Ablation Of Prefrontal Cortex Research Articles

A neural model of normal and abnormal learning and memory consolidation: adaptively timed conditioning, hippocampus, amnesia, neurotrophins, and consciousness

How do the hippocampus and amygdala interact with thalamocortical systems to regulate cognitive and cognitive-emotional learning? Why do lesions of thalamus, amygdala, hippocampus, and cortex have differential effects depending on the phase of learning when they occur? In particular, why is the hippocampus typically needed for trace conditioning, but not delay conditioning, and what do the exceptions reveal? Why do amygdala lesions made before or immediately after training decelerate conditioning while those made later do not? Why do thalamic or sensory cortical lesions degrade trace conditioning more than delay conditioning? Why do hippocampal lesions during trace conditioning experiments degrade recent but not temporally remote learning? Why do orbitofrontal cortical lesions degrade temporally remote but not recent or post-lesion learning? How is temporally graded amnesia caused by ablation of prefrontal cortex after memory consolidation? How are attention and consciousness linked during conditioning? How do neurotrophins, notably brain-derived neurotrophic factor (BDNF), influence memory formation and consolidation? Is there a common output path for learned performance? A neural model proposes a unified answer to these questions that overcome problems of alternative memory models.

Medial prefrontal cortex ablation results in impaired spatial memory and hippocampal long-term potentiation with increased functional connectivity in vivo

Event Abstract Back to Event Medial prefrontal cortex ablation results in impaired spatial memory and hippocampal long-term potentiation with increased functional connectivity in vivo Amira Latif-Hernandez1*, Disha Shah2, Adrian Lo1, Tariq Ahmed1, Zsuzsanna Callaerts-Vegh1, Joris De Wit3, Annemie Van Der Linden2, Detlef Balschun1 and Rudi D'Hooge1 1 Katholieke Universiteit Leuven, Belgium 2 University of Antwerp, Biomedical Sciences, Belgium 3 VIB center for the biology of disease, Human genetics, Belgium Hippocampus (HC) and prefrontal cortex (PFC) are two brain regions that are essential for cognitive flexibility, ability to adapt to new situational demands (Hampshire, Chaudhry, Owen, & Roberts, 2012). PFC/HC projections are activated during attention and dissociable types of flexible behavior (Hok V, Lenck-Santini PP, Roux S, Save E, Muller RU, 2007). Furthermore, impaired PFC/HC communications might contribute to the cognitive rigidity observed in a variety of neurodegenerative disorders such as Alzheimer’s and frontotemporal dementia (Ittner & Götz, 2011). In the present study, we investigated the functional role of the PFC/HC network in cognitive flexibility by combining behavioral, electrophysiological, molecular readouts and brain imaging “in vivo” with excitotoxic inactivation (quinolinic acid, 30 mM). C57/BL6J mice were trained in the Morris water maze for ten consecutive days, a hippocampus-dependent spatial learning task. Immediately after acquisition learning, excitotoxic lesions were applied to the PFC (comprising infralimbic -IL/prelimbic –PrL-cortices) and cognitive flexibility was assessed during spatial reversal trials for five days. PFC lesions impaired reversal learning and affected search strategies to locate the hidden platform. Lesioned animals used a significantly higher percentage of non-spatial search strategies during reversal learning whereas control mice benefitted significantly more from spatial search strategies. Furthermore, the lesions in the IL/PrL area altered long-term potentiation (LTP) in the hippocampal CA1-region of slices prepared ex-vivo immediately after reversal learning. PFC-lesioned mice showed reduced hippocampal LTP and decreased amplitude in the Input/Output curve, as a measure of basal synaptic transmission. We also examined whether the reduced LTP was a consequence of the missing PFC input or rather an acute effect of the excitotoxic hyperactivation of NMDA receptors in the PFC caused by quinolinic acid. Importantly, twenty-four hours after the excitotoxic injection, hippocampal LTP was similar to controls. Moreover, the analysis of synaptic proteins revealed that PSD95, AMPA receptors and the NR2A subunit of the NMDA receptors were not affected in the hippocampi tissue from the lesioned mice compared with sham treated. In addition, resting state magnetic resonance imaging (rsfMRI) on day seven after the QA injection into PFC revealed stronger functional connectivity of the CA1 region of the HC with the rest brain areas, which might indicate an hippocampal hyperactivation caused by compensatory mechanisms to counteract the prefrontal impairment. In conclusion, mPFC lesions impair behavioral flexibility that is needed to adjust behavior to new environmental demands and hippocampal synaptic plasticity. Figure 1 Figure 2 Figure 3 Acknowledgements This work was supported by research grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G058714 and G0D76114) and an interdisciplinary research grant from KU Leuven (GOA 12/008).

Neurotoxic lesions of ventrolateral prefrontal cortex impair object‐in‐place scene memory

Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal–temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-d-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex rather than to interruption of fibres of passage through the lesioned area.

Prefrontal cortex and hippocampus in posttraumatic functional recovery: Spatial delayed alternation by rats subjected to transection of the fimbria–fornix and/or ablation of the prefrontal cortex

Lesions of the prefrontal cortex and the hippocampus often lead to impairment of the same behavioural tasks (e.g., allocentric as well as egocentric spatial orientation and spatial delayed alternation). In case of allocentric and egocentric spatial orientation we have previously found that the two structures mutually contribute to the posttraumatic functional recovery of such tasks. We therefore presently tested the hypothesis that this would even be true in case of spatial delayed alternation. The acquisition of a spatial delayed alternation task in a T-maze was studied in four groups of rats: animals in which the fimbria–fornix had been transected bilaterally, rats who had received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham operated control group. All three lesion groups demonstrated an impaired task acquisition. The group given prefrontal cortical lesions in isolation underwent a complete functional recovery. Both of the fimbria–fornix transected groups were significantly impaired even when compared to the group given prefrontal cortical ablations in isolation. The two fimbria–fornix lesioned groups did, however, exhibit levels of functional recovery. The group in which both structures had been lesioned demonstrated a task acquisition, which was significantly inferior to that of the group given fimbria–fornix transections in isolation. After completion of the task acquisition period, all animals were subjected to two behavioural challenges including a session on which the duration of the inter-trial delay was doubled. This expansion of the inter-trial delay rather selectively impaired the task performance of the group given fimbria–fornix transections in isolation. Consequently, both during the acquisition period and in one of the challenges a differentiation of functional recovery was seen between the combined lesioned group and the group given fimbria–fornix lesions only. This indicates that even in case of a spatial delayed alternation task the prefrontal cortex normally contributes significantly to mediation of posttraumatic functional recovery after isolated lesions of the fimbria–fornix. The results are discussed in the context of models of posttraumatic functional recovery.

The role of prefrontal cortex in object‐in‐place learning in monkeys

Previous ablation studies in monkeys suggest that prefrontal cortex is involved in a wide range of learning and memory tasks. However, monkeys with crossed unilateral lesions of frontal and temporal cortex are unimpaired at concurrent object-reward association learning but are impaired at conditional learning and the implementation of memory-based performance rules. We trained seven monkeys preoperatively on an associative learning task that required them to associate objects embedded in unique complex scenes with reward. Three monkeys then had crossed unilateral lesions of frontal and inferior temporal cortex and the remaining monkeys had bilateral prefrontal cortex ablation. Both groups were severely impaired postoperatively. These results show that both bilateral prefrontal cortex ablation and frontal-temporal disconnection impair associative learning for objects embedded in scenes. The results provide evidence that the function of frontal-temporal interactions in memory is not limited to conditional learning tasks and memory-dependent performance rules. We propose that rapid object-in-place learning requires the interaction of frontal cortex with inferotemporal cortex because visual object and contextual information which is captured over multiple saccades must be processed as a unique complex event that is extended in time. The present results suggest a role for frontal-temporal interaction in the integration of visual information over time.

Egocentric spatial orientation in a water maze by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex

The acquisition of a water maze based task requiring egocentric spatial orientation in the absence of distal cues was studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats that received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham-operated control group. Isolated lesions of both the anteromedial prefrontal cortex and the hippocampus were associated with a significantly impaired task acquisition. Both of these individually lesioned groups did, however, eventually demonstrate full functional recovery by reaching the task proficiency of the sham-operated control group. In contrast, the group in which both of these structures had been lesioned failed to demonstrate full functional recovery and was severely and long-lastingly impaired when compared to all other groups. Behavioural challenges in the form of a no-platform session and two reversals of platform position demonstrated that while the sham-operated control group and the group subjected to fimbria-fornix transections in isolation utilized rather pure egocentric orientation strategies, the two prefrontally lesioned groups (and especially the combined lesion group) employed a different set of solution strategies which at least partly relied on a “circling” method. Even in the behaviour of the prefrontally lesioned groups, however, indications of a certain level of cognitive representations of the platform positions were seen. It is concluded that both the prefrontal cortex and the hippocampus contribute to the mediation of egocentric spatial orientation. Furthermore, the hippocampus is a significant and potentially irreplaceable part of the neural substrate of functional recovery of the presently studied task after prefrontal lesions—while the prefrontal cortex may play a similar role with respect to hippocampal lesions.

Place learning and object recognition by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex

The acquisition of a water maze-based allocentric place learning task and an exploration based object recognition task were studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats who had received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham operated control group. None of the groups showed impairments of object recognition. Ablations of the prefrontal cortex caused a mild impairment in the acquisition of the place learning task. The two fimbria-fornix transected groups exhibited a severe impairment during the acquisition of this task. All groups reached criterion level task performance eventually. All groups were subjected to a number of behavioural and pharmacological challenges in order to elucidate the neural and cognitive mechanisms of this behavioural recovery. During a no-platform session both the fimbria-fornix transected group and the prefrontally ablated group demonstrated a normal preference for the former platform position. The combined lesion group, however, failed to show a similar preference for this position. The outcome of the pharmacological challenges demonstrated that while the task performance of all four groups relied equally on catecholaminergic mediation, only the task solution of the fimbria-fornix transected group was significantly impaired by disturbance of the catecholaminergic systems. The data indicated a high likelihood that prefrontal cortical mechanisms contribute to the recovery of allocentric place learning after fimbria-fornix transections.

Progesterone facilitates the acquisition of avoidance learning and protects against subcortical neuronal death following prefrontal cortex ablation in the rat

Following a cortical injury, neurons in areas near and connected to the site of injury begin to degenerate. The observed neuronal death may contribute to the severity of the observed behavioral impairments. The purpose of the present study was to examine if progesterone, a hormone known for its effectiveness at reducing cerebral edema, could protect against secondary neuronal death and facilitate the acquisition of an avoidance learning task in an ablation model of cortical injury. Rats served as sham controls or received bilateral ablation of the medial prefrontal cortex followed by a 10-day regimen of progesterone (4 mg/kg) or oil vehicle (1 ml/kg) beginning 1 h after cortical lesions. Progesterone-treated lesion rats showed a significant facilitation of avoidance learning compared to oil-treated lesion controls. In addition, progesterone-treated lesion animals did not differ from either progesterone- or oil-treated sham controls in avoidance learning. Anatomical analysis revealed that progesterone treatment decreased the amount of neuronal death seen in the striatum and the mediodorsal nucleus of the thalamus. The findings are consistent with the notion that progesterone is an effective neuroprotective agent and suggest that the hormone can reduce the behavioral impairments associated with frontal cortical ablation injury.

Asymmetrical modulation of immune reactivity in left- and right-biased rats after ipsilateral ablation of the prefrontal, parietal and occipital brain neocortex.

We report here on the lateralized brain immunomodulation in male Wistar rats, a phenomenon related to the rotational bias of animal and the site of cortical lesion. Rats assigned to left- and right-rotators in a cylindrical Plexiglass rotometer were subjected to the ablation of the ipsilateral prefrontal cortex (PFC), parietal cortex (PC) and occipital cortex (OC) and sensitized with bovine serum albumin (BSA) in complete Freund's adjuvant. Intact and sham-lesioned left-biased animals demonstrated increased Arthus and delayed hypersensitivity skin reactions and antibody production to BSA in comparison with corresponding right-biased animals. PFC ablation decreased humoral and cellular immune responses to BSA in left- but increased in right-biased rats. Lesioning of PC decreased humoral immune reactions in left- but increased in right-rotating animals. OC ablation failed to produce immunological abnormalities. These results suggest that immunopotentiation is associated with the left neocortex, and immunosuppression with the right neocortex. The prefrontal cortex appears to be particularly associated with immune reactions.

Neurocognitive potentials, cortico-cortical homohemispheric two-way connections and prefrontal cortex ablation or degeneration

Neurocognitive potentials, cortico-cortical homohemispheric two-way connections and prefrontal cortex ablation or degeneration

Effects of stimulation of the mediodorsal nucleus and its projection cortex on heart rate in the rabbit

Electrical stimulation of prefrontal cortex in anesthetized rabbits evoked small (< 10%) changes in heart rate. In contrast, stimulation of the thalamic mediodorsal nucleus (MD) elicited decreases in heart rate proportional to the stimulating current. The maximal peak reductions in heart rate evoked by higher current intensities were 85% from prestimulus levels. The bradycardiac response had a short latency after stimulus onset (< 1 s, peak within 5 s), and the heart rate usually returned to baseline within 30 s after stimulation. Vagal cholinergic innervation of the heart was suggested as the final effector pathway since bilateral vagotomy or administration of atropine (sulfate or methyl nitrate, 0.15–0.4 mg/kg, i.v.) virtually abolished the rapid bradycardiac responses. Administration of a β-adrenergic receptor blocker (propranolol, 3 mg/kg, i.v.) was without effect on the heart rate response. The effective medial thalamic area for evoking a response was localized to MD, the thalamic midline nuclei between both MDs and a region continuous with, but posterior to MD (e.g. parafascicular nucleus). A descending effector pathway from the thalamus was implicated since complete bilateral ablation of prefrontal cortex did not reduce the stimulus-produced bradycardia evoked from MD. Similar large bradycardiac responses were obtained in an unanesthetized preparation to both MD stimulation and to sensory stimuli, suggesting a possible physiological correlate for these intracranially-evoked heart rate changes.

Differential effects of prefrontal cortex ablation in neonatal, juvenile, and young adult rats.

Rats sustaining lesions restricted to the medial (MF) or the orbital (OF) pre-frontal cortex at various ages (10, 25, 40, or 60 days postnatally) were tested as adults on a series of behavioral tasks that are known to be sensitive to such lesions in adults. On spatial alternation learning, both the 40- and 60-day MF operates were seriously impaired, whereas neither the 10- nor the 25-day MF operates differed from control. On a hoarding task, 25- and 60-day MF operates hoarded less food than either controls or 10-day MF operates. Lesions of OF cortex in males at 40 or 60 days of age produced a significant increase in running-wheel activity; OF lesions in both sexes at 25 days of age or later produced a decrease in the rate of continuous reinforcement reacquisition (following experience with differential reinforcement of low rates of responding and bar-press extinction) relative to controls, whereas 10-day OF operates did not differ from controls on either task. Thus, rats with lesions of either frontal area at 10 days of age showed complete behavioral sparing on all measures. The effects of lesions at later ages varied with the behavioral tasks employed and with lesion locus. Although the 10-day operates received a somewhat longer postoperative recovery interval than most of the later operates, these results cannot be explained on the basis of recovery time alone. A control group of 60-day operates with the same recovery interval as the 10-day operates did not differ on any measure from the 60-day operates with shorter recovery intervals.

Activity changes following sulcal, but not medial, ablation of the prefrontal cortex of the guinea pig

Running activity of guinea pigs was compared before and after ablation of the cortical projection areas of the medial and lateral sectors of the thalamic mediodorsal nucleus (sulcal vs. medial prefrontal cortex). Only ablation of the sulcal prefrontal cortex was followed by a significant increase in running activity. This result corresponds to similar observations made in another rodent species, the rat, and also made in nonrodent species. Therefore, it is concluded that, with respect to basic or unlearned functions, interspecies parallels can be drawn for the cortical projection area of the medial portion of the mediodorsal nucleus. At the same time, it is, however, emphasized that the prefrontal cortex cannot be considered to be structurally and/or functionally homogeneous among species.

Functional recovery after serial ablation of prefrontal cortex in the rat

In two experiments, adult rats with 1-stage or 2-stage ablation of discrete subfields of the prefrontal cortex were compared on spatial delayed alternation, one way active avoidance, food hoarding, ingestive behavior, and postoperative body weight. Single stage removal of the ventrolateral (sulcal or orbital) cortex produced aphagia and adipsia for several days postoperatively and a chronic reduction in body weight. Serial removal of this same cortex produced a milder effect on postoperative food and water intake, and there was no chronic reduction of body weight. Ablation of dorsomedial cortex either in one or two stages did not significantly reduce food or water intake or body weight. In contrast, single stage removal of dorsomedial cortex produced dramatic impairment on spatial delayed alternation, active avoidance, and food hoarding; whereas ventrolateral lesions either in one or two stages did not significantly affect performance on these tasks. Animals with dorsomedial lesions produced in two stages were not significantly impaired on delayed alternation or active avoidance, but on food hoarding they were just as impaired as the animals with comparable lesions induced in a single stage. It is apparent that removal of either dorsomedial or ventrolateral prefrontal cortex in two stages causes an amelioration of the deficit that is obtained with single stage destruction of these areas on some tasks, but sparing of function is not an invariant consequence of serial destruction of rat prefrontal cortex.

The origin of the afferent supply to the mediodorsal thalamic nucleus: Enhancement of HRP transport by selective lesions

This experiment attempted to identify the cell bodies of origin of axons in the forebrain which supply the mediodorsal thalamic nucleus (MD). Injections of horseradish peroxidase (HRP) were placed into MD in 60 rats. Survival times varied from 1–4 days. Following injections placed into different portions of MD, HRP positively labeled cells were observed in a variety of forebrain structures which lie rostral to the injection sites. Discrete injections of HRP placed into the midline of MD labeled cells situated exclusively in the extreme ventromedial aspect of central levels of the reticular nucleus. HRP injections which included anterior levels of MD labeled cells situated principally in layers V–VI of the sulcal prefrontal cortex, while injections which involved more posterior and lateral portions of MD labeled cells in the deepest layers of the dorsomedial prefrontal cortex. Injections of this region of MD also labeled cells in adjacent portions of the deepest layers of anterior cingulate gyrus, polymorphic cell layer of prepyriform cortex and olfactory tubercle and sites immediately lateral to the vertical limb of the diagonal band and dorsal to its horizontal limb. Positively labeled cells were observed in the cortical, medial, basolateral and basomedial amygdaloid nuclei and adjacent pyriform cortex only when ablations of prefrontal cortex preceded HRP injections of MD. This findings indicates that lesions of the prefrontal cortex dramatically enhance the HRP labeling process in the amygdala and suggests the possibility that the technique involving the placement of selective lesions may be used to advangate in other anatomical systems which receive multiple inputs from widely distributed sources.

Emotional behavior in feral cats with ablations of prefrontal cortex and subsequent lesions in amygdala.

Bilateral ablations of gyrus proreus in 6 feral cats did not significantly alter either the intensity or the pattern of flight behavior during confrontation with a human. The scores for defense behavior were reduced in only 2 animals. Subsequent lesions in the rostral part of the basolateral nuclei of amygdala reduced flight and transiently decreased defense scores in all cats. The prefrontal cortex does not seem necessary for the flight and defense responding observed in feral cats. The role of amygdala in the regulation of these behaviors was confirmed.

Performance under temporal schedules by monkeys with partial ablations of prefrontal cortex

Three groups of three monkeys (normal controls and monkeys with ablations confined to orbitofrontal or dorsolateral frontal cortex) were trained to lever press for food reinforcement under a fixed-interval schedule. Monkeys with orbital lesions, and only those monkeys, showed significantly elevated response rates and little evidence of response patterning. Neither acquisition nor asymptotic performance under a second temporal schedule, differential-reinforcement-of-low-rates, was abnormal for either these orbital frontal monkeys or monkeys with dorsolateral frontal lesions. Rate of response declined equally rapidly for all groups when this schedule was changed to extinction but orbitals failed to display the accompanying shift toward longer interresponse times shown by the controls. These findings confirm the functional independence of dorsolateral and orbital frontal cortex. They also suggest that characterizing the behavioral changes following orbital lesions as either perseveration or disinhibition is not entirely accurate. An explanation emphasing alternation between two incompatible behaviors is offered as an improvement.

Effects of prefrontal cortex ablation on two-bar ratio performance in primates.

Abstract Squirrel and Cebus monkeys were trained on a two-bar ratio schedule, underwent prefrontal cortex ablations, and were retested on the two-bar problem, using a variety of stimulus situations. Results revealed large behavioral deficits after surgery during the first ten days of testing, with monkeys showing improvements back to near preoperative levels with continued postoperative practice. Results could not be adequately interpreted solely on the basis of a loss of ability to utilize response-produced cues after surgery.

Recovery of Function after Serial Ablation of Prefrontal Cortex in the Rhesus Monkey

Rhesus monkeys with one-stage or serial ablation of sulcus principalis (prefrontal association cortex) were compared on three spatial tasks. On all tests, the serial monkeys made fewer errors than did the monkeys with onestage lesions. These results indicate that partial recovery of function can occur after extensive destruction of association cortex in the mature primate brain if the damage is distributed over a number of operations.

Preservation of delayed response following combined lesions of prefrontal and posterior association cortex in infant monkeys

The preservation of delayed response capacity in monkeys sustaining bilateral ablations of prefrontal cortex in infancy has been attributed to the intactness of the caudate nucleus, since combined prefrontal-caudate lesions in infant monkeys produce severe delayed response deficits at later testing. However, before concluding that the integrity of the caudate is essential, it must be shown that another type of combined lesion sustained in infancy is without substantial effect on later test performance. Since bilateral ablations of parieto-temporo-preoccipital (posterior association) cortex in adult monkeys are known to produce delayed-response deficits, a combined prefrontal-posterior association cortex lesion was judged to be the appropriate control. Accordingly, three infant monkeys were subjected to two-stage bilateral ablations of prefrontal and posterior association cortex prior to postnatal day 18. Testing on a series of delayed response problems was initiated between the eighth and tenth postnatal months. Test performances were found to be essentially equivalent to those of animals sustaining only a prefrontal ablation in infancy. In one preparation, a transient delayed response deficit during initial testing was attributed to minor caudate involvement. Although subtotal ablations in posterior association cortex were found in all cases, the massive lesions that were sustained make it unlikely that this area is functionally involved in preserving delayed response capacity in the early lesioned prefrontal monkey. These results tend to confirm our previous conclusion as to the functional importance of the caudate nucleus, possibly via its capacity to regulate locomotion and attention.