Deficient passive and one-way active avoidance acquisition following medial forebrain bundle lesions in rats.

Cathodal electrolytic lesions of the medial forebrain bundle (MFB) at posterior hypothalamic levels in male hooded rats produced a mild, transient hypodipsia and lowered jump thresholds to footshock. The lesions produced marked deficits in passive avoidance performance in a paradigm that paired discrete, linearly incrementing footshock intensities with contact of a water spout following 48 hr of water deprivation. Intraperitoneal injections of DL-5-hydroxytryptophan (75 mg/kg), the immediate metabolic precursor of serotonin, had no effect on the passive avoidance performance of either experimental or operated control subjects. Lesions of the MFB also resulted in deficient acquisition in a one-trial step-through passive avoidance paradigm not using motivation to drink and caused a severe acquisition deficit in a one-way active avoidance task. Lesions of the septal nuclei produced lowered jump thresholds but did not affect acquisition in the first passive avoidance task. The results are interpreted as indicating a lesion-induced deficiency in fear learning, independent of the serotonergic functions of the MFB.     

Hormonal dissociation of limbic lesion effects on shuttle box avoidance in rats.

Rats with septal or hippocampal lesions, relative to normal rats, showed facilitated acquisition of a shuttle box avoidance response. The rats with septal lesions were also highly resistant to extinction compared with normal rats. When the same lesion effects were examined in hypophysectiomized rats, the animals with septal lesions continued to show facilitated performance, and those rats with hippocampal lesions performed no differently than nonoperated control animals. These findings are consistent with the hypothesis that the facilitated avoidance performance found in rats with hippocampal lesions is attributable to lesion-induced changes in hypophyseal activity, but similar changes induced by septal lesions are not.     

Some behavioral effects of transecting ventral or dorsal fiber connections of the septum in the rat.

The behavioral effects of large electrolytic lesions in the septal area were compared with those of knife cuts that severed the ventral or dorsal connections of this structure. Rats with septal lesions lost weight and were transiently hyperdipsic. Ventral cuts produced similar effects, but dorsal cuts did not. All three operations decreased the latency to eat in a novel environment, increased the intake of sweetened milk, enhanced acquisition of a food-rewarded running response, and facilitated acquisition of a shuttle box avoidance response, The lesion, but neither of the knife cuts, reduced the effects of punishment and impaired the acquisition of a one-way avoidance response.     

Intracerebroventricular effects of angiotensin II on a step-through passive avoidance task in rats

A wealth of evidence indicates that angiotensin II (Ang II) is involved in learning and memory. However, the precise role of this peptide in these cognitive processes is still controversial, with data indicating either an inhibitory or an enhancing action. The present study was designed to further investigate the effects of intracerebroventricular injections of Ang II (0.5, 1 or 3nmol/5microl) on a step-through passive avoidance task in male adult Wistar rats. When administered pretraining, Ang II did not affect the acquisition of passive avoidance, but markedly improved avoidance performance when given before the retrieval test. The latter effect was observed in retest sessions performed up to 72h after training. Administration of the peptide five minutes after training impaired retention of inhibitory avoidance. Therefore, Ang II may exert opposite effects on passive avoidance memory according to its interference with brain mechanisms leading to the storage or retrieval of this aversively motivated task.     

Functional organization of the rat amygdala with respect to avoidance behavior.

Bilateral electrolytic lesions in the periamygdaloid piriform cortex of female albino rats produced marked disruptive effects on the acquisition of active avoidance responses in a 1-way as well as a 2-way test situation, significantly impaired passive avoidance behavior, and inhibited feeding in a novel environment. Lesions in each of the 6 major subdivisions of the amygdala (cortical, medial, central, intercalated, lateral, and basolateral nuclei) consistently produced facilitatory effects on active avoidance behavior in 1-way as 2-way situations. Passive avoidance behavior was impaired in animals with lesions in the central, intercalated, and basolateral nuclei. Damage to the anterior amygdaloid area or the the nuclei of the lateral olfactory tract did not reliably affect active or passive avoidance behavior.     

An ACTH4-9 analog (ORG 2766) speeds recovery from septal hyperemotionality in the rat

The amount of hyperemotionality initially demonstrated after septal area lesions was reduced, and the rate at which the hyperemotionality attenuated over repeated testing, was enhanced by the administration of an ACTH4-9 analog, ORG 2766. This ACTH fragment was given for 4 consecutive days after surgery but terminated before testing began. Two weeks after the daily tests of emotionality, the animals were trained in a two-way active avoidance task. The typical increase in avoidance behavior seen in animals with septal lesions was observed in the lesioned animals tested with ORG 2766, but the usual high number of intertrial responses was greatly reduced in these animals. The results indicate that even after a brief series of ORG 2766 administration, there are changes in emotionality that may last for an extended period of time after the cessation of treatment.     

Scopolamine amnesia of passive avoidance: a deficit of information acquisition

Despite its increasing use as an animal model of memory deficit in human dementia, relatively few studies have attempted to assess the memory processes involved in the anticholinergic-induced impairment of passive avoidance retention. In the present experiments, the influence of scopolamine administered prior to or immediately following training on 24-h retention of step-through passive avoidance was studied in NMRI mice. In low doses (0.3-3.0 mg/kg ip) pretraining administration (-5 min) of scopolamine induced a very strong amnesia. Post-training scopolamine induced a significant effect only at the highest dose tested (30 mg/kg). In a retention test of longer than normal duration (600 vs 180 s), which resulted in a more favorable comparison value in the control group, an intermediate post-training dose (10 mg/kg) induced a small effect which approached significance; a finding which may account for conflicting reports in the literature concerning the ability of scopolamine to induce a post-training deficit. The pretraining effect does not appear to have been solely the result of state-dependent learning; scopolamine (3 mg/kg) administered before both the training and test sessions induced a deficit of approximately the same magnitude as that found when administered before training or before testing only. The results indicate that scopolamine can induce a small post-trial effect, presumably through an influence on consolidation processes. The much larger effect of pretrial scopolamine, however, indicates a primary influence on processes related to information acquisition. Together with findings from the literature, the present experiments suggest that scopolamine-induced amnesia partially, but not completely, models the memory deficits of human dementia.     

Effects of the selective M1 muscarinic receptor antagonist dicyclomine on emotional memory

The nonselective muscarinic antagonist scopolamine is known to impair the acquisition of some learning tasks such as inhibitory avoidance. There has been recent research into the effects of this drug in contextual fear conditioning and tone fear conditioning paradigms. The purpose of the present study was to assess the role of the selective M1 muscarinic antagonist dicyclomine in these paradigms and in the inhibitory avoidance test. Rats were administered different doses of dicyclomine or saline 30 min before acquisition training. The animals were tested 24 hr later, and it was observed that 16 mg/kg of dicyclomine impaired both contextual fear conditioning and inhibitory avoidance. However, dicyclomine (up to 64 mg/kg) did not affect tone fear conditioning. These results suggest that the selective M1 muscarinic antagonist dicyclomine differentially affects aversively motivated tasks known to be dependent on hippocampal integrity (such as contextual fear conditioning and inhibitory avoidance) but does not affect similar hippocampus-independent tasks.     

Central action of substance P: possible role in reward

A series of studies had revealed a dualistic role of post-trial injections of substance P in affecting avoidance behavior depending on the site of the brain in which it is applied. Based on these data, the hypothesis was formulated that substance P has brain site-dependent rewarding and punishing properties, a possibility which was assessed in rats trained on a modified T-maze task. Injections of substance P into the medial forebrain bundle (100 ng) or medial septal nucleus (500 ng) served as a positive reinforcer for conditioned place preference learning in the T maze. Injections into the amygdala (50 ng) or substantia nigra (100 ng) did not have such reinforcing properties.     

The memory-impairing effects of septal GABA receptor activation involve GABAergic septo-hippocampal projection neurons

Septal infusions of the gamma-aminobutyric acid (GABA)(A) agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA(A) receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are involved in the memory-impairing effects of septal GABA(A) receptor activation. Experiment 1 tested whether combining septal co-infusions of subeffective doses of muscimol with scopolamine, a drug that selectively influences GABA SH projections, would produce memory deficits. Experiment 2 tested whether hippocampal infusions of a GABA(A) receptor antagonist would block the effects of septal muscimol infusions. Fifteen minutes prior to assessing spontaneous alternation (SA) or training in a multiple trial inhibitory avoidance (CMIA) task, male Sprague-Dawley rats were given septal infusions of vehicle, muscimol, scopolamine, or co-infusions of muscimol with scopolamine, or septal infusions of vehicle or muscimol combined with hippocampal infusions of vehicle or bicuculline. Septal co-infusions of muscimol with scopolamine significantly impaired SA and CMIA. Hippocampal bicuculline infusions blocked deficits produced by septal muscimol infusions in SA and attenuated deficits produced in CMIA. Combined, these findings suggest that GABAergic SH projections are involved in the memory-impairing effects of septal GABA receptor activation.     

ACTH4-10 produces a transient decrease in septal hyperemotionality

The administration of doses of ACTH4-10 that have been shown to be effective in producing enhanced peripheral nerve regeneration did not produce the enhanced rate of decline in hyperemotionality produced by administration of the ACTH4-9 variant Org 2766. Long-term changes in septal reactions in training situations were likewise not affected by ACTH4-10. These results indicate that, despite similar peripheral nerve growth effects, these two ACTH-related agents (ACTH4-10 and Org 2766) produce quite different long- and short-term effects on rats with septal area damage.     

Sparing of function after infant lesions of selected limbic structures in the rat.

The effects, in adult animals, of limbic lesions produced in infancy were studied in 273 male Wistar rats using weight gain and conditioned emotional response (CER) and conditioned avoidance response (CAR) acquisition as the critical measures. Subjects received bilateral lesions of the amygdala, septum, posteroventral hippocampus (PH), anterodorsal hippocampus (AH), or frontal cortex either as infants (at 10 days of age) or as adults (at 60 days). Normal and anesthetized control groups were also used. Frontal cortical lesions, AH lesions, and anesthetization had no effect on weights or on CER and CAR acquisition. Both infant and adult amygdala and septal lesions significantly disrupted normal weight gain. Adult-accrued amydala and PH lesions significantly retarded CER acquisition, and adult septal and PH lesions significantly facilitated CAR acquisition. Infant-accrued amygdala lesions significantly retarded CER acquisition but had no effect on CAR acquisition. Infant septal lesions significantly facilitated CAR acquisition, and infant PH lesions had no effect on either task. The results were interpreted to mean that the observed task-specific recovery in early-operated animals may have been due to some form of functional reorganization.     

Peripheral 8-OH-DPAT and scopolamine infused into the frontal cortex produce passive avoidance retention impairments in rats

The present study determined whether peripheral injections of the 5HT(1A) agonist (8-OH-DPAT), scopolamine infusions into the frontal cortex, or a combination of both drug treatments would produce impairments in rats trained on passive avoidance. Using a 2x2 design, rats were infused with either bacteriostatic water or 30 microg/1 microl of scopolamine HCl into the frontal cortex 30 min before being trained on passive avoidance. This was followed by injections (ip) of either 0.1% ascorbic acid/bacteriostatic water or 30 microg/kg of 8-OH-DPAT 15 min later. All subjects were tested for retention 72h later. At test, the initial latency to enter into the black shocked compartment and the total time spent in the white safe compartment (TTW) were recorded. Analysis of the latency data indicated that scopolamine and 8-OH-DPAT, when administered singly or in combination, produced amnesia for the task. Assessment of TTW scores, however, revealed that of the three drug-treated groups, only animals treated with 8-OH-DPAT alone tended to avoid the previously shocked black compartment and spend more time in the white safe compartment. These data indicate that either stimulating 5-HT(1A) or blocking frontal cortical muscarinic receptors at training impairs passive avoidance performance and that the deficit following the latter treatment is somewhat more extensive. Implications for the role frontal cortical muscarinic and 5HT(1A) receptors play in learning and memory are discussed.     

Exploration and avoidance learning after ibotenic acid and radio frequency lesions in the rat amygdala

Open-field activity, avoidance behavior, and plasma corticosterone levels were studied after intraamygdala injections of 3.0 micrograms ibotenic acid (IBO) and radio-frequency (RF) lesions in the amygdala complex of male Wistar rats. The experiments were undertaken to evaluate the importance of amygdala neurons versus axons of passage in fear-motivated behavior. The IBO lesions led to increased open-field activity, but no impairments in active avoidance learning, nor changes in basal or experimental levels of plasma corticosterone. The RF lesions, on the other hand, led to an increase in experimental plasma corticosterone levels. In the one-way avoidance task the RF lesions, in contrast to the IBO lesions, led to significant impairments in the acquisition of the avoidance response. Although the long-term axon-sparing effect of IBO is questioned since cavities were detected in the affected areas 8 weeks after the injections, the differences in avoidance learning and in corticosterone levels between the RF and the IBO lesions indicate that the axons were functionally active at the time of testing (14-26 days postoperatively). The increase in open-field activity is attributed to the destruction of amygdala neurons and neurons in the overlying cortex, while an avoidance deficit seem to depend on the destruction of axons. On the basis of the behavioral results and the corticosterone data in these experiments, it is suggested that the behavioral changes are not attributable to a general reduction in the arousal of fear. However, since the IBO lesions did not affect the most medial parts of the amygdala complex including the central amygdala nucleus, the role of this nucleus in fear arousal has to be investigated further.     

Comparison of the effects of scopolamine administered before and after acquisition in a test of visual recognition memory in monkeys

The effect of scopolamine on visual recognition memory in rhesus monkeys was assessed with a delayed nonmatching-to-sample task employing trial-unique stimuli. During the acquisition phase, 40 sample stimuli were presented sequentially. During the test phase, these same stimuli were presented in the reverse order, each paired with a novel stimulus. The animal was rewarded for choosing the novel stimulus in each pair. Two versions of this design were used. In Task 1, scopolamine (10.0 or 17.8 micrograms/kg) was administered 20 min prior to acquisition, which was followed immediately by the test phase. In Task 2, the drug was administered immediately after acquisition, which was followed 20 min later by the test phase. Performance was impaired in a dose-related manner in Task 1, but not at all in Task 2, indicating that the effects of scopolamine on performance cannot be attributed to an impairment either in the retrieval of stored information or in the attentive or perceptual discriminative processes needed for such retrieval, or, by implication, for storage. In addition, the forgetting curves for scopolamine in Task 1 were parallel to those of the control sessions; i.e., the curves did not diverge with increasing delay intervals, indicating that scopolamine did not increase the rate of forgetting. Taken together, the results suggest that scopolamine interferes selectively with the initial storage of the information to be remembered.     

Lesions of the intermediate medial hyperstriatum ventrale impair sickness-conditioned learning in day-old chicks.

Lesion studies show that the intermediate medial hyperstriatum ventrale (IMHV), a forebrain visual association area in chicks, is involved in learning and memory for one-trial passive avoidance and imprinting. We examined the effects of IMHV lesions in a one-trial, nongustatory, sickness-conditioned learning task. This task is similar to passive avoidance and imprinting because all three tasks require the chick to remember visual cues in order to respond correctly. However, sickness-conditioned learning differs from imprinting and passive avoidance because it uses sickness as the aversive stimulus and there is a longer conditioned stimulus-unconditioned stimulus interval (30-min delay compared to seconds). Bilateral IMHV lesions given 24 h before training impaired the ability of the chicks to avoid a bead associated with sickness produced by lithium chloride injection, as did pretraining unilateral left or right IMHV lesions. Post-training IMHV lesions given 1 h after training did not impair avoidance of the test bead in the sickness-conditioned learning task. However, lesioned chicks showed generalized avoidance of all test beads. The pretraining lesion results are similar to those found in imprinting and passive avoidance learning; however, the effects of unilateral IMHV lesions differed. Post-training lesion effects are similar to those found in passive avoidance learning. We propose that both left and right IMHV are necessary for sickness-conditioned learning and that post-training IMHV lesions impair the ability of the chick to learn or remember the association between the color of the bead and the aversive consequences of LiCl injection.     

Cholinergic receptor antagonists impair formation of intermediate-term memory in the chick

Several experiments examined the effects of cholinergic receptor antagonists on formation of memory in the chick. Scopolamine produced amnesia in chicks trained on a one-trial peck avoidance task in a dose-dependent manner. Pretraining injection of scopolamine produced amnesia that developed between 15 and 30 min after training, suggesting that scopolamine interferes with intermediate-term memory (ITM), previously described to be active during this time (Patterson, Alvarado, Warner, Bennett, & Rosenzweig, 1986). Pretraining injection of scopolamine or ouabain, an inhibitor of ATPase activity shown previously to inhibit formation of ITM, produced identical time courses of amnesia development, supporting the hypothesis that scopolamine interferes with ITM. Pirenzepine, an inhibitor of M1 muscarinic receptors, was effective in producing amnesia, whereas gallamine, an M2 receptor inhibitor, did not produce amnesia. These results suggest that M1, but not M2, receptors are involved in memory formation in the chick.     

Septal influences on operant responding in the rat.

The afferent and efferent connections of the septum with the hippocampus (fornix) of with the hypothalamus and lower brain stem (medial forebrain bundle) were transected by means of an encephalotome near the point where these pathways enter or leave the septal area. A transection of the fornix that produced minimal direct damage to cellular components of the septum of hippocampus reproduced the effects of large septal lesions on responding in several temporally defined paradigms that involve periods of response suppression (differential reinforcement of low rates, discriminated Sidman avoidance, fixed interval). Transection of the medial forebrain bundle fibers that interconnect the septum with the hypothalamus and lower brain stem did not affect behavior in any of these paradigms. These observations should be veiwed in the context of the results of earlier investigations which demonstrated that transection of the medial forebrain bundle reproduces several other components of the septal lesion syndrome.     

The effects of concurrent manipulations of cholinergic and noradrenergic systems on neocortical EEG and spatial learning

In the spatial learning test, young animals were divided into three groups receiving saline, scopolamine (0.15 mg/kg), or scopolamine (0.8 mg/kg). Half of the animals in each group were lesioned with DSP-4 to destroy noradrenergic fibers. DSP-4 lesions did not produce any significant impairment alone or in combination with a lower dose of scopolamine (0.15 mg/kg), but they did further augment the scopolamine (0.8 mg/kg)-induced defect. In the electroencephalography (EEG) experiment, both control rats and DSP-4-lesioned rats were recorded after receiving saline, scopolamine (0.15 mg/kg), and scopolamine (0.8 mg/kg) injections. Scopolamine induced a dose- and behavioral state-dependent EEG slowing, whereas DSP-4 lesions did not change either baseline EEG activity or EEG reactivity to scopolamine.     

Glucose effects on memory: behavioral and pharmacological characteristics

Recent findings indicate that post-training glucose injections can modulate memory storage for inhibitory (passive) avoidance training. Experiment I extended these findings to determine whether glucose, like other memory modulating treatments, enhances memory storage when administered after training with low footshock and impairs memory storage after high footshock training. In Experiment I, male Sprague-Dawley rats were trained in a one-trial inhibitory avoidance task using either a brief footshock (0.5 mA, 0.7 s) or slightly more intense footshock kept on until escape (0.7 mA, mean escape latency = 3.4 s). Immediately after training, each rat received a subcutaneous injection of glucose (100 mg/kg). When tested for retention performance 24 h later, the glucose-injected animals exhibited enhanced retention performance for low footshock training and impaired retention for high footshock training. Experiment II determined whether pretreatment with adrenergic antagonists blocked the effects of glucose on memory. Pretreatment with the alpha- or beta-adrenergic receptor antagonists, phenoxybenzamine, or propranolol, respectively, had no effect on acquisition or retention in animals trained with the brief footshock and did not affect glucose facilitation of that memory. In animals trained to escape footshock, phenoxybenzamine did not attenuate the amnesia produced by glucose. Propranolol-pretreated animals had impaired retention whether or not they received post-training amnestic injections of glucose; glucose had no effect on retention in these amnestic animals. These findings add further support to the view that glucose release after training and treatment may represent a physiological response subsequent to epinephrine release in modulating memory storage processing.