Effects of GABAergic drugs, fornicotomy, hippocampectomy and septal lesions on the extinction of a discrete-trial fixed ratio 5 lever-press response

The effects of certain GABA-modulating drugs, fornicotomy, hippocampectomy and various septal lesions were analysed in a discrete-trial fixed ratio 5 (FR5) bar-press paradigm. Chlordiazepoxide, fornicotomy, hippocampectomy, electrolytic lateral septal lesions and ibotenic acid medial septal lesions facilitate extinction of the FR5 response. Some of these treatments (chlordiazepoxide, hippocampectomy, electrolytic lateral septal lesions) have previously been found to increase resistance to extinction of alley-running after continuously reinforced (CRF) acquisition training. The treatments which facilitated extinction in the discrete-trial FR5 paradigm have been found to reduce or abolish the partial reinforcement extinction effect in the alley. These results indicate that the discrete-trial FR5 paradigm is not analogous to a runway CRF schedule, but may be analogous to a runway partial reinforcement schedule.     

Distribution of cytochrome oxidase in response to rewarding brain stimulation: Effect of different pulse durations

Cytochrome oxidase histochemistry was used to evaluate neuronal changes in oxidative metabolism in response to rewarding brain stimulation of the medial forebrain bundle. Rats with single lateral hypothalamic electrodes self-stimulated daily for ten days for trains of either 0.1 or 2.0 ms pulses that corresponded to about 75% of maximum responding. Quantitative comparison of stimulated-to-unstimulated sides revealed differences in relative optical density in few structures, notably in the lateral septal nucleus and the nucleus accumbens, when the brief pulse duration was used. In contrast, the longer pulse duration gave rise to metabolic increases in several dopaminergic projections, including the frontal cortex, olfactory tubercle, and lateral habenula, and also enhanced activity in the lateral septal nucleus. These data suggest that mesocorticolimbic structures may be implicated in medial forebrain bundle self-stimulation.     

Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory

Functional dissociations between the medial septal area (MSA) and the nucleus basalis magnocellularis (NBM) were examined using the concepts and experimental procedures developed by scalar timing theory. Rats were tested in variations of a signalled discrete-trial peak-interval schedule of reinforcement in which the response rate functions identified the time when the rats expected reinforcement. The variations assessed aspects of both reference and working memory for information obtained from prior trials and from the current trial. A double dissociation was found in reference memory. Rats with NBM lesions, like those with frontal cortex (FC) lesions, remembered the time of reinforcement as having occurred later than it actually did; rats with MSA lesions, like those with fimbria-fornix (FF) lesions, remembered the time of reinforcement as having occurred earlier than it did. A single dissociation was found in working memory. MSA lesions and FF lesions impaired working memory, while NBM and FC lesions had no effect on it. These data begin to identify the brain mechanisms underlying temporal memory; they indicate that the frontal and hippocampal systems are both involved, but in complementary ways; and they provide information that helps specify more clearly the functions of the frontal and hippocampal systems.     

Effects of lesions of various medial forebrain bundle components on lateral hypothalamic self-stimulation.

Unilateral lesions of various medial forebrain bundle components were assessed for their effects on lateral hypothalamic self-stimulation. Damage of areas containig nigrostriatal dopaminergic or ascending noradrenergic neurons had negligible effects on bar pressing, tail moving and alley running for hypothalamic stimulation. Lesions which appeared to destroy most or all of the catecholaminergic fibers in the posterior medial forebrain bundle virtually eliminated reinforced bar pressing and tail moving, but only partially suppressed alley running. The results suggest that brain stimulation reinforcement of the bar press and tail movement tasks depends upon the integrity of neural tissue in the area of the catecholaminergic pathways of the medial forebrain bundle, but not upon specific dopaminergic or noradrenergic systems. The data further suggest that the reinforcement of alley running is at least partially mediated by different neural tissue (possibly non-catecholaminergic) at the level of the posterior medial forebrain bundle lesions.     

Hypothalamic afferent connections mediating adrenocortical responses that follow hippocampal stimulation

This study identified some neural pathways which mediate the adrenocortical responses that follow hippocampal stimulation. The increase in plasma corticosterone following dorsal hippocampus stimulation, in rats with electrodes chronically implanted under pentobarbital anesthesia, was blocked by dorsal fornix and lateral septal lesions and by small posterior hypothalamic deafferentation. Fimbria transection, lateral septal lesions, and posterior hypothalamic deafferentation, but not midbrain reticular formation lesions, also blocked the adrenocortical responses to ventral hippocampus stimulation. Our present and previous studies indicate that the dorsal and ventral hippocampal effects on the hypothalamus, which increase plasma corticosterone concentrations, are mediated by the dorsal fornix and fimbria, respectively, as well as by the lateral septum. A posterior hypothalamic input, which does not involve the medial forebrain bundle or the midbrain reticular formation is also essential for the activation of this response.     

Parallel information processing in the dorsal striatum: relation to hippocampal function.

We investigated the effects of localized medial and lateral CPu lesions and fornix/fimbria lesions on responses to a local cue and to behavior based on cognitive-spatial information in the water maze. Rats were trained concurrently on the cue (visible platform) and spatial (submerged platform) components of the task, followed by a test in which responses to the two types of information were dissociated by a measure of competing response tendencies. Bilateral lesions of lateral CPu did not affect acquisition of either cue or spatial responding but produced a preference for the spatial response on the competition test. Bilateral lesions of the medial CPu retarded but did not prevent learning both components and produced a preference for the cue response on the competition test. The latter effect was accompanied by increased thigmotaxis (swimming in the periphery of the pool), primarily during the early acquisition trials, which was attributed to an impaired ability to respond to learned spatial information. Fornix/fimbria lesions prevented spatial but not cue learning and produced a preference for the cue response on the competition test. Asymmetric lesions (unilateral hippocampus and contralateral medial CPu) produced mild retardation of acquisition of both the cue and spatial tasks and a preference for the cue response on the competition test. These findings dissociate the functions of the lateral and medial CPu and suggest that the hippocampus and medial CPu may be parts of a system that promotes responding based on learned cognitive-spatial information, particularly in competitive cue-place response situations.     

Dissociation of the contributions of the prefrontal cortex and dorsomedial thalamic nucleus to spatially guided behavior in the rat

Rats with lesions of the medial frontal cortex or dorsomedial nucleus of the thalamus (MD) were studied in two spatial localization tasks: the Morris water task and the 8-arm radial arm maze. Rats with medial frontal lesions failed to learn to swim from different locations to a hidden platform located at a specific place in a large tank (Morris task) and were impaired at learning the location of reward in the radial arm maze. Rats with MD lesions were not impaired at spatial orientation in either task. The results provide the first unequivocal evidence of a spatial orientation deficit following frontal lesions and lend support to the notion that the frontal cortex forms part of a ‘spatial mapping system’. The results suggest that although MD is the major afferent to the frontal cortex, it does not provide necessary spatially-relevant input.     

Effects of lateral and medial septal lesions on exploratory behavior in the albino rat

The effects of selective medial and lateral septal lesions on exploratory behavior were studied in the rat. Three types of open-field test and two tests of object exploration were used. In the firts experiments, medial but not lateral septal lesions abolished exploration of an open-field accessible from the home-cage. No effects of either of the lesions were found in a standard open-field (Experiment 2). In the third experiment, rats with medial septal lesions were less active and showed a preference for the smaller compartments of the testing apparatus. These results suggest that a change in exploratory behavior following medial septal lesions may be primarily due to their effect on emotionality (increased fear). Two tests of object exploration (Experiments 4 and 5) showed that both types of selective septal lesions enhanced approaches to the novel object placed in the home-cage, but they did not affect object exploration and object preference in other conditions (Experiment 5). The same experiments revealed an increased level of activity (rearing and ambulation) in the rats with lateral septal lesions.It is concluded that the effect of medial septal lesions on exploration is due to increased fear of novel places (but not objects). Lateral septal lesions, on the other hand, increase activity in the rats but there is no evidence that this activity represents enhanced exploration.     

The septo-hippocampal system and cognitive mapping

Rats were trained on a rewarded alternation task, run as a spatial working memory task on an elevated T-maze. Experiment 1 tested the effects of fornix-fimbria (FOFI) lesions on the acquisition, and of medial septal (MS) lesions on the acquisition and retention of this task, when the rats had to use information provided by being forced to run to a selected goal arm. The FOFI lesion produced an enduring impairment; the MS rats showed a severe impairment initially, but subsequently showed some behavioural recovery, when tested in acquisition or in retention. Experiment 2 similarly tested the effects of lateral septal (LS) lesions on acquisition of the task, and found an impairment which again showed signs of recovery with further testing. Experiment 3 was a transfer test conducted on the rats which had shown recovery in Experiments 1 and 2. The rats were now forced to use information provided by simply being placed on a selected goal arm. Both control animals and lesion animals showed identical choice accuracy, lower than that seen in Experiments 1 and 2. Experiment 4 tested acquisition of the task used in Experiment 3, and acquisition of a task in which the rat had to use information provided by running to the goal arm via a different route. Control rats again performed poorly, and scarcely differed from MS rats. It was concluded that rats have difficulty in using information about ‘places’, and that controls and lesion rats learn the tasks in the same way. The implications for ‘cognitive mapping’ hypotheses are discussed.     

Hippocampal influence on hyperreactivity induced by septal lesions.

Rats were tested for their responses to 4 stimuli in order to measure hyperreactivity. Animals with septal lesions emitted the expected hyperreactivity. Lesions of the postcommisural fornix, precommissural fornix, or anterior hippocampus, administered 16 days prior to a septal lesion, blocked the expected hyperreactivity. Lesions localized to the medial or the lateral fibers of the fornix decreased the magnitude the duration of the expected hyperreactivity following septal lesions but did not block it. Lesions of the posterior hippocampus-entorhinal cortex had no reliable effect on the expected hyperreactivity after septal lesions. These data indicate that the appearance of hyperreactivity following a septal lesion depends upon a circuit involving the septum, precommissural fornix, anterior hippocampus, postcommissural fornix, and hypothalamus, and document an important functional relationship between the septum, anterior hippocampus, and hypothalamus.     

Effects of nicotine on spatial memory deficits in rats with septal lesions.

Impaired septohippocampal function has been implicated in the memory deficits associated with Alzheimer's disease (AD), and septal lesions have been used to model the cognitive deficits associated with AD. In this study, we assessed the effects of systemic administration of nicotine on lesion-induced deficits in the acquisition of a spatial discrimination version of the Morris water maze. Rats with radiofrequency lesions of the medial septum were required to learn which of two visible platforms in a pool of water provided a means of escape. On each of the first 4 days of training, the rats received an injection of (-)nicotine (0, 0.1 or 0.3 mg/kg, i.p.) before training. Nicotine markedly improved the performance of septal rats. This enhanced performance was maintained in rats subsequently tested 1 and 15 days later without additional drug treatment. Septal rats initially trained under nicotine were impaired, however, when the platform locations were reversed and training was conducted under saline. Our findings suggest that nicotinic receptor stimulation might be useful in the treatment of cognitive deficits.     

The role of the medial septal nucleus in mediating adrenocortical responses to somatosensory stimulation

In view of the demonstrated involvement of the hippocampus in the mediation of adrenocortical responses following sciatic nerve stimulation, the role of the septum and the preoptic area in the transmission of this response was investigated. Changes in plasma corticosterone following ether stress and photic, acoustic, or sciatic nerve stimulation were studied in intact rats and in animals with lesions in the medial septal nucleus and the preoptic area. The response to ether stress and to photic and acoustic stimulation was normal in these animals. However, the adrenocortical response to sciatic nerve stimulation was partially reduced in the rats with lesions in the superior, but not in the inferior preoptic area, and it was completely blocked in those with medial septal lesions. Our previous and present experiments indicate that the ventral hippocampus, the fimbria, the septum, and anterior hypothalamic afferents mediate the adrenocortical response to somatosensory stimulation.     

Effects of the lateral septum and latent inhibition on successive discrimination learning.

Damage to the lateral nucleus of the septum in the rat resulted in atypical learning to a previously meaningless stimulus. Nonreinforced preexposure to a stimulus normally makes more difficult subsequent use of that stimulus for learning. The effect of this preexposure on learning is termed latent inhibition and was demonstrated in sham operated animals. Rats in which the lateral septum was damaged demonstrated a paradoxically smaller learning deficit in the presence of a conditioned stimulus that was previously presented without reinforcement, when compared to the performance of both septal lesioned rats no receiving nonreinforced preexposure and sham operates receiving preexposure. The interaction of nonreinforced preexposure and lateral septal lesions can be explained using a proposed sensitization hypothesis.     

Effects of dorsal and ventral striatal lesions on delayed matching trained with retractable levers

Recent evidence has suggested that thalamic amnesia results from damage to the intralaminar nuclei, an important source of input to striatum. To test the hypothesis that intralaminar damage disrupts functions mediated by striatum, we studied the effects of striatal lesions on a delayed matching task known to be affected by intralaminar lesions. Rats were trained to perform the task and given one of five treatments: sham surgery or a lesion of medial or lateral caudate/putamen, nucleus accumbens, or ventral striatum. Rats with ventral striatal lesions were impaired compared to all other groups. Rats with medial caudate/putamen or nucleus accumbens lesions were impaired compared to controls. The effects of ventral striatal lesions were sufficient to account for impairments in the accuracy and latency of delayed matching responses observed in previous studies of intralaminar and medial frontal cortical lesions. The ventral striatal lesions involved portions of ventral pallidum and thus it seems likely that they affected functions mediated by the nucleus accumbens as well as striatal areas of the tubercle. Serial reversal learning trained in the same apparatus with the same reinforcer was unaffected by all of the lesions. These results are discussed in terms of the roles of midline thalamic nuclei and of thalamo-cortico-striatal circuits in delayed conditional discrimination tasks.     

Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it

Hypothalamic electrodes can generate positive reinforcement, as shown by self-stimulation, and negative reinforcement shown by stimulation-escape. It was hypothesized that acetylcholine (ACh) is released in the nucleus accumbens during the aversive state that underlies stimulation-escape. If this is correct, escape behavior should lower extracellular ACh. Rats were prepared with microdialysis probes in the accumbens (posterior shell region) and electrodes in the perifornical lateral hypothalamus. Animals learned to press a lever for 0.5 s trains of stimulation (typically 3600 responses/h). Then they were given automatic stimulation to determine which animals would also learn to press a lever to turn stimulation off for 5 s at a time (typically 75 responses/h). Accumbens microdialysis showed that automatic stimulation caused extracellular ACh to double, but only in the rats that were motivated to learn stimulation-escape. When allowed to escape stimulation, these animals lowered extracellular ACh significantly. It is concluded that ACh release in the accumbens is related to the neural state that animals work to escape.     

Septum and medial frontal cortex contribution to spatial problem-solving

An attempt was made to contrast the effects of lesions to the medial frontal cortex and septum in two spatial tasks. In the fixed-goal (FG) task, the food was located on the same table throughout testing, and the start table was randomly varied from day to day. In the variable-goal (VG) task, the start table remained constant but the food was randomly distributed on one or the other of the two remaining tables. In both tasks, normal animals performed better than frontal and septal rats whose performance, however, improved over days in the FG, but not in the VG, task. In both tasks, significant improvement within days was found in medial frontal animals, but not in septal animals. Additional analyses revealed that septal animals had a general pattern of disrupted exploration and a tendency to use a response strategy (i.e. to repeat the same response both within and between days) which decreased over days in the FG task. In contrast, medial frontal animals did not demonstrate disrupted exploration nor any response tendency. It is concluded that both septal and medial frontal cortical damage produce a common spatial working memory impairment. However, there is some evidence to suggest that this common memory impairment could result from disruption of distinct mechanisms in septal and frontal animals. It is proposed that medial frontal lesions could affect some specific mechanism related either to attentional processes or to the ability to anticipate future events, whereas septal damage would interfere with the building of comprehensive and flexible spatial memories.     

Conditional engagement of medial frontal cortex during responding under uncertain reinforcement in rats: a paradigm for subjective behavior.

Rats were studied for their performance on DRL 10 s and 5 s with 50% probability of reinforcement, before and after medial frontal cortical lesions. A sequential analysis of interresponse times (IRTs) was carried out. It suggested 1. that the medial frontal cortex mediates subjective risk of response choice in rats and 2. that the tolerated risk levels in human decision-making may have a biological basis.     

A [14C]2-deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. V. The septal area

The [14C]2-deoxyglucose (2-DG) metabolic mapping technique has been used to identify the regions responding with an augmented rate of metabolism following focal electrical stimulation of various sites within the lateral septal nucleus and medial septal nucleus/diagonal band (MSN/DB) complex in the rat. Since 2-DG uptake has been correlated with rates of functional activity, it was the intention of this study to suggest the anatomical substrates underlying various physiological and behavioral responses elicited by stimulation of the septal area. The results show that stimulation of any region within the lateral septal nucleus produced a profound bilateral activation of both the lateral septal nucleus, as well as the hippocampal formation. While stimulation of a number of different fiber systems associated with the lateral septum could contribute to the observed pattern of labeling, the data suggest that, functionally, a major consequence of such stimulation is the antidromic activation of CA3----lateral septum fibers to axonal branch points, beyond which, orthodromic propagation of the impulse produces activation in CA3 target regions, including subfields CA1 and CA3, as well as the lateral septal nucleus, bilaterally. In addition, regions typically manifesting metabolic activation following stimulation of the lateral septal nucleus included the ipsilateral diagonal band of Broca, nucleus accumbens, lateral preoptic area and lateral hypothalamus, posteriorly, and the prelimbic cortex, anteriorly. Occasionally, target regions of the postcommissural fornix, including the medial mammillary nucleus and anterior thalamic nuclei were also activated following stimulation of the lateral septal nucleus. In contrast to the widespread pattern of activation resulting from stimulation of the lateral septal nucleus, stimulation of the MSN/DB complex produced activation which was largely confined to the medial forebrain bundle. In a final phase of the experiment, afterdischarge activity was elicited by sodium penicillin injection into the lateral septal nucleus. Such treatment produced more widespread 2-DG uptake, including more extensive activation within the lateral septal nucleus, hippocampal formation, amygdala, and thalamus. Additionally, the prefrontal cortex and temporal neocortex were activated.     

Mapping of sensory-responsive cells in the septal area of the rat

A study of sensory-responsive characteristics of single cells of the septal area of male rats was undertaken to determine the distribution of stimulation-induced changes in septal activity. Single cells were systematically sampled in six planes transecting the rostral-caudal axis of the septal area and were tested for responsiveness to visual, auditory, tactual, gustatory and olfactory stimuli. Approximately 50% of the sampled population of septal cells was responsive to at least one stimulus. Most of the responses of septal cells to stimulation were excitatory and occurred at the onset of stimulation. Regions of concentration of sensory-responsi veness cells in the system were found to lie in medial areas of the septum consisting of the dorsomedial portion of the lateral septal nucleus, the medial septal nucleus and the ventral portions of the medial and lateral nuclei. Visual, auditory and tactual stimuli were most effective in producing changes in spontaneous activity of units in these regions. On the basis of relationships of the medial septal region to other limbic areas having sensory-responsive properties, it is concluded that the medial septal area is one component of a limbic sensory system.     

A genetically mediated relationship between the readiness to self stimulate lateral hypothalamus and the intensity of the septal and ventromedial hypothalamic rage syndromes

Rats from two genetically high self stimulating lines (LC1-Hi, LC2-Hi) and from two genetically low self stimulating lines (LC1-Lo, LC2-Lo) were subjected to septal lesions at various ages. The genetically high self stimulators exhibited the typical marked increase in emotionality following septal lesions, while the genetically low self stimulators showed an attenuated emotional response following septal lesions. In a subsequent experiment, animals from the same lines were subjected to VMH lesions. Once again, animals from the genetic high self stimulating lines showed a marked increase in emotionality following the lesions while the animals from the genetic low self stimulating lines showed an attenuated emotional response. Hyperphagia was observed in all lines with no relation to the self stimulation genetic background. It is suggested that the septal and VMH systems modulating affective behavior are functionally related to the system modulating self stimulation, while these mechanisms seem to be basically independent of the VMH systems involved in maintenance of body weight.