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Influence of the mesocortical dopaminergic system on activity, food hoarding, social^agonistic behavior, and spatial delayed alternation in male rats.

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... Dopaminergic afferents originating in the brain stem innervate PFC pyramidal neurons and modulate their excitability (Williams & Goldman-Rakic, 1993. Selective chemical lesions to prefrontal dopamine afferents results in significant behavioural impairments in animals during spatial working memory tasks (Brozoski et al., 1979;Kessler & Markowotsch, 1981;Nonneman & Corwin, 1981;Roberts et al., 1994;Simon, Scatton & Moal, 1980;Stam et al., 1989;Wilcott & Xuemei, 1990). Thus dopamine afferents may exhert their effects on working memory through their actions on the PFC. ...
... The open-field test (OF-test) is one of the oldest and most frequently used behavioural tests [Hall 1934, Prut andBelzung 2003]. There are different opinions whether it reflects the animal's needs for locomotion and/or for exploration, or rather fear reactions and behavioural inhibition of an animal in a novel surrounding [Stam et al. 1989, Ossenkopp et al. 1994, Prut and Belzung 2003, Ramos et al. 2003]. The OFtest has widely been used for a variety of purposes, e.g. for comparison of lines and strains of rats [Schmitt and Hiemke 1998] and rabbits [Zelnik et al. 1990, Ferrante et al. 1992, to evaluate crossbreeding effects and heterosis in rabbits [Brun et al. 2002], or to assess effects of handling [Denenberg et al. 1977]. ...
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Twenty males were used from generation 8 of rabbits divergently selected for high (line H, n=10) vs. low (line L, n=10) locomotor activity in the open-field (OF-test). At the age of 98 days, blood samples were withdrawn from the ear vein and the rabbits were killed. Immediately, liver, kidney and the left femoral muscle samples were excised. In lysosomal fractions of blood serum and three tissues mentioned the activity of lysosomal enzymes AlaAP, LeuAP, ArgAP, Cat D and L, AcP, EL, LAL, BGRD, BGAL, BGLU, aGlu, MAN and HEX was determined. Significant interline differences were identified in activity of blood and tissue enzymes in question. The results suggest that the divergent selection for high vs. low locomotor activity in the open-field (OF-test) alters the lysosomal degradation processes in the organism.
... In humans, compulsive hoarding (CH) is an obsessive-compulsive spectrum disorder characterized by difficulties in discarding several types of objects [1]. Similarly to other obsessive-compulsive spectrum disorders, CH is associated to a deficiency in mechanisms that inhibits normal hoard [33] [34]. Pharmacotherapy for CH, however, is different from that for other obsessive-compulsive spectrum disorders-it comprises administration of dopaminergic D2 antagonists (SSRI do not alleviate the symptoms) [35]. ...
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Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts, images etc.) and compulsions (repetitive, stereotyped and perseverant acts). Animal models of OCD are specifically devoted to simulating compulsive features of the disorder. In OCD, compulsive behaviors are recognized as repetitive and maladaptive and symptoms relief can be experienced due to treatment with selective serotonin reuptake inhibitors. Many animal models of OCD are provided with some degree of validity. Genetically based differences in behavior in animal models of OCD are of great value, given that human OCD is reported to involve genetic factors. Some animal models of OCD were already used in studies for the evaluation of strain differences. These works were explored in the present review.
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Lesions of the medial prefrontal cortex (mPFC) disrupt performance in a variety of delay tasks, which suggests that the mPFC supports short-term memory processes. The putative involvement of the dopaminergic innervation of the mPFC in these mnemonic processes was investigated by evaluating the effects of local infusions of dopaminergic drugs into the mPFC of rats in an operant delayed-matching-to-position (DMTP) task. Trained animals were provided with bilateral guide cannulae aimed at the dorsal part of the mPFC. Two separate groups of rats were tested after microinfusion of several doses of either the dopamine agonist apomorphine (APO) or the dopamine antagonist cis-flupenthixol (FLU). In addition, all animals were tested after infusion of several doses of the muscarinic antagonist scopolamine (SCO). Animals were tested 0 and 135 min after each infusion. At the 0 min interval, neither APO nor FLU affected accuracy of DMTP performance, while both drugs dose-dependently increased response latencies and decreased nosepoke frequencies. At the 135 min interval, APO had almost no effect, whereas the effects of FLU were very prominent. A number of animals no longer responded after infusion of the highest doses of FLU and those that did showed a delay-independent decrease in response accuracy. In contrast, SCO infusions into the mPFC induced a dose- and delay-dependent deterioration of DMTP performance. Taken together, these results support a direct involvement of the rat mPFC in short-term memory processes, although they implicate cholinergic rather than dopaminergic mechanisms in this function.
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Turnover of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites has been measured after a 15-day vitamin E-deficient diet in adult rat prefrontal cortex. Turnover rates of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxy-3-indoleacetic acid have been assayed from the disappearance rates after blocking by pargyline inhibition of monoamine oxidase. NA, DA, and 5-HT turnover rates have been measured as accumulation rates of NA, DA, and 5-HT after pargyline inhibition of monoamine oxidase. No change was found in the turnover rate of NA between control and experimental animals. In contrast, turnover rates of DA and homovanillic acid significantly increased in the animals fed on a low-vitamin E diet. However, the most striking results were found on the serotoninergic system. Levels of 5-HT and its main metabolite, 5-hydroxy-3-indoleacetic acid, and their respective turnover rates were lower in the vitamin E-deficient diet. These results could indicate that vitamin E is necessary for the normal functioning of the serotoninergic neurons in the rat prefrontal cortex. The involvement of vitamin E in preventing the formation of free radicals is well known. Therefore, this lack of protective effect after a 15-day vitamin E-deficient diet could be responsible for the neuronal damage to the serotoninergic system. The opposing results found in DA (increase) and 5-HT (decrease) turnover could provide further evidence for an inhibitory control of the serotoninergic ascending pathways to the dopaminergic system in the prefrontal cortex.
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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.
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The effect of acute stress on the acquisition of an instrumental action reinforced by electrical stimulation of the medial prefrontal cortex (MPC) was investigated by exposing rats to either escapable, inescapable or no footshock prior to daily self-stimulation training sessions. Treatment with inescapable footshock did not affect the number of sessions required for acquisition of MPC self-stimulation but did increase the rate of responding over acquisition sessions compared with the no-shock group. When the treatment footshock was escapable, however, both a facilitation in acquisition, as indexed by a reduction in the number of sessions to criterion, and an increase in the rate of MPC self-stimulation was found. These data were interpreted as offering evidence for the operation of a dopaminergic mechanism in the acquisition of MPC self-stimulation. Further, they indicate, contrary to the reported effects of footshock on self-stimulation of other brain areas, that exposure to acute stress has a facilitatory effect on the rate of self stimulation of the MPC.
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The effects of lesions to the mesolimbic dopamine system on maternal and sexual behaviors in the female rat was assessed. Rat dams that were given ventral tegmental area microinfusions of 6-hydroxydopamine (6-OHDA) during lactation showed a persistent deficit in pup retrieval but were not impaired with respect to nursing, nest building, or maternal aggression. In addition, 6-OHDA-lesioned females failed to respond to amphetamine by showing locomotor hyperactivity. Administration of the dopamine blocker raclopride to neurologically intact dams also inhibited pup retrieval but had no effect on nursing. Females given 6-OHDA during pregnancy appeared completely unresponsive to pups, whereas no maternal deficits were seen in females that received 6-OHDA 8 weeks before parturition. Proceptive (hopping and darting) and receptive (lordosis) components of sexual behavior, assessed after ovariectomy and exogenous steroid hormone treatment, were not affected by mesolimbic 6-OHDA lesions.
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Performance in food hoarding, a species-typical task, and spatial delayed alternation, a learning task, was investigated in male rats with bilateral medial prefrontal cortex (mPFC) lesions sustained in adulthood or at the age of 6 days. Animals with adult mPFC lesions hoarded significantly fewer food pellets than their controls. The mPFC lesion effect on hoarding behaviour of the neonatally operated rats was unclear because of the unexpectedly low hoarding score of their controls. In the spatial delayed alternation task, the animals with mPFC lesions in adulthood exhibited a permanent deficit, while the animals with neonatal mPFC lesions showed no significant deficits. It is concluded that a bilateral lesion in adulthood, mainly affecting the frontal area 2 and the dorsal anterior cingulate area of the mPFC, results in a permanent deficit in food hoarding and spatial delayed alternation performance, whereas a similarly restricted mPFC lesion at the age of 6 days shows a complete sparing of the spatial delayed alternation task performance.
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Levels of dopamine, noradrenaline and serotonin and their metabolites and the activities of monoamine oxidase A and B, have been determined in the prefrontal cortex of the rat during ageing. Serotonin turnover rate has been measured as 5-hydroxytryptophan accumulation rate after central decarboxylase inhibition. The major changes were an increase of dopamine and noradrenaline levels and a decrease of serotonin in aged animals compared with control animals. A decrease of the MAO-A to MAO-B ratio was found in aged rats.
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This chapter provides an overview of the behavioral and morphological effects of the depletion of the mesocortical DA (dopaminergic) system, either in early life or in adulthood. It also explores when and where the DA-containing fibers arrive in the prefrontal cortex (PFC) and at what age the adult innervation pattern is accomplished. The pre- and postnatal development of the DA innervation in the PFC is reviewed in the chapter. It also describes the procedures to lesion the DA fibers as early and selectively as possible. After the completion of behavioral experiments, different parameters of PFC development are measured and compared in the chapter. Neonatal depletion of DA and 5HT (serotonin) from the developing PFC, prior to synaptogenesis, has best effects on the gross features of cortical morphology, such as lamination, cortical thickness, and volume. The results of biochemical experiments show that the damaged DA system can compensate for lesion-induced loss of DA containing terminals by increasing the DA metabolism of the remaining terminals.
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In order to examine the effect of neonatal depletion of the dopaminergic mesocortical projection on the development of prefrontal cortex-mediated behaviors, male and female adult rats with neonatally applied thermal lesions of the dopaminergic A10 cell group in the ventral tegmental area were studied in a food-hoarding situation. Control male animals hoarded significantly more pellets than females. Neonatal depletion of dopamine in the prefrontal cortex strongly decreased food-hoarding activity in contrast with previous studies by others which have shown that neonatal lesions of the prefrontal cortex allow sparing of food-hoarding activity. Biochemical analysis demonstrated an approximately 50% depletion of both dopamine and serotonin in the prefrontal cortex of males, whereas noradrenaline levels were unchanged. The brains of the female rats were used to visualize the decreased dopaminergic and serotonergic innervation of the forebrain. Hoarding scores showed a significant positive correlation with the measured dopamine content of the medial prefrontal cortex, and not with the serotonin content. These results imply that the integrity of the dopaminergic projection to the prefrontal cortex is essential for food-hoarding behavior to occur and that food-hoarding activity is not spared after neonatal depletion of dopamine.
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A single dose of methamphetamine (25 mg/kg i.p.) was administered to young adult gerbils (Meriones unguiculatus) aged 90 days and the number of spices was determined along 40-microns segments of basal, lateral and apical dendrites of pyramidal cells in layers III and V of the prefrontal cortex, after 1.5, 7, 20 and 30 days. The density of spines rapidly increased by more than 80% within 7 days after drug challenge, and subsequently returned to the original normal values within about 2 weeks. Thirty days after drug administration the density of dendritic spines was slightly, but significantly, less than control values (about 5%). The density of spines was likewise affected in layer III and V neurones, irrespective of the spatial domain of their dendritic ramifications. Since several lines of investigation indicate that methamphetamine can cause the destruction of dopaminergic nerve terminals in the mammalian forebrain, the present results are discussed against the background of current concepts about reactive synaptic reorganization and adaptive remodelling of neural circuits in the central nervous system.
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Procholinergic drugs have failed to overcome the memory deficit induced by alterations of the cholinergic system because their neurochemical target in the brain is either lacking or disorganised. However, there are many reports on a relative involvement of the dopaminergic system in learning and memory that may compensate for the cholinergic deficit because of the interaction or balance between neurotransmitters and the redundancy of the brain. The aim of our experiments is to examine the activation of the dopaminergic system on the performance of normal and medial septal lesioned rats in the radial maze test involving continuous choices. In the first experiment different groups of normal rats were treated with either 0.5, 1.0 or 2.0 mg/kg of D-amphetamine and tested in the radial maze. In the second experiment, medial septal lesioned rats which had learnt pre-op the radial maze test were retested a month later. Amphetamine had no effect on the memory measures provided by the radial maze test in normal and lesioned rats, but non-memory measures were significantly affected: amphetamine decreased the sequential choice responses and the time taken by the rats to perform the test. The present results show that the activation of the dopaminergic system does not compensate for the alteration of the cholinergic activity inducing amnesia, however, they support the recent data on the improving effect of amphetamine on locomotor activity. The interpretation of drug/lesion interaction effects is discussed in this paper in relation to the literature on the effect of promnesic drugs.
Article
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.
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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.
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In an earlier study it was found that partial neonatal lesions of the medial prefrontal cortex (mPFC) resulted in an increased dopaminergic innervation in the remaining part of mPFC along with functional sparing. The present study assessed whether this response is restricted to this part of the cortex or whether also other structures of the mesolimbocortical system are involved. Furthermore, it was investigated whether the other monoaminergic systems were affected by neonatal mPFC lesions. In 6-day-old rats, the mPFC was partially ablated or a sham operation was made. The concentrations of dopamine (DA) and its metabolites increased to 250-350% in the remaining part of the mPFC compared to the sham-operated controls. The response was most prominent in this part of the cortex; no other mesolimbocortical structure showed such major changes of DA and its metabolites. In addition, a small increase in the concentrations of noradrenaline, serotonin and their metabolites was also spotted in the remaining mPFC and some other mesolimbocortical structures of the lesioned animals. The present data support the suggested involvement of DA in the neural mechanism of sparing of function, and this DA response seems to be most prominent in the remaining mPFC. However, the responses of the noradrenergic and serotonergic systems may also be important for sparing of function to occur.
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A single dose of methamphetamine (50 mg/kg; i.p.) was administered to neonatal male gerbils (Meriones unguiculatus) aged 14 days, and adult prefrontal cortex (PFC)-related behaviours were analysed and compared with saline-treated controls at the age of postnatal day 90. For that purpose, animals were tested for open-field activities and y-maze delayed alternation. This solitary and non-invasive drug challenge, which has recently been found to initiate serious restraint in maturation of the mesoprefrontal dopamine (DA)-system (Dawirs et al., 1994), induces a significant delayed alternation impairment as well as significant increases in open-field motor activity and emotionality. Since an undisturbed development of the prefrontal DA-innervation seems to be a precondition for the maturation of normal PFC-related behaviours, a single early methamphetamine impact may be a suitable animal model for further investigation of structural and functional aspects of non-invasively induced behavioural deficits in rodents. The present results are discussed with regard to the assumption that hypofunctional mesoprefrontal DA-systems might be basic to schizophrenic behaviours in man.
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The medial prefrontal cortex (mPFC) is usually considered to be a brain area important for working memory processes. In rats this statement is evidenced by their diminished performance in delay-type tasks following mPFC damage, notably in spatial delayed alternation (SDA) in a T-maze. This study has addressed two questions. First, to examine whether the functional deficiency in SDA, observed in rats with (usually large) mPFC damage, can be ascribed to an anatomically defined subarea of mPFC, the dorsal anterior cingulate area (ACd). Small, bilateral, NMDA-induced lesions were made, restricted to the dorsal part of mPFC. The performance of such animals in a T-maze paradigm, using delays of 0 and 15 s, was compared with sham-operated animals. Although these small lesions resulted in an increased number of perseverative errors, this effect was not delay-dependent, and, moreover, by the end of the training group differences had disappeared. The second aim was to study whether or not spatial (extra-maze) cues are important for the performance of this task. This was achieved by subjecting the well-trained sham-operated animals to a series of systematic trial-to-trial variations in the position of the maze in the experimental room. These spatial manipulations severely impaired the performance of the SDA task, indicating that extra-maze information is required to solve this task. In animals with ACd lesions, subjected to the same manipulations, the deficiency was comparable to that of the sham-operated animals.
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Chronic experiments on five cats using a model of a conditioned feeding movement reflex were used to study the effect of functional exclusion of the orbital cortex (by anodic polarization with a constant current) on the nature of rearrangements in spike activity in the ventral part of the tegmentum of the midbrain, as well as on the movement component of a conditioned feeding response. Changes in the frequency characteristics, their latent periods, and histogram analyses of spike impulse structure, as compared with increases in the latent period of the conditioned movement response, its duration, and phasicity, demonstrated that the orbital cortex had an activating effect on the responses of ventrotegmental neurons, which correlate with changes in the conditioned movement in this type of feeding behavior. Changes in the conditioned cellular responses were statistically significant only during the start signal (a tone of 600 Hz) before the start of the electromyographic component of the response, i.e., during the preparation and launching period of the movement response.
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Using a selective antibody serum against glutaraldehyde-conjugated gamma-aminobutyric acid (GABA), GABAergic neurons were identified in the medial prefrontal cortex of young adult gerbils (Meriones unguiculatus) following a single non-invasive dose of methamphetamine (25 mg/kg i.p.) applied at the age of 90 days. GABA-immunoreactive profiles were electron microscopically counted in a defined test field (0.875 mm2) covering the prefrontal prelimbic area after a single dose of either methamphetamine or saline. Within 30 days following the drug challenge the density of GABAergic innervation significantly increased by about 20%. Several lines of previous investigation indicate that a single dose of methamphetamine is an appropriate stimulus to cause selective autotoxic destruction of certain prefrontal dopamine fibres due to drug-induced hyperactivation. There is further indication of postsynaptic and transneuronal neuroplasticity since the densities of dendritic spines on prefrontal pyramidal cells went through a significant sequence of post-drug gain and loss. These structural dynamics resemble typical alterations seen after classical mechanical or chemical lesioning in other regions of the brain. The present results on drug-induced reactive neuroplasticity are discussed together with the current understanding of stimulus-induced adaptive reorganization in the mammalian central nervous system.
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questions. Studies were carried out using ten cats, using a conditioned food-related movement reflex with simultaneous recording of neuron activity [1] in the midbrain ventral tegmental area, both in normal conditions and during functional exclusion of the orbital cortex and head of the caudate nucleus by anodic polarization using constant currents of 180-200 and 120-140/~A/mm 2. Analysis of spike activity included construction of post-stimulus histograms, histograms of interstimulus intervals, and mean discharge frequencies. Movement food reflexes were assessed using electromyograms of the flexor muscles of the anterior limb. The activity of 140 neurons of the midbrain ventral tegmental area was recorded, in normal conditions and during reversible exclusion of the caudate nucleus (80 cells) and orbital cortex (60 cells); 29% of neurons were cells with low-frequency background activity (3.7 + 0.34 spikes/see) and a unimodal distribution of interspike intervals with a mode of 100-250 msec; 12% were cells with intermediate-frequency background rhythms (13.1 + 1.44 spikes/see), dominated by three values for the interspike intervals (10-30, 100-180, and _>500 msec); and 59% were cells with high-frequency background activity (37 + 2.5 spikes/sec) with two dominant interspike intervals (10-20 and 100-150 msec). The general effect of excluding the dorsal, medial, and ventromedial parts of the head of the caudate nucleus on activity throughout the ventral tegmental area consisted of an increase in the discharge frequency in 50% of cases (40 cells), and a reduction in only 15% of cases (12 cells); there was also an increase in grouped spikes to 85%. The caudate effect was seen most clearly in the lateral regions, involving 80% (31 + 9) of the cellstested in this region, compared with changes in 65 % of cells affected by exclusion of the medial and ventromedial parts of the head of the caudate nucleus. Activity was analyzed in 80 neurons in different phases of food reinforcement. In normal animals, the sight of meat had no significant effect on the mean spike frequency, though activation was recorded, reaching a maximum at the peak of the electromyogram component, in 88% of cells (in 74 cells of the 80 studied). Polarization of the caudate nucleus did not alter the level of responses in the ventral tegmental area to the sight of meat, though as meat was taken there were significant increases in the discharge frequency in 40 neurons in animals with exclusion of the medial and ventromedial parts of the head of the caudate nucleus, and in 10 neurons in animals with exclusion of the dorsal part. Analysis of interval histograms revealed a shift in the mode to the left, and loss of peaks at 500 and _> 1000 msec. Spreading occurred in the latent periods of neuronal responses, from 50-250 msec to 25-500 msec, and the electromyogram latent periods reached 1200 msec. Neuronal discharges from 50 cells with pronounced conditioned responses (33 activational and 12 inhibitory)were studied in conditions of polarization of the caudate nucleus. Although the directions of responses were
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Single Oreochromis niloticus and O. mossambicus were placed in an unfamiliar white basin for 21 min, and their activity in this open-field situation was recorded from overhead on video. Apomorphine added to the water (2-8 mg/liter) caused a significant increase in locomotor activity, as assessed by the frequency that a fish swam over a rectilinear array of lines drawn on the base. This effect was attenuated by chlorpromazine (2 mg/liter) and abolished by the D1 antagonist SCH-23390 (1 mg/liter); the D2 antagonist metoclopramide (8 mg/liter) had no effect. Removal of both hemispheres of the telencephalon abolished the response to apomorphine, whereas removal of only one hemisphere or cauterization of the nostrils had no effect. It is concluded that the role of the dopaminergic system in the regulation of locomotor activity is reminiscent of the mammalian mesolimbic, rather than the nigrostriatal, system but that further studies are required to determine the source of the dopaminergic innervation and its likely telencephalic targets.
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The data reviewed here are compatible with the hypothesis that telencephalic dopamine activity is elicited by motivationally significant stimuli which in turn creates a neural state in which animals are more prepared to respond to significant stimuli in the environment. This analysis may be viewed as extensions of both the sensorimotor hypothesis, which depicts dopamine as potentiating the ability of stimuli to elicit responses (Clody and Carlton, 1980; Marshall et al., 1974; White, 1986) and of the incentive motivational hypothesis, which emphasizes the importance of dopamine in responding to stimuli that serve as signals of biologically significant events (Blackburn et al., 1989a; Crow, 1973; Mogenson and Phillips, 1976). In addition, we have sought to emphasize that not all responses are equally dependent upon the integrity of forebrain dopamine activity. Some responses, such as ingestion of standard foods by hungry animals, copulation, and escape, are relatively impervious to dopamine disruption. Further, once other behaviours, such as avoidance or appetitive operant responses, have been acquired, they can be maintained at an initially high rate despite perturbation of dopamine systems, although performance deteriorates with repeated testing. This analysis has emerged from the joint consideration of how both appetitive and defensive behaviours are influenced by dopamine antagonists, along with an examination of dopamine release during sequences of behaviour. The data reviewed suggest that dopamine is involved in fundamental psychological processes through which environmental stimuli come to exert control over certain aspects of behaviour. In the future, as knowledge in this field advances, there will have to be an integration of the literature on dopamine and motivation with the literature on dopamine and motor systems. We expect that dopamine release will be seen as a mechanism by which important environmental cues, of innate or learned significance, lead to a general enhancement of motor skeletal responses directed towards distal cues. We conclude with a caveat: Caution must be exercised when attempting to infer a general role of any neurotransmitter in motivated behaviour based on the study of a limited number of motivational systems. Although neurotransmitter pathways may figure prominently in the control of certain behaviours, it is incorrect to think of neurotransmitters as having a single role in behaviour. However, when comparative analyses reveal a common thread among different motivational systems, as is becoming apparent for the general role of mesotelencephalic dopamine pathways in behaviour, then the goal of generating coherent and comprehensive theory concerning a neurotransmitter's function in behaviour will begin to be realised.(ABSTRACT TRUNCATED AT 400 WORDS)
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The prefrontal cortices mediate cognitive functions that critically depend on local dopamine levels. In male rats, many prefrontal tasks where performance is disrupted by changes in dopamine signaling are also impaired by gonadectomy, a manipulation that increases cortical dopamine concentration, prefrontal dopamine axon density and possibly extracellular prefrontal dopamine levels as well. Because these actions could be responsible for the impairing effects of gonadectomy on prefrontal function, the question of how they might arise comes to the fore. Accordingly, the present studies asked whether dopamine levels might be increased via a hormone sensitivity of transporter-mediated dopamine uptake. Specifically, (3)H WIN 35,428 and (3)H nisoxetine, ligands selective for the dopamine (DAT)- and norepinephrine transporter (NET) respectively, were used in in vitro binding assays to ask whether gonadectomy altered transporter affinity (Kd) and/or binding site number (Bmax) in prefrontal cortex, sensorimotor cortex and/or caudate. Assays performed on tissues dissected from sham-operated, gonadectomized and gonadectomized rats supplemented with testosterone propionate or estradiol for 4 or 28 days revealed no significant group differences or obvious trends in Kd or Bmax for DAT binding or in measures of Bmax for NET binding. However, affinity constants for (3)H nisoxetine were found to be significantly higher in sensorimotor and/or prefrontal cortex of rats gonadectomized and gonadectomized and supplemented with estradiol for 4 or 28 days but similar to control in gonadectomized rats given testosterone. Because the NET contributes substantially to extracellular prefrontal dopamine clearance, these androgen-mediated effects could influence prefrontal dopamine levels and might thus be relevant for observed effects of gonadectomy on dopamine-dependent prefrontal behaviors. A hormone sensitivity of the NET could also have bearing on the prefrontal dopamine dysfunction seen in disorders like schizophrenia that disproportionately affect males, whose severity correlates with abnormal testosterone levels, and for which the NET is among suspected sites of pathology.
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Groups of rats with 6-hydroxydopamine (6-OHDA) lesions of either the medial prefrontal cortex (PFC), nucleus accumbens (NAC), or caudate putamen (CPu) were given daily tests for locomotor activity in photocell cages while food deprived. Two separate groups of NAC-lesioned rats were prepared with either large [NACT (90% NAC dopamine depletion)] or partial [NACP (67% NAC dopamine depletion)] lesions. NACT rats were spontaneously hypoactive whereas NACP rats were hyperactive compared with sham-operated controls. PFC-lesioned rats were also hyperactive compared to their respective controls. Spontaneous locomotor activity in CPu-lesioned rats did not differ from shams. When daily food supplements were paired with the photocell cages, all subjects developed a conditioned locomotor response. During the first few days of conditioning, the response to this conditioning procedure was markedly greater in the NACP group whereas the response in the NACT group was unaffected initially and actually enhanced during the latter days of testing. The locomotor response to the conditioning procedure was unaffected in either the PFC- or CPu-lesioned groups. Both the NACT and NACP lesions attenuated the locomotor response to 1.5 mg/kg d-amphetamine sulphate IP, and the NACT group showed a supersensitive response to 0.1 mg/kg apomorphine HCl SC. PFC or CPu 6-OHDA lesions did not alter the response to either drug. These results differentiate the role of PFC, NAC, and CPu dopamine in spontaneous, conditioned, and drug-induced locomotor activity and further implicate dopaminergic mechanisms of the NAC in the magnitude of the behavioural response to incentive stimuli.
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Both acetylcholinergic (ACh) and dopaminergic (DA) systems have been found to be crucial for the maintenance of accurate cognitive performance. In a series of studies examining those aspects of cognitive function revealed by the radial-arm maze, we have found that these two neurotransmitter systems interact in a complex fashion. Choice accuracy deficits in the radial-arm maze can be induced by blockade of either muscarinic- or nicotinic-ACh receptors. The choice accuracy deficit induced by blockade of muscarinic receptors with scopolamine can be reversed by the DA receptor blocker, haloperidol. The specific DA D1 blocker SCH 23390 also has this effect, whereas the specific D2 blocker raclopride does not, implying that it is D1 blockade that is critical for reversing the scopolamine effect. On the other hand, the choice accuracy deficit induced by nicotinic blockade with mecamylamine is potentiated by haloperidol. This effect is also seen with the D2 antagonist raclopride, but not with the D1 antagonist SCH 23390, implying that it is the D2 receptor which is important for the potentiation of the mecamylamine effect. The relevance of the D2 receptor for nicotinic actions on cognitive function is emphasized by the finding that the selective D2 agonist LY 171555 reverses the choice accuracy deficit caused by mecamylamine. Nicotinic and muscarinic blockade are synergistic in the deficit they produce. Antagonist doses subthreshold when given alone produce a pronounced impairment when given together. This latter deficit can be reversed by the D2 agonist LY 171555. These studies have outlined the complex nature of ACh—DA interactions with regard to cognitive function. Possible neural circuits for these interactions are discussed. The effectiveness of these selective DA treatments in reversing cognitive deficits due to ACh underactivation suggests a novel approach to treating cognitive dysfunction in syndromes such as Alzheimer's disease.
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Expanding on research showing that radio-frequency-induced lesions of the habenular complex disrupt the hormonal onset of maternal behavior in rats, we explored the importance of neurons in the lateral (Lhb) subdivision of the habenular complex for the onset of maternal behavior. On Day 12 of pregnancy, bilateral cytotoxic lesions were produced in the Lhb with kainic acid or, as a control, just dorsal in the medial hippocampus. A 3rd group had radio-frequency-induced Lhb and medial (Mhb) lesions. On Day 16 of pregnancy, Ss were hysterectomized-ovariectomized, given estradiol, and tested 48 hr later for 10 days. Neuroanatomical tracing with fluoro-gold was then used to directly quantify the extent and location of Lhb neuron loss and to verify that Mhb neurons were intact. Cytotoxic lesions of the entire Lhb prevented the onset of all components of maternal behavior compared with controls. Results show that neurons in the Lhb, not the Mhb, are important for onset of maternal behavior in rats.
Article
Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. Copyright © 2015. Published by Elsevier Inc.
Article
Gonadectomy in adult male rats significantly impairs spatial working memory, behavioral flexibility and other functions associated with the prefrontal cortex (PFC). However, the mechanisms through which this occurs are largely unknown. In this study, intracortical drug challenge with the selective N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) was combined with Barnes maze testing, gonadectomy and hormone replacement (17β estradiol, testosterone propionate) to explore the contributions of NMDAR-mediated activity within the PFC to hormone effects on spatial cognition in adult male rats. Previous studies have shown that Barnes maze testing reveals significant estrogen-dependent, gonadectomy-induced deficits in spatial working memory and androgen-sensitive, gonadectomy-induced deficits in spatial search strategy. Here we found that bilateral infusion of APV into the medial prefrontal cortex prior to testing significantly improved both sets of behaviors in gonadectomized rats and significantly worsened performance measures in gonadally intact controls. In hormone-replaced cohorts, we further found that behaviors that are normally similar to controls were significantly disrupted by APV, and those that are normally similar to gonadectomized rats were rescued by intracortical APV infusion. There were, however, no residual effects of APV on retention testing conducted 24 hours later. Together these findings suggest that hormone regulation of NMDAR-mediated activity specifically within the PFC may be fundamental to the effects of gonadal steroids on spatial cognition in males. Our findings further identify NMDAR antagonists as potentially novel, non-steroidal means of attenuating the cognitive deficits that can accompany gonadal hormone decline in human males in aging, clinical cases of hypogonadalism and in certain neurologic and psychiatric illnesses. Accordingly, it may be important to obtain in males the kind of detailed knowledge concerning hormone effects on, for example, the channel and electrophysiological properties of NMDAR that currently exists for the female brain. Copyright © 2014. Published by Elsevier Ltd.
Article
[Correction Notice: An Erratum for this article was reported in Vol 18(1) of Review of General Psychology (see record 2014-20691-006). The affiliation and name of author Jenna G. Andrews of Morehouse College were incorrectly listed in the byline and author note as Jennifer G. Andrews-McClymont of Stephens College. The online version of this article has been corrected.] Recently, researchers have begun to advocate use of an animal model for understanding compulsive hoarding in humans. Nevertheless, a comprehensive review of the literature for this argument is lacking. We compare data for compulsive hoarding behavior in humans with hoarding in several vertebrates (rat, bird, and primate) to examine the potential validity of an animal model of hoarding. Although the strength of each animal model varies, there is provisional evidence in support of an analogue between hoarding in nonhuman animals (especially rodents) and humans, most notably on neurobiological grounds. Nevertheless, substantially more evidence is needed before this relationship can be confirmed with confidence. We identify gaps in the literature and offer suggestions for further investigation of the validity of animal models of human hoarding. (PsycINFO Database Record (c) 2014 APA, all rights reserved)
Article
In addition to the hallmark motor disorders in Parkinson's disease (PD) patients, nonmotor symptoms have attracted increasing attention. Among the nonmotor symptoms, sleep disturbances and cognitive deficits are frequently reported and contribute to a decrease in the quality of life. The pathophysiology of cognitive and sleep-wake abnormalities in PD is poorly understood partially due to the lack of appropriate animal models that fully replicate the entire pathological and behavioral spectrum of the disease. In this study, we undertook a long-term evaluation of circadian, locomotor and cognitive abilities in both acute and chronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mouse models. Activity rhythms and locomotor activity were assayed under light-dark cycles, constant darkness, or constant light, re-entrainment to shifts of the light-dark cycle, and a behavioral masking paradigm. Cognitive abilities were assessed using a radial water maze task. Although both acute and chronic treatment regimes induced 70% degeneration of dopaminergic neurons in the substantia nigra, neither circadian nor cognitive alterations were observed even after nearly 1 yr. During aging, there was a significant decrease of locomotor activity and of several circadian parameters without any exacerbation in MPTP-treated animals. These results emphasize the limitations of the MPTP-treated mouse as an animal model of nonmotor symptoms of PD in addition to the already well-documented inadequacy to replicate cardinal motor features of the disease.
Article
Behavioral analyses of mice intoxicated by the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) have generated conflicting results. We therefore analyzed the relationship between behavioral changes, loss of monoamine levels, and loss of dopaminergic cell bodies in groups of mice intoxicated with acute or subchronic MPTP protocols. Despite a higher degree of neuronal loss in the mice intoxicated using subchronic protocols, dopamine loss was severe and homogeneous in the striatum in all groups. Dopamine levels were less severely reduced in the frontal cortex in the three groups of MPTP-intoxicated mice. Norepinephrine and serotonin levels in the striatum were decreased only in the mice intoxicated with the acute protocol. The most surprising result was that the mice intoxicated with the subchronic protocols were more active than the saline-treated mice. As reported in rats with dopamine depletion in the prefrontal cortex, the hyperactivity observed in our mice could be due to the reduced dopamine levels detected in this structure.
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Parkinson's disease is usually characterized as a movement disorder; however, cognitive abilities that are dependent on the prefrontal cortex decline at an early stage of the disease in most patients. The changes that underlie cognitive deficits in Parkinson's disease are not well understood. We hypothesize that reduced dopamine signalling in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental synaptic changes in pyramidal neurons in the prefrontal cortex, whose function is necessary for normal cognition. Our previous data showed that monkeys exposed to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but not exhibiting overt motor deficits (motor-asymptomatic), displayed cognitive deficits in prefrontal cortex-dependent tasks. The present results demonstrate that motor-asymptomatic MPTP-treated monkeys have a reduced dopamine concentration and a substantially lower number (50%) of asymmetric (excitatory) spine synapses in layer II/III, but not layer V, of the dorsolateral prefrontal cortex, compared to controls. In contrast, neither dopamine concentration nor asymmetric synapse number was altered in the entorhinal cortex of MPTP-treated monkeys. Together, these findings suggest that the number of asymmetric spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and that the loss of synapses may be a morphological substrate of the cognitive deficits induced by a reduction in dopamine neurotransmission in this region.
Article
The involvement of the hippocampus and the prefrontal cortex in cognitive processes and particularly in learning and memory has been known for a long time. However, the specific role of the projection which connects these two structures has remained elusive. The existence of a direct monosynaptic pathway from the ventral CA1 region of the hippocampus and subiculum to specific areas of the prefrontal cortex provides a useful model for conceptualizing the functional operations of hippocampal-prefrontal cortex communication in learning and memory. It is known now that hippocampal to prefrontal cortex synapses are modifiable synapses and can express different forms of plasticity, including long-term potentiation, long-term depression, and depotentiation. Here we review these findings and focus on recent studies that start to relate synaptic plasticity in the hippocampo-prefrontal cortex pathway to two specific aspects of learning and memory, i.e., the consolidation of information and working memory. The available evidence suggests that functional interactions between the hippocampus and prefrontal cortex in cognition and memory are more complex than previously anticipated, with the possibility for bidirectional regulation of synaptic strength as a function of the specific demands of tasks. Hippocampus 10:438–446, 2000 © 2000 Wiley-Liss, Inc.
Article
Previous studies have shown that gonadectomy in adult male rats induces a complex series of region- and time-specific changes in the density of presumed cerebral cortical dopamine axons that are immunoreactive for tyrosine hydroxylase. The present study asked whether noradrenergic cortical afferents also show hormone sensitivity by assaying axons immunoreactive for the enzyme dopamine-β-hydroxylase in representative areas of acutely and chronically gonadectomized and sham-operated adult male rats. Catecholamine afferents (both tyrosine hydroxylase-immunoreactive and dopamine-β-hydroxylase-immunoreactive) were also quantified in gonadectomized rats supplemented with testosterone propionate, with 17-β-estradiol, or with 5-α-dihydrotestosterone. Analyses of noradrenergic (dopamine-β-hydroxylase) afferents revealed no differences in axon appearance or density among the hormonally intact and hormonally manipulated groups. However, analyses of tyrosine hydroxylase immunoreactivity revealed an unexpected division of labor among ovarian and testicular hormones in ameliorating the effects of acute verses chronic hormone deprivation on these afferents. Estradiol replacement attenuated the decreases in immunoreactivity induced by acute gonadectomy, but was ineffective in suppressing changes in immunoreactivity stimulated by chronic gonadectomy. In contrast, supplementing gonadectomized animals with dihydrotestosterone provided no protection from acute decreases in innervation, but fully attenuated both the supragranular decreases and infragranular increases in tyrosine hydroxylase-immunoreactive axon density that mark the association cortices of chronically gonadectomized rats. Together these findings indicate both long- and short-term effects of gonadectomy on cortical catecholamines, principally target dopamine afferents, and that chronic gonadectomy, which selectively disturbs dopamine innervation in the prefrontal cortices, involves a compromise in androgen signaling pathways. J. Comp. Neurol. 427:617–633, 2000. © 2000 Wiley-Liss, Inc.
Article
Many animal species hoard food by carrying it to their home area. In this experiment we evaluated the interaction between persistent (formalin) pain and food-hoarding behaviour. A food-hoarding apparatus, consisting of a home cage connected with an alley at the end of which were placed food pellets, was used to test (60 min each day) food-restricted rats which had been familiarized with the apparatus for three days. Three groups of animals were used, one of which was tested in the apparatus in the absence of pellets. On the day of testing, the two groups of rats allowed to perform food-hoarding were either sham- or formalin-injected (50 μl, 10%) in the dorsal surface of the hind paw immediately before testing; the third group, not allowed to hoard pellets, was also injected with formalin. In animals treated with formalin, the availability of food resulted in shorter durations of Licking, Self-Grooming and Inactivity. In animals allowed to hoard food, formalin injection affected neither hoarding parameters nor exploratory activities. Our results show that, in food-restricted rats, food-hoarding behaviour is not modified by persistent nociceptive stimuli while Licking, a complex response to formalin pain, is decreased by the drive to relieve hunger.
Article
In rodents, gonadal steroids play a critical yet variable role in behaviors such as social interaction and cognitive performance. Gonadal steroids organize sex differences observed in spatial working memory, while the absence of activational effects induced by castration generally impedes spatial learning and memory. Although male sexual behavior is typically inhibited following castration, a significant proportion of gonadectomized B6D2F1 hybrid males retains the complete repertoire of male reproductive behavior. In a prior study, amyloid precursor protein and tau, proteins involved in cognitive behavior, facilitated steroid-independent male sex behavior in B6D2F1 hybrid male mice. We used this strain to investigate the relationship between gonadal steroid-independent male sexual behavior and cognition. After identifying “maters” (animals retaining steroid-independent male sex behavior) and “non-maters,” we tested spatial memory in an 8-arm radial arm maze. Although neither group demonstrated a decrease in errors as a function of time, maters committed fewer errors compared to non-maters overall (p < 0.05). Maters also completed the maze more quickly than non-maters (p < 0.05). We measured mRNA expression of APP and MAPT as well as LEPR and D2R to probe potential roles of metabolism and motivation. Uniquely among maters, increased relative expression of D2R and LEPR in the hippocampus was associated with a longer latency to complete the maze during the last 3 or across all trials, respectively. These data demonstrate that maters outperform non-maters in the radial arm maze, warranting further study of potential differences in acquisition of spatial memory tasks or learning strategy between these groups.
Article
We evaluated the cognitive effects of two moderate doses (30 mg/kg × 3 every 12 h and 20 mg/kg × 6 every 8 h, i.p.) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. The dose of 30 mg/kg × 3 caused about 60% depletion of striatal dopamine but did not reduce the levels of its metabolites. Mice treated with MPTP did not differ from controls in their motor behavior in the open field. Mice treated with MPTP were comparable to controls in T-maze delayed alternation with fixed delays but were impaired when trials with mixed 20 s and 120 s delays were presented, indicative of a spatial working memory impairment. Dexmedetomidine at 10 μg/kg (s.c.) slightly improved delayed alternation performance in all groups but also slowed initiation of the motor response. Mice treated with MPTP at the dose of 30 mg/kg × 3 were less sensitive to this adverse effect of dexmedetomidine. The impairment in spatial working memory after MPTP exposure in mice parallels the findings in monkeys, but the deficit is much less severe.
Article
The putative involvement of the dopaminergic innervation of the medial part of the prefrontal cortex (PFC) in short-term memory functioning was investigated by evaluating the effects of local infusions of dopaminergic drugs into the ventral part of the medial PFC of rats in an operant delayed-matching-to-position (DMTP) task. Two separate groups of rats were tested after bilateral microinfusion of several doses of either the dopamine receptor agonist apomorphine (APO) or the dopamine receptor antagonist cis-flupenthixol (FLU) into the ventromedial PFC. In addition, all animals were tested after infusion of several doses of the muscarinic receptor antagonist scopolamine (SCO) and the dopamine D1 receptor antagonist SCH-23390 (SCH). The drugs tested affected DMTP performance differentially. APO had no effect on response accuracy, although it dose-dependently affected nose poke activity and response latencies. FLU and SCH both induced a dose-dependent, but delay-independent deterioration of response accuracy that was paralleled by increased in response latencies and decreases in nose poke frequencies, causing some animals to stop responding after infusion of the highest doses of both drugs. In contrast, SCO infusions into the ventromedial PFC induced a dose- and delay-dependent deterioration of response accuracy, that was accompanied by an increase in response latencies only. Taken together, these results provide additional support for the involvement of cholinergic, rather than dopaminergic mechanisms in short-term memory processes supported by the medial PFC of the rat, and they are not in favor of a functional dissociation between the dorsomedial PFC and the ventromedial PFC in this role.
Article
Food hoarding was examined in male and female Long Evans rats. During a three-week period the animals were regularly submitted to the testing procedures, with food pellets in the home cage being either unrestricted (first week), or restricted (second and third week). When food pellets were present ad libitum, the hoarding scores were low, lower in females than in males. When food deprivation was imposed (second week), the animals responded by hoarding more pellets. This increase was more pronounced in males than in females. During the third week the hoarding scores became more or less stable, with males hoarding significantly more pellets than females.
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Small mammals usually face energetic challenges, such as food shortage, in the field. They have thus evolved species-specific adaptive strategies for survival and reproductive success. In the present study, we examined male Brandt's voles (Lasiopodomys brandtii) for their physiological, behavioral, and neuronal responses to food deprivation (FD) and subsequent re-feeding. Although 48 hr FD induced a decrease in body weight and the resting metabolic rate (RMR), such decreases did not reach statistical significance when compared to the control males that did not experience FD. During the first 2 hr of re-feeding following 48 hr FD, voles showed higher levels of feeding than controls. However, when permitted to hoard food, FD voles showed an increase in food hoarding, rather than feeding, compared to the controls. Further, both feeding and food hoarding induced an increase in neuronal activation, measured by Fos-ir, in a large number of brain areas examined. Interestingly, feeding and food hoarding also induced an increase in the percentage of tyrosine hydroxylase immunoreactive (TH-ir) cells that co-expressed Fos-ir in the ventral tegmental area (VTA), whereas both FD and feeding induced an increase in the percentage of orexin-ir cells that co-expressed Fos-ir in the lateral hypothalamus (LH). Food hoarding also increased orexin-ir/Fos-ir labeling in the LH. Together, our data indicate that food-deprived male Brandt's voles display enhanced feeding or food hoarding dependent upon an environmental setting. In addition, changes in central dopamine and orexin activities in selected brain areas are associated with feeding and hoarding behaviors following FD and subsequent re-feeding.
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Although androgens are known to modulate dopamine (DA) systems and DA-dependent behaviors of the male prefrontal cortex (PFC), how this occurs remains unclear. Because relatively few ventral tegmental area (VTA) mesoprefrontal DA neurons contain intracellular androgen receptors (ARs), studies presented here combined retrograde tracing and immunolabeling for AR in male rats to determine whether projections afferent to the VTA might be more AR enriched. Results revealed PFC-to-VTA projections to be substantially AR enriched. Because these projections modulate VTA DA cell firing and PFC DA levels, influence over this pathway could be means whereby androgens modulate PFC DA. To assess the hormone sensitivity of glutamate stimulation of PFC DA tone, additional studies utilized microdialysis/reverse dialysis application of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor subtype-selective antagonists which act locally within the PFC and tegmentally via inhibition or disinhibition of PFC-to-VTA afferents to modulate intracortical DA levels. Here, we compared the effects of these drug challenges in control, gonadectomized, and gonadectomized rats given testosterone or estradiol. This revealed complex effects of gonadectomy on antagonist-stimulated PFC DA levels that together with the anatomical data above suggest that androgen stimulation of PFC DA systems does engage glutamatergic circuitry and perhaps that of the AR-enriched glutamatergic projections from PFC-to-VTA specifically.
Article
The prefrontal cortex has traditionally been implicated in a variety of cognitive processes, including memory, attention and decision making. The detection of effects of prefrontal cortex lesions on attention has been shown to depend on the procedure used to assess the attentional process. We therefore investigated the effects of lesions of the prefrontal cortex in two different visual attention tasks, i.e. a three-choice serial reaction time task involving sustained and divided attention processes and a visual timing task involving sustained attention and response inhibition processes. In two rat strains that are frequently used in behavioural analysis, i.e. albino Wistar rats and pigmented Lister Hooded rats, lesions of the medial prefrontal cortex caused a deterioration of performance in both tasks, although the effect lasted much longer in the visual timing task. This latter task proved to be especially sensitive to detect the consequences of medial prefrontal cortex lesions, consisting of a loss of both attention control and response inhibition. In both attention tasks, Wistar rats performed less accurate and made more anticipatory responses than Listers. Strain differences could not entirely be attributed to possible visual deficits in albinos, which was also evident when locomotor activity in an open field and food-motivated behaviour in a hoarding paradigm were assessed. Due to slower habituation rates, Lister rats were more active and displayed little food hoarding behaviour. In Wistar rats, hoarding was disrupted by medial prefrontal cortex lesions, showing the effectiveness of the lesion. The results indicate that, although different rat strains provide different baseline levels of behaviour for testing lesion- or drug-induced behavioural changes, lesions of the medial prefrontal cortex do not only disrupt sustained attention processes, but also induce a strong impairment in response inhibition in both Wistar and Lister rats.
Article
Latent inhibition is a measure of retarded conditioning to a previously presented nonreinforced stimulus that is impaired in schizophrenic patients and in rats treated with amphetamine. In terms of neural substrates, latent inhibition depends on the integrity of the nucleus accumbens and the inputs to this structure from the hippocampal formation and adjacent cortical areas. Since another major source of input to the nucleus accumbens is the medial prefrontal cortex, and there are numerous demonstrations that manipulations of this region can modify ventral striatal dopamine, we investigated the effects of N-methyl-D-aspartate lesion to the medial prefrontal cortex on latent inhibition, assessed in an off-baseline conditioned emotional response procedure in rats licking for water. In addition, the effects of the medial prefrontal cortex lesion were assessed on a battery of tasks potentially sensitive to medial prefrontal cortex damage, including spontaneous and amphetamine-induced activity, elevated plus maze exploration, food hoarding, prepulse inhibition, and active avoidance. The lesion decreased hoarding behaviour and increased spontaneous exploratory activity in the open field, while exerting only mild effects on amphetamine-induced activity. Prepulse inhibition, exploration of the elevated plus maze, and the acquisition of two-way active avoidance were unaffected by the lesion. Likewise, latent inhibition was left intact following the lesion, suggesting that neither the destruction of the intrinsic cells of the medial prefrontal cortex nor any potential lesion-induced changes in subcortical dopamine, affect latent inhibition.
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Gonadectomy in adult male rats is known to impair performance on dopamine (DA)-dependent prefrontal cortical tasks and selectively dysregulate end points in the mesoprefrontal DA system including axon density. In this study, in vivo microdialysis and high-pressure liquid chromatography were used to determine whether short (4 day)- and/or long-term (28 day) gonadectomy and hormone replacement might also influence the more functionally relevant metric of basal extracellular DA level/tone. Assessments in medial prefrontal cortex revealed that DA levels were significantly lower than control in 4-day gonadectomized rats and similar to control in 4-day gonadectomized animals supplemented with both testosterone and estradiol. Among the long-term treatment groups, DA levels were significantly higher than control in gonadectomized rats and gonadectomized rats given estradiol but were similar to control in rats given testosterone. In contrast, extracellular DA levels measured in motor cortex were unaffected by long- or short-term gonadectomy. The effects of gonadectomy and hormone replacement on prefrontal cortical DA levels observed here parallel previously identified effects on prefrontal DA axon density and could represent hormone actions relevant to the modulation of DA-dependent prefrontal cortical function and perhaps its dysfunction in disorders such as schizophrenia, attention deficit hyperactivity disorder, and autism where males are disproportionately affected relative to females.
Article
Three common dosing regimens of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson's disease (PD) were compared in C57BL/6 mice on behavior, striatal and extra-striatal neurotransmission, and brain cytokines, to clarify the differences between regimens on these variables. Acute regimen: Rotorod performance and open field grooming were decreased. Striatal dopamine (DA) was depleted, but DA turnover increased. Striatal noradrenalin (NA), frontal cortex serotonin (5-HT) and midbrain NA and DA were all depleted. Sub-acute regimen: Opposite to the acute regimen, rotorod and pole test performance, and open field grooming were all increased. Striatal DA was depleted, but DA turnover was increased more than in the acute regimen. Striatal 5-HT turnover and cortical NA were increased as well. Chronic regimen: Rotorod performance was impaired, but open field distance moved increased. Striatal DA was severely depleted and DA and 5-HT turnover strongly increased. Striatal 5-HT, frontal cortex NA and DA, and cortical DA were all depleted. Pro-inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-10 were only increased in the chronic regimen, but these cytokines were found to be similarly related to striatal DA turnover in all regimens. The study demonstrated that the presence of behavioral differences between regimens may depend on the type of behavioral tests used and the extent to which dopaminergic, non-dopaminergic and extra-striatal neurotransmission are affected in the regimens. The study also provided additional evidence for the validity of the relatively new chronic MPTP/probenecid model. In all, the results suggested that dosing regimens should be carefully pre-considered.
Article
The catecholamine innervation of the cerebral cortex is essential for its normal operations and is implicated in cortical dysfunction in mental illness. Previous studies in rats have shown that the maturational tempo of these afferents is highly responsive to changes in gonadal hormones. The present findings show that perinatal hormone manipulation also has striking, region- and hemisphere-specific consequences for cortical catecholamines in adulthood. The effect of perinatal gonadectomy on catecholamines was examined in representative sensory, motor, and association cortices of adult male rats by combining hormone manipulation with immunocytochemistry for tyrosine hydroxylase, a rate-limiting enzyme in catecholamine biosynthesis. Qualitative and quantitative comparison of immunoreactivity in rats perinatally gonadectomized or sham-operated revealed complex changes in gonadectomized subjects; in cingulate cortex, TH immunoreactivity was strongly and bilaterally diminished, in sensory and motor cortices, axon density was decreased in left hemispheres, but was minimally affected on the right, and in a premotor cortex, gonadectomy was without significant effect in either hemisphere. Corresponding analyses in gonadectomized rats supplemented with testosterone revealed a protective influence, albeit one in which TH immunoreactivity so showed regional and hemispheric variability in responsiveness to hormone replacement. These complex patterns of TH sensitivity suggest highly asymmetric hormone stimulation of cortical catecholamines. Such discriminative action may contribute to sex differences in the functional maturation and lateralization of the cortex and may also have bearing on disorders such as dyslexia, which show sexual dimorphisms, and in which functional laterality of the cortex may be particularly at issue.
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Direct administration of 6 OHDA into the ventral tegmental A 10 cell area caused aggressive behavior and locomotor activation accompanied by a marked decrease in 5 HIAA contents in all cerebral regions but there was no effect on DNA and DOPAC contents in the mesolimbic olfactory tubercle. Neurochemical determination is thus considered a prerequisite for functional analysis after the 6 OHDA administration into the discrete cerebral regions.
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Reports results of 2 experiments with 27 male Wistar and 27 male hooded Long-Evans rats. Lesions to the medial frontal cortex produced severe deficits on spatial reversal learning and on delayed response, while lesions of the orbital frontal cortex produced perseverative response tendencies on a differential reinforcement of low rates 20-sec schedule and on barpressing extinction. Results are strikingly similar to those resulting from dorsolateral frontal and orbital frontal lesions, respectively, in rhesus monkeys. (24 ref)
Article
A new system, combining the advantages of cheap portable recording units with the power of computer analysis, has been described. The recording medium is quarter inch magnetic tape which is used on an ordinary domestic tape recorder. An electronic scanner fitted inside the recorder case accepts up to 40 inputs from a keyboard, which can be of any design, and converts these into a time-multiplexed form suitable for recording on a single track of the tape. The recording process incorporates a check system to detect tape errors, and has a basic time resolution of 0.1 sec. The cost of the components of a complete recording unit (keyboard, tape recorder, scanner) is less than £200; thus, sufficient machines can be available to avoid problems of sharing. Further, a battery powered system could be used for field work, because the way in which information is encoded makes the timing of the system independent of variations in tape speed. A small computer (PDP8/S) is programmed to transcribe the original recordings into permanent condensed form on paper tape by punching information only at times corresponding to changes in the keyboard. Additional programs analyse data from the paper tape transcriptions. Some specialized decoding hardware has been interfaced to the computer to perform the preliminary operations of recovering signals from the tape, in order to reduce the demands on the computer. Transcription time is reduced by replaying tapes at up to eight times the original recording speed and, if necessary, detailed results can be obtained within 30 minutes of completing an experiment.
Article
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.
Article
Aspiration lesions of orbital frontal cortex in the rat produced adipsia and aphagia persisting from 4–7 days. After recovery, food hoarding behavior was normal. Medial frontal cortical lesions did not affect food or water intake but produced a permanent deficit in food hoarding behavior. These results are taken as evidence that, like the rhesus monkey, the prefrontal cortex of the rat is dissociable into discrete subfields.
Article
The biphasic effect of morphine on intracranial self-stimulation (ICSS) (suppression followed by facilitation) was examined in rats following injections of 6-OHDA or vehicle into the ventral tegmental area (VTA). During 7 days of chronic administration of morphine, sham-lesioned animals gradually developed tolerance to the rate-reducing effects of the drug and a concurrent sensitization to its rate-enhancing effects (measured 1 and 3 h post-injection, respectively). VTA lesioned rats showed neither tolerance to the rate suppression nor any facilitation of ICSS throughout testing. Amphetamine's facilitation of ICSS remained intact in all subjects. The lesion was restricted to the VTA cell bodies but produced a significant depletion of dopamine (DA) in both the nucleus accumbens and in the striatum. Morphine facilitation of ICSS is suggested to be dependent on an indirect opiate receptor-VTA DA cell interaction. It is also proposed that amphetamine facilitation of ICSS is a ‘mass action’ effect involving the full DA terminal area of the forebrain rather than a subregion of that area.
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Dopamine was coupled to bovine serum albumin (BSA) with glutaraldehyde, precautions were taken in order to preserve the catechol ring. After injection of this immunogen into rabbits, antidopamine antibodies were obtained and tested using radioimmunochemical binding studies and adsorption to catecholamine covered sepharose beads. A good correlation was found between the results of the different test systems, allowing us to visualize dopamine specifically in glutaraldehyde-fixed rat brains.
Article
The social behavior of rats with chronic lesions to the medial frontal cortex, orbital frontal cortex, hippocampus, septum or amygdala was studied in four different situations: large open field, small open field, shock induced aggression and muricide. All lesions altered social behavior but the effects of the different lesions could be dissociated from one another. Lesions to the hippocampus dramatically reduced contact in open field tests and almost totally eliminated shock induced aggression. Lesions to the amygdala and septum also reduced the level of shock induced aggression but whereas amygdala lesions significantly decreased contact, septal lesions did not. Rats with lesions to the medial or orbital aspects of the prefrontal cortex differed from one another as the rats with orbital lesions exhibited consistently low contact scores and the rats with medial lesions did not, while both groups showed increased levels of shock induced aggression. None of the lesions significantly altered muricide.
Article
Four monkeys were injected with 0.5 mg/kg im haloperidol, daily for 19 days. A "challenge" dose of 1.0 mg/kg haloperidol was injected im to the chronically pretreated group and to an additional 4 monkeys that had not been previously treated with haloperidol. A control group of 4 monkeys was injected with saline. The sensitivity of the putamen to the homovanillic acid-elevating effects of haloperidol was attenuated by chronic treatment, whereas the sensitivity of the frontal and cingulate cortex was unchanged or enhanced in the same group of Ss. There was a marked activation of tyrosine hydroxylase in the putamen of previously untreated Ss 4 hrs after acute administration of 1.0 mg/kg haloperidol. Results support the speculation that the development of tolerance to the extrapyramidal side effects of antipsychotic drugs may be due to neurochemical adaptations in the dopaminergic nigrostriatal pathway. (20 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Single unit activity was recorded from the dorsolateral prefrontal cortex and the anterior cingulate cortex while monkeys were performing a modified differential reinforcement of long latencies (DRLL) task. A total of 252 prefrontal units and 218 anterior cingulate units showed an obvious change in discharge rate (increase or decrease) in association with one or more of the events of a DRLL task. Related units were classified into 3 main groups: S--R event units, reward-error units, and timing units. S--R event units consisted of three subtypes: stimulus-related, response-related, and stimulus--response-related units. Reward-error units contained reward-related units and error-recognition units. Error-recognition units showed a vigorous increase in firing only after incorrect responses. These units were also responsive to omission of reinforcement on correct trials. Three types of timing units were distinguishable. The first one showed an anticipatory change prior to stimulus onset, and the second one exhibited a gradual anticipatory change preceding the time of responding. The third one manifested a sustained change during delay and an abrupt cessation of change in firing at the time of response initiation.
Article
Prefrontal system dysfunction are revealed in rats in delayed response tasks. In view of the anatomical projections existing from the ventral mesencephalic tegmentum to the prefrontal system we have done this research in order to determine whether cognitive processes are impaired after mesencephalic lesions. Rats learned spatial delayed alternation in a T-maze. After acquisition they were randomly divided in two groups; the experimental group received lesions in the ventral mesencephalic tegmentum at the level of the A10 cell bodies. These lesions induced definitive disruption of the retention of the delayed alternation and the rats were unable to relearn the task. However, these animals were able to perform normally in an operant conditioning with food reinforcement indicating the specificity of the deficit observed with respect to the delayed alteration task. The possible modulating role of dopaminergic A10 neurones is hypothetized.
Article
Previous studies in the rat have shown that the neocortical dopaminergic afferents, originating in the mesencephalon, terminate in those areas of the frontal lobe which receive projections from the mediodorsal thalamic nucleus i.e., the prefrontal cortex. In order to clarify whether this overlap is accidental for the rat or a consistent feature of several species we have compared the projection areas of the ventral tegmental area and the mediodorsal thalamic nucleus in three species, rat, opossum and tree shrew, using HRP injections in combination with glyoxylic acid histofluorescence method. The results have shown, first, that the area innervated by the mediodorsal nucleus of the thalamus is localized in a different part of the frontal lobe in each species: dorsolateral in the opossum, anteromedial, polar and suprarhinal in the rat and frontopolar in the tree shrew. Secondly, this area alone in each species receives projections from the ventral tegmental area. Thirdly, this area alone receives a dense innervation in the deep cortical layers by fluorescent fibres probably containing dopamine. The neighbouring neocortical areas receive afferents neither from the mediodorsal nucleus of the thalamus nor from the ventral mesencephalic tegmentum; their catecholamine innervation is mainly confined to the superficial layers and appears to be of noradrenergic nature. Although the techniques used did not allow a precise determination of the borders of the two projection areas and, therefore, the exact degree of overlap, it appears that mesencephalic dopaminergic innervation is a characteristic feature of the prefrontal cortex in the mammalian brain.
Article
The consequences of 6-hydroxydopamine lesions of the mesolimbic dopamine system on hoarding behavior were investigated in the rat. Specific lesions of this system, at the level of either the ventral tegmental area or the nucleus accumbens, resulted in abolition or severe reduction of hoarding activity. Similar lesions of the forebrain noradrenaline neurons did not affect hoarding. In further experiments, amphetamine and apomorphine locomotor responses, spontaneous motor behavior, food intake and eating patterns, and the existence of any regulatory deficits were examined. A subtle disorganization of eating patterns was found in animals with mesolimbic-dopamine lesions. It was determined that the hoarding deficit could not be due to motor, ingestive, or regulatory impairments. In a final experiment, it was demonstrated that hoarding behavior can be restored to control levels in dopamine-lesion rats by prior treatment with the catecholamine presursor L-dopa. These findings suggest that hoarding activity is mediated by mesolimbic dopamine neurons, and it is hypothesized that this system is necessary for the facilitation of certain types of foraging responses under a high level of arousal.
Article
Unilateral morphine application to sites in the ventral tegmentum caused contralateral circling. Positive sites were restricted to the region of the dopamine-containing cells in the ventral tegmental area and substantia nigra; rates were highest with ventral tegmental application. The opiate receptor antagonists naltrexone and naloxone blocked morphine-induced circling whether given before or during the sessions. Pimozide pretreatment also blocked morphine-induced circling at doses that spared muscimol-induced circling. Morphine induced little postural asymmetry and induced forward locomotion in all 4 limbs. The radius of morphine-induced circling was large or small depending on the size of the test environment; thus the behavior was controlled by environmental (sensory) and not central (motor) constraints. These studies suggest that morphine-induced circling results from activation of dopaminergic circuitry involved in sensory-motor integration, particularly that involved in forward locomotion.
Article
The cortical projection field of the mediodorsal nucleus of the thalamus (MD) was identified in the rat using the Fink-Heimer silver technique for tracing degenerating fibers. Small stereotaxic lesions confined to MD were followed by terminal degeneration in the dorsal bank of the rhinal sulcus (sulcal cortex) and the medial wall of the hemisphere anterior and dorsal to the genu of the corpus callosum (medial cortex). No degenerating fibers were traced to the convexity of the hemisphere. The cortical formation receiving a projection from MD is of a relatively undifferentiated type which had been previously classified as juxtallocortex.A study of the efferent fiber connections of the rat's MD-projection cortex demonstrated some similarities to those of monkey prefrontal cortex. A substantial projection to the pretectal area and deep layers of the superior colliculus originates in medial cortex, a connection previously reported for caudal prefrontal (area 8) cortex in the monkey. Sulcal cortex projects to basal olfactory structures and lateral hypothalamus, as does orbital frontal cortex in the monkey. The rat's MD-projection cortex differs from that in the monkey in that it lacks a granular layer and appears to have no prominent direct associations with temporal and juxtahippocampal areas. Furthermore, retrograde degeneration does not appear in the rat thalamus after damage to MD-projection areas, suggesting that the striatum or thalamus receives a proportionally larger share of the MD projection in this animal than it does in the monkey. Comparative behavioral investigations are in progress to investigate functional differences between granular prefrontal cortex in the primate and the relatively primitive MD-projection cortex in the rat.
Article
The destruction of ascending noradreniergic pathways by bilateral microinjections of 6-hydroxydopamnine made laterally to the pedunculus cerebellaris superior completely abolished the in vitro synthesis of [3H]norepinephrine from L-[3H]tyrosine in slices and in synaptosomes of the rat cortex. However, normal [3H]dopamine synthesis could still be observed in both cortical preparations from animals with lesions. These results provide the first biochemical support for the existence of dopaminergic terminals independent of noradrenergic terminals in the rat cortex.
Article
Intact rats acquired spatial delayed alternation in a T maze. Lesions in the anteromedial cortex or the caudate nucleus impaired retention of alternation; removal of the frontal poles did not. Delayed alternation was mediated by the cortical projection field of the mediodorsal thalamic nucleus and the caudate nucleus in a rodent species as in primates and carnivores, possibly indicating inheritance of this structure function relation from a common ancestor. No functional resemblance between the frontal poles of rats and the prefrontal cortex of monkeys, cats, and dogs was found.
Article
This review summarizes the anatomical and functional organization of the frontal cortex of the rat in comparison to primates. Lesions of the primary motor or of the prefrontal cortex of both primates and rodents produce a consistent constellation of symptoms that are strikingly similar across species as diverse as rats and humans. Thus, in spite of the tremendous difference in the relative volume of the frontal cortex of mammals, as well as the obvious diversity of behavioral repertoires across mammalian phylogeny, there appears to be a remarkable unity in frontal cortex function across the class mammalia. Hence, motor and prefrontal lesions produce analogous alterations in motor control in rodents and primates even though humans walk upright and have fine control of digit movement and rats walk on all fours and have less dextrous control of distal movements. Similarly, there are analogous changes in behaviors that can be labeled response inhibition, temporal ordering, spatial orientation, social or affective behavior, behavioral spontaneity, olfaction and habituation following prefrontal cortex lesions in both primates and rodents. Finally, it is proposed that the principal function of the prefrontal cortex of mammals is the temporal organization of behavior.
Article
Ablation of medial prefrontal cortex impairs spatial discrimination learning in adult but not in neonatally lesioned rats. Orbital prefrontal cortex and adjacent convexity neocortex need not be left intact to observe this sparing of function. This study examined the possibility that the caudate nucleus, remaining intact after early medial prefrontal cortex lesions, might be involved in the observed behavioral sparing. Neonatal rats given combined lesions of the medial prefrontal cortex and head of the caudate nucleus were compared to age/litter-matched sham-operated controls on spatial alternation and place response acquisition and "reversal" tests. The results show that the performance of these neonatally lesioned subjects was deficient on both tests. The discussion centers on possible recovery mechanisms in rats given prefrontothalamic system damage early in life.
Article
Since the medial prefrontal cortex receives converging projections from the mediodorsal nucleus of the thalamus (MD) and the dopaminergic neurons located in the ventromedial mesenscephalic tegmentum (VMT) the responses of cortical neurons to ipsilateral VMT and MD stimulation (50-150 microA; 0.2-0.5 ms duration) were analyzed in ketamine anaesthetized rats. MD stimulation at 1 Hz blocked the firing of 99% of the spontaneously active cortical units tested (mean latency, 15 ms; mean duration, 182 ms). MD stimulation at 5-10 Hz evoked single spike responses (mean latency, 16 ms) in 80% of the units tested. Ten to 15 days after kainic acid injection into the MD the number of cortical neurons inhibited (1 Hz) or excitated (5-10 Hz was reduced to 57 and 18%, respectively. Following stimulation of the VMT (at a frequency of 1-5 Hz), 85% of cortical neurons showed an arrest of spontaneous firing occurring after a mean latency of 17 ms and lasting 109 ms on the average. Most of the cells displaying the VMT inhibitory effect were excitated by MD stimulation. Moreover VMT stimulation, applied 3-45 ms before that of MD, blocked the excitation induced by MD in 75% of the units tested. After injection of 6-hydroxydopamine into the medial forebrain bundle or intraperitoneal administration of alpha-methyl-paratyrosine (alpha-MpT), the number of units tested responding to VMT stimulation was of 19 and 35%, respectively. Moreover in these treated rats, the proportion of excitatory responses to MD blocked by VMT stimulation was reduced to 5 and 6%.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The present study evaluated the effects of microinjections of 6-hydroxydopamine into the ventral mesencephalic tegmental area (nucleus A10) on aggressive behavior in rats. This treatment resulted in a reduction in foot-shock-induced fighting but failed to influence muricide (mouse-killing) behavior in chronically isolated rats. The general activity of animals tested in the open field was significantly increased two weeks after lesions. These behavioral changes were accompanied by a significant depletion of forebrain dopamine, with no difference between lesioned and sham-lesioned rats in norepinephrine and 5-hydroxyindole acetic acid levels.
Article
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.
Article
This experiment examined the potential for behavioral recovery in juvenile, adult, and senescent rats following serial lesions of medial frontal cortex. The subjects were trained on spatial delayed alternation in a T-maze under conditions designed to enhance the probability of a serial lesion effect. All subjects were given extensive handling and adaptation to the maze, interoperative training, and long interoperative and postoperative intervals. There were several major behavioral findings: (a) the aged intact subjects were not impaired in their ability to learn spatial delayed alternation, (b) one-stage bilateral lesions of frontal cortex produced equivalent deficits on spatial delayed alternation at all ages, (c) subjects in all of the age categories demonstrated a serial lesion effect, but (d) the 150 day and 570 day serial lesions groups demonstrated significantly better performances than the 35 day serial lesions group on several measures of performance.
Article
Lesions of mediofrontal cortex in adult rats produce behavioral impairments on spatial alternation tasks as well as retrograde degeneration in the mediodorsal thalamic nucleus. The severity of the behavioral deficits and of the thalamic degeneration correlates positively with lesion size. In contrast, similar lesions in neonatal rats (10 days or younger) produce neither spatial alternation deficits nor thalamic degeneration, even after extensive lesions removing all of the mediofrontal cortex. This study examined the possibility that residual anterior cortex remaining intact after early mediofrontal lesions might be involved in the observed anatomical and behavioral sparing. The results show that the sparing of spatial alternation after neonatal frontal cortex lesions does not depend on functional substitution by intact regions of anterior cortex. Neonatal rats receiving extensive lesions including both the medial and orbital frontal cortex or the entire anterior neocortex remained unimpaired on this task. However, these same animals suffered severe retrograde degeneration in the mediodorsal thalamus. Therefore, although some form of neural plasticity cannot be entirely dismissed as the basis for the behavioral results, it seems more likely that behavioral rather than neural plasticity is involved. We suggest that rats deprived of frontal cortex from infancy are able to perform the spatial alternation task in a manner that differs from that used by most intact rats.
Article
Activity of dorsolateral prefrontal cortical neurons was examined in rhesus monkeys while they performed a spatial delayed-response task with delays of 2, 4, 8 or 12 s interposed between cue and response. Of the 600 neurons recorded for at least 10 trials under each delay condition, 95 displayed a pattern of discharge during the delay period which was significantly different from neuronal firing before or after this period. Changes in the duration of the delay elicit two distinct patterns of activity in these neurons: some (59/95, 62%) exhibit a fixed pattern of discharge regardless of the duration of the ensuing delay; others (31/95, 33%) alter their pattern of activity in relation to the temporal changes. Although both types of delay-related neurons display a variety of discharge profiles, more than half of each class exhibit their highest activity in the early part of the delay period. A related finding concerns a small subclass of spatially selective neurons which fire significantly more when the cue is presented on the left than on the right or vice versa. A striking 80% of these spatially discriminative neurons exhibit peak activity in the first few seconds of the delay period. These findings provide cellular evidence that (1) prefrontal neurons are responsive to temporal as well as spatial features of the delayed-response task; and (2) the involvement of a subset of these is particularly critical in the first few seconds of the delay. The latter finding emphasizes that prefrontal neurons may play an important role in the registration process of spatial memory.
Article
Catecholamine levels in the two subareas of the prefrontal cortex and in one non-prefrontal region of the rat frontal lobe were measured radioenzymatically. In contrast with noradrenaline (NA), the distribution of dopamine (DA) in the frontal lobe is markedly heterogeneous. DA levels of the orbitofrontal and medial prefrontal subarea are, respectively, 3 and 4 times higher than those of a non-prefrontal region of the frontal lobe, confirming the expectation of neuroanatomical findings. Furthermore, it appears that at the population level, DA levels of the medial prefrontal subarea are lateralized, the left hemisphere being significantly higher than the right hemisphere.
Article
The effects of 6-hydroxydopamine (6-OHDA) lesions of catecholamine terminals within the medial prefrontal cortex on spontaneous motor activity, dopamine (DA)-dependent stereotyped behaviour and subcortical dopamine turnover were investigated in the rat. Two types of lesions were examined, bilateral injection of 6-OHDA into the medial prefrontal cortex of untreated rats (6-OHDA alone), and bilateral injection of 6-OHDA into the medial prefrontal cortex of animals pretreated with the noradrenaline (NA) uptake blocking agent desmethylimipramine (6-OHDA/-DMI). Ten days after surgery the 6-OHDA lesions produced no significant change in spontaneous motor activity and had no overall effects on stereotyped behaviour induced by apomorphine or (+)-amphetamine. This lesion caused gross depletion of NA within the medial prefrontal cortex and curiously, elevated DA concentrations within this site. No changes in DA concentration were recorded within subcortical sites, although concentrations of DA metabolites within striatum and nucleus accumbens were reduced. In contrast, the 6-OHDA/DMI lesion of the medial prefrontal cortex significantly enhanced spontaneous motor activity and amphetamine-induced stereotyped behaviour. Apomorphine-induced stereotypy, on the other hand, was significantly reduced. Biochemically the lesion caused a large depletion of DA with relatively little loss of NA within the medial prefrontal cortex. In addition, from this and another study (ref. 33), increases in DA and its metabolite concentrations were measured in striatum and nucleus accumbens, together with an apparent increase in DA turnover within these subcortical sites. It is thus apparent that in the absence of a substantial portion of the DA innervation of the medial prefrontal cortex, with a largely intact NA innervation, there is an increase in motor activity and amphetamine-induced stereotypy which may be related to functional changes in DA activity within subcortical telencephalic structures. Such a finding might suggest that DA within the frontal cortex has a behaviourally inhibitory role in the rat, although further work is required to substantiate this.
Article
The relative importance of two subcortical structures, projecting to the rat's prefrontal cortex, in mediation of delayed-alternation performance, was tested. These structures, the thalamic mediodorsal nucleus and the ventral tegmental area, were lesioned with kainic acid after the rats had learned a spatial delayed-alternation task. It was found that both structures are apparently involved to a similar degree in the performance of this task and that the behavior of both experimental groups differed from that of a sham-operated control group of rats.
Article
Adult rats with complete removals of medial prefrontal cortex (MF) either in 1-stage or 2-stages were tested on a spatial delayed alternation task with a 50 day interoperative interval and with specific training during the interoperative interval. There were two groups receiving 2-stage lesions: one group received a complete lesion of MF cortex in one hemisphere at first surgery followed by a comparable lesion in the other hemisphere at second surgery; the second group received a bilateral lesion of the dorsal component of MF cortex at first surgery followed by bilateral removal of the remaining ventral component at second surgery. The animals in both serial lesion groups were imparied relative to sham operated controls, but they were significantly less impaired than animals receiving similar lesions in a single stage. Several conclusions are drawn from these results: (1) significant sparing of function can be demonstrated after complete serial destruction of MF cortex, but the sparing is not complete. (2) the provision of interoperative experience and a prolonged interoperative interval enhances the degree of sparing observed with 2-stage MF removals as it does with serial lesions of other brain areas. (3) equivalent sparing of function was observed with both serial lesion techniques. Thus, it is not necessary that one hemisphere remain undamaged during the interoperative interval; nor is it necessary that any portion of MF cortex be spared bilaterally during the interoperative interval.
Article
Rats with complete removal of the cortex anterior to bregma in adulthood (frontal cortex) were compared behaviorally and neuroanatomically with rats with similar removals at 7 or 25 days of age. Excision of the frontal cortex in adult rats produced transient aphagia, chronic motor abnormalities in feeding, a chronic drop in body weight, increased activity in running wheels, impaired performance at a spatial reversal learning task, and chronic abnormalities in a variety of species-typical behaviors, including swimming, food hoarding, and defensive burying. In contrast, similar lesions in infant rats failed to produce aphagia, a chronic drop in body weight, increased activity, or impaired learning of a spatial reversal task. Infant lesions did not allow sparing of complex species-typical behaviors, however, such as those involved in feeding, swimming, hoarding, or defensive burying. Furthermore, when the brains of neonatally operated rats were compared with those of control rats or rats operated on in adulthood, there were striking differences. The cerebral hemispheres of the neonatal operates were smaller both in surface dimensions and weight, the thalamus was smaller, and the cerebral cortex was thinner. These data imply that there may be substantially less sparing of function following frontal cortex lesions in infancy than previously believed and that neonatal frontal lesions in rats have significant effects on brain development in regions far removed from the actual site of surgical excision.
Article
Delayed response tasks are widely considered to be particularly sensitive in demonstrating cognitive deficits after lesions of the prefrontal cortex in all species of mammals1. In rodents, these deficits are usually tested in a T-maze and are more pronounced after lesion of the anterior part of the striatum than after prefrontal cortex ablation2. In effect, the striatum is capable of assuming cortical functions either when the prefrontal cortex is poorly developed as in the lower mammals3 or immature as in the early life of primates4. The prefrontal cortex and anterior striatum-the so-called prefrontal system5-are functionally and anatomically related. The prefrontal area specifically involved in delayed alternation6 receives projections from the mediodorsal thalamic nucleus (MD)7 and sends axons to the anterior striatum as well as to the MD3,7. Recently, a detailed anatomical study of the connections of the prefrontal system revealed the existence of important projections from the mesencephalic dopaminergic A10 neurones and the mediodorsal nucleus that converge on the prefrontal cortex8. Axons of the A10 system also project to the anterior part of the striatum9,10. The influence of dopaminergic A10 neurones on frontal lobe functions remains obscure, but some observations concerning the behavioural, pharmacological and biochemical effects of neuroleptics and psychostimulants have supported the idea that these dopaminergic neurones could have a role in the pathogenesis of schizophrenia 11-13. Furthermore, the major symptoms observed in schizophrenic patients such as cognitive and attention disturbances have been attributed to a dysfunction of both prefrontal cortex and striatum14-16. Thus, in addition to their anatomical connections, the dopaminergic A10 neurones may be functionally related to the prefrontal cortex and striatum. These data encouraged us to investigate whether A10 neurones are functionally related to the prefrontal system and in particular if they are involved in cognitive processes measured in a delayed alternation task. We demonstrate here that selective lesions of dopaminergic A10 neurones in the rat produce a severe and specific impairment in retention of delayed alternation. On anatomical and behavioural grounds the dopaminergic A10 system could therefore be considered as a rather better indicator of frontal system function than the mediodorsal thalamic nucleus.
Article
Two experiments using contingently reinforced T-maze alternation with rats found that (a) normal rats, after achieving high accuracy in alternation with brief (0 sec) intertrial intervals (ITIs), dropped to chance levels with longer ITIs (90 sec) but reacquired effective alternation with additional practice; (b) small lesions in mediodorsal pregenual cortex had no effect on postoperative retention of alternation at either short or long ITIs; (c) contrariwise, small lesions in posterodorsal septum temporarily disrupted alternation at brief ITIs whereas at long ITIs animals chose randomly and never recovered; and (d) large lesions in medial frontal cortex disrupted retention of alternation at brief ITIs of 10 sec but significant recovery did occur with additional experience. Implications regarding task difficulty and locus of lesion for recovery of function are discussed.
Article
When the post-operative hoarding behavior of rats with dorsolateral cortical ablations and those with medial cortical ablations are compared, it is demonstrated that the medial lesions produce a large and significant deficit in hoarding, whereas the lateral lesions have no effect.
Neurochemical correlates of stress
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