Effects of stimulus preexposure on the generalization of conditioned taste aversions in infant rats

Generalization of a conditioned taste aversion in infant rats and how this is affected by stimulus preexposure was investigated in a series of experiments. In Experiment 1 generalization of a conditioned aversion between two tastes (sweet and salty) was found, and the effect of tastes preexposure was a reduction in generalization (Experiment 2). However, when these tastes were combined with a common taste (acid) that was less (Experiment 3) or more intense (Experiment 3b), the effect of stimulus preexposure was a stronger generalization of the conditioned aversion. In this case, a reduction on generalization was again observed by increasing the number of preexposure trials to the taste compounds (Experiment 4). In all cases the generalization levels were directly related to the effect of stimulus preexposure on the acquisition rate of conditioning. It can be concluded that, with the appropriate parameters, a reduction of generalization of a conditioned taste aversion can be obtained after taste exposure in preweanling rats.     

Bilateral destruction of neocortical and perirhinal projection targets of the acoustic thalamus does not disrupt auditory fear conditioning.

The present study examined whether complete bilateral destruction of auditory cortex would interfere with auditory fear conditioning in rats. Complete destruction of auditory cortex required lesions of temporal neocortical and perirhinal periallocortical areas. Fear conditioning was assessed by measuring freezing and arterial pressure responses elicited by an acoustic stimulus after pairing with footshock. Animals with complete bilateral lesions of auditory cortex showed conditioned arterial pressure and freezing responses comparable to those of unoperated controls. In contrast, bilateral destruction of the acoustic thalamus interfered with the conditioning of both responses. These results demonstrate that the auditory cortex is not required for the conditioning of fear responses to simple acoustic stimuli and add to the growing body of evidence that fear conditioning can be mediated by subcortical (amygdaloid) projections of the acoustic thalamus.     

The role of perirhinal cortex in visual discrimination learning for visual secondary reinforcement in rats

Perirhinal cortex in monkeys has been thought to be involved in visual associative learning. The authors examined rats' ability to make associations between visual stimuli in a visual secondary reinforcement task. Rats learned 2-choice visual discriminations for secondary visual reinforcement. They showed significant learning of discriminations before any primary reinforcement. Following bilateral perirhinal cortex lesions, rats continued to learn visual discriminations for visual secondary reinforcement at the same rate as before surgery. Thus, this study does not support a critical role of perirhinal cortex in learning for visual secondary reinforcement. Contrasting this result with other positive results, the authors suggest that the role of perirhinal cortex is in "within-object" associations and that it plays a much lesser role in stimulus-stimulus associations between objects.     

Stimulus preexposure reduces generalization of conditioned taste aversions between alcohol and non-alcohol flavors in infant rats

Results of 3 experiments showed that infant rats (age 13-17 days) generalize conditioned taste aversions between alcohol and non-alcohol tastes such as a mixture of sucrose and quinine, apple cider vinegar, or coffee. Nonreinforced preexposure to those tastes reduced generalized aversions between them. Generalization between alcohol and sucrose-quinine was reduced not only after preexposure to both tastes, but also when only the nonconditioned taste was preexposed, whereas with alcohol and vinegar, both tastes had to be preexposed to obtain that effect. In no case was generalization reduced when only the to-be-conditioned taste was preexposed. Previous experience with alcohol alone, as well as with similar gustatory stimuli, may enhance subjects' ability to differentiate them during infantile stages in rats.     

Perirhinal cortex lesions impair simultaneous but not serial feature-positive discrimination learning

The role of the perirhinal cortex in discriminative eyeblink conditioning was examined by means of feature-positive discrimination procedures with simultaneous (A-/XA+) and serial (A-/X-->A+) stimulus compounds. Lesions of the perirhinal cortex severely impaired acquisition of simultaneous feature-positive discrimination but produced no impairment in serial feature-positive discrimination. The results suggest that the perirhinal cortex plays a role in discriminative eyeblink conditioning by resolving ambiguity in discriminations with overlapping stimulus elements.     

Spatial pattern of BOLD fMRI activation reveals cross-modal information in auditory cortex

Recent findings suggest that neural representations in early auditory cortex reflect not only the physical properties of a stimulus, but also high-level, top-down, and even cross-modal information. However, the nature of cross-modal information in auditory cortex remains poorly understood. Here, we used pattern analyses of fMRI data to ask whether early auditory cortex contains information about the visual environment. Our data show that 1) early auditory cortex contained information about a visual stimulus when there was no bottom-up auditory signal, and that 2) no influence of visual stimulation was observed in auditory cortex when visual stimuli did not provide a context relevant to audition. Our findings attest to the capacity of auditory cortex to reflect high-level, top-down, and cross-modal information and indicate that the spatial patterns of activation in auditory cortex reflect contextual/implied auditory information but not visual information per se.     

Pattern separation deficits may contribute to age-associated recognition impairments

Normal aging is associated with impairments in stimulus recognition. In the current investigation, object recognition was tested in adult and aged rats with the standard spontaneous object recognition (SOR) task or two variants of this task. On the standard SOR task, adult rats showed an exploratory preference for the novel object over delays up to 24 h, whereas the aged rats only showed significant novelty discrimination at the 2-min delay. This age difference appeared to be because of the old rats behaving as if the novel object was familiar. To test this hypothesis directly, rats participated in a variant of the SOR task that allowed the exploration times between the object familiarization and the test phases to be compared, and this experiment confirmed that aged rats falsely "recognize" the novel object. A final control examined whether or not aged rats exhibited reduced motivation to explore objects. In this experiment, when the environmental context changed between familiarization and test, young and old rats failed to show an exploratory preference because both age groups spent more time exploring the familiar object. Together these findings support the view that age-related impairments in object recognition arise from old animals behaving as if novel objects are familiar, which is reminiscent of behavioral impairments in young rats with perirhinal cortical lesions. The current experiments thus suggest that alterations in the perirhinal cortex may be responsible for reducing aged animals' ability to distinguish new stimuli from ones that have been encountered previously.     

The perirhinal cortex of the rat is necessary for spatial memory retention long after but not soon after learning

Many observations in humans and experimental animals support the view that the hippocampus is critical immediately after learning in order for long-term memory formation to take place. However, exactly when the medial temporal cortices adjacent to the hippocampus are necessary for this process to occur normally is not yet well known. Using a spatial task, we studied whether the perirhinal cortex of rats is necessary to establish representations in long-term memory. Results showed that, in a spatial task sensitive to hippocampal lesions, control and perirhinal lesioned rats can both learn at the same rate (Experiment 1). Interestingly, a differential involvement of the perirhinal cortex in memory retention was observed as time passes after learning. Thus, 24 days following the end of learning, lesioned and control rats remembered the task perfectly as measured by a retraining test. In contrast, 74 days after the learning the perirhinal animals showed a profound impairment in the retention of the spatial information (Experiment 2). Taken together, these results suggest that the perirhinal region is critical for the formation of long-term spatial memory. However, its contribution to memory formation and retention is time-dependent, it being necessary only long after learning takes place and not during the phase immediately following acquisition.     

Interaction between amygdala and neocortical inputs in the perirhinal cortex

The rhinal cortices play a critical role in high-order perceptual/mnemonic functions and constitute the main route for impulse traffic to and from the hippocampus. However, previous work has revealed that neocortical stimuli that activate a large proportion of perirhinal neurons are unable to discharge entorhinal cells. In search of mechanisms that might facilitate impulse transfer from the neocortex to the entorhinal cortex, we have examined changes in excitability produced by activation of the lateral amygdala (LA) in isoflurane-anesthetized animals. LA stimulation activated a large proportion of peri- and entorhinal neurons. However, conditioning LA stimuli did not increase the ability of neocortical inputs to activate entorhinal cells even though such pairing produced marked increases in neocortically evoked field potentials and orthodromic firing in the perirhinal cortex. Moreover, increased neocortically evoked perirhinal field potentials and unit responses persisted when the conditioning LA shock was replaced by another neocortical stimulus at the same or at a different site as the testing shock. This perirhinal paired-pulse facilitation (PPF) was maximal with interstimulus intervals of approximately 100 ms. Intracellular recordings of perirhinal neurons revealed that the PPF was generally associated with a rapid shift in the balance between inhibition and excitation, leading to an overall increase in perirhinal responsiveness. The significance of these findings for the role of the perirhinal cortex is discussed.     

Role of the medial prefrontal cortex in acquired distinctiveness and equivalence of cues

In the present study, the authors examined the role of the medial prefrontal cortex in acquired equivalence and distinctiveness of cues. Rats were placed in 4 experimental contexts (A, B, C, and D) where they received presentations of 2 auditory stimuli (X and Y). In Contexts A and B, X was paired with food and Y was not, whereas in Contexts C and D, Y was paired with food and X was not. Rats that received sham lesions and those with lesions of the medial prefrontal cortex acquired this configural discrimination equally readily. Rats then received many pellets in A but not in C. After this training, sham-lesion rats exhibited more magazine activity in B than in D (an acquired distinctiveness/acquired equivalence effect), whereas those with medial prefrontal cortex lesions did not. These results indicate that the medial prefrontal cortex is involved in the process by which experience with stimuli influences the degree of generalization between them.     

大鼠吻侧前扣带皮层的传入投射纤维联系——荧光金逆行追踪法研究

本文采用荧光金(FG)逆行束路追踪技术研究了大鼠前扣带皮层吻侧(rostralanteriorcingulatecortex,rACC)的传入投射纤维联系。将0.2μl的3%荧光金注入到大鼠单侧rACC,7d后灌注取材,将切片贴于载玻片上,在荧光显微镜下观察FG标记神经元的分布。FG标记神经元主要位于注射区同侧的许多皮层和皮层下结构,如丘脑中线核群和板内核群、杏仁核、次级视皮层、次级听皮层、外嗅皮层和嗅周皮层等。上述结果表明rACC不但接受来自丘脑的伤害性信息传入,也接受来自视、听、嗅皮层等的环境信息的传入。本研究的结果为rACC参与痛的情绪反应提供了形态学证据。     

Generalization of conditioned suppression during salicylate-induced phantom auditory perception in rats.

Tonal frequency generalization was examined in a total of 114 pigmented male rats, 60 of which were tested under the influence of salicylate-induced phantom auditory perception, introduced before or after lick suppression training. Thirty control subjects received saline injections, and the remaining 24 subjects served as noninjected controls of tonal background effects on generalization. Rats were continuously exposed to background noise alone or with a superimposed tone. Offset of background noise alone (Experiment I), or combined with onset or continuation of the tone (Experiments II and III) served as the conditioned stimulus (CS). In Experiment I, tone presentations were introduced only after suppression training. Depending on the time of salicylate introduction, a strong and differential influence on generalization gradients was observed, which is consistent with subjects' detection of salicylate-induced, high-pitched sound. Moreover, when either 12- or 3 kHz tones were introduced before or after Pavlovian training to mimic salicylate effects in 24 rats, the distortions in generalization gradients resembled trends obtained from respective salicylate injected groups. Experiments II and III were aimed at evaluating the masking effect of salicylate-induced phantom auditory perception on external sounds, with a 5- or a 10-kHz tone imposed continuously on the noise or presented only during the CS. Tests of tonal generalization to frequencies ranging from 4- to 11- kHz showed that in this experimental context salicylate-induced perception did not interfere with the dominant influence of external tones, a result that further strengthens the conclusion of Experiment I.     

Perirhinal cortical kindling in rats with genetic absence epilepsy

Two genetic models of absence epilepsy, GAERS and WAG/Rij rat strains, are resistant to progression of partial seizures induced by amygdaloid or hippocampal kindling. Perirhinal cortex is one of the crucial areas for the secondary generalization of partial seizures. Therefore we focused on perirhinal cortical kindling in both epileptic rat strains and examined whether the resistance to limbic epilepsy is restricted to the amygdala and hippocampus or whether it can also occur with perirhinal cortical kindling. The mean afterdischarge (AD) thresholds were significantly higher in WAG/Rij and GAERS compared to the Wistar rats. Analysis of the rate of perirhinal cortical kindling for the 3 strains indicated highly significant differences. The mean number of stimulations for the development of the first stage 2, 3, 4 or 5 seizures was significantly higher in WAG/Rij and GAERS groups than in Wistar rats. Further, the cumulative total duration and number of SWDs increased during the first epoch of the post-stimulation period at the first stage 2 and 4/5 seizures in the WAG/Rij and GAERS rats compared to the pre-stimulation period. The higher AD threshold and delays to all stages of kindling in WAG/Rij and GAERS indicate that the perirhinal cortex is a part of the circuits involved in the kindling resistance in genetic models of absence epilepsy.     

Neurotoxic lesions of the rat perirhinal cortex fail to disrupt the acquisition or performance of tests of allocentric spatial memory

Rats with neurotoxic lesions of the perirhinal cortex (n = 9) were compared with sham controls (n = 14) on a working memory task in the radial arm maze. Rats were trained under varying levels of proactive interference and with different retention intervals. Finally, performance was assessed when the maze was switched to a novel room. None of these manipulations differentially impaired rats with perirhinal lesions. Rats were next trained on delayed matching-to-place in the water maze. Even with retention delays of 30 min, there was no evidence of a deficit. Although interactions between the perirhinal cortex and hippocampus may be important for integrating object-place information, the perirhinal cortex is often not necessary for tasks that selectively tax allocentric spatial memory.     

The lesional and epileptogenic consequences of lithium-pilocarpine-induced status epilepticus are affected by previous exposure to isolated seizures: effects of amygdala kindling and maximal electroshocks

In temporal lobe epilepsy, the occurrence of seizures seems to correlate with the presence of lesions underlying the establishment of a hyperexcitable circuit. However, in the lithium-pilocarpine model of epilepsy, neuronal damage occurs both in the structures belonging to the circuit of initiation and maintenance of the seizures (forebrain limbic system) as in the propagation areas (cortex and thalamus) and in the circuit of remote control of seizures (substantia nigra pars reticulata). To determine whether or not we could protect the brain from lesions and epileptogenesis induced by status epilepticus and identify cerebral structures involved in the genesis of epilepsy, we studied the effects of the chronic exposure to non-deleterious seizures, either focalized with secondary generalization (amygdala kindling, kindled-pilocarpine rats), or primary generalized (ear-clip electroshocks, electroshock-pilocarpine rats) on neuronal damage and epileptogenesis induced by lithium-pilocarpine status epilepticus. These animals were compared to rats subjected to status epilepticus but not pretreated with seizures (sham-kindled-pilocarpine or sham-electroshock-pilocarpine rats). Compared to sham-pilocarpine rats, neuronal damage was prevented in the limbic system of the kindled-pilocarpine rats, except in the hilus of the dentate gyrus and the entorhinal cortex, while it was enhanced in rats pretreated with electroshocks, mainly in the entorhinal and perirhinal cortices. Most sham-kindled- and sham-electroshock-pilocarpine rats (92-100%) developed recurrent seizures after a silent period of 40-54days. Likewise, all kindled-pilocarpine rats developed spontaneous seizures after the same latency as their sham controls, while only two of 10 electroshock-pilocarpine rats became epileptic after a delay of 106-151days.The present data show that the apparent antiepileptic properties of electroshocks correlate with extensive damage in midbrain cortical regions, which may prevent the propagation of seizures from the hippocampus and inhibit their motor expression. Conversely, the extensive neuroprotection of the limbic system but not the hilus and entorhinal cortex provided by amygdala kindling does not prevent epileptogenesis. Thus, the hilus, the entorhinal and/or perirhinal cortex may be key structure(s) for the establishment of epilepsy.     

Contributions of postrhinal and perirhinal cortex to contextual information processing

The role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information was examined with Pavlovian fear conditioning. Rats with electrolytic or neurotoxic lesions of the POR or PER were tested in 2 contextual fear conditioning paradigms. In Experiment 1, electrolytic lesions of the POR or PER produced impairments in contextual fear conditioning but not in conditioning to a phasic auditory conditioned stimulus. Neurotoxic lesions of the POR or PER likewise resulted in anterograde (Experiment 2) and retrograde (Experiment 3) deficits in fear conditioning to the training context in an unsignaled shock paradigm. The results suggest that operations performed on sensory information by the POR and PER are necessary to support contextual learning.     

A gradient of plasticity in the amygdala revealed by cortical and subcortical stimulation, in vivo

Projections to the amygdala from various cortical and subcortical areas terminate in different nuclei. In the present study we examined long-term potentiation of synaptic transmission in the lateral or the basal amygdaloid nuclei by theta burst stimulation of thalamic vs. cortical sensory projections in the anesthetized rat. Although both the medial geniculate nucleus and the dorsal perirhinal cortex have direct projections to lateral nucleus, only the thalamic stimulation induced long-term potentiation of field potentials recorded in the lateral nucleus. In contrast, cortical (ventral perirhinal cortex) but not thalamic stimulation induced long-term potentiation in the basal nucleus.Since the thalamic pathway is believed to process simple/unimodal stimulus features, and the perirhinal cortex complex/polymodal sensory representations, the dissociation of long-term potentiation in lateral and basal nuclei suggests that the basal nucleus may serve as an amygdaloid sensory interface for complex stimulus information similar to the role of the lateral nucleus in relation to relatively simple representations. Thus plasticity of simple and complex representations may involve different amygdala inputs and circuits.     

Amygdala input promotes spread of excitatory neural activity from perirhinal cortex to the entorhinal-hippocampal circuit

A number of sensory modalities most likely converge in the rat perirhinal cortex. The perirhinal cortex also interconnects with the amygdala, which plays an important role in various motivational and emotional behaviors. The neural pathway from the perirhinal cortex to the entorhinal cortex is considered one of the main paths into the entorhinal-hippocampal network, which has a crucial role in memory processes. To investigate the potential associative function of the perirhinal cortex with respect to sensory and motivational stimuli and the influence of the association on the perirhinal-entorhinal-hippocampal neurocircuit, we prepared rat brain slices including the perirhinal cortex, entorhinal cortex, hippocampal formation, and amygdala. We used an optical imaging technique with a voltage-sensitive dye to analyze 1) the spatial and functional distribution of inputs from the lateral nucleus of the amygdala to the perirhinal cortex; 2) the spread of neural activity in the perirhinal cortex after layers II/III stimulation, which mimics sensory input to the perirhinal cortex; and 3) the effect of associative inputs to the perirhinal cortex from both the lateral amygdaloid nucleus and layers II/III of the perirhinal cortex on the perirhinal-entorhinal-hippocampal neurocircuit. Following stimulation in the superficial layers of the perirhinal cortex, electrical activity only propagated into the entorhinal cortex when sufficient activation occurred in the deep layers of perirhinal area 35. We observed that single stimulation of either the perirhinal cortex or amygdala did not result in sufficient neural activation of the deep layers of areas 35 to provoke activity propagation into the entorhinal cortex. However, the deep layers of area 35 were depolarized much more strongly when the two stimuli were applied simultaneously, resulting in spreading activation in the entorhinal cortex. Our observations suggest that a functional neural basis for the association of higher-order sensory inputs and emotion-related inputs exists in the perirhinal cortex and that transfer of sensory information to the entorhinal-hippocampal circuitry might be affected by the association of that information with incoming information from the amygdala.     

Perirhinal cortex and place-object conditional learning in the rat

The present study examined whether excitotoxic lesions of the perirhinal cortex can affect acquisition of a place-object conditional task in which object and spatial information must be integrated. Testing was carried out in a double Y-maze apparatus, in which rats learned a conditional rule of the type, "In Place X, choose Object A, not Object B (A+ vs. B-); in Place Y, choose Object B, not Object A (A- vs. B+)." Perirhinal cortex lesions significantly impaired acquisition of this task while sparing performance of an allocentric spatial memory task performed in a radial arm maze. Perirhinal cortex lesions also had no apparent effect on a 1-pair object discrimination task performed in the double Y maze or on retention and acquisition of 4-pair concurrent discrimination problems performed in a computer-automated touch screen testing apparatus. The results suggest that, although the perirhinal cortex and hippocampus can be functionally dissociated, their normal mode of operation includes the integration of object and spatial information.     

What have ablation studies told us about the neural substrates of stimulus memory?

Recent studies examining the neural substrates of stimulus memory in monkeys have found that the ‘rhinal’ cortex (i.e. the entorhinal and perirhinal cortex), makes a pivotal contribution to memory. Indeed, the rhinal cortex appears to be the only critical medial temporal lobe structure for stimulus recognition and certain kinds of associative memory as well. Thus, the mnemonic contributions of certain medial temporal structures, especially the amygdala and hippocampus, appear to have been overemphasized, and should be reconsidered.