Amygdala and Periaqueductal Gray Lesions Only Partially Attenuate Unconditional Defensive Responses in Rats Exposed to a Cat

Defensive responses to a cat were observed in rats given excitotoxic lesions of the central nucleus of the amygdala (ACe), dorsolateral periaqueductal gray (dlPAG), ventral periaqueductal gray (vPAG), or sham lesions. Rats were placed adjacent to a compartment containing a cat. Sham-lesioned rats avoided the area nearest the cat and preferred the area furthest away from the cat. They also exhibited numerous defensive responses including, climbing, escape from the apparatus, and freezing. Rats with lesions of the ACe reacted like the sham lesioned rats by preferring the area of the apparatus furthest from the cat, however they climbed and escaped significantly less than sham lesioned rats. Avoidance of the area adjacent to the cat was attenuated in rats with lesions of the vPAG. Climbing along the walls of the apparatus was also attenuated in rats with lesions of the vPAG. Escapes from the apparatus were not significantly reduced by lesions of the vPAG and dlPAG. Thus, ACe lesions attenuated climbing and eliminated escapes, but did not impair locomotion of the rat away from the cat.     

Lesion of the ventral periaqueductal gray reduces conditioned fear but does not change freezing induced by stimulation of the dorsal periaqueductal gray

Previously-reported evidence showed that freezing to a context previously associated with footshock is impaired by lesion of the ventral periaqueductal gray (vPAG). It has also been shown that stepwise increase in the intensity of the electrical stimulation of the dorsal periaqueductal gray (dPAG) produces alertness, then freezing, and finally escape. These aversive responses are mimicked by microinjections of GABA receptor antagonists, such as bicuculline, or blockers of the glutamic acid decarboxylase (GAD), such as semicarbazide, into the dPAG. In this work, we examined whether the expression of these defensive responses could be the result of activation of ventral portion of the periaqueductal gray. Sham- or vPAG electrolytic–lesioned rats were implanted with an electrode in the dPAG for the determination of the thresholds of freezing and escape responses. The vPAG electrolytic lesions were behaviorally verified through a context-conditioned fear paradigm. Results indicated that lesion of the vPAG disrupted conditioned freezing response to contextual cues associated with footshocks but did not change the dPAG electrical stimulation for freezing and escape responses. In a second experiment, lesion of the vPAG also did not change the amount of freezing and escape behavior produced by microinjections of semicarbazide into the dPAG. These findings indicate that freezing and escape defensive responses induced by dPAG stimulation do not depend on the integrity of the vPAG. A discussion on different neural circuitries that might underlie different inhibitory and active defensive behavioral patterns that animals display during threatening situations is presented.     

Influence of dorsolateral periaqueductal grey (dlPAG) lesions on contextual conditioning with massed and distributed shock

Three experiments investigated the conditions under which electrolytic lesions of the dorsolateral periaqueductal grey (dlPAG) facilitate conditioned defensive freezing in the rat ( Rattus norvegicus ). Experiment 1 found that dlPAG lesions placed before context-shock pairings facilitated conditioned defensive freezing with massed but not distributed shock. No such effect was found in Experiment 2, when the lesions were placed after context-shock pairings. Experiment 3 found that dlPAG lesions facilitated subsequent conditioning with massed but not a single shock. In addition, no differences in sensitivity to thermal or shock pain were evident in lesioned and unlesioned rats. Taken together, these results are consistent with the suggestion that dlPAG activation interferes with the processing of contextual cues during association formation.     

Lesions of Periaqueductal Gray Dissociate-Conditioned Freezing From Conditioned Suppression Behavior in Rats

It is commonly assumed that suppression of an ongoing behavior is an indirect measure of freezing behavior. We tested whether conditioned suppression and freezing are the same or distinct conditioned responses. Rats were trained to press a bar for food and then given fear-conditioning sessions in which a tone was paired with a foot shock (two pairings a day for 2 days). They then received either sham or electrolytic lesions of the periaqueductal gray (PAG). Post-training PAG lesions blocked freezing to the conditioned stimulus (CS), but had no effect on the suppression of operant behavior to the same CS. Thus, conditioned suppression and freezing, which both cause a cessation in activity, appear to be mediated by separate processes.     

The effect of amygdala lesions on conditional and unconditional vocalizations in rats

Electrolytic lesions centered on the amygdaloid central nucleus (ACe) resulted in the inability of rats to acquire a Pavlovian conditional vocalization response. Conditioning consisted of pairing a light conditional stimulus with a tailshock unconditional stimulus (US). The thresholds of three unconditional responses (URs) to tailshock were assessed prior to conditioning. These URs are organized at spinal (spinal motor reflexes), medullary (vocalizations during shock), and forebrain (vocalization afterdischarges, VADs) levels of the neuraxis. Compared to sham-lesioned controls, rats with amygdala lesions exhibited a selective elevation in the threshold of VADs. During conditioning the amplitude and duration of VADs were selectively reduced in amygdala-lesioned rats. These findings support earlier observations of that elicitation of VADs by tailshock correlates with the capacity of this US to support fear conditioning. The ACe may be involved in both associative and non-associative aspects of fear conditioning, but for progress in our understanding it is essential to evaluate its role in the generation of conditioning relevant URs.     

Habituation of the hiding response to cat odor in rats (Rattus norvegicus)

Cat odor-induced hiding was examined in rats (Rattus norvegicus) using an apparatus with a "hide box" at one end and a piece of a worn cat collar at the other end. Rats spent most of their time hiding on exposure to the cat collar, but this response gradually habituated over repeated daily exposures. Hiding was reversed by administering the anxiolytic drug midazolam (0.375 mg/kg). Rats showed increased anxiety on the elevated plus-maze after exposure to the collar. This response was absent in habituated rats, suggesting that habituation of hiding reflects decreased odor-induced anxiety. It was established that rats located in the hide box of the apparatus might not have detected the odor of the cat collar placed at the other end of the apparatus. This implies that habituation occurs after relatively modest levels of odor exposure. Overall, the results cast some doubt on claims that predatory odors in rats are akin to phobic stimuli in humans.     

Influence of long-term sensitization on long-term habituation of the acoustic startle response in rats: central gray lesions, preexposure, and extinction

The relation between long-term decrements of the acoustic startle response in rats and the development of freezing behavior during habituation training was examined. Freezing behavior developed over the initial trials of habituation training, and the rate of long-term response decrements was found to be inversely related to the development of freezing. Manipulations (neurological or behavioral) that either reduced the level of freezing or retarded its development promoted startle response decrements. In Experiment 1, rats receiving electrolytic lesions of the ventrolateral periaqueductal gray demonstrated both accelerated long-term startle response decrements and retarded development of freezing behavior. In Experiment 2, preexposure to the startle apparatus (i.e., latent inhibition) accelerated long-term startle decrements and inhibited development of freezing. In Experiment 3, exposure to the startle apparatus following initial habituation training (i.e., extinction) reduced both freezing behavior and startle response amplitudes. The results are discussed in terms of the influence of Pavlovian fear conditioning on long-term habituation of the acoustic startle response.     

Role of the medial and lateral caudate-putamen in mediating an auditory conditional response association

Rats with quinolinic acid lesions of the medial or lateral caudate-putamen (CPu) and controls were tested for performance of a previously learned auditory conditional response association task. The task involved the selection of two possible responses when presented with one of two different tones. Results indicated that lesions of either the medial or the lateral CPu produced a sustained deficit in the auditory conditional response association task. Only the lateral CPu lesioned rats exhibited transient motor problems immediately following surgery, but these problems did not interfere with the execution of the appropriate responses. It is suggested that both the medial and the lateral CPu are involved in response selection and response separation within egocentric space.     

The awareness of thirst: proposed neural correlates

The neural and endocrine bases of the generation of thirst are reviewed. Based on this review, a hierarchical system of neural structures that regulate water conservation and acquisition is proposed. The system includes primary sensory-receptive areas; secondary sensory structures (circumventricular organs), which detect levels of hormones, including angiotensin II and vasopressin, which are involved in generating thirst; preoptic and hypothalamic structures; and an area within the ventrolateral quadrant of the periaqueductal gray matter. Hodological and other data are used to determine the hierarchical organization of the system. Based on studies of the effects of lesions to various structures within the hierarchy of the system, it is proposed that the awareness of thirst in rodents is either entirely or predominantly due to neuronal activities in a subsection of the ventrolateral periaqueductal gray matter. It is also hypothesized that the awareness of thirst in primates is due to neuronal activities in both the ventrolateral periaqueductal gray and in a region within the medial prefrontal and anterior cingulate cortex.     

Lesions of orbitofrontal cortex and basolateral amygdala complex disrupt acquisition of odor-guided discriminations and reversals

Recent work indicates that both orbitofrontal cortex (OFC) and the basolateral complex of the amygdala (ABL) are involved in processes by which cues are associated with predicted outcomes. To examine the respective roles of these structures in discrimination learning, rats with bilateral sham or neurotoxic lesions of either OFC or ABL were trained on a series of four 2-odor discrimination problems in a thirst-motivated go, no-go task. After acquisition of the series of odor problems, the rats were trained on serial reversals of the final odor problem. Performance on each problem was assessed by monitoring accuracy of choice behavior, and also by measuring latency to respond for fluid outcomes after odor sampling. During discrimination learning, rats in both lesioned groups had similar deficits, failing to show normal changes in response latency during learning, while at the same time exhibiting normal choice behavior relative to controls. Choice behavior was affected only during the reversal phase of training, in which OFC and ABL lesions produced distinctive deficits. Rats with ABL lesions were impaired on the first reversal (S1−/S2+), but were unimpaired at acquiring a reversal back to the original odor-outcome contigencies (S1+/S2−), whereas rats with OFC lesions were impaired on both types of reversals. These findings suggest that OFC and ABL serve partially overlapping roles in the use of incentive information that supports normal discrimination performance.     

The role of the insular cortex in taste function

In spite of over 30 years of research, the role of the Insular Cortex (IC) in taste memory still remains elusive. To study the role of the IC in taste memory, we used conditioned taste aversion (CTA) for two different concentrations of saccharin; 0.1% which is highly preferred, and 0.5% which is non-preferred. Rats that had been IC lesioned bilaterally with ibotenic acid (15 mg/ml) before CTA showed significant learning impairments for saccharin 0.1% but not for saccharin 0.5%. To test CTA memory retention, rats lesioned a week after CTA training became completely amnesic for saccharin 0.1% yet only mildly impaired for saccharin 0.5%. Interestingly, the resulting preference for either concentration matched that of IC lesioned animals when exposed to either saccharin solution for the first time, but not those of sham animals, implying that IC lesions after CTA for either saccharin solution rendered complete amnesia, irrespective of the original preference. Our data indicate that an intact IC is essential for CTA learning and retention, as well as for an early neophobic response, but not for taste preference itself. Our data supports a model where the IC is involved in general taste rejection.     

Ventral and dorsolateral regions of the midbrain periaqueductal gray (PAG) control different stages of defensive behavior: Dorsolateral PAG lesions enhance the defensive freezing produced by massed and immediate shock

Rats that receive nociceptive electric shock in an environment normally show the conditional fear-induced defensive response of freezing when returned to that environment. If several electric shocks are given in a massed manner they will condition less freezing than the same shocks given in a distributed manner. If a single shock is given immediately after placement in the chamber it does not support any conditioning, although the same shock given after a brief delay does. Electrolytic lesions of the dorsolateral periaqueductal gray (PAG), which damaged dorsomedial, dorsolateral, and lateral PAG, enhanced freezing under these conditions. Lesions of the ventral PAG, which caused extensive damage to the central gray below the aqueduct, reduced conditioning under the more optimal parameters (distributed or delayed shock). This was taken to indicate that both of these regions support different modes of defensive behavior and that when activated, the dorsolateral PAG inbits conditional fear-induced defensive behavior. © 1995 Wiley-Liss, Inc.     

Visual discrimination learning in rats with lesions of superior colliculus: Door-push and approach errors in modified jumping stand

It has been suggested that, for some species, lesions of the superior colliculus affect visual discrimination learning, but only in certain conditions: (a) when problems are first learnt only after operation, or (b) when discriminanda require detailed scanning, or (c) when “approach” responses to the discriminanda are measured, rather than the response of actually touching them. These suggestions were examined in rats learning visual discriminations in a modified jumping-stand apparatus, after sustaining large lesions of the superior colliculus (and in some cases also of the pretectum). The lesions produced open-field hyperactivity and reduced exploration, indicating effective tectal damage, but the rats learnt a series of difficult discriminations in a door-push task as fast as normal rats, and they did not make more approach errors. Their main abnormality in the discrimination apparatus was that they looked less often between the stimulus doors before stepping across to one of them from the central platform. It is suggested that in rats, as in other animals, lesions of the superior colliculus disrupt the control of scanning head and eye movements; in rats, however, such disruption need not affect discrimination learning (at least in some kinds of apparatus), possibly because the retina of the rat has a relatively poorly developed area centralis.     

Open Field Motor Patterns and Object Marking, but Not Object Sniffing, Are Altered by Ibotenate Lesions of the Hippocampus

Objectmarking and object sniffing were assessed in an open field during six 5-min trials in unoperated Long-Evans rats and rats with ibotenate lesions of the hippocampus and/or neocortex. Object marking was higher in hippocampally lesioned rats than in unoperated rats. Object marking did not differ between neocortically lesioned rats and unoperated rats. Object sniffing durations and visits did not differ between unoperated and hippocampally lesioned rats nor between unoperated and neocortically lesioned rats. A new object elicited longer sniffing by both unoperated and hippocampally lesioned rats. Neocortically lesioned rats did not show this effect. There were no effects of the new object on marking. Computerized tracing of open field paths revealed a smaller perimeter track for hippocampally lesioned rats than for unoperated rats. This difference reflected distinct ambulatory patterns. Hippocampally lesioned rats made stereotyped hind-limb pivots at each corner, while normal rats used forelimb pivots or reared and reoriented adjacent to the wall. Rearing was lower in hippocampally lesioned rats, and higher in neocortically lesioned rats, than in unoperated rats. These data indicate that investigative object behavior (sniffing) is resistant to the effects of hippocampal damage, while object-elicited marking and motoric output may be profoundly altered. The data on sniffing suggest either that (1) the noticeability of the objects used elicited investigative behaviors in hippocampally damaged rats comparable to those of novelty-induced exploration in normal rats or (2) object exploration is not used to create a spatial map, and, hence, not disturbed by hippocampal loss. Object marking may require spatial locale information to be exercised normally, or may index the mediation of an olfactory-modulated behavioral pattern through the hippocampal system.     

Lesions of the dorsal subiculum and the dorsal hippocampus impaired pattern separation in a task using distinct and overlapping visual stimuli

The contribution of the dorsal subiculum (DS) and of the dorsal hippocampus (DH) to memory for distinct and overlapping visual stimuli was examined. Rats with selective lesions of the DS or the DH were compared to sham-operated rats on a delayed matching-to-place task guided by distal visual cues in a modified radial-arm maze. Overlapping distal visual cues could be perceived from three arm entrances (adjacent arms) and a unique set of distal cues were more likely to be seen from the other two arm entrances (distinct arms). Rats with DS lesions were impaired on trials with baited adjacent arms, but not on trials with baited distinct arms. Rats with DH lesions were impaired on both types of trials. These results suggest that the DS and the DH are necessary for pattern separation and that they may have different contributions to memory.     

The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward

The hippocampus is believed to play a role in processing information relative to the context in which emotionally salient experiences occur but evidence on the specific contribution of the hippocampal dentate gyrus (DG) to these processes is limited. Here, we have used two classical behavioral paradigms to study the participation of the dorsal DG in context-conditioned reward and context-conditioned fear. Rats received intra-hippocampal vehicle or colchicine injections (4 microg/microl solution; 0.2 microl injections at 10 sites) that damaged the DG but spared other hippocampal subfields. In the first experiment, we used a place conditioning procedure pairing cocaine exposure (20 mg/kg, i.p.) with a specific context and vehicle treatment with another. While rats with sham lesions exhibited preference for the cocaine-paired context following conditioning, rats with lesions of the DG showed no evidence of cocaine-induced place preference. In the second experiment, rats with sham or colchicine lesions received a foot shock in a given context and conditioned freezing was measured upon reexposure to the shock-paired context (2, 24, 48 and 96 h after conditioning). Rats with sham lesions exhibited high levels of conditioned freezing when exposed to the conditioning context but rats with lesions of the DG showed impaired conditioning, behaving as controls that had experienced shock in a different context. These observations indicate that the integrity of the DG is essential for establishing a coherent representation of the context to which emotional experiences, either hedonic or aversive, are bound.     

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.     

The GM1 ganglioside hastens the reduction of hyperemotionality after septal lesions

The purpose of the present study was to assess the effects of ganglioside treatment on changes in emotional, activity, and avoidance behaviors following septal brain damage. Rats were treated with GM1-gangliosides either before and after septal lesions, or only after septal lesions and tested for emotionality on 10 consecutive days beginning on the second day after surgery. The ganglioside treatment decreased the emotionality of rats with septal damage on the first test day, and enhanced their rate of recovery to control levels of emotionality. Septal rats treated with gangliosides had activity, rearing, and avoidance behaviors equivalent to nontreated septal rats; however, lesioned rats treated with GM1 showed reduced intertrial crossings during avoidance conditioning. These results suggest that the changes in emotional behavior of septal rats treated with GM1 occur shortly after the lesion.     

Perirhinal cortex lesions impair context aversion learning

Rats with perirhinal cortex lesions were compared with sham controls on a conditional discrimination in which saccharin was paired with LiCl in context 1, but paired with saline in context 2. Perirhinal-lesioned rats were slightly slower to acquire the discrimination but reached control levels by the end of acquisition. Both groups showed transfer to familiar tap water, consuming less in context 1 than in context 2. Unlike sham rats, perirhinal rats failed to show an aversion to context 1 on a place choice test. These data provide neuroanatomical support for the postulated difference between Pavlovian conditioning and conditional learning.     

Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts

Rats have a natural tendency to spend more time exploring novel objects than familiar objects, and this preference can be used as an index of object recognition. Rats also show an exploratory preference for objects in locations where they have not previously encountered objects (an index of place memory) and for familiar objects in contexts different from those in which the objects were originally encountered (an index of context memory). In this experiment, rats with cytotoxic lesions of the hippocampal formation were tested on all three versions of the novelty-preference paradigm, with a 5-min retention interval between the familiarization and test phases. Rats with sham lesions displayed a novelty preference on all three trial types, whereas the rats with hippocampal lesions displayed a novelty preference on Object trials but did not discriminate between the objects on Place trials or Context trials. The findings indicate that hippocampal damage impairs memory for contextual or spatial aspects of an experience, whereas memory for objects that were part of the same experience are left relatively intact.