextual retrieval of fear memory after extinction. Our results reveal reciprocal activity in prefrontal-amygdala circuits involved in extinction and renewal and implicate the hippocampus in hierarchical control of contextual memory retrieval within these circuits.     

Distinct contributions of the basolateral amygdala and the medial prefrontal cortex to learning and relearning extinction of context conditioned fear

We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but post-extinction infusion spared retention. Pre-extinction infusion of the GABA(A) agonist, muscimol, depressed freezing and impaired retention as did post-extinction infusion. In Experiment 2, pre-extinction mPFC infusion of ifenprodil spared the development of inhibition whereas muscimol depressed freezing. Both impaired retention when infused pre- or post-extinction. Thus, the development of inhibition involves NMDAr activation in the BLA, whereas its consolidation involves both NMDAr activation in the mPFC and NMDAr-independent mechanisms in the BLA. In Experiment 3, BLA infusion of ifenprodil impaired relearning and retention of inhibition when infused before but did not impair retention when infused after re-extinction. BLA infusion of muscimol depressed freezing but did not impair retention when infused before or after re-extinction. In Experiment 4, mPFC infusion of ifenprodil impaired relearning when infused before re-extinction, whereas muscimol depressed responses. Both drugs impaired retention when infused into the mPFC before or after re-extinction. Thus, relearning to inhibit fear responses involves NMDAr activation in both the BLA and mPFC and consolidation of the inhibitory memory involves NMDAr activation in the mPFC. However, relearning and consolidation occur in the absence of neuronal activity within the BLA. We propose that NMDAr in the mPFC supports relearning inhibition when the BLA is inactivated.     

Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear

We investigated whether postextinction training infusion of PD098059, a selective inhibitor of mitogen-activated protein kinase (MAPK) activation, into the medial prefrontal cortex, would impair retention of extinction learning in rats. We found that immediate, but not late (2 or 4 h), postextinction infusion of PD098059 provoked a full return of conditioned freezing. These results suggest that activation of prefrontal MAPK in early stages of postextinction training participates in processes that protect against spontaneous recovery of aversive responses.     

Dissociating affective evaluation and social cognitive processes in the ventral medial prefrontal cortex

In recent studies, various regions of the ventral medial prefrontal cortex (vmPFC) have been implicated in at least two potentially different mental functions: reasoning about the minds of other people (social cognition) and processing reward related information (affective evaluation). In this study, we test whether the activation in a specific area of the vmPFC, the para-anterior cingulate cortex (PACC), correlates with the reward value of stimuli in general or is specifically associated with social cognition. Participants performed a time estimation task with trial-to-trial feedback in which reward and social context were manipulated separately. Reward was manipulated by giving either positive or negative feedback in the form of small squirts of fluid delivered orally. Social context was manipulated by instructing participants that positive and negative feedback was determined by another person or a computer. The data demonstrate a main effect of feedback, but not social context, in the PACC, suggesting that this area of the vmPFC serves a general function in evaluating and/or representing reward value. In addition, activity in a more anterior subregion of the vmPFC demonstrated reward-related sensitivity only in the social context. Another area that showed a similar interaction was the subgenual cingulate, but this region was only sensitive to negative feedback in the social condition. These findings suggest that, within the vmPFC, the PACC subserves primarily an affective function, whereas in other regions social context can modulate affective responses.     

Trace and contextual fear conditioning are impaired following unilateral microinjection of muscimol in the ventral hippocampus or amygdala, but not the medial prefrontal cortex

Trace fear conditioning, in which a brief empty "trace interval" occurs between presentation of the CS and UCS, differs from standard delay conditioning in that contributions from both the hippocampus and prelimbic medial prefrontal cortex (PL mPFC) are required to form a normal long term memory. Little is currently known about how the PL interacts with various temporal lobe structures to support learning across this temporal gap between stimuli. We temporarily inactivated PL along with either ventral hippocampus or amygdala in a disconnection design to determine if these structures functionally interact to acquire trace fear conditioning. Disconnection (contralateral injections) of the PL with either the ventral hippocampus or amygdala impaired trace fear conditioning; however, ipsilateral control rats were also impaired. Follow-up experiments examined the effects of unilateral inactivation of the PL, ventral hippocampus, or amygdala during conditioning. The results of this study demonstrate that unilateral inactivation of the ventral hippocampus or amygdala impairs memory, while bilateral inactivation of the PL is required to produce a deficit. Memory deficits after unilateral inactivation of the ventral hippocampus or amygdala prevent us from determining whether the mPFC functionally interacts with the medial temporal lobe using a disconnection approach. Nonetheless, our findings suggest that the trace fear network is more integrated than previously thought.     

Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex

The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a conditional stimulus (CS) and an aversive unconditional stimulus (UCS) across a temporal gap. In both rat and human subjects, frontal regions show increased activity during the trace interval separating the CS and UCS. We investigated the contribution of prefrontal neural activity in the rat to the acquisition of trace fear conditioning using microinfusions of the γ-aminobutyric acid type A (GABA_A) receptor agonist muscimol. We also investigated the role of prefrontal N-methyl-d-aspartate (NMDA) receptor-mediated signaling in trace fear conditioning using the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Temporary inactivation of prefrontal activity with muscimol or blockade of NMDA receptor-dependent transmission in mPFC impaired the acquisition of trace, but not delay, conditional fear responses. Simultaneously acquired contextual fear responses were also impaired in drug-treated rats exposed to trace or delay, but not unpaired, training protocols. Our results support the idea that synaptic plasticity within the mPFC is critical for the long-term storage of memory in trace fear conditioning.The prefrontal cortex participates in a wide range of complex cognitive functions including working memory, attention, and behavioral inhibition (Fuster 2001). In recent years, the known functions of the prefrontal cortex have been extended to include a role in long-term memory encoding and retrieval (Blumenfeld and Ranganath 2006; Jung et al. 2008). The prefrontal cortex may be involved in the acquisition, expression, extinction, and systems consolidation of memory (Frankland et al. 2004; Santini et al. 2004; Takehara-Nishiuchi et al. 2005; Corcoran and Quirk 2007; Jung et al. 2008). Of these processes, the mechanisms supporting the acquisition of memory may be the least understood. Recently, the medial prefrontal cortex (mPFC) has been shown to be important for trace fear conditioning (Runyan et al. 2004; Gilmartin and McEchron 2005), which provides a powerful model system for studying the neurobiological basis of prefrontal contributions to memory. Trace fear conditioning is a variant of standard “delay” fear conditioning in which a neutral conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS). Trace conditioning differs from delay conditioning by the addition of a stimulus-free “trace” interval of several seconds separating the CS and UCS. Learning the CS–UCS association across this interval requires forebrain structures such as the hippocampus and mPFC. Importantly, the mPFC and hippocampus are only necessary for learning when a trace interval separates the stimuli (Solomon et al. 1986; Kronforst-Collins and Disterhoft 1998; McEchron et al. 1998; Takehara-Nishiuchi et al. 2005). This forebrain dependence has led to the hypothesis that neural activity in these structures is necessary to bridge the CS–UCS temporal gap. In support of this hypothesis, single neurons recorded from the prelimbic area of the rat mPFC exhibit sustained increases in firing during the CS and trace interval in trace fear conditioning (Baeg et al. 2001; Gilmartin and McEchron 2005). Similar sustained responses are not observed following the CS in delay conditioned animals or unpaired control animals. This pattern of activity is consistent with a working memory or “bridging” role for mPFC in trace fear conditioning, but it is not clear whether this activity is actually necessary for learning. We address this issue here using the γ-aminobutyric acid type A (GABA_A) receptor agonist muscimol to temporarily inactivate cellular activity in the prelimbic mPFC during the acquisition of trace fear conditioning.The contribution of mPFC to the long-term storage (i.e., 24 h or more) of trace fear conditioning, as opposed to a strictly working memory role (i.e., seconds to minutes), is a matter of some debate. Recent reports suggest that intact prefrontal activity at the time of testing is required for the recall of trace fear conditioning 2 d after training (Blum et al. 2006a), while mPFC lesions performed 1 d after training fail to disrupt the memory (Quinn et al. 2008). The findings from the former study may reflect a role for prelimbic mPFC in the expression of conditional fear rather than memory storage per se (Corcoran and Quirk 2007). However, blockade of the intracellular mitogen-activated protein kinase (MAPK) cascade during training impairs the subsequent retention of trace fear conditioning 48 h later (Runyan et al. 2004). Activation of the MAPK signaling cascade can result in the synthesis of proteins necessary for synaptic strengthening, providing a potential mechanism by which mPFC may participate in memory storage. To better understand the nature of the prefrontal contribution to long-term memory, more information is needed about fundamental plasticity mechanisms in this structure. Dependence on N-methyl-d-aspartate receptors (NMDAR) is a key feature of many forms of long-term memory, both in vitro and in vivo. The induction of long-term potentiation (LTP) in the hippocampus, a cellular model of long-term plasticity and information storage, requires NMDAR activation (Reymann et al. 1989). Genetic knockdown or pharmacological blockade of NMDAR-mediated neurotransmission in the hippocampus impairs several forms of hippocampus-dependent memory, including trace fear conditioning (Tonegawa et al. 1996; Huerta et al. 2000; Quinn et al. 2005), but it is unknown if activation of these receptors is necessary in the mPFC for the acquisition of trace fear conditioning. Data from in vivo electrophysiology studies have shown that stimulation of ventral hippocampal inputs to prelimbic neurons in mPFC produces LTP, and the induction of prefrontal LTP depends upon functional NMDARs (Laroche et al. 1990; Jay et al. 1995). If the role of mPFC in trace fear conditioning goes beyond simply maintaining CS information in working memory, then activation of NMDAR may be critical to memory formation. We test this hypothesis by reversibly blocking NMDAR neurotransmission with 2-amino-5-phosphonovaleric acid (APV) during training to examine the role of prefrontal NMDAR to the acquisition of trace fear conditioning.Another important question is whether mPFC contributes to the formation of contextual fear memories. Fear to the training context is acquired simultaneously with fear to the auditory CS in both trace and delay fear conditioning. Conflicting reports in the literature suggest the role of mPFC in contextual fear conditioning is unclear. Damage to ventral areas of mPFC prior to delay fear conditioning has failed to impair context fear acquisition (Morgan et al. 1993). Prefrontal lesions incorporating dorsal mPFC have in some cases been reported to augment fear responses to the context (Morgan and LeDoux 1995), while blockade of NMDAR transmission has impaired contextual fear conditioning (Zhao et al. 2005). Post-training lesions of mPFC impair context fear retention (Quinn et al. 2008) in trace and delay conditioning. Contextual fear responses were assessed in this study to determine the contribution of neuronal activity and NMDAR-mediated signaling in mPFC to the acquisition of contextual fear conditioning.     

Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear

Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.     

Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex

Phosphatidylinositol 3-kinase (PI3K) and its downstream targets, including Akt (also known as protein kinase B, PKB), mammalian target of rapamycin (mTOR), the 70-kDa ribosomal S6 kinase (p70S6k), and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), may play important roles in long-term synaptic plasticity and memory in many brain regions, such as the hippocampus and the amygdala. The present study investigated the role of the PI3K/Akt-mTOR signaling pathway in the medial prefrontal cortex (mPFC), also a crucial neural locus for the control of cognition and emotion. Western blot analysis of mPFC tissues showed an activation of phosphorylation of Akt at the Ser473 residues, mTOR, p70S6k, and 4E-BP1 in response to long-term potentiation (LTP)-inducing high-frequency stimulation (HFS). Infusion of PI3K inhibitors (wortmannin and LY294002) and an mTOR inhibitor (rapamycin) into the mPFC in vivo suppressed HFS-induced LTP as well as the phosphorylation of PI3K/Akt-mTOR signaling pathway. In parallel, these inhibitors interfered with the long-term retention of trace fear memory examined 3 d and 6 d after the trace fear conditioning training, whereas short-term trace fear memory and object recognition memory were kept intact. These results provide evidence of involvement of activation of the PI3K/Akt-mTOR signaling pathway in the mPFC for LTP and long-term retention of trace fear memory.     

Inverse temporal contributions of the dorsal hippocampus and medial prefrontal cortex to the expression of long-term fear memories

Retrograde amnesia following disruptions of hippocampal function is often temporally graded, with recent memories being more impaired. Evidence supports the existence of one or more neocortical long-term memory storage/retrieval site(s). Neurotoxic lesions of the medial prefrontal cortex (mPFC) or the dorsal hippocampus (DH) were made 1 day or 200 days following trace fear conditioning. Recently encoded trace fear memories were most disrupted by DH lesions, while remotely encoded trace and contextual memories were most disrupted by mPFC lesions. These data strongly support the consolidation theory of hippocampus function and implicate the mPFC as a site of long-term memory storage/retrieval.     

Value, pleasure and choice in the ventral prefrontal cortex

Rapid advances have recently been made in understanding how value-based decision-making processes are implemented in the brain. We integrate neuroeconomic and computational approaches with evidence on the neural correlates of value and experienced pleasure to describe how systems for valuation and decision-making are organized in the prefrontal cortex of humans and other primates. We show that the orbitofrontal and ventromedial prefrontal (VMPFC) cortices compute expected value, reward outcome and experienced pleasure for different stimuli on a common value scale. Attractor networks in VMPFC area 10 then implement categorical decision processes that transform value signals into a choice between the values, thereby guiding action. This synthesis of findings across fields provides a unifying perspective for the study of decision-making processes in the brain.     

Right-sided human prefrontal brain activation during acquisition of conditioned fear

This H2(15)O positron emission tomography (PET) study reports on relative regional cerebral blood flow (rCBF) alterations during fear conditioning in humans. In the PET scanner, subjects viewed a TV screen with either visual white noise or snake videotapes displayed alone, then with electric shocks, followed by final presentations of white noise and snakes. Autonomic nervous system responses confirmed fear conditioning only to snakes. To reveal neural activation during acquisition, while equating sensory stimulation, scans during snakes with shocks and white noise alone were contrasted against white noise with shocks and snakes alone. During acquisition, rCBF increased in the right medial frontal gyrus, supporting a role for the prefrontal cortex in fear conditioning to unmasked evolutionary fear-relevant stimuli.     

Neural mediation of memory for time: Role of the hippocampus and medial prefrontal cortex

Within the context of the neurobiology of attribute model, memory for the temporal attribute is composed of at least three features—memory for duration, memory for succession, or temporal order, and memory for past and future time perspective within a dual-based (data and knowledge) memory system. Research aimed at testing the assumption that the hippocampus and interconnected neural circuits mediate the temporal attribute within the data-based memory system and the prefrontal cortex and interconnected neural circuits mediate the temporal attribute within the knowledge-based memory system in animals and humans is reviewed. The research indicates that (1) memory for the duration feature of the temporal attribute is mediated by the hippocampus, but not prefrontal cortex, in both animals and humans, (2) memory for the temporal order feature of the temporal attribute based on new information is subserved by both the hippocampus and the prefrontal cortex, but that based on prior knowledge or the ability to use prior knowledge is supported only by prefrontal cortex, and not the hippocampus, in both animals and humans, and (3) memory for the past (time perspective) feature of the temporal attribute is mediated by the hippocampus, whereas memory for the future (time perspective) feature of the temporal attribute is supported by the prefrontal cortex in both animals and humans. There is a clear parallel between animals and humans in terms of hippocampal and prefrontal cortex mediation of the temporal attribute, supporting the assumption of evolutionary continuity. There is support for a greater involvement of the hippocampus in comparison with the prefrontal cortex in mediating temporal attribute information within the data-based memory system. Conversely, there is support for a greater involvement of the prefrontal cortex in comparison with the hippocampus in mediating temporal attribute information within the knowledge-based memory system. Future research needs to concentrate on the development of new paradigms to measure memory for different temporal features and to uncover the critical neural circuits that subserve these temporal features.     

Concept-based behavioral planning and the lateral prefrontal cortex

Many lines of evidence implicate the lateral prefrontal cortex (LPFC) in the executive control of behavior. In early studies, neuronal activity in this area was thought to retain information about forthcoming movements for a short period until they were executed. However, later studies have stressed its role in the cognitive aspects of behavioral planning, such as behavioral significance, behavioral rules and behavioral goals. The consequence of the intended action (i.e. a change in the state of the target object), rather than the intended movement, is primarily represented in the LPFC during planning. Recent studies show that the LPFC is involved in more abstract aspects of conceptual processes, such as in representing categories of multiple actions at the stage of behavioral planning.     

Neonatal ventral hippocampus lesions disrupt extra-dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats

Recent data showed that neonatal ventral hippocampus (VH) lesions, an approach used to model schizophrenia symptoms in rodents, produce premature deficits of working memory believed to be associated with early medial prefrontal cortex (mPFC) maldevelopment. This experiment expands the investigation of mPFC integrity in juvenile rats with neonatal VH lesions by assessing behavioral flexibility and dendritic spine density. Sixteen Sprague-Dawley male pups received bilateral microinjections of ibotenic acid in the VH or SHAM surgery on postnatal day (PND) 6. On PND 29 and 30, rats were subjected to a spatial shift task in a cross-maze; an attentional set-shifting task was then administered on two consecutive days, between PND 33 and PND 35. Rats were sacrificed at PND 36 and dendritic spine density in the mPFC was assessed using Golgi-Cox staining procedure. Results revealed impaired extra-dimensional shift in VH-lesioned rats and inconsistent reversal discrimination outcomes. Although lesioned animals displayed intact performance in the spatial shift, rates of perseverative responses were higher than normal in this task. Neonatal VH damage resulted in lower dendritic spine density in the mPFC than measured in control brains; however, no significant correlation was found between this outcome and behavioral data. Juvenile morphological and cognitive perturbations are consistent with the early emergence of mPFC anomalies following neonatal VH lesions. Results are discussed in relation with potential common mechanisms linking pre- and post-pubertal onsets of behavioral dysfunction.     

Medial prefrontal cortex activation facilitates re-extinction of fear in rats

It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training. Immediately prior to extinction, rats received microinfusions into the IL of the GABA(A) receptor antagonist, picrotoxin, or the NMDA receptor partial agonist, D-cycloserine. Although neither drug facilitated extinction, they both facilitated the subsequent re-extinction of fear when animals were trained in a drug-free state, suggesting that activating the IL primes behavioral extinction.     

Emotional processing in anterior cingulate and medial prefrontal cortex

Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.     

An analysis of rat prefrontal cortex in mediating executive function

While it is acknowledged that species specific differences are an implicit condition of comparative studies, rodent models of prefrontal function serve a significant role in the acquisition of converging evidence on prefrontal function across levels of analysis and research techniques. The purpose of the present review is to examine whether the prefrontal cortex (PFC) in rats supports a variety of processes associated with executive function including working memory, temporal processing, planning (prospective coding), flexibility, rule learning, and decision making. Therefore, in this review we examined changes associated with working memory processes for spatial locations, visual objects, odors, tastes, and response domains or attributes, temporal processes including temporal order, sequence learning, prospective coding, behavioral flexibility associated with reversal learning and set shifting, paired associate learning, and decision making based on effort, time discounting, and uncertainty following damage to the PFC in rats. In addition, potential parallel processes of executive function in monkeys and humans based on several theories of subregional differentiation within the PFC will be presented. Specifically, theories based on domain or attribute specificity (Goldman-Rakic, 1996), level of processing (Petrides, 1996), rule learning based on complexity (Wise, Murray, & Gerfen, 1996), executive functions based on connectivity with other brain regions associated with top-down control (Miller & Cohen, 2001), are presented and applied to PFC function in rats with the aim of understanding subregional specificity in the rat PFC. The data suggest that there is subregional specificity within the PFC of rats, monkey and humans and there are parallel cognitive functions of the different subregions of the PFC in rats, monkeys and humans.