Lesions Of Medial Prefrontal Cortex Research Articles

Memory for temporal order of new and familiar spatial location sequences: role of the medial prefrontal cortex.

Rats with medial prefrontal cortex or sham control lesions were tested on an eight-arm radial maze task to examine memory for the temporal order of a variable and a constant sequence of spatial locations as a function of temporal distance. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected or fixed for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal distance (0, 2, 4, or 6) or the number of arms that occurred between the two test arms in the study phase. For the variable sequences based on new information, control rats showed an increasing temporal distance function. Relative to control rats, medial prefrontal cortex-lesioned rats displayed a temporal order memory deficit across all distances. For the constant sequence based on familiar information, control rats performed well across all distances. Relative to controls, the medial prefrontal cortex-lesioned rats displayed a performance deficit. The results support the idea that the medial prefrontal cortex contributes to mnemonic operations associated with temporal order for new and familiar spatial location information.

Enhanced Amphetamine Sensitivity and Increased Expression of Dopamine D2 Receptors in Postpubertal Rats after Neonatal Excitotoxic Lesions of the Medial Prefrontal Cortex

Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dopamine (DA) neurotransmission are thought to be the key pathologies in schizophrenia. To understand the role of MPFC in the pre- and postpubertal development of the subcortical DA system, the effects of neonatal [postnatal day 7 (PD7)] MPFC excitotoxic lesions on locomotor behaviors and the expression of DA receptor subtypes and DA transporter were investigated in Sprague Dawley rats at PD35 and PD56, respectively. No significant differences in the novelty of d-amphetamine-induced locomotion were observed between sham-operated and ibotenic acid-lesioned rats at PD35. Postpubertally (at PD56), however, the locomotor activity of lesioned rats in the novel environment and after d-amphetamine administration was enhanced significantly compared with controls. The expressions of DA D1, D2, D3, and D4 receptors and DA transporter were then estimated in MPFC-lesioned and sham-operated rats at PD59 and PD60. The levels of DA D2 receptors, measured using [3H]-YM-09151-2 binding, and its mRNA by in situ hybridization, were observed to be significantly increased at PD60 in striatal and limbic areas of lesioned rats. Levels of other DA receptor subtypes were not significantly affected at any time points. Lesioned rats at PD39 show a small increase in DA transporter level in the shell of nucleus accumbens; however, this effect seems to wear off at PD60. The data suggest that neonatal MPFC lesions may alter the functional development and maturation of mesolimbic/nigrostriatal DA systems in that neonatally lesioned rats grow into a behavioral/neurochemical deficit.

P-3-11 - Blockade of brain serotoninergic receptors deteriorates amphetamine-induced self-stimulation in rats with lesion of medial prefrontal cortex

Timm's and horseradish peroxidase histochemical methods were used to demonstrate a small, distal infrapyramidal mossy fiber projection at midtemporal hippocampal levels in the rat. The Timm's sulfide silver method revealed sparse granules of dark, mossy fiber-like staining at an infrapyramidal location in an area roughly equivalent to hippocampal subfield CA3a (close to the CA1 border). The use of anterograde transport of horseradish peroxidase enabled the visualization of short mossy fiber axons that left the suprapyramidal bundle, penetrated the pyramidal cell layer, and terminated in a distal infrapyramidal position. The HRP-labeled axons possessed periodic swellings that are characteristic of mossy fiber morphology. The HRP studies also provided evidence for longitudinally oriented mossy fibers at midtemporal hippocampal levels. The distal tip of the suprapyramidal band of mossy fibers turned temporally and could be detected up to 1140 micrometers ventral to the main suprapyramidal band.

Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D2 dopamine receptor activation. The loss of startle gating after D2 activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D2-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.

Central nervous stimulants facilitate sexual behavior in male rats with medial prefrontal cortex lesions

Male rats with lesions of the cerebral cortex near the midline in the frontal region destroying most of the cingulate cortex and producing some dammage to adjacent frontal areas have very long mount and intromission latencies. Otherwise their sexual behavior is essentially normal. The dopamine releasers amfonelic acid, 0.5 mg/kg, and amphetamine, 1 mg/kg, reduced the mount and intromission latencies in males with such lesions. Caffeine, 30 mg/kg, had similar effects. None of the drugs modified sexual behavior in intact males. It has been suggested that medial prefrontal lesions reduce the animal's reactivity to environmental stimuli, and hence renders the activation of sexual behavior difficult. Present results show that stimulant drugs are capable of compensating for this reduced reactivity. The possible mechanisms behind this effect are discussed. The lesion had also a small but consistent effect on the intromission ratio, suggesting some motor impairment. The effect on intromission ratio was not reduced by the drugs, suggesting that the lesion's motor consequences are mediated by mechanisms different from those controlling behavioral reactivity. The noradrenaline precursor dl-threo-dihydroxyphenylserine, 10 mg/kg, in combination with carbidopa, 50 mg/kg, increased mount and intromission latencies in both intact and lesioned males. Thus, activation of noradrenergic neurotransmission had effects opposite to those found after activation of dopaminergic transmission. Noradrenergic stimulation cannot, therefore, be important for the effects of amphetamine or amfonelic acid.

Effects of 6-hydroxydopamine lesions of the medial prefrontal cortex on local cerebral blood flow and D 1 and D 2 dopamine receptor binding in rats: a quantitative autoradiographic study

The effects of lesions of the dopamine (DA) nerve terminals in the medial prefrontal cortex (MPFC) on local cerebral blood flow (LCBF) and DA receptor binding in rats were investigated. 4 μg of 6-hydroxydopamine (6-OHDA) was infused stereotaxically into the area of the bilateral MPFC of rats pretreated with desmethylimipramine, and control rats received a vehicle solution. Twenty-four days after the operation LCBFs of 23 brain regions were measured using the quantitative autoradiographic N-isopropyl- p-[ 125I]iodoamphetamine technique. D 1 and D 2 DA receptor binding in various brain regions was also quantified autoradiographically using [ 3H]SCH 23390 and [ 3H]YM 09151-2 as the respective ligands. 6-OHDA lesions of MPFC produced significant increases in LCBF of the nucleus accumbens, the dorsolateral portion of the caudate-putamen and the anterior cingulate cortex. The lesioned animals did not show decreased LCBF in MPFC per se. D 1 and D 2 DA receptor binding was not affected in any brain region examined. These results suggest that lesions of the DA nerve terminals in MPFC induce an enhancement of functional activity in the terminal regions of the subcortical DA systems, and that hypofunction of the mesocortical dopamine system does not elicit reduced metabolic activity in the prefrontal cortex.

Deficient sensorimotor gating after 6-hydroxydopamine lesion of the rat medial prefrontal cortex is reversed by haloperidol.

The present study sought to test the hypothesis that dopamine in the prefrontal cortex exerts an inhibitory influence on subcortical dopamsine systems and that depletion of prefrontal dopamine may affect behaviour via an increase in dopamine release in the basal ganglia. We used prepulse inhibition of the acoustic startle response, i.e. the inhibition of the acoustic startle response by a preceding non-startling stimulus, as the behavioural test, because this phenomenon of sensorimotor gating is modified in opposite directions by dopamine in the prefrontal cortex and in the basal ganglia. Rats were tested for prepulse inhibition before and after injections of the neurotoxin 6-hydroxydopamine into the medial prefrontal cortex. We attempted to differentiate the contributions of prefrontal dopamine and noradrenaline by pretreating the animals with desipramine (6-OHDAMI rats) or bupropion (6-OHDABUP rats), selective inhibitors of noradrenaline and dopamine reuptake respectively. 6-Hydroxydopamine lesion reduced prefrontal dopamine by 90% and noradrenaline by 80% in 6-OHDADMI rats, while prefrontal dopamine was reduced by 54% and noradrenaline by 95% in 6-OHDABUP rats. The ability of an acoustic prepulse (75 dB, 10 kHz) to inhibit the response to a startle pulse (100 dB noise burst) was maintained in sham-lesioned rats and in 6-OHDABUP rats. However, there was a marked reduction of prepulse inhibition (by 26%) in the 6-OHDADMI rats. Systemic administration of the dopamine antagonist haloperidol (0.05 mg/kg), which did not affect prepulse inhibition in sham-lesioned and in 6-OHDABUP rats, antagonized the lesion-induced deficit in prepulse inhibition in 6-OHDADMI rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of combined prefrontal cortical and hippocampal damage on dopamine-related behaviors in rats

The effects of excitotoxic damage to both the medial prefrontal cortex (MPFC) and the ventral hippocampus (VH) on behaviors related to mesolimbic/nigrostriatal dopamine (DA) transmission were investigated in the rat. Locomotor activity in a novel environment, after injection of saline, and after d-amphetamine was assessed 2 and 4 weeks after ibotenic acid lesion of both MPFC and VH in adult rats. In addition, stereotypic behaviors and locomotion after apomorphine were evaluated 8 weeks after the lesion. Locomotor activity was significantly enhanced in all testing conditions in lesioned rats as compared with sham-operated animals, while oral stereotypic behaviors elicited by apomorphine were attenuated possibly because they were eclipsed by excessive locomotion. These data indicate that coexisting lesions of the MPFC and VH in adult rats produce potent and long-lasting effects on behaviors believed to be dependent primarily on the mesolimbic DA system. The profile of changes resembles more closely that observed after excitotoxic lesions of the VH alone rather than that after separate MPFC lesion.

A behavioural analysis of rats with damage to the medial prefrontal cortex using the morris water maze: evidence for behavioural flexibility, but not for impaired spatial navigation

In this study, the functional properties of the medial prefrontal cortex (mPFC) of the rat were examined in a task for spatial navigation. The dorsomedial (dmPFC) and ventromedial (vmPFC) parts of the PFC differ in their connectivity with the hippocampus, vmPFC being the main recipient of hippocampal input. Therefore, it is hypothesised that in a spatial task known to be particularly sensitive to hippocampal, but also to prefrontal cortical damage, especially vmPFC is committed to proper spatial learning and memory. Using the Morris water maze task, with an invisible platform, male rats with either partial (dmPFC or vmPFC) or whole (mPFC) bilateral lesions were subjected to various procedures reflecting spatial learning and memory, including a spatial reversal. Animals with dmPFC, vmPFC and mPFC lesions learned and remembered the spatial task equally well as their controls, regardless of the size or site of the bilateral lesion learned and remembered the spatial task equally animals with whole mPFC lesions were initially slower in locating the invisible platform than controls and animals with partial mPFC damage, but this effect was only short-lasting. When subsequently presented with a visible platform, all animals with partial (dmPFC or vmPFC) or whole mPFC damage needed significantly more time to locate the platform than the controls. This effect was transient and lasted longer in the animals with whole mPFC damage than in animals with partial damage. On the basis of these findings we conclude that an intact mPFC is not necessary for proper spatial learning and memory. The impairments in the reversal task and especially in the visually-cued task can best be explained as a diminished behavioural flexibility when a shift in task demands occurs. Since the degree of this impairment was related to the size of these lesions, but not to their sites, these differences are ascribed to a ‘mass action’ of medial prefrontal cortex lesions.

The relationship between self-stimulation and sniffing in rats: does a common brain system mediate these behaviors?

The relationship between brain self-stimulation and brain-stimulation induced sniffing behavior was examined at three brain sites (frontal cortex, hypothalamus and lower brain stem). In the first experiment, sniffing was elicited in the prefrontal cortex and pontine reticular formation (PRF) of anesthetized rats. These sites corresponded to reported self-stimulation sites. In non-anesthetized animals (Expt. 2), all self-stimulation sites in the medial prefrontal cortex (MPC) and lateral hypothalamic-medial forebrain bundle (LH-MFB) also supported sniffing. In the PRF, this was also the case except for one subject which exhibited self-stimulation and jaw movements without sniffing. After unilateral lesions either in the MPC or PRF, stimulation-induced sniffing from the ipsilateral LH-MFB was not influenced. While MPC lesions did not affect self-stimulation either, medial PRF lesions disrupted ipsilateral self-stimulation. In summary, stimulation-induced sniffing and self-stimulation behavior appear to share strikingly similar anatomical loci, but the PRF appears to be differentially involved in these behaviors. The results were discussed from an appetitive motivational hypothesis of self-stimulation.

Memory for spatial location as a function of temporal lag in rats: Role of hippocampus and medial prefrontal cortex

Rats with medial prefrontal cortex, hippocampus, or cortical control lesions were tested on an eight-arm radial maze task, in order to examine memory for the temporal order of spatial locations as a function of temporal lag. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal lag (0-6) or the number of arms that occurred between the two test arms in the study phase. The control rats performed at chance at a temporal lag of zero, but their performance was above chance for the remaining lags, improving after the temporal lag exceeded zero. The hippocampal-lesioned rats showed a marked deficit, performing at chance for all lags, with some savings for those items occurring at the end of the list. The medial prefrontal cortex-lesioned rats showed a less severe deficit. The results of these data support the notion that both the hippocampus and the medial prefrontal cortex play significant roles in memory for the temporal order of spatial locations.

Light deprivation produces accelerated behavioral recovery of function from neglect produced by unilateral medial agranular prefrontal cortex lesions in rats

Environmental manipulations involving 48 h of light deprivation have been found to produce sparing of function from neglect produced by unilateral destruction of the medial agranular prefrontal cortex (AGm) in rats. The present study is an extension of these findings and examined whether light deprivation would produce recovery in subjects with demonstrated severe neglect produced by unilateral AGm destruction. The orientation behavior of the subjects, 25 left and 16 right AGm operates, was tested at 4 h post injection and if severe neglect was demonstrated, the subjects were placed into one of three environmental conditions: (1) 48 h of total light deprivation, (2) 48 h of continuous light, or (3) 48 h of a 12:12 light dark cycle. The left vs. right hemisphere comparisons indicated that the left hemisphere operates were significantly more responsive by 4 h postsurgery than the right hemisphere operates, and only five of the right hemisphere operates demonstrated severe neglect. Therefore, the effects of environment on behavioral recovery of function were only examined in left AGm operates with severe neglect. The results indicated that 48 h of light deprivation could produce dramatic behavioral recovery in left AGm operates with demonstrated severe neglect, and that these effects were not produced by disruption of the light dark cycle.

The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress

In the studies reported here we have examined the role of the medial prefrontal cortex (MpFC) in regulating hypothalamic-pituitary-adrenal (HPA) activity under basal and stressful conditions. In preliminary studies we characterized corticosteroid receptor binding in the rat MpFC. The results revealed high-affinity (Kd approximately 1 nM) binding with a moderate capacity (42.9 +/- 3 fmol/mg) for 3H-aldosterone (with a 50-fold excess of cold RU28362; mineralocorticoid receptor) and high-affinity (Kd approximately 0.5-1.0 nM) binding with higher capacity (183.2 +/- 22 fmol/mg) for 3H-RU 28362 (glucocorticoid receptor). Lesions of the MpFC (cingulate gyrus) significantly increased plasma levels of both adrenocorticotropin (ACTH) and corticosterone (CORT) in response to a 20 min restraint stress. The same lesions had no effect on hormone levels following a 2.5 min exposure to ether. Implants of crystalline CORT into the same region of the MpFC produced a significant decrease in plasma levels of both ACTH and CORT with restraint stress, but again, there was no effect with ether stress. Neither MpFC lesions nor CORT implants had any consistent effect on A.M. or P.M. levels of plasma ACTH or CORT. Manipulations of MpFC function were not associated with changes in the clearance rate for CORT or in corticosteroid receptor densities in the pituitary, hypothalamus, hippocampus, or amygdala. Taken together, these findings suggest that MpFC is a target site for the negative-feedback effects of glucocorticoids on stress-induced HPA activity, and that this effect is dependent upon the nature of the stress.

Paired associate learning in the rat: Role of hippocampus, medial prefrontal cortex, and parietal cortex

Rats were tested for their ability to learn a list of four paired associates (foods paired with spatial locations). In this task, rats display increased levels of correct orienting responses as a function of serial position of the paired associate within the list (temporal order function) when short inter-trial intervals are used between paired associates. Furthermore, the rats are more likely to use intramaze rather than extramaze cues. These data suggest that rats utilize a temporal strategy to remember a list of paired associates. After training in this task, new rats received medial prefrontal cortex, hippocampus, parietal cortex, or cortical control lesions and were retested. The data indicate that rats with cortical control lesions continued to display a temporal order function, whereas rats with medial prefrontal cortex lesions showed a reduction in the number of correct orienting responses and failed to demonstrate the temporal order function, suggesting that the medial prefrontal cortex might mediate the selection of temporal strategies. Rats with hippocampal lesions also showed a marked reduction in level of correct orienting responses, but they continue to display a temporal order function, suggesting that these rats can still utilize a temporal strategy, but may have difficulties in remembering the appropriate paired associate items. Rats with parietal lesions did not display any significant changes in their temporal order function.

Effects of ibotenic acid lesion of the medial prefrontal cortex on dopamine agonist-related behaviors in the rat

Behavioral responses to apomorphine and to the selective D 1 and D 2 dopamine receptor agonists SK&F38393 and quipirole were evaluated in rats following ibotenic acid (IA) or sham lesion of the medial prefrontal cortex (MPFC). IA-lesioned rats showed an increased responsiveness to the postsynaptic effects of all of the dopamine agonists. Patterns of the responses to the selective agonists administered alone and in combination suggest that these effects might be due to selective increases in the sensitivity of postsynaptic D 1 receptor-associated mechanisms. In addition, IA-lesioned rats pretreated with saline were hyperactive in comparison to sham-lesioned rats when animals were exposed to a novel open field, but spontaneous motor activity did not differ between these two groups when animals were pretreated with low doses (0.03 mg/kg) of quinpirole. The fact that hyperactivity observed in lesioned animals is inhibited by a dose of quinpirole that is felt to act presynaptically, selectively attenuating endegenous dopaminergic tone, suggests that effects of the MPFC lesion may be mediated presynaptically as well.

Ineffectiveness of GM1 and ORG2766 on behavioural recovery after prefrontal cortical lesions in adult rats

This study examines whether treatment with GM1 ganglioside or the corticotropin (ACTH)(4–9) analogue ORG2766 can facilitate the behavioural recovery of adult rats with medial prefrontal cortex (mPFC) lesions, as animals are impaired in their food hoarding and spatial delayed alternation performance following mPFC lesions. No ameliorating effects of GM1 treatment on performance of these behaviours were observed. Although treatment with ORG2766 somewhat improved the hoarding performance of lesioned animals, the intermediate amount of pellets hoarded was not significantly different from that of either sham-operated or vehicle-treated lesioned rats. No effect of ORG2766 treatment was observed in the spatial delayed alternation test. Further, no changes were detected in the mesocortical dopamine innervation, presumed to be involved in the neural mechanism of behavioural sparing, in response to either treatment.

Activation of mesocortical dopaminergic system in the rat in response to neonatal medial prefrontal cortex lesions. Concurrence with functional sparing

Neonatal lesions of the medial part of the rat prefrontal cortex (mPFC) (performed at the age of 6 days) resulted in a sparing in the performance of spatial delayed alternation (SDA) and an increase in dopaminergic (DA) innervation. The increased DA innervation was primarily observed in the remaining part of the mPFC. The DA fibre density was considerably higher in the non-ablated part of the mPFC, and the fibres were thicker with more large varicosities compared with sham-operated controls. Biochemical measurements showed a 3.5-fold increase in DA concentration in the remaining part of the mPFC of the animals with neonatal lesions when compared with the mPFC of sham-operated animals. In addition the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased. The metabolite/transmitter ratios, indicating DA utilisation, did not significantly differ from controls. The increased DA innervation and the increased concentration of DA and its metabolites in the animals with neonatal lesions further support our hypothesis that the mesocortical DA system is involved in the neural mechanism of sparing of function observed after neonatal mPFC lesions. However, sparing of function in animals with no discernable mPFC forces us to conclude that this DA response cannot be the only factor involved in the mechanism of sparing of function.

Ibotenic acid lesions of medial prefrontal cortex augment swim-stress-induced locomotion

Locomotor activity of rats with sham or ibotenic acid lesions of the medial prefrontal cortex (MPFC) was assessed after animals were exposed to a 15-min swim or control stress. Swim-stress-induced locomotor activity was augmented in the MPFC-lesioned rats. These and other data suggest that lesions of the MPFC are followed by an exaggeration of the normal behavioral response to stress. Dysregulation of dopamine transmission in the basal ganglia may be involved.

Medial prefrontal cortex lesions and spatial delayed alternation in the developing rat: recovery or sparing?

In Experiment 1, Long-Evans rat pups received medial prefrontal cortex (PFC) aspirations or sham surgery on Postnatal Day 10 (PND10) and were then trained on PND23 to perform one of two T-maze tasks: discrete-trials delayed alternation (DA) or simple position discrimination. Early PFC damage produced a selective failure to learn the DA task. In Experiment 2, pups given the same lesion or sham surgery were trained on DA on PND19, PND27, or PND33. In relation to sham-operated controls, pups with PFC damage were impaired on PND19, somewhat impaired on PND27, and entirely unimpaired when tested on PND33. In Experiment 3, pups given larger lesions of the frontal cortex on PND10 were impaired on DA when tested on PND23 but not when tested on PND33. These findings indicate that early PFC lesions result in a memory deficit around the time of weaning, which then recovers over the next 10-14 days of development. Moreover, the early deficit is selective for a late developing cognitive process (or processes) that is involved in acquisition of DA.

Medial prefrontal cortex lesions and spatial delayed alternation in the developing rat: Recovery of sparing?

Medial prefrontal cortex lesions and spatial delayed alternation in the developing rat: Recovery of sparing?