Ablation Of Frontal Cortex Research Articles

Early growth hormone (GH) treatment promotes relevant motor functional improvement after severe frontal cortex lesion in adult rats

A number of studies, in animals and humans, describe the positive effects of the growth hormone (GH) treatment combined with rehabilitation on brain reparation after brain injury. We examined the effect of GH treatment and rehabilitation in adult rats with severe frontal motor cortex ablation. Thirty-five male rats were trained in the paw-reaching-for-food task and the preferred forelimb was recorded. Under anesthesia, the motor cortex contralateral to the preferred forelimb was aspirated or sham-operated. Animals were then treated with GH (0.15mg/kg/day, s.c) or vehicle during 5 days, commencing immediately or 6 days post-lesion. Rehabilitation was applied at short- and long-term after GH treatment. Behavioral data were analized by ANOVA following Bonferroni post hoc test. After sacrifice, immunohistochemical detection of glial fibrillary acid protein (GFAP) and nestin were undertaken in the brain of all groups.Animal group treated with GH immediately after the lesion, but not any other group, showed a significant improvement of the motor impairment induced by the motor lesion, and their performances in the motor test were no different from sham-operated controls.GFAP immunolabeling and nestin immunoreactivity were observed in the perilesional area in all injured animals; nestin immunoreactivity was higher in GH-treated injured rats (mainly in animals GH-treated 6 days post-lesion). GFAP immunoreactivity was similar among injured rats. Interestingly, nestin re-expression was detected in the contralateral undamaged motor cortex only in GH-treated injured rats, being higher in animals GH-treated immediately after the lesion than in animals GH-treated 6 days post-lesion.Early GH treatment induces significant recovery of the motor impairment produced by frontal cortical ablation. GH effects include increased neurogenesis for reparation (perilesional area) and for increased brain plasticity (contralateral motor area).

Monkeys Quickly Learn and Generalize Visual Categories without Lateral Prefrontal Cortex

Categorization is a basic mental process that helps individuals distinguish among groups of negative and positive objects, e.g., poisons and nutrients, or predators and prey. Monkey experiments have suggested that lateral prefrontal cortex (LPFC) participates in learning and processing visual categories. However, in humans category specific visual agnosia follows inferior temporal cortex but not LPFC damage. Here, we use a new behavioral approach to show that both normal monkeys and those with bilateral removal of LPFC learn and generalize perceptual categories of related visual stimuli rapidly without explicit instruction. These results strongly indicate that visual categorization occurs at some earlier stage of feed-forward processing, presumably in temporal cortex, without top-down information from LPFC.

Frontal-Temporal Disconnection Abolishes Object Discrimination Learning Set in Macaque Monkeys

Two previous studies have shown that frontal-temporal disconnection in monkeys, produced by unilateral ablation of frontal cortex in one hemisphere and of visual inferior temporal cortex in the opposite hemisphere is entirely without effect on visual object-reward association learning in concurrent discrimination tasks. This is a surprising finding in light of the severe impairments that follow frontal-temporal disconnection in many other tests of visual learning and memory, including delayed matching-to-sample and several conditional learning tasks. To explore the limits of this preserved object-reward association learning, we trained monkeys on visual object discrimination learning set (DLS) prior to frontal-temporal disconnection. As a result of training with single object-reward associations, the monkeys acquired a proficient learning set, evidenced by the rapid learning of new single object-reward association problems. This rapid learning was not affected by unilateral ablations of either inferior temporal cortex alone or frontal cortex alone but was severely impaired after final surgery to complete the disconnection. Moreover, each individual monkey now learned single object-reward association problems at the slow rate at which that individual had learned such problems before the formation of learning set. This result shows that frontal-temporal disconnection abolishes visual learning set.

Orbital frontal cortex ablations of rock squirrels (Spermophilus variegatus) disinhibit innate antisnake behavior.

The antisnake behavior of rock squirrels (Spermophilus variegatus) was examined to determine the role of the orbital frontal cortex in regulating physiological arousal and behavioral excitability during encounters with a rattlesnake predator. Rock squirrels with orbital frontal cortex ablations and sham-surgery control squirrels were presented with a caged rattlesnake pre- and postsurgery. Orbital frontal cortex ablations had no substantial effect on the expression of gross motor behavior in dealing with the rattlesnake, but they augmented the speed of snake recognition and clearly disinhibited sympathetic arousal as manifested by increased tail piloerection and tail-flagging activity, which is a specific antisnake behavior. Natural selection from snakes has probably shaped the neural organization of the orbital frontal cortex to afford adaptive behavioral flexibility during snake encounters.

Frontal and parieto-temporal cortical ablations and diaschisis-like effects on auditory neurocognitive potentials evocable from apparently intact ipsilateral association areas in humans: five case reports

The aim of this study was to investigate the effects of disruption on the warning auditory S1-elicited ERP and CNV complexes recordable on the site and on remote ipsilateral apparently normal anatomo-functionally interconnected brain regions. These effects in some cases showed aspects of a probable diaschisis-like phenomenon, due to resections of extensive frontal association cortex or of primary and secondary sensory parieto-temporal areas damaged by differing pathological processes. Using a standard CNV paradigm, 21/19 EEG electrodes connected with three different references, and scalp-topographic bidimensional mapping analysis, the S1 auditory binaural/monaural clicks N1a,b,c, P2, N2, P3 and CNV waves were recorded in 10 normal subjects and 11 patients. Nine of the latter had been submitted to unilateral frontal dorsolateral cortex ablation, one to bihemispheric dorsomedial cortex ablation, and one to unilateral ablation of sensory parieto-temporal cortex and underlying white matter, verified through CT/MRI examinations. No true S1ERP/CNV components were recordable over the ablated cortical areas, whereas normal ERP/CNV complexes were observable on the intact hemispheres. In five patients, four of whom with frontocortical ablations, the S1 ERP/CNV complexes appeared severely diminished or disrupted, in two cases in a slow, partially-reversible manner, also in the neuroradiologically normal ipsilateral functionally-connected post-rolandic sensory and association areas. Similar deactivation of some ERP components was observed in reverse on the unilateral dorsolateral frontocortical region in the fifth patient with parieto-temporal cortex ablation. Even when they are partially reversible, these ipsilateral remote ERP changes in apparently intact brain regions, due to ablations of functionally-interconnected cortical formations, probably reflect cortical deactivation or simply dysfacilitation deriving from functional unilateral diaschisis. If these changes are instead irreversible they may probably be interpreted as transneuronal degeneration phenomena, though they are not at present easy to document either neuroradiologically or electroclinically.

Reversal effect of sulpiride on rotational behaviour of rats with unilateral frontal cortex ablation: an alternative explanation for the pharmacological mechanism of its antidepressant effect.

The antidepressant effect of sulpiride has been generally explained as the result of its preferential blocking effect on self-inhibitory presynaptic dopamine autoreceptors at low doses. Low dose haloperidol has the same blocking effect. In rats with unilateral ablation of the frontal cortex, methamphetamine administration induced mild contralateral rotation 10 days after the operation. We examined whether low dose sulpiride and haloperidol would have the same effect on this rotational model. High dose sulpiride (100 mg/kg) or low dose haloperidol (0.05 mg/kg) prevented this methamphetamine-induced rotation. However, low dose (15 mg/kg) sulpiride clearly reversed the direction of rotation. This reversal effect of low dose sulpiride is not explained by the preferential blocking effect on dopamine autoreceptors. The results suggest that low dose sulpiride, unlike low dose haloperidol, has a prominent blocking effect on D2 receptors in the frontal cortex. This unique effect of sulpiride may be relevant to its clinical antidepressant and anxiolytic effects at low doses.

Object retrieval/detour deficits in monkeys produced by prior subchronic phencyclidine administration: evidence for cognitive impulsivity

Background: Impulsivity associated with frontal cortical dysfunction appears to be a direct consequence of chronic consumption of drugs of abuse, though few investigations in animals have attempted to directly address this issue. In this study the effects of repeated, intermittent administration of a psychotomimetic drug of abuse, phencyclidine, on the acquisition and performance of a task sensitive to corticostriatal function was examined in nonhuman primates. Methods: Monkeys were repeatedly exposed to phencyclidine (0.3 mg/kg) twice daily for 14 days. Acquisition and performance on an object-retrieval detour task was subsequently examined for up to 28 days after drug withdrawal. Results: Animals treated with phencyclidine exhibited impaired acquisition of the task. The performance of trials requiring inhibitory control (as opposed to solely sensory-guided responding) was specifically impaired by prior phencyclidine administration. Impairments were found to be due to increased perseveration and barrier reaching. As is the case after frontal cortex ablation, the behavioral deficits were particularly evident during acquisition and appeared to be alleviated by prolonged training. Conclusions: The current data demonstrate that subchronic administration of phencyclidine can produce deficits in inhibitory response control that are manifest as impulsivity (increased control of behavior by unconditioned, appetitive stimuli). These data suggest that long-term phencyclidine exposure induces frontostriatal-like cognitive impairments and may represent a potential (drug induced) model for the study of prefrontal cortical cognitive and dopaminergic dysfunction.

Alterations in Rat Striatal Glutamate Synapses Following a Lesion of the Cortico- and/or Nigrostriatal Pathway

Ultrastructural changes within the ipsilateral dorsolateral striatum were investigated 1 month following a unilateral ablation of the rat frontal cortex (CTX), removing corticostriatal input, or injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), into the substantia nigra pars compacta, removing nigrostriatal input. In addition, a combined ipsilateral cortical and 6-OHDA lesion (CTX/6-OHDA) was carried out. We find that following a CTX, 6-OHDA, or CTX/6-OHDA lesion, there was a significant decrease in the density of striatal nerve terminal glutamate immunoreactivity compared to the control group. There was also a significant increase in all three lesion groups in the mean percentage of asymmetrical synapses associated with a perforated postsynaptic density. There was a large increase within the CTX/6-OHDA-lesioned group and a smaller but still significant increase in the CTX-lesioned group in the percentage of terminals or boutons with multiple synaptic contacts (i.e., multiple synaptic boutons, MSBs), compared to either the 6-OHDA or the control group. There was no change in any of these measurements within the contralateral striatum. There was a significant decrease in the number of apomorphine-induced contralateral rotations in the CTX/6-OHDA versus the 6-OHDA-lesioned group. Animals receiving just the single CTX or 6-OHDA lesion recovered in motor function compared to the control group as measured by the Rotorod test, while the CTX/6-ODA-lesioned group recovered to less than 50% of the control level. The data suggest that following a CTX and/or 6-OHDA lesion, there is an increase in striatal glutamatergic function. The large increase in the percentage of MSBs in the combined lesion group suggests that dopamine or other factors released by the dopamine terminals assist in regulating synapse formation.

The effects of anterior arcuate and dorsomedial frontal cortex lesions on visually guided eye movements in the rhesus monkey:: 1. Single and sequential targets

This study examined the effects of anterior arcuate and dorsomedial frontal cortex lesions on visually guided eye movements in three rhesus monkeys. Lesions of the anterior bank of the arcuate, where the frontal eye fields reside, produced major deficits in the execution of saccadic eye movements to sequentially presented targets that did not recover even after 1 year after the lesions. Ablations of the dorsomedial frontal cortex, wherein the medial eye fields reside, produced much smaller and shorter-duration deficits on this task. Deficits after paired lesions of the anterior arcuate and dorsomedial frontal cortex were of approximately the same magnitude as after single anterior arcuate lesions. Anterior arcuate lesions also increased saccadic reaction times to single visual targets and decreased saccadic velocities that recovered gradually over a period of 2–5 months. Dorsomedial frontal cortex lesions produced only small increases in saccadic latencies that recovered rapidly. None of the lesions produced deficits in executing combined saccadic and pursuit eye movements to moving targets. The results suggest that the anterior arcuate area plays a central role in the execution of sequences of eye movements to successively appearing targets.

Localization of ionotropic glutamate receptors in caudate‐putamen and nucleus accumbens septi of rat brain: Comparison of NMDA, AMPA, and kainate receptors

Changes in binding of selective radioligands at NMDA ([3H]MK-801), AMPA ([3H]CNQX), and kainate ([3H]kainic acid) glutamate (GLU) ionotropic receptors in rat caudate-putamen (CPu) and nucleus accumbens (NAc) were examined by quantitative autoradiography following: 1) unilateral surgical ablation of frontal cerebral cortex to remove descending corticostriatal GLU projections, 2) unilateral injection of kainic acid (KA) into CPu or NAc to degenerate local intrinsic neurons, or 3) unilateral injections of 6-hydroxydopamine (6-OH-DA) into substantia nigra to degenerate ascending nigrostriatal dopamine (DA) projections. Cortical ablation significantly decreased NMDA receptor binding in ipsilateral medial CPu (20%), and NAc (16%), similar to previously reported losses of DA D4 receptors. KA lesions produced large losses of NMDA receptor labeling in CPu and NAc (both by 52%), AMPA (41% and 45%, respectively), and kainate receptors (40% and 45%, respectively) that were similar to the loss of D2 receptors in CPu and NAc after KA injections. Nigral 6-OH-DA lesions yielded smaller but significant losses in NMDA (17%), AMPA (12%), and kainate (11%) receptor binding in CPu. The results indicate that most NMDA, AMPA, and kainate receptors in rat CPu and NAc occur on intrinsic postsynaptic neurons. Also, some NMDA, but not AMPA or kainate, receptors are also found on corticostriatal projections in association with D4 receptors; these may, respectively, represent excitatory presynaptic NMDA autoreceptors and inhibitory D4 heteroceptors that regulate GLU release from corticostriatal axons in medial CPu and NAc. Conversely, the loss of all three GLU receptor subtypes after lesioning DA neurons supports their role as excitatory heteroceptors promoting DA release from nigrostriatal neurons. Synapse 30:227–235, 1998. © 1998 Wiley-Liss, Inc.

Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain: comparison of D 1-, D 2- and D 4-like receptors

Changes in D 1-, D 2- and D 4-like dopamine receptor binding in rat brain were examined by quantitative autoradiography following: (i) unilateral surgical ablation of frontal cerebral cortex to remove descending projections to corpus striatum and nucleus accumbens, (ii) unilateral injections of kainic acid into corpus striatum or nucleus accumbens to degenerate local intrinsic neurons, (iii) unilateral injections of 6-hydroxydopamine into substantia nigra to degenerate ascending dopamine projections. Rats were killed one week after lesioning, with contralateral tissue controls. Radioligands were: [ 3H]SCH-23390 for D 1-like ( D 1/D 5 ) receptors, [ 3H]nemonapride alone for D 2-like (D 2/D 3/D 4) receptors, and [ 3H]nemonapride with 300 nM S[−]-raclopride and other masking agents for D 4-like receptors (identified by blockade with D 4 selective L-745, 870). Frontal cerebral cortex ablation did not alter D 1- or D 2-like receptor density, but D 4-like binding decreased significantly in both corpus striatum (18%) and nucleus accumbens (23%). Kainic acid markedly reduced D 1-like (75% and 84%) and D 2-like binding (44% and 52%), with smaller D 4-like losses (28%, and 27%) in corpus striatum and nucleus accumbens, respectively. Nigral 6-hydroxydopamine lesions (verified by autoradiographic loss of dopamine transporters labelled with [ 3H]GBR-12935) did not significantly change D 1-, D 2-, or D 4-like binding in the corpus striatum. These results suggest that the majority of D 1-, and D 2 -like, and a smaller portion of D 4-like receptors in corpus striatum and nucleus accumbens arise on intrinsic postsynaptic neurons, and that some D 4-like, but neither D 1- nor D 2-like, receptors are found on presynaptic corticostriatal afferents.

Reduced eticlopride-induced fos expression in caudate–putamen and globus pallidus after unilateral frontal cortex injury: relation to neglect

Unilateral ablation of medial agranular cortex in rats results in neglect of contralateral stimuli and reductions in amphetamine-induced expression of the immediate early gene, c-fos, in both caudate–putamen and globus pallidus. Both unilateral neglect and the reductions in dopamine agonist induction of subcortical Fos immunoreactivity dissipate over a matter of weeks. Dopamine agonism induces Fos predominantly in striatonigral cells and in globus pallidus via striatopallidal disinhibition, whereas Fos is induced in striatopallidal cells by administration of antagonists of the D2 dopamine receptor subfamily. To examine more directly effects of cortical injury on striatopallidal function, induction of striatal Fos by the D2 antagonist eticlopride (0.1mg/kg, s.c.) was examined in rats with medial agranular cortex ablation. In the same animals, eticlopride-induced Fos in globus pallidus was also examined. Five days after unilateral cortex injury, in rats showing neglect, the numbers of Fos immunoreactive nuclei induced by eticlopride were reduced by 50% in caudate–putamen and 25% in globus pallidus of the ipsilateral hemisphere. These lesion effects were restricted to dorsolateral caudate–putamen and dorsal pallidum. Three or more weeks after cortical injury, in rats recovered from neglect, eticlopride-induced Fos was normalized in caudate–putamen, but still decreased by 20% in globus pallidus.Along with previous findings, these results suggest that behavioral recovery from neglect produced by cortical injury may be at least partially mediated by normalizations of function of both striatopallidal and striatonigral neurons. In addition, the present findings suggest that normalization of function of pallidal cells activated by eticlopride is not necessary for behavioral recovery from frontal cortex ablation. Lingering reductions in excitatory cortico-subthalamo-pallidal input may be responsible for the longer-lasting dysfunctions of these pallidal cells.

Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors

This study's goal is to identify adaptations involving striatal glutamate (GLU) or dopamine (DA) receptors that may contribute to recovery of function following cortical injury. Unilateral aspiration of the medial agranular region of frontal cortex (AGm) in rats produces neglect of contralateral stimuli. Pharmacological and immunocytochemical studies suggest that glutamatergic and dopaminergic processes within striatum may contribute to spontaneous recovery from this neglect. This study examined by autoradiography radioligand binding to striatal GLU and DA receptor subfamilies in AGm-ablated rats surviving 5 days (unrecovered) or 3 or more weeks (recovered) postsurgery. Density of radioligand binding was quantified in striatal subregions by computerized image analysis. Compared to striatal binding densities in the intact hemisphere, [3H]kainate binding and [3H]GLU binding to NMDA receptors were decreased in the lesioned hemisphere of unrecovered AGm-ablated rats, but normalized (for kainate) or increased (for NMDA) in the lesioned hemisphere of recovered rats. Ablation of AGm did not affect [3H]AMPA binding or the binding of [3H]SCH23390, [3H]spiperone, or [3H]mazindol to dopaminergic D1 or D2 receptor subfamilies, or to DA uptake sites, respectively. The results suggest that a small percentage of NMDA and kainate receptors are located on corticostriatal axon terminals, and that over time an upregulation of striatal NMDA and/or kainate receptors may offset the loss of cortical glutamatergic input caused by cortical injury. These time-dependent alterations in GLU receptors may contribute to the recovery of function and normalizations of immediate early gene expression seen weeks after AGm ablation. Upregulation of striatal dopamine receptors was not evident, and thus is unlikely to mediate recovery from neglect produced by cortical injury.

Frontal cortex ablation reversibly decreases striatal zif/268 and junB expression: temporal correspondence with sensory neglect and its spontaneous recovery.

This study's goal is to identify subcortical adaptations that may contribute to recovery of function following cortical injury. After unilateral aspiration of the medial agranular region of frontal cortex (AGm), rats demonstrate neglect of contralateral stimuli and recover within 3-4 weeks. Previous studies indicate that compensatory neural alterations involving dopamine (DA) occur following this cortical injury and that recovery from neglect produced by frontal injury is accompanied by normalization of glucose utilization within subcortical structures including the basal ganglia. The current study examined Zif and JunB, IEG protein products constitutively expressed in striatum, rendering it possible to investigate the effects of unilateral AGm ablation on striatal function during unstimulated as well as amphetamine-stimulated conditions. Five days after surgery, when contralateral neglect was still evident, the numbers of Zif-like or Jun-like immunoreactive (IR) nuclei in the ipsilateral striata of AGm-ablated rats were reduced. These lesion effects were similar for both constitutive and amphetamine-stimulated IEG expression and were restricted to the dorsolateral caudate-putamen, where excitatory input from AGm is most dense. In contrast, 3 or more weeks after AGm ablation, in rats demonstrating recovery, normal striatal Zif- and JunB-like immunoreactivity occurred. Thus, striatal zif/268 and junB expression is reduced 5 days after AGm injury in rats demonstrating neglect and normalized 3 or more weeks later in recovered rats. These findings indicate that adaptations involving the striatal medium spiny neuron, a site of convergence of cortical glutamatergic and nigral dopaminergic afferents, may contribute to behavioral recovery following neocortical injury.

Frontal cortex ablation reversibly decreases striatal zif/268 and junB expression: Temporal correspondence with sensory neglect and its spontaneous recovery

Frontal cortex ablation reversibly decreases striatal zif/268 and junB expression: Temporal correspondence with sensory neglect and its spontaneous recovery

Cognitive potentials: ipsilateral corticocortical interconnections in prefrontal human cortex ablations

The research deals with the possible role of the essentially monosynaptic bidirectional corticocortical connections between occipitotemporo-parietal association cortical areas and frontal areas in the genesis of some contingent negative variation (CNV) components, especially on the supramodal dorsolateral prefrontal regions. With standard averaging and topographic mapping methods of analysis, the multicomponent CNV complex formation was examined in 7 patients with extensive frontal cortex ablations exactly identified through CTIMRI examinations, and in 10 normal subjects. On the scalp over the ablated frontocortical areas, no consistent post-warning auditory N100 a-b-c, P200, P300, early and late CNV components were recordable. The hypothesis is proposed that the bidirectional ipsilateral long-distance pathways which interconnect uni-polymodal occipito-temporo-parietal cortical areas to prefrontal ones, in particular the arcuate-superior longitudinal and superior/inferior occipito-frontal fasciculi, play an important role in the genesis of several CNV complex components, especially the multicomponent post-S1 auditory N100. The posteroanterior sequential latency differences of these neurocognitive components, roughly measured along the scalp or on MRI imagings, is probably accounted for by the transcortical ipsilateral conduction time of about 1 cm/ms (10 m/s).

Effects of neonatal decortication on the social play of juvenile rats

The effects of radical neonatal decortication on the social play of juvenile rats, as well as the effects of neonatal ablation of frontal or parietal cortex, were examined in this series of experiments. When total decorticates were tested in like-lesioned pairs, the frequency of pinning was reduced by about 50% and their average pin durations were shorter. Nevertheless, the play of decorticates appeared essentially normal in general appearance, and did not differ from controls in a measure of overall play vigor using an electronic activity platform. Further, there were no differences in pin frequencies when controls and decorticates were paired together in cross-lesion testing. Separate tests of play solicitation behaviors did not detect any differences between controls and decorticates suggesting that play motivation was essentially intact after decortication. No deficits in pinning resulted from frontal ablations; however, pin durations were shorter in like-lesion testing. In cross-lesion testing, there was an increase in dorsal contacts and a trend toward shortening of pin durations. Parietal aspirations resulted in a 65% reduction in pin frequency, without substantially altering dorsal contacts. Anesthetization of the anterior surface of the animal's back with xylocaine reduced pinning in controls but eliminated pinning in parietals. Although the results generally indicate little participation of the neocortex in the instigation of rough-and-tumble play, the reliable numerical changes that were observed may be explained by apparent motor changes as well as reduced somatosensory sensitivity.

Scopolamine induces recovery of shuttle box avoidance behavior after frontal cortex ablation

The learning and reversal of shuttle box active avoidance behavior in animals with a bilateral frontal cortex ablation was investigated during and after scopolamine or pilocarpine treatment. Scopolamine facilitated the performance of the avoidance task in normal animals and in those with frontal cortex lesions and also increased the number of intertrial responses, while pilocarpine increased the deleterious effects of the lesions. Furthermore, in the absence of scopolamine, the animals previously treated with the drug showed that its beneficial effects persisted while the number of intertrial responses were no longer increased. The results indicate that the beneficial effects of scopolamine treatment on active avoidance behavior are independent from the effects observed on intertrial activity since only the former are observed after drug withdrawal. Therefore, scopolamine treatment seems to induce a long lasting recovery process in frontal cortex ablated animals.

Cortical lesions attenuate the opposing effects of amphetamine and haloperidol on neostriatal neurons in freely moving rats.

Neuronal activity was recorded from the neostriatum of freely moving rats at least 1 week following either sham or bilateral ablations of frontal and somatosensory cortex. In both groups of animals, the majority of neurons increased firing rate in close temporal association with spontaneous movement. No group differences emerged either with respect to baseline firing rates or open-field behavior. Following amphetamine administration, however, the excitatory response of motor-related neurons was suppressed in cortical-lesioned rats. A behavioral clamping procedure, which assessed neuronal activity during matched pre- and post-amphetamine behaviors, confirmed these results, suggesting that the amphetamine-induced changes in neuronal activity reflect a direct drug effect independent of behavioral feedback. In animals that received a subsequent injection of 1.0 mg/kg haloperidol, cortical lesions attenuated the ability of this neuroleptic to block both the behavioral and neuronal effects of amphetamine. Collectively, these results support mounting evidence for an important modulatory influence of cortical afferents on the amphetamine-induced excitation of neostriatal neurons and the reversal of this effect by haloperidol.

Transforming growth factor β1 and fibronectin messenger RNA in rat brain: Responses to injury and cell-type localization

Transforming growth factor-β1 rapidly increases in adult rat brain in response to experimental lesions. This study characterized the schedule of changes, regional distribution, and cellular localization of striatal transforming growth factor-β1 messenger RNA and fibronectin messenger RNA following partial striatal deafferentation by frontal cortex ablation. Frontal cortex ablation induced striatal transforming growth factor-β1 messenger RNA elevations that coincided temporally and overlapped anatomically with the course of degeneration of cortico-striatal afferent fibers. Within three days post-lesioning, transforming growth factor-β1 messenger RNA was localized at the cortical wound. By 10 days, the anatomical site of transforming growth factor-β1 messenger RNA expression shifted to the dorsal half of the deafferented striatum and co-localized with OX-42 + immunostained microgliamacrophage at the site of degenerating afferent terminals. Similarly, fibronectin messenger RNA also shifted from the cortical wound to the deafferented striatum by 10 days post-lesioning. Fibronectin messenger RNA was localized to glial fibrillary acidic protein + immunostained astrocytes surrounding degenerating corticostriatal afferents. Infusion of transforming growth factor-β1 peptide elevated striatal and cortical fibronectin messenger RNA. These findings suggest that microglia-macrophage associated with degenerating afferent fibres can upregulate transforming growth factor-β1 messenger RNA and may influence fibronectin messenger RNA synthesis in reactive astrocytes. This study suggests that transforming growth factor-β1 has a role in controlling extracellular matrix synthesis following brain injury, which is analogous to that in peripheral wound healing.