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.     

Memory for frequency in rats: role of the hippocampus and medial prefrontal cortex

On a radial arm maze rats were tested for frequency memory of specific spatial locations, a task that presumably involves the coding of temporal information. On any trial during the study phase rats were allowed to visit three different spatial locations only once and one spatial location twice. During the test phase the rats were given a choice between a spatial location that had been visited once and spatial location that had been visited twice. The rats were reinforced for selecting the twice-visited spatial location. The number of spatial locations between a repetition (lag) was varied from one to three. After extensive training rats displayed memory for frequency only for a lag of three spatial locations, i.e., they displayed a repetition lag effect. Animals then received control, medial prefrontal cortex, or hippocampal lesions. Upon subsequent retests control rats continued to display frequency memory, but animals with medial prefrontal cortex or hippocampal lesions displayed a marked impairment. These data support the idea that both the hippocampus and medial prefrontal cortex code temporal order information.     

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.     

The roles of the medial prefrontal cortex and hippocampus in a spatial paired-association task

Although the roles of both the hippocampus and the medial prefrontal cortex (mPFC) have been suggested in a spatial paired-associate memory task, both areas were investigated separately in prior studies. The current study investigated the relative contributions of the hippocampus and mPFC to spatial paired-associate learning within a single behavioral paradigm. In a novel behavioral task, a pair of different objects appeared repeatedly across trials, but in different arms in a radial maze, and different rules were associated with those arms for reward. Specifically, in an "object-in-place" arm, the rat was required to choose a particular object associated with the arm. In a "location-in-place" arm, the animal was required to choose a certain within-arm location (ignoring the object occupying the location). Compared to normal animals, rats with ibotenic acid-based lesions in the hippocampus showed an irrecoverable impairment in performance in both object-in-place and location-in-place arms. When the mPFC was inactivated by muscimol (GABA(A) receptor agonist) in the normal animals with intact hippocampi, they showed the same severe impairment as seen in the hippocampal lesioned rats only in object-in-place arms. The results confirm that the hippocampus is necessary for a biconditional paired-associate task when space is a critical component. The mPFC, however, is more selectively involved in the object-place paired-associate task than in the location-place paired-associate task. The current task powerfully demonstrates an experimental situation in which both the hippocampus and mPFC are required and may serve as a useful paradigm for investigating the neural mechanisms of object-place association.     

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.     

Role of the ventral medial prefrontal cortex in mediating behavioral control-induced reduction of later conditioned fear

A prior experience of behavioral control over a stressor interferes with subsequent Pavlovian fear conditioning, and this effect is dependent on the activation of the ventral medial prefrontal cortex (mPFCv) at the time of the initial experience with control. It is unknown whether mPFCv activity is necessary during fear learning and/or testing for this interference to occur. One week following controllable stress, the infralimbic cortex (IL) was temporarily inactivated either before fear learning or later testing. Inactivation of the IL before the test for conditioned fear, but not before conditioning, blocked the fear reducing effects of prior controllable stress. This suggests that the experience with control interferes with the expression of fear behavior and not the learning of the association, and that the mPFCv is needed to regulate conditioned fear behavior.     

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.     

Spatial strategy elaboration in egocentric and allocentric tasks following medial prefrontal cortex lesions in the rat

We evaluated the role of the medial prefrontal cortex (mPFC) in the elaboration of egocentric navigation strategies in a water maze (WM). Lesions of mPFC cell bodies was achieved in 21 rats using bilateral injections of ibotenic acid (IA); 13 control rats were injected with saline. After 17 days, rats had to learn an allocentric (using external cues: 10 lesioned, 7 saline rats) or an egocentric WM (using internal/kinetic cues: 10 lesioned, 6 saline rats) over six trials in a same session. The initial trajectory on the sixth trial was used as an index of the elaboration of a navigation strategy. In the egocentric test, lesioned rats were more rarely located in the target quadrant than control rats. No differences were found between lesioned and control rats in the allocentric test. These results show that lesions of the mPFC impairs the capacity to elaborate an egocentric navigation strategy.     

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.     

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.     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

The medial prefrontal cortex and memory of cue location in the rat

We developed a single-trial cue-location memory task in which rats experienced an auditory cue while exploring an environment. They then recalled and avoided the sound origination point after the cue was paired with shock in a separate context. Subjects with medial prefrontal cortical (mPFC) lesions made no such avoidance response, but both lesioned and control subjects avoided the cue itself when presented at test. A follow up assessment revealed no spatial learning impairment in either group. These findings suggest that the rodent mPFC is required for incidental learning or recollection of the location at which a discrete cue occurred, but is not required for cue recognition or for allocentric spatial memory.     

Reevaluating the role of the medial prefrontal cortex in delay eyeblink conditioning

It has been proposed that the medial prefrontal cortex (mPFC) is not necessary for delay eyeblink conditioning (DEC). Here, we investigated the involvement of the mPFC in DEC with a soft or loud tone as the conditioned stimulus (CS) by using electrolytic lesions or muscimol inactivation of guinea pig mPFC. Interestingly, when a soft tone was used as a CS, electrolytic lesions of the mPFC significantly retarded acquisition of the conditioned response (CR), and muscimol infusions into mPFC distinctly inhibited the acquisition and expression of CR, but had no significant effect on consolidation of well-learned CR. In contrast, both electrolytic lesions and muscimol inactivation of mPFC produced no significant deficits in the CR when a loud tone was used as the CS, or in the unconditioned response (UR) when a soft or loud tone was used as the CS. These results demonstrate that the mPFC is essential for the DEC with the soft tone CS but not for the DEC with the loud tone CS.     

Neonatal hippocampal lesion alters the functional maturation of the prefrontal cortex and the early cognitive development in pre-juvenile rats

Mnemonic and executive performance is encoded into activity patterns of complex neuronal networks. Lesion studies revealed that adult recognition memory critically depends on the activation of the prefrontal cortex (PFC) and hippocampus (HP). However, its developmental profile remains poorly elucidated. We previously showed the rat PFC and HP are functionally coupled in theta- and gamma-band oscillations during neonatal [postnatal day (P) 5-8] and pre-juvenile (P10-15) stages of development. Here, we assess the behavioral readout of this early prefrontal-hippocampal activation by investigating the ontogeny and the mechanisms of novelty detection and recognition memory in relationship to the functional integrity of the PFC and HP. Excitotoxic lesion of the HP at birth led to abnormal oscillatory entrainment of the PFC throughout neonatal and pre-juvenile development. Although the onset of novelty detection correlated rather with the maturation of sensory perception and motor skills than with hippocampal integrity, the pre-juvenile performance in item, spatial and temporal order recognition memory significantly decreased after HP lesion at birth. This poorer performance does result neither from abnormal developmental milestones and locomotion nor from increased anxiety. Thus, novelty recognition in rat emerges during the second postnatal week and requires functional integrity of communication within neuronal networks including the PFC and HP.     

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.     

Subregion-specific dendritic spine abnormalities in the hippocampus of Fmr1 KO mice

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and is caused by the lack of fragile X mental retardation protein (FMRP). In the brain, spine abnormalities have been reported in both patients with FXS and Fmr1 knockout mice. This altered spine morphology has been linked to disturbed synaptic transmission related to altered signaling in the excitatory metabotropic glutamate receptor 5 (mGluR5) pathway. We investigated hippocampal protrusion morphology in adult Fmr1 knockout mice. Our results show a hippocampal CA1-specific altered protrusion phenotype, which was absent in the CA3 region of the hippocampus. This suggests a subregion-specific function of FMRP in synaptic plasticity in the brain.     

Phosphorylation of mitogen-activated protein kinase in the medial prefrontal cortex and the amygdala following memory retrieval or forgetting in developing rats

We examined neuronal correlates of forgetting in rats by detection of phosphorylated mitogen-activated protein kinase (pMAPK) in the medial prefrontal cortex (mPFC) and amygdala. In Experiment 1, postnatal day (P)23 and P16 rats received paired noise CS-shock US presentations. When tested immediately after conditioning, P23 and P16 rats exhibited similar levels of conditioned fear; when tested after 2 days, however, P16 rats showed poor CS-elicited freezing relative to P23 rats. In Experiment 2, P16 and P23 rats received either paired or unpaired CS-US presentations, and then were tested 48 h later. Consistent with Experiment 1, P16 rats showed forgetting whereas P23 rats exhibited good retention at test. Additionally, unpaired groups showed poor CS-elicited freezing at test. Immunohistochemistry showed that P23 and P16 rats given paired presentations exhibited significant elevation of pMAPK-immunoreactive (ir) neurons in the amygdala compared to rats given unpaired presentations. That is, MAPK phosphorylation in the amygdala tracked learning history rather than behavioral performance at test. In contrast, only the P23-paired group showed an elevated number of pMAPK-ir neurons in mPFC, indicating that MAPK phosphorylation in the mPFC tracks memory expression. Different test-perfusion intervals were employed in Experiment 3, which showed that the developmental dissociation in the pMAPK-ir neurons observed in the mPFC in Experiment 2 was not due to age differences in the rate of phosphorylation of MAPK. These findings provide initial evidence suggesting that while the mPFC is involved in memory retrieval, MAPK phosphorylation in the amygdala may be a persisting neural signature of fear memory.     

Involvement of the medial prefrontal cortex in two alternation tasks using different environments

Spatial alternation performance in rats is usually evaluated with the T-Maze. The first aim of this study was to analyze the effect of a selective lesion of medial prefrontal cortex (mPFC) on performance in a T-maze. Second, we wanted to validate a new test using alternation in a water maze (AWM). The mPFC of 21 male Sprague-Dawley rats was lesioned bilaterally using in situ microinjection of ibotenic acid. Thirteen control rats received injections of the vehicle only. Results show that mPFC lesioned rats were significantly impaired in the T-Maze as well as in the AWM compared to controls. These results validate the AWM as a frontal cortex dependent task probing working memory and/or behavioral flexibility. We suggest that the AWM may be more powerful than the T-maze as an investigational tool, given that is can be easily compared to other water maze tasks that evaluate other (nonfrontal) cognitive modules.     

Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use

Previously, the authors found that partial denervation of the motor cortex in adult animals can enhance this region's neuronal growth response to relevant behavioral change. Rats with partial corpus callosum transections that were forced to rely on one forelimb for 18 days had increased dendritic arborization of layer V pyramidal neurons in the opposite motor cortex compared to controls. This was not found as a result of denervation alone or of forced forelimb use alone. However, it seemed possible that each independent manipulation (i.e., forced forelimb use alone and callosal transections alone) resulted in neural structural alterations that were simply not revealed in measurements of dendritic branch number and/or not inclusive of layer V dendrites. This possibility was assessed in the current study with a reexamination of the Golgi-Cox impregnated tissue generated in the previous study. Tissue was quantified from rats that received either partial transections of the rostral two-thirds of the corpus callosum (CCX) or sham operations (Sham) followed either by 18 days of forced use of one forelimb (Use) or unrestricted use of both forelimbs (Cont). Measurements of apical and basilar dendrites from pyramidal neurons of layer II/III and layer V were performed to detect spine addition resulting from either increased spine density or the addition of dendritic material. As hypothesized, significant spine addition was found following forced forelimb use alone (Sham+Use) and callosal transections alone (CCX+Cont). However, forced use primarily increased spines on layer II/III pyramidal neurons, whereas callosal transections primarily increased dendritic spines on layer V pyramidal neurons in comparison to Sham+Cont. A much more robust increase in layer V dendritic spines was found in animals with the combination of forced forelimb use and denervation (CCX+Use). In contrast to the effects of forced use alone, however, CCX+Use rats failed to show major net increases in spines on layer II/III neurons. These results indicate that while callosal denervation may greatly enhance the neuronal growth and synaptogenic response to behavioral change in layer V, it may also limit spine addition associated with forced forelimb use in layer II/III of the motor cortex.