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Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys.

While studies have shown that estrogen affects hippocampal spine density and function, behavioral studies in humans and nonhuman primates have also implicated the prefrontal cortex in the effects of estrogen on cognition. However, the potential for similar estrogen-induced increases in spines and synapses in the prefrontal cortex has not been investigated in primates. Moreover, it is not known if such an estrogen effect would be manifested throughout the neocortex or primarily in the regions involved in cognition. Therefore, we investigated the effects of estrogen on dendritic spines in the prefrontal and primary visual cortices of young rhesus monkeys. Young female monkeys were ovariectomized and administered either estradiol cypionate or vehicle by intramuscular injection. Using an antibody against the spine-associated protein, spinophilin, spine numbers were estimated in layer I of area 46 and in layer I of the opercular portion of area V1 (V1o). Spine numbers in layer I of area 46 were significantly increased (55%) in the ovariectomy + estrogen group compared to the ovariectomy + vehicle group, yet spine numbers in layer I of area V1o were equivalent across the two groups. The present results suggest that estrogen's effects on synaptic organization influence select neocortical layers and regions in a primate model, and provide a morphological basis for enhanced prefrontal cortical functions following estrogen replacement.

Animals↗

Reciprocal connections between medial prefrontal cortex and lateral posterior nucleus in rats.

The connections of the posterior part of the medial prefrontal cortex with the thalamic lateral posterior nucleus in rats were studied using anterograde and retrograde axonal transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and tritiated leucine. After injections of WGA-HRP into the medial prefrontal cortex, an area confirmed to receive direct projections from the visual cortex, retrogradely labeled neurons were observed ipsilaterally in the lateral posterior nucleus of the thalamus, as well as in the mediodorsal, anteromedial, ventromedial, ventrolateral, laterodorsal, centrolateral, paracentral, rhomboid, parafascicular and posterior nuclei. In the lateral posterior nucleus, the labeled cells were located mainly in the lateroventral portion of its anterior half. In contrast, the posterior half of this nucleus was free of label. Axons labeled by the anterograde transport of tritiated leucine were dispersed over the same region which contained retrogradely labeled cells. The functional significance of these connections is discussed with special reference to their possible role in visuomotor integration in rats.

Animals↗

Fewer dopamine transporter receptors in the prefrontal cortex of cocaine users.

The authors investigated dopamine transporter receptor binding in the post-mortem prefrontal cortex of 13 subjects with histories of cocaine use who had positive blood screens for cocaine at autopsy and 13 comparison subjects with no history of cocaine use and negative blood screens for cocaine at autopsy. Synaptosomes from pulverized prefrontal cortex were assayed with [3H]GBR 12935 for dopamine transporter receptor. There was a 38% decrease in number of binding sites but no change in affinity constants in the cocaine users.

Adult↗

The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization.

Recent findings in primates indicate that the connections of the frontal lobe, the basal ganglia, and the thalamus are organized in a number of parallel, functionally segregated circuits. In the present account, we have focused on the organization of the connections between the prefrontal cortex, the basal ganglia and the mediodorsal thalamic nucleus in the rat. It is concluded that in this species, in analogy with the situation in primates, a number of parallel basal ganglia-thalamocortical circuits exist. Furthermore, data are presented indicating that the projections from particular parts of the amygdala and from individual nuclei of the midline and intralaminar thalamic complex to the prefrontal cortex and the striatum are in register with the arrangements in the parallel circuits. These findings emphasize that the functions of the different subregions of the prefrontal cortex cannot be considered separately but must be viewed as components of the integrative functions of the circuits in which they are involved.

Amygdala↗

A monosynaptic pathway from an identified vasomotor centre in the medial prefrontal cortex to an autonomic area in the thoracic spinal cord.

Chemical microstimulation (1 mM L-glutamate or 25 mM KCl) of the medial prefrontal cortex of anaesthetized rats produced falls in systolic and diastolic blood pressure of similar magnitude, without a change in heart rate. Application of the lectin Phaseolus vulgaris leucoagglutinin by iontophoresis from an adjacent barrel of the same micropipette revealed a direct projection to the central autonomic area of the thoracic spinal cord from this vasomotor area, which is equivalent to the region called prelimbic cortex by Krettek and Price [J. comp. Neurol. (1977) 171, 157-192] or Cg3 by Paxinos and Watson [The Rat Brain in Stereotaxic Coordinates (1986)]. Labelled axons descended in the dorsal corticospinal tract in the cervical spinal cord, where they displayed a few varicosities. In the thoracic spinal cord, labelled fibres occurred bilaterally in the gray matter, predominantly in the central autonomic area, where they displayed many varicosities. Electron microscope studies revealed that the anterogradely labelled varicosities in the central autonomic area were vesicle-filled boutons that formed asymmetric synaptic contacts. The synaptic targets were small dendrites or dendritic protrusions that were characterized by a high incidence of multivesicular bodies and coated vesicles. We conclude that a monosynaptic pathway that originates from a physiologically-defined vasomotor area in the medial prefrontal cortex terminates on a characteristic type of neuron in the central autonomic area of the thoracic spinal cord.

Animals↗

Deep layer prefrontal cortex unit discharge in a cue-controlled open-field environment in the freely-moving rat.

The activity of single units in prefrontal cortex (prelimbic and anterior cingulate subregions) was recorded as rats performed a 'pellet-chasing' task in a cue-controlled, open-field environment in which the position of a single salient cue card was manipulated. Spike train analyses revealed three different types of unit. The first type was characterized by rhythmic bursts of spiking with inter-burst intervals of approximately 200 ms (66% of units), the second by bursts with inter-burst intervals of approximately 80 ms (33% of units), and the third by non-rhythmic firing characteristics (33% of units). None of the units had spatially-selective firing characteristics, nor were their discharge patterns affected by manipulation of the cue card. Instead, the firing of the units had multiple behavioural correlates that occurred as the rat explored the environment. These results are in line with previous studies that suggest that prefrontal cortex unit discharge is not related to spatial processing but to behaviours necessary for exploration.

Action Potentials↗

Corticotropin-releasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freely moving rats as assessed by microdialysis.

In vivo microdialysis was used to measure changes in extracellular concentrations of catecholamines and indoleamines in freely moving rats in response to administration of corticotropin-releasing factor (CRF). Dialysis probes were placed stereotaxically in either the medial hypothalamus or the medial prefrontal cortex. We used a repeated-measures design in which each rat received artificial CSF or one dose of CRF 3-4 h apart, and each subject was retested with the same treatments in the reverse order 5-7 days later. With the dialysis probe in the hypothalamus, intracerebroventricular administration of CRF (17 or 330 pmol) dose-dependently increased dialysate concentrations of norepinephrine (NE), dopamine (DA), and all their measurable catabolites except normetanephrine. The effects on NE were substantially greater than those on DA. Dialysate concentrations of serotonin could not be measured reliably, but those of its catabolite, 5-hydroxyindoleacetic acid, were also elevated. Concentrations of NE and DA were elevated within the first one or two (20 min) collection periods, with a peak response at approximately 1-2 h. Dialysate concentrations of catecholamines and metabolites normally returned to baseline within 3 h. Similar data were obtained with dialysis probes in the medial prefrontal cortex after intracerebroventricular administration of 17 or 167 pmol of CRF, except that the increases in DA exceeded those of NE in this region. Intraperitoneal administration of CRF (1 nmol) similarly elevated dialysate concentrations of NE, DA, 5-hydroxyindoleacetic acid, and all catecholamine catabolites except normetanephrine in both medial hypothalamus and medial prefrontal cortex. These results support earlier neurochemical data suggesting that CRF administered both centrally and peripherally stimulates the release of both DA and NE in the brain.

3,4-Dihydroxyphenylacetic Acid↗

Neuroanatomical correlates of sparing of function after neonatal medial prefrontal cortex lesions in rats.

In rats, the possibility of neuroanatomical changes in response to partial medial prefrontal cortex lesions at postnatal day 6, concomitant with behavioural sparing, was investigated. The projections from the mediodorsal nucleus of the thalamus (MD) and the mesocortical dopaminergic (DA) projection were examined. No indications were found for a changed pattern of projection from MD in response to either a neonatal or an adult medial prefrontal cortex (mPFC) lesion. However, the DA innervation was changed after neonatal mPFC lesions. In the remainder of the mPFC, the DA fibre network proved to be denser, fibres were thicker, had more varicosities, and often the background staining was higher. None of these phenomena were seen in operated adult rats or in controls. It is postulated that the changes in DA innervation might contribute to the sparing of function observed in the spatial delayed alternation task.

Aging↗

Effects of ibotenic acid lesions of the ventral striatum and the medial prefrontal cortex on ethanol consumption in the rat.

The purpose of this study was to to assess the effect on ethanol drinking of ibotenic acid lesions in the medial prefrontal cortex and the ventral striatum of female rats with continuous access to water and a 6% ethanol solution. Ibotenic acid infusions in the prefrontal cortex did not affect ethanol intake at any time, but a significant increase in water intake was observed on the third postoperative week. Ventral striatal lesions significantly increased ethanol intake during the first 2 postoperative weeks. On the third week consumption was not significantly different from vehicle-infused controls. Apparently, then, severe excitoxic injury to the ventral striatum is compatible with normal, or increased, intake of ethanol; in contrast, similar lesions reduce the intake of other drugs of abuse such as psychostimulants and opioids.

Alcohol Drinking↗

Alteration in dendritic morphology of pyramidal neurons from the prefrontal cortex of rats with renovascular hypertension.

We have studied, in the rat, the dendritic morphological changes of the pyramidal neurons of the medial part of the prefrontal cortex induced by the chronic effect of high blood pressure. Renovascular hypertension was induced using a silver clip on the renal artery by surgery. The morphology of the pyramidal neurons from the medial part of the prefrontal cortex was investigated in these animals. The blood pressure was measured to confirm the increase in the arterial blood pressure. After 16 weeks of increase in the arterial blood pressure, the animals were sacrificed by overdoses of sodium pentobarbital and perfused intracardially with a 0.9% saline solution. The brains were removed, processed by the Golgi-Cox stain method and analyzed by the Sholl method. The dendritic morphology clearly showed that the hypertensive animals had an increase (32%) in the dendritic length of the pyramidal cells with a decrease (50%) in the density of dendritic spines when compared with sham animals. The branch-order analysis showed that the animals with hypertension exhibit more dendritic arborization at the level of the first to fourth branch order. This result suggests that renovascular hypertension may in part affect the dendritic morphology in this limbic structure, which may implicate cognitive impairment in hypertensive patients.

Animals↗

Acetylcholine release in the rat prefrontal cortex in vivo: modulation by alpha 2-adrenoceptor agonists and antagonists.

We have previously shown that the release of acetylcholine (ACh) in the medial prefrontal cortex of the conscious rat, as measured by microdialysis, is increased following intraperitoneal injection of the selective alpha 2-adrenoceptor antagonist (+)-efaroxan. To characterize further the receptor pharmacology of this response, the effects of other selective alpha 2-adrenoceptor ligands were examined. The alpha 2-adrenoceptor antagonists idazoxan (2.5 and 20 mg/kg), atipamezole (2.5 mg/kg), and fluparoxan (10 mg/kg) increased ACh outflow by up to 250-325% of basal levels over a 3-h period following intraperitoneal injection. The alpha 2-adrenoceptor agonists UK-14304 (2.5 mg/kg) and guanabenz (2.5 mg/kg) reduced ACh outflow by 80 and 60%, respectively. Clonidine (0.00063-0.16 mg/kg) had no significant depressant effect and at 2.5 mg/kg increased ACh outflow to 233% of basal levels. These results indicate a modulatory role for alpha 2-adrenoceptors on the release of ACh in the rat prefrontal cortex in vivo. Based on the facilitatory effects produced by the antagonists alone, this alpha 2-adrenoceptor modulation appears to be tonic and inhibitory. The ability of alpha 2-adrenoceptor antagonists to enhance ACh outflow suggests a therapeutic usefulness in disorders where cortical ACh release deficits have been implicated.

Acetylcholine↗

The functional roles of prefrontal cortex in episodic memory. II. Retrieval.

Functional neuroimaging studies of memory retrieval show consistent activation of the right prefrontal and superior parietal cortex. We examined the specific role of the prefrontal cortex during retrieval with the hypothesis that this region mediates monitoring processes necessary for optimal recall. During functional neuroimaging with PET, subjects retrieved verbal material under two conditions. In the first, an organizational structure had been provided, prior to scanning, and this formed the basis for a monitored memory search while the scan took place. A comparison condition did not require a monitored search because recall was externally cued. In both conditions, when compared with baseline tasks prefrontal cortex and medial parietal activation was observed. Within the right prefrontal cortex activation an anatomical dissociation was seen between the dorsal and ventral prefrontal cortex. The dorsal region showed greater activation when monitoring demands were emphasized, while the ventral region showed greater activation when external cueing was emphasized. An unpredicted dissociation within the superior parietal activation was also observed, a dorsal region showing activation during the monitored search task and a more ventral region showing activation under the externally cued condition. The results provide evidence for functional specialization of the right prefrontal cortex for discrete cognitive processes during episodic memory retrieval.

Adult↗

Effects of prenatal cocaine exposure in the prefrontal cortex of the rat. A morphometric evaluation.

This work was undertaken in order to assess the organization of the prelimbic area of the medial prefrontal cortex of rats exposed prenatally to cocaine. Pregnant Wistar rats were assigned to the following groups: 1. Cocaine--60 mg/kg body wt/d sc, from gestational days 8-22; 2. Saline; 3. Pair-fed; and 4. Nonmanipulated. Male offspring were perfused on postnatal days 14 and 30. Six brains per group and per age were embedded in celloidin to calculate the volumes of the prelimbic area; sections from the other six brains were embedded in resin and processed for electron microscopy. Using semithin sections (2 microns) of layers II-III and V-VI, the following parameters were calculated: 1. The fraction of the neuropil occupied by neurons (VV); 2. The packing (NA) density; and 3. The numerical (NV) density. Qualitative alterations consisted of dispersed profiles of degenerated neurons and dendrites in the medial prefrontal cortex. No significant differences were found in the gross morphometric parameters when the cocaine group was compared with the other groups. A high interanimal variation was shown in the prelimbic volumes of postnatal day (PND) 14 cocaine-treated rats, and a a decrease in volumes was detected at PND30. Although there are some alterations in the main afferent cortical target area for dopaminergic input, its gross morphometric parameters do not seem to be sufficiently affected to account for the behavioral alterations referred to as being dependent on this brain region.

Aging↗

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.

Animals↗

Suprachiasmatic nucleus projection to the medial prefrontal cortex: a viral transneuronal tracing study.

The viral transneuronal labeling method was used to examine whether the suprachiasmatic nucleus (SCN) is linked by multisynaptic connections to the medial prefrontal cortex of the rat. In separate experiments, pseudorabies virus (PRV) was injected into one of the three different cytoarchitectonic regions that comprise the medial prefrontal cortex: infralimbic (Brodmann area 25), prelimbic (Brodmann area 32), and cingulate (Brodmann area 24) cortical areas. After 4-days survival, extensive SCN transneuronal labeling was found following infralimbic cortex (ILC) injections, but almost none occurred when the PRV injections were centered in the prelimbic or cingulate areas. In the ILC cases, transneuronal labeling was localized mainly in the dorsomedial SCN, although a moderate number of labeled neurons were found in the ventrolateral SCN. About 13% of the infected neurons were vasopressin immunoreactive and 4% were vasoactive intestinal polypeptide-positive. Another set of experiments was performed in which the paraventricular thalamic nucleus (PVT) was destroyed 2 weeks prior to making PRV injections into the ILC. Almost no SCN transneuronal labeling occurred in these animals, suggesting that the SCN projection to the ILC is dependent on a relay in the PVT. We propose that the SCN sends timing signals, via its relay in the PVT, to the ILC. This pathway may modulate higher-level brain functions, such as attention, mood, or working memory. Assuming that a homologous circuit exists in humans, we speculate that neurochemical changes affecting this pathway may account for some of the symptoms associated with clinical depression and attention-deficit/hyperactivity disorder.

Affect↗

Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex.

A variety of lines of converging evidence implicates the prefrontal cortex (PFC) in schizophrenia. Previous neuroanatomical studies have shown schizophrenia-associated changes in neuron density, soma size and spine number. We recently demonstrated a schizophrenia-associated decrease in microtubule-associated protein 2 (MAP2) immunostaining in laminae III and V of medial prefrontal area 32 and interpreted that finding as suggestive of a loss of dendritic material. We now present data from medial prefrontal area 32 of 11 schizophrenics and 11 comparison subjects. In Golgi-stained material, we describe a significant decrease in the number of both primary (29%) and secondary (46%) basilar dendrites on pyramidal neurons in layer V. Similarly, in layer III there was also a decrease in both primary (17%) and secondary (15%) basilar dendrites. These findings suggest a decrease in synaptic surface area which could lead to aberrant information processing.

Adult↗

Activity and distribution of learning-related neurons in monkey (Macaca fuscata) prefrontal cortex.

The involvement of monkey (Macaca fuscata) prefrontal cortex (PFC) neurons in motor output decisions was studied by recording single neuron activity during 3 tasks: (a) go-left, go-right, or no-go decisions, (b) operant bar press feeding based on discrimination of food and nonfood, and (c) either delayed matching-to-sample (DMS) or DMS with response delay. Combinations of single neuron responses during the 3 tasks suggested 7 types of PFC neurons that were related to attention, choice, task-unique memory, reward anticipation, laterality, initiation of movement, and suppression of movement. The authors suggest that responses of PFC neurons do not depend on physical properties of the stimuli, but on their behavioral significance. PFC neurons might be important for appropriate behavior in response to external stimuli and internal or motivational factors.

Animals↗

Memory of monkeys (Macaca mulatta) with lesions in prefrontal cortex.

It is controversial whether damage to prefrontal cortex causes an impairment of memory. In this experiment, the tissue in sulcus principalis was removed in rhesus monkeys, and they were given 25 spatial locations to remember. They were poor at the task from the first. The same animals were able to indicate which of two locations they had touched if there was no delay before they were allowed to make their report. One possibility is that frontal mechanisms operate on information in working memory.

Animals↗