Anteromedial Prefrontal Cortex Research Articles

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.

Autobiographical memory and the self in time: Brain lesion effects, functional neuroanatomy, and lifespan development

Autobiographical remembering reflects an advanced state of consciousness that mediates awareness of the self as continuous across time. In naturalistic autobiographical memory, self-aware recollection of temporally and spatially specific episodes and generic factual information (both public and personal) operate in tandem. Evidence from both laboratory and real-life studies, however, suggests that these two processes can be dissociated. This paper reviews aging, lesion, and functional neuroimaging research on the anatomical substrates of autobiographical memory processes using a new measure, the Autobiographical Interview, and prospective collection of autobiographical material. Results indicate that autobiographical recollection is mediated by a distributed fronto-temporo-parietal system, with the anteromedial prefrontal cortex positioned to integrate sensory information with self-specific information. The emergence of autobiographical recollection at around age four coincides with the timing of prefrontal regressive cortical and progressive white matter changes that may support the development of this high-level capacity.

Place Learning in Scopolamine-Treated Rats: The Roles of Distal Cues and Catecholaminergic Mediation

Experiments 1 and 2 tested the hypothesis that cholinergic receptor antagonists impair place learning in a water maze by interfering with the processing of distal, visual cues. Extramaze cues were offered to rats in the form of geometrical patterns arranged on the inner circumference of a curtain surrounding the water maze. In Experiment 1 the animals were offered both the distal cues and proximal cues in the form of pingpong balls in fixed positions on the surface of the water while only distal cues were present in Experiment 2. Animals were injected with either scopolamine (0.5 mg/kg body wt) or saline 20 min prior to the daily place learning sessions. Upon reaching criterion level performance the animals were tested on “rotation” sessions on which the distal cues were displaced. The outcome of such “rotations” demonstrated that—regardless of the presence or absence of proximal cues—scopolamine-treated rats relied at least as much as normal animals on the distal cues. The acquisition phase of both Experiments 1 and 2 demonstrated an almost complete lack of scopolamine-associated impairment in acquisition and performance of the place learning task. In Experiment 3 (when scopolamine was no longer administered) the subjects of Experiment 2 were exposed to a series of pharmacological “challenges” of their place learning performance and eventually to surgical ablation of the anteromedial prefrontal cortex. The outcome of the pharmacological challenges and the postoperative test of task performance demonstrated that the place learning performance of animals which had acquired the task under scopolamine was mediated by a neural substrate dissimilar to the substrate of task performance in normal animals. Rats acquiring the task while deprived of the cholinergic system demonstrated above-normal contributions to task mediation from catecholaminergic—probably dopaminergic—mechanisms and tentative results pointed to a “shift” toward prefrontal task mediation.

Citalopram versus venilafaxine in the treatment of major depression : N. Kaya, H. Herken, R. Raşkin, M. Telcioĝlu, A.S. Çilli. Medical Faculty of Selçuk University, Department of Psychiatry, 42080, Konya, Turkey

Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive and low-cost functional neuroimaging technique in psychiatric research, and it has been wildly used for detecting the spatiotemporal characteristics of brain activity. In order to evaluate the clinical value of NIRS data in the assistant diagnosis of major depressive disorder (MDD), prefrontal cortex (PFC) hemoglobin concentration exchange of 30 MDD patients combined with anxious and obsessive–compulsive symptom was detected by NIRS under voice fluency task (VFT), then the relationship between the severity of depressive, anxious and obsessive–compulsive symptom assessed by Hamilton Rating Scale for Depression (HAMD), Hamilton Anxiety Rating Scale (HAMA) and Yale-Brown Obsessive Compulsive Scale (Y-BOCS) with NIRS data in PFC was analyzed. Hypoactivation in lateral and lower PFC of MDD patients was confirmed in this study. Furthermore, Spearman correlation found that oxy-hemoglobin concentration ([oxy-Hb]) exchange in right-lateral PFC was associated with the severity of anxiety, while bilateral PFC and antero-medial PFC were associated with severity of depression. Meanwhile, no statistical correlation was observed on the severity of obsessive–compulsive symptom. The results prompted that MDD patients with anxiety and obsession–compulsion symptom showed a PFC hypoactivation state in NIRS. Furthermore, the function of right-lateral PFC was associated with anxiety symptom, while bilateral PFC and antero-medial PFC were associated with depression symptom. Different from depression and anxiety, obsession–compulsion may have a different biological character in PFC function.

Role of the Amygdala in the Coordination of Behavioral, Neuroendocrine, and Prefrontal Cortical Monoamine Responses to Psychological Stress in the Rat

Exposure to mild stress is known to activate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) metabolism in the anteromedial prefrontal cortex (m-PFC). Neuroanatomical site(s) providing afferent control of the stress activation of the m-PFC monoaminergic systems is at present unknown. The present study used a conditioned stress model in which rats were trained to fear a substartle-threshold tone paired previously with footshock and assessed for behavioral, neuroendocrine, and neurochemical stress responses. Bilateral NMDA-induced excitotoxic lesioning of the basolateral and central nuclei of the amygdala was performed before or after training. Pretraining amygdala lesions blocked stress-induced freezing behavior, ultrasonic vocalizations, adrenocortical activation, and dopaminergic metabolic activation in the m-PFC. Post-training amygdala lesions blocked stress-induced m-PFC DA, 5-HT, and NE metabolic activation. Post-training amygdala lesions also blocked stress-induced freezing and defecation, and greatly attenuated adrenocortical activation. These data provide evidence of amygdalar control of stress-induced metabolic activation of the monoaminergic systems in the m-PFC, as well as amygdalar integration of behavioral and neuroendocrine components of the rat stress response. These results are discussed in terms of possible relevance to stress-induced exacerbation of schizophrenic symptoms and the pathophysiology of posttraumatic stress disorder.

Glutamate-dependent long-term presynaptic changes in corticostriatal excitability.

We have previously shown that brief high frequency stimulation of the anteromedial prefrontal cortex induces a long-term decrease in excitability of the glutamatergic corticostriatal terminal field. In contrast, a long-term increase in presynaptic corticostriatal excitability may be induced by presenting two brief cortical tetanizing stimuli separated by 2-3 min such that the second tetanus coincides with a period of increased excitability elicited by the first. In the present study, we examined the glutamate receptor subtypes involved in these long-term changes in presynaptic excitability. A specific glutamate receptor antagonist was infused into the rat striatum 10-25 min prior to either a single or double cortical tetanic stimulation. To eliminate the participation of intrinsic striatal cells, a subset of animals received a striatal kainic acid lesion eight to 20 days before the recording experiment. Antagonists of the N-methyl-D-aspartate and metabotropic glutamate receptor subtypes were effective in blocking the decrease in excitability induced by single cortical tetanic stimulation whereas an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor did not prevent the induction of a long-term reduction in excitability. In contrast, each of these antagonists prevented the induction of a long-term increase in excitability. These long-term modifications in excitability of the presynaptic glutamate axon terminals appear to be induced by similar mechanisms to those postulated to operate in long-term potentiation and depression. These enduring changes in presynaptic excitability are likely to represent important mechanisms for the selective modification of information processing in the striatum.

Prefrontal cortical mediation of rats' place learning in a modified water maze

The acquisition of a place learning task in a water maze modified from the “standard” set-up by restriction of distal cues and addition of “proximal” cues (ping-pong balls in fixed positions on the surface of the water) was tested in three groups of rats: (I) animals subjected to bilateral ablation of the anteromedial prefrontal cortex, (II) rats in which the parietal “association” cortex had been removed bilaterally, and (III) a sham operated control group. The task acquisition of the prefrontaly ablated group was significantly impaired, whereas the animals in which the parietal cortex had been removed acquired the task as quickly as the control group. Upon reaching criterion level performance all animals were tested on “challenge” sessions on which the cues were manipulated. Such “challenges” demonstrated that the animals of all three groups discriminated between the distal cues and utilized such a discrimination for navigational purposes.

Up-regulation of dopamine receptors in the brain of the spontaneously hypertensive rat: An autoradiographic analysis

Recent evidence points to a dysfunction of brain dopaminergic mechanisms in the spontane- ously hypertensive rat. Using in vitro receptor autoradiography, we assessed the density of D 1 and D 2 dopamine receptors in the brain of spontaneously hypertensive rats and their normotensive controls the Wistar-Kyoto rat. Brain sections from five- and 15-week-old rats were incubated with 1 nM [ 3H]SCH 23390 (D 1 receptor antagonist) or 15nM [ 3H]sulpiride (D 2 receptor antagonist), and exposed along with radioactive standards to 3H-Hyperfilm. The binding density of selected brain regions (anteromedial prefrontal cortex, cingulate cortex, lateral septal nucleus, nucleus accumbens, caudate-putamen, globus pallidus, amygdaloid complex) were quantified using computer-assisted densitometry. These experiments showed a significant increase in the binding density of [ 3H]SCH 23390 in the nucleus accumbens and caudate-putamen of five- and 15-week-old spontaneously hypertensive rats. The binding density of [ 3H]SCH 23390 was increased in the lateral septal nucleus of five-week-old and globus pallidus of 15-week-old spontaneously hypertensive rats. The binding density of [ 3H]sulpiride was also greater in the nucleus accumbens of five-week-old spontaneously hypertensive rats. The present investigation demonstrates an up-regulation of D 1 dopamine receptors in spontaneously hypertensive rats with established hypertension. More importantly, up-regulation of D 1 and D 2 dopamine receptors in the striatum of young prehypertensive spontaneously hypertensive rats suggests that dopamine may be involved in the pathogenesis of hypertension in this strain of genetically hypertensive rats.

Differential Effects of Forced Locomotion, Tail‐Pinch, Immobilization, and Methyl‐β‐Carboline Carboxylate on Extracellular 3,4‐Dihydroxyphenylacetic Acid Levels in the Rat Striatum, Nucleus Accumbens, and Prefrontal Cortex: An In Vivo Voltammetric Study

In vivo voltammetry with carbon fiber electrodes was used to assess extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) levels in striatum, nucleus accumbens, and anteromedial prefrontal cortex of freely moving rats subjected to altered motor activity or anxiogenic stimuli. Forced locomotion on a rotarod for 40 min caused an increase in extracellular DOPAC levels in the striatum and to a lesser extent in the nucleus accumbens but not in the prefrontal cortex. Subcutaneous injection of the anxiogenic agent methyl-beta-carboline carboxylate (10 mg/kg) increased extracellular DOPAC levels to a similar extent in prefrontal cortex and nucleus accumbens. Immobilization for 4 min augmented dopamine (DA) metabolism preferentially in the nucleus accumbens and to a lesser extent in the prefrontal cortex. Tail-pinch caused a selective activation of DA metabolism in the nucleus accumbens. None of these stimuli altered extracellular striatal DOPAC levels. These results confirm the involvement of dopaminergic systems projecting to the striatum and nucleus accumbens in motor function and suggest that mesolimbic and mesocortical dopaminergic systems can be specifically activated by certain kinds of anxiogenic stimuli; the relative activation of either of these latter systems could depend primarily on the nature (sensory modality, intensity) of the acute stressor.

3-Acetylpyridine results in degeneration of the extrapyramidal and cerebellar motor systems: loss of the dorsolateral striatal dopamine innervation

3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), potently inhibited in vitro MAO B activity and in contrast weakly inhibited MAO A activity. However, in vitro inhibition of MAO B by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.

The anxiogenic β-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex

Systemic administration of the anxiogenic β-carboline FG-7142, a benzodiazepine inverse agonist, results in a regionally selective increase in dopamine (DA) utilization in the anteromedial prefrontal cortex (PFC). We have examined both in vivo and in vitro tyrosine hydroxylation in the PFC and other mesotelencephalic DA system terminal fields in order to determine if FG-7142 effects changes in DA synthesis, and to determine if the β-carboline biochemically activates certain DA neurons through an action occurring at the cell body level (impulse-dependent regulation) or at the terminal field level (presynaptic regulation). FG-7142 increased in vivo tyrosine hydroxylation in the PFC and in the ventral tegmental area, midbrain source of the DA innervation of the PFC; no changes were observed in mesolimbic or nigrostriatal regions. The β-carboline also increased in vitro tyrosine hydroxylation in the PFC, but decreased tyrosine hydroxylation in striatal slices. The effects of FG-7142 were blocked by the benzodiazepine antagonist RO 15-1788. Another β-carboline inverse agonist, methyl-β-carboline-carboxylate, also increased in vitro tyrosine hydroxylation in the PFC. GABA exerted opposite effects to those of the β-carbolines, decreasing in vitro tyrosine hydroxylation increasing DA synthesis in the CP. These data indicate that the benzodiazepine inverse agonists increase both in vivo and in vitro tyrosine hydroxylation in the PFC, and that the β-carboline may act to increase DA synthesis at both the terminal field and the cell body level.

3-Acetylpyridine-induced degeneration of the nigrostriatal dopamine system: An animal model of olivopontocerebellar atrophy-associated parkinsonism

The effects of 3-acetylpyridine (3-AP) administration to rats on the mesotelencephalic dopamine system were assessed. A single 3-AP injection resulted in biochemical and immunohistochemical evidence of degeneration of the nigrostriatal dopamine system. Six weeks after 3-AP treatment decreases in both striatal dopamine content and the activity of the catecholamine biosynthetic enzyme tyrosine hydroxylase were observed. Immunohistochemical examination suggested a decreased density of striatal tyrosine hydroxylase-immunoreactive fibers and revealed the emergence of a distinctly patchy organization of the dopamine innervation to the dorsolateral striatum. While 3-AP administration resulted in biochemical and anatomical data consistent with the degeneration of nigrostriatal dopamine fibers, no significant changes in dopamine content or the density or pattern of tyrosine hydroxylase-immunoreactive fibers in the anteromedial prefrontal cortex or nucleus accumbens were seen. These data suggest that 3-AP administration may result in a relatively specific degeneration of the nigrostriatal dopamine system. Since 3-AP causes both a profound loss of the climbing fiber input to the cerebellum derived from the inferior olivary nucleus, and the degeneration of nigrostriatal dopamine neurons, 3-AP administration may provide a useful model of olivopontocerebellar atrophy-associated parkinsonism. Moreover, the differences in the neurotoxicity caused by 3-AP and that elicited by another pyridine which causes striatal dopamine depletion (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) may offer important insights into the mechanisms of both species- and site-specific pyridine neurotoxins.

Substance P, neurotensin and enkephalin injections into the ventral tegmental area: comparative study on dopamine turnover in several forebrain structures

A comparison of dopaminergic (DAergic) turnover changes in several forebrain structures was investigated after local injection of substance P (SP), neurotensin and D-Ala-Met-enkephalin (DALA) into the ventral tegmental area (VTA). A dose-dependent increase in the DOPAC/DA ratio was elicited by all 3 peptides in the nucleus accumbens and the septum. DAergic turnover was enhanced in the anteromedial prefrontal cortex only after SP injection and in the amygdala only after neurotensin injection. In the anteromedial striatum as well as in the posterolateral striatum, a significant increased DOPAC/DA ratio was observed following SP and DALA injection into the VTA. No significant changes were noticed in the olfactory tubercles after injection of the 3 peptides in the VTA. From these results, it appears that each peptide induced a different profile of DAergic activation. Taking into account the facilitatory role of the DA neurons at the level of the forebrain integrative structures, the differential activation may explain the difference in behavioral response obtained after injection of the 3 peptides in the VTA.

Stressful environmental stimuli increase extracellular DOPAC levels in the prefrontal cortex of hypoemotional (Roman high-avoidance) but not hyperemotional (Roman low-avoidance) rats. An in vivo voltammetric study

The effects of a variety of stressful environmental situations on dopamine metabolism in the prefrontal cortex (as assessed by in vivo voltammetry with carbon fiber electrodes) have been compared in two genetically selected lines of rat (Roman high (RHA/Verh) and low (RLA/Verh) avoidance) which differ drastically in their level of emotionality. Heart rate was continuously monitored in these animals (via chronically implanted subcutaneous electrodes) so as to index the emotional reaction to the stressors. An electrochemical signal corresponding to the oxidation of dihydroxyphenylacetic acid (DOPAC) was recorded in the deeper laminae of the anteromedial prefrontal cortex in both lines of rats. Under normal condition, this signal was stable for at least 4 h and its amplitude was similar in both lines. Introduction of the animals into an unfamiliar environment (30 min), application of a mild tail pinch (10 min) or of a high-intensity loud noise (30 min) or immobilization (20 min) were all associated with an increase in extracellular cortical DOPAC levels in the hypoemotional RHA/Verh line but not in the hyperemotional RLA/Verh line. Similarly, forced locomotion on a rotarod (40 min) provoked a dramatic increase in the amplitude of the cortical DOPAC oxidation peak in RHA/Verh rats and only a mild increase in this parameter in RLA/Verh rats. In RHA/Verh rats, tolerance to this increase was observed when animals were subjected to forced locomotion every day for 5 days. All of the stressful situations investigated provoked an immediate augmentation of heart rate which resumed gradually after cessation of the stressful stimulus; the magnitude and duration of this increase were much greater in RLA/Verh than in RHA/Verh rats. Moreover, in all stress situations, RLA/Verh but not RHA/Verh rats showed behavioral signs of emotional response e.g. defecation, freezing and self-grooming. It is concluded that the increase in cortical dopamine metabolism induced by stress is not connected to the emotional reaction caused by the aversive nature of the stressor but may rather reflect a heightened attention of the animal or activation of cognitive processes in an attempt to cope with the stressor.

In vivo voltammetric measurement of extracellular DOPAC levels in the anteromedial prefrontal cortex of the rat

Differential pulse voltammetric recordings with carbon fiber electrodes performed in vivo in the anteromedial prefrontal cortex of the rat yielded 3 oxidation peaks at -100, +100 and +300 mV, respectively. Pharmacological manipulations revealed that 3,4-dihydroxyphenylacetic acid (DOPAC) is the main contributor to the oxidation current recorded at +100 mV (peak 2). Thus, systemic administration of FLA 63 did not alter whereas pargyline caused a disappearance of cortical peak 2. Moreover, haloperidol and sulpiride increased peak 2 amplitude both in normal and in N-(2-chloroethyl)N-ethyl-2-bromobenzylamine (DSP4)-lesioned rats. Peak 2 was detected only in those prefrontal cortex regions known to receive a dopamine input. It is concluded that in vivo voltammetry with carbon fiber electrodes is a useful means of monitoring dopaminergic activity in the prefrontal cortex of the rat.

Prefrontal cortex neuron activity during a discriminative conditioning paradigm in unanesthetized rats.

Single neuron responses were recorded from the prefrontal cortex of unanesthetized, restrained rats trained to a discriminative conditioning paradigm. The animals were preconditioned to a tone paired with footshock (CS+) and a second tone presented unpaired (CS-). Only neurons with large amplitude, positive first deflection action potentials were studied. Eighty-five percent of the units (17 of 20) emitted conditioned responses in that the response to either one or both of the conditioned stimuli (CS) was significantly different from spontaneous activity. Thirty-five percent of the units emitted differential conditioned responses in that the responses to one of the CS was significantly different than the response to the other CS and that the response was subsequently shown to extinguish when the footshock was withheld. The neurons which emitted the differential conditioned responses appeared to be located in the deeper layers of the anteromedial prefrontal cortex while the remaining neurons were located either in more superficial layers or anterior aspects of the prefrontal cortex. The results suggest that the anteromedial prefrontal cortex may be involved in neural mechanisms related to discriminative conditioning.

Cortical cholinergic projections from the basal forebrain of the rat, with special reference to the prefrontal cortex innervation

The topographic organization of cells containing choline-acetyltransferase (CAT) and located within the magnocellular nuclei of the basal forebrain was studied by correlating maximum CAT decrease in one or another cortical region with a given localization of the cell lesions. Lesions were made by using ibotenic acid. Lesions affecting the ventral pallidum decreased CAT activity in the antero-medial prefrontal cortex and lesions of the internal and ventral borders of the pallidum decreased CAT activity in sensori-motor and parieto-temporal cortices. None of these lesions produced a decrease of CAT activity in the hippocampus. These results suggest that it is possible to show the presence of a specific cholinergic projection from the basal forebrain to the medial-associative prefrontal cortex of the rat.

Selective ablations within the prefrontal cortex of the rat and performance of delayed alternation

Ablations of the pregenual area of the anteromedial prefrontal cortex produced a significantly larger impairment in delayed alternation than did removal of the supragenual area. Both ablations caused significant impairments as compared with lesions of the posteromedial cortex. Only one of four rats with ablations of the dorsal bank and lip of the anterior part of the rhinal sulcus was impaired. The results indicate than in the rat, as in the monkey and dog, one part of the prefrontal cortex is particularly involved in mediation of delayed alternation.

A Cortico-Subcortical System Controlling Differentiation Ability

Publisher Summary This chapter discusses the results of a study analyzing a cortico-subcortical system controlling differentiation ability. The study was undertaken to reveal the role of cortical and subcortical structures of the dog that are involved in the suppression of conditioned responses in inhibitory trials. A local conditioned reflex type 11 of the foreleg reinforced by food and an inhibitory reflex were trained. Daily 10–15 positive and inhibitory trials with an interval of 1 min were used. The animals were trained to a criterion of stability of the positive and inhibitory reflexes. Upon completion of the preoperative training, each animal underwent a bilateral full or partial lesion of one of the following brain regions—the prefrontal cortex, the cingulate cortex, the dorsomedial and anterior nuclei of the thalamus, and the amygdaloid complex. Immediately after lesions of the medial frontal areas, errors occurred in positive trials. Within a few days, the positive reflexes recovered, however, and errors of disinhibition then occurred. It was suggested that the anteromedial prefrontal cortex, together with the genual area of the cingulate gyrus and the basolateral amygdaloid complex, constitutes a system, concerned with the type of inhibition trained in a situation where food is presented in positive trials.