Involvement of the retrosplenial cortex in processing multiple conditioned stimuli

Lesions of retrosplenial cortex (RSP) disrupt spatial and contextual learning, suggesting that RSP may have a fundamental role in processing overlapping, or simultaneously presented stimuli. If so, then RSP lesions might also be expected to disrupt learning that requires the concurrent processing of phasic conditioned stimuli. In Experiment 1, rats were trained in a compound feature negative discrimination task in which a tone was presented and immediately followed by food on some trials, while on other trials a visual stimulus was simultaneously presented along with the tone and not reinforced. Normal rats learned to discriminate between the trials but RSP-lesioned rats exhibited low levels of conditioning on both types of trials. Experiment 2 demonstrated that this effect was not simply due to a general inability to form associations, since RSP-lesioned rats exhibited normal responding when the visual stimulus was presented alone and paired with food. These findings support the view that RSP has an important role in learning that involves the processing of simultaneously presented stimuli and have implications for understanding the functional relationship between the hippocampus and RSP.     

Early Pavlovian conditioning impairs later Pavlovian conditioning

Four experiments tested the effects in the rat of very early experience with stimuli to be used later for Pavlovian conditioning. Beginning on postnatal Day 12, prior to the development of substantial detection and effective perception of visual and auditory stimuli, rats were given five daily experiences with either lights or tones and a footshock known to be an effective unconditioned stimulus at these ages. Twenty-four hours after the last of these experiences, pairings of either the light or tone and the unconditioned stimulus were given with parameters established to yield a moderate degree of conditioning in untreated preweanlings (Experiment 1). Experiment 2 determined that early experience with paired or unpaired presentations of either the light or tone and the unconditioned stimulus resulted in a failure to condition to these same lights or tones on postnatal Day 17, although nontreated pups from the same litters conditioned quite effectively. Experiment 3 determined that this early conditioning experience with either paired or unpaired presentations of the lights or tones and the unconditioned stimulus yielded impaired conditioning on postnatal Day 17 in the alternative sensory modality as well, although again nontreated siblings conditioned quite effectively. Experiment 4 replicated the results of each of Experiments 2 and 3 and determined in addition that despite the impairment in conditioning that resulted from early paired or unpaired experience with the stimuli of conditioning, early experience with the individual stimuli of conditioning—with only the CS, the US, or the context—did not result in a similar impairment in conditioning. Although the results were unexpected, they may be understood in part in terms of intersensory competition during development, and there is precedent in the literature for similar interfering effects of early learning on later learning in a variety of species. © 1996 John Wiley & Sons, Inc.     

Conditioned hippocampal cellular response to a behaviorally silent conditioned stimulus.

Multiunit activity (MUA) was chronically recorded in the hippocampal CA3 field of rats using a blocking paradigm with conditioned suppression of lever pressing for food as the measure of conditioning. In Experiment 1, a classical blocking paradigm demonstrated the good conditionability of 2 stimuli (a light and a tone) and their respective ability to block each other. In Experiment 2, MUA was recorded in CA3 cells in rats submitted to a similar paradigm. Four groups received either tone (groups B and B1) or click (groups BC and B1C) conditioned stimulus (CS) presentations that were followed immediately by an electrical footshock (unconditioned stimulus, US). The rats were then given either 40 (groups B and BC) or 1 (groups B1 and B1C) tone + light-footshock presentations. During test sessions, the animals showed MUA responses to the added CS (light), with no conditioned suppression of lever presses occurring during CS presentations. The results of Experiment 3 strongly suggest that hippocampal increase in cellular activity to the light appeared at the first compound trial presentation. Conditioning to the light obtained by increasing the US intensity after the single compound trial suggests that the hippocampal response reflects a redundant CS-US association (light-shock). Long-term retention tests given 45 days after the end of conditioning revealed that behavioral and hippocampal responses could still be detected but only in response to the stimulus that had elicited a behavioral response during learning.     

Lesions of the middle cerebellar peduncle disrupt acquisition and retention of the rabbit's classically conditioned nictitating membrane response

Rabbits were classically conditioned to emit a nictitating membrane response (NMR) to either a light or tone conditioned stimulus (CS) paired with an eye shock unconditioned stimulus (UCS). They then received lesions of the middle cerebellar peduncle (MCP) or served as unoperated controls. Following surgery, they were given separate presentations of tone, light, and vibratory CSs, each paired with the eye shock UCS. In this way, conditioned responses (CR) to the previously trained light or tone served as a test of retention, whereas CRs to the remaining two conditioned stimuli (tone and vibratory or light and vibratory) served as a test of acquisition. The results of the study revealed that rabbits with complete lesions of the MCP showed disrupted acquisition and retention of the conditioned NMR to all stimuli, rabbits with partial MCP lesions also showed disrupted acquisition and retention to all CSs, but to a lesser degree, and animals with lesions that missed the MCP and unoperated controls both showed normal acquisition and retention of the conditioned NMR. These data are consistent with the view that the cerebellum is an essential part of the circuit for classical conditioning of the NM response and that information about CSs in the auditory, visual, and tactile modalities reach the cerebellum by way of the MCP.     

Ontogeny of eyeblink conditioning using a visual conditional stimulus

The developmental emergence of associative learning in rodents is determined by interactions among sensory, motor, and associative systems that are engaged in a particular experimental preparation (Carter & Stanton, 1996; Hunt & Campbell, 1997; Rudy, 1992). In fear conditioning, chemosensory, auditory, and visual cues emerge successively as effective conditional stimuli (CS) during postnatal ontogeny. In the present study, we begin to examine the generality of this principle of sensory system development for eyeblink conditioning, a form of associative learning that develops substantially later than conditioned fear (Carter & Stanton, 1996). We asked whether the developmental emergence of eyeblink conditioning to a visual CS occurs at an age that is the same or different from conditioning to an auditory CS. In Experiment 1, rat pups were trained on postnatal Day 17 or 24 with experimental parameters (and design) that were identical to our previous studies of eyeblink conditioning except that presentation of a light rather than a tone served as the CS. The outcome was also identical: no eyeblink conditioning on Day 17 and strong conditioning on Day 24. In Experiment 2, conditioning to tone versus light was directly compared by means of a discrimination learning design on postnatal Days 19, 21, 23, and 31. There was no evidence for differential development of auditory versus visual eyeblink conditioning. The difference between this outcome and previous ones involving conditioned fear (Hunt & Campbell, 1997; Rudy, 1992) suggests that principles concerning sensory maturation and learning may be different for early- versus late-developing associative systems.     

Multisensory warning signals: when spatial correspondence matters

We report a study designed to investigate the effectiveness of task-irrelevant unimodal and bimodal audiotactile stimuli in capturing a person’s spatial attention away from a highly perceptually demanding central rapid serial visual presentation (RSVP) task. In “Experiment 1”, participants made speeded elevation discrimination responses to peripheral visual targets following the presentation of auditory stimuli that were either presented alone or else were paired with centrally presented tactile stimuli. The results showed that the unimodal auditory stimuli only captured spatial attention when participants were not performing the RSVP task, while the bimodal audiotactile stimuli did not result in any performance change in any of the conditions. In “Experiment 2”, spatial auditory stimuli were either presented alone or else were paired with a tactile stimulus presented from the same direction. In contrast to the results of “Experiment 1”, the bimodal audiotactile stimuli were especially effective in capturing participants’ spatial attention from the concurrent RSVP task. These results therefore provide support for the claim that auditory and tactile stimuli should be presented from the same direction if they are to capture attention effectively. Implications for multisensory warning signal design are discussed.     

Ontogeny of eyeblink conditioning in the rat: Auditory frequency and discrimination learning effects

The present study sought to determine whether acoustic properties of the auditory conditioned stimulus (CS) or the use of a discrimination learning procedure would alter the emergence of eyeblink conditioning between postnatal Days 17 and 24 (Days 17–24) in the rat. In Experiment 1, we employed a 3 × 2 × 2 factorial design, involving pitch of the auditory CS (2.8, 5.0, and 9.0 kHz), training condition (paired vs. unpaired), and age (Days 17 or 24). Associative learning was evident at all tone frequencies on Day 24, but increased across frequencies on Day 17, although large age differences in conditioning remained at all tone frequencies. In Experiment 2, rat pups were trained to discriminate 2.8 versus 9.0-kHz tones on Day 17 or Day 24. Eyeblink conditioning increased with tone frequency on Day 24 but discriminative conditioning failed to appear on Day 17. These findings are discussed in relation to the role of auditory system maturation in the ontogeny of eyeblink conditioning. © 1995 Johnv Wiley & Sons, Inc.     

Arousal-related associative response characteristics of dorsal lateral geniculate nucleus neurons during acoustic Pavlovian fear conditioning

This research determined whether fear-conditioned, acoustic stimuli induce thalamic arousal reflected in associative responses in dorsal lateral geniculate nucleus (dLGN) neurons. Rabbits received a Pavlovian discriminative fear conditioning procedure in which one tone conditioned stimulus (CS +) was always paired with an aversive unconditioned stimulus (US) and another tone (CS-) was never paired with the US. Responses of single dLGN neurons to random CS+ and CS- presentations were then recorded. Nine of 15 recorded neurons demonstrated significantly greater firing during the CS+ versus the CS-. Their spontaneous activity demonstrated tonic firing during increased neocortical arousal and burst firing during decreased neocortical arousal. The results demonstrate that dLGN neurons show associative responses to fear-conditioned, acoustic stimuli and present a model for investigating the neural circuits by which such stimuli affect sensory processing at the thalamic level.     

CER to discrete and contextual stimuli: effects of stimulus modality depend on strain of rat

Strain differences in perception, cognition and affect have been found to interact with the effect of experimental treatments on learning. The present study tested Dark Agouti (DA) and Wistar rats in conditioning to discrete and contextual stimuli, for strain differences in conditioned emotional response (CER) and effects of stimulus modality. A Pavlovian trace-conditioning procedure was used in which a discrete target stimulus (flashing light or tone, counterbalanced across groups) was paired either contiguously or at a 30-s trace with footshock. Contextual conditioning was assessed using a background (continuously presented) experimental stimulus (alternate to that used as target). Experiment 1 used 5 x 0.5 mA, 0.5-s footshock and Experiment 2 used 2 x 0.5 mA, 1-s footshock. In both experiments, conditioning to the discrete (target) and background stimuli interacted with strain of rat and stimulus modality. For conditioning to the target stimulus, the trace-conditioning effect (of relatively greater suppression in contiguously conditioned than trace-conditioned groups) differed by stimulus and strain. It was greater for the Wistar strain with the flashing light stimulus and for the DA strain with the click stimulus (although the latter was not significant in Experiment 1). In addition, suppression to the background stimulus was affected by stimulus modality for the DA but not Wistar strain in both experiments. DAs conditioned more to the click than the light as background, whereas there was no difference by stimulus modality for Wistars, although the exact pattern of how this stimulus modality effect was mediated differed between experiments. These results demonstrate that stimulus modality can be an issue when considering apparent strain differences in conditioning.     

Dissociation of autonomic and behavioral components of conditioned fear during development in the rat

Classical conditioning of heart rate (HR) was examined in unrestrained preweanling and weanling (16-, 19-, 21-, 25-, and 28-day-old) rats, with tone and light as the conditioned stimuli (CS) and electric shock as the unconditioned stimulus. The conditioned cardiac response was a sustained deceleration in HR which did not emerge until Day 21 for the tone CS and until Day 28 for the light CS. In contrast, when suppression of a behavioral response (running in a straight alley for dry suckling as reward) was used as the index of conditioning, the suppressive effects of the CS were evident around Day 16 for the tone and around Day 19 for the light. These findings indicate that during ontogenesis (a) the behavioral and autonomic responses to the same conditioned stimulus do not develop at the same pace, (b) the emergence of conditioned responses to tone and light stimuli parallel the sequential order in which the relevant sensory modalities achieve maturity (first audition, next vision), and (c) there is no clear-cut interdependence between development of the HR orienting response and conditionability of HR because unconditioned cardiac deceleration to both auditory and visual stimuli first appears about Day 16 in the developing rat, well before conditioned HR responses can be established to either stimulus.     

Acute alcohol intoxication disrupts brightness but not olfactory conditioning in preweanling rats

The present experiments tested the effect of acute alcohol administration on Pavlovian conditioning of 21-day-old rats using conditioned stimuli of two different sensory modalities--olfaction, an early developing sensory capacity functional at birth, and vision, a later developing sensory system not becoming functional until approximately 15 days of age. Conditioning and testing were conducted between 30 and 60 min following gastric infusion with either physiological saline or a mildly intoxicating alcohol dose (1.5 g/kg body weight). Brain alcohol levels were observed to remain at a peak and stable concentration during this period (Experiment 1). Alcohol impaired acquisition or expression of conditioned aversions to a visual cue paired with footshock when presented either as a single-element conditioned stimulus or as part of an odor/visual compound stimulus (Experiment 2), but it had no discernible effect on conditioned aversions to an olfactory stimulus that had similarly been paired with footshock (Experiments 2 and 3). The results suggest that alcohol may impair some aspects of learning but spare others, depending perhaps on the particular sensory modality to be conditioned.     

A neuroleptic-like effect of ceronapril on latent inhibition.

Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contributions of the retrosplenial and posterior parietal cortices to cue-specific and contextual fear conditioning

The retrosplenial cortex (RSP) and the posterior parietal cortex (PPC) are the primary sources of cortical sensory input to the postrhinal cortex (POR) in rodents. Together, these areas compose a major corticohippocampal circuit that is involved in processing visuospatial information. The POR has been implicated in contextual learning and memory, consistent with the type of information presumably being processed by this region. By comparison, little is known about the role of the RSP or the PPC in contextual learning. In the present study, rats were trained either before or after surgery in a standard signaled fear conditioning task in which an auditory cue was paired with foot shock. Contextual fear and tone-specific fear were assessed in subsequent test sessions. In Experiment 1, electrolytic damage to the RSP either before or immediately after training impaired the expression of contextual fear but not tone-specific fear. In contrast, electrolytic damage to the PPC had no effect on conditional fear to the context or the tone in Experiment 2. These findings indicate that the RSP, but not the PPC, contributes to the processing of contextual information by the POR corticohippocampal processing stream.     

Novel factors contributing to the expression of latent inhibition

Behavioral and neural correlates of latent inhibition (LI) during eyeblink conditioning were studied in 2 experiments. In Experiment 1, rabbits (Oryctolagus cuniculus) were conditioned after 8 days of tone conditioned stimulus (CS) presentations or 8 days of context-alone experience. LI was seen in the CS-preexposed rabbits when a relatively intense (5 psi) airpuff unconditioned stimulus was paired with the CS. In Experiment 2, rabbits were given 0, 4, or 8 days of CS preexposures or context-alone experience. Hippocampal activity was monitored from the 8-day CS- or context-exposure rabbits. The LI effect was seen only in rabbits given 4 days of CS preexposure, thus suggesting that LI depended largely on the rate of acquisition in the context-preexposed control group. The neural recordings showed that the hippocampus was sensitive to the relative novelty of the stimuli and the overall context, regardless of whether exposure to stimuli and context promoted LI.     

Conditioning and contextual retrieval in hippocampal rats

The role of the hippocampus in associative learning was investigated in 3 experiments with rats as subjects. Hippocampal rats were impaired in the acquisition of conditioned responding both when food was signaled by the insertion of a lever (Experiment 1) and when the presentation of auditory or visual events served as the conditioned stimuli (Experiment 2). Experiment 2 also evaluated the suggestion that deficits in the acquisition of conditioned responding reflect the failure of hippocampal subjects to use contextual cues to retrieve associative information. This experiment showed that hippocampal rats were impaired in learning that a given stimulus was reinforced in Context A but nonreinforced in Context B. Experiment 3 demonstrated that hippocampal rats were unimpaired in learning a simple Pavlovian contextual discrimination. This pattern of results suggests that the hippocampus is involved in a higher order contextual retrieval process.     

Conditioned diminution of the unconditioned skin conductance response

During Pavlovian conditioning the expression of a conditioned response typically serves as evidence that an association between a conditioned stimulus (CS) and an unconditioned stimulus (UCS) has been learned. However, learning-related changes in the unconditioned response (UCR) produced by a predictable UCS can also develop. In the present study, we investigated learning-related reductions in the magnitude of the unconditioned skin conductance response (SCR). Healthy volunteers participated in a differential conditioning study in which one tone (CS+) was paired with a loud white-noise UCS and a second tone (CS-) was presented alone. In addition, probe trials that consisted of UCS presentations paired with the CS+ (CS + UCS) and CS- (CS - UCS), as well as presentations of the UCS alone were included to assess UCR diminution. SCR and participants' expectations of UCS presentation were monitored during conditioning. Greater diminution of the UCR was observed to the UCS when it followed the CS+ compared to when it followed the CS- or was presented alone. Further, UCR amplitude showed an inverse relationship with the participants' ratings of UCS expectancy. However, conditioned UCR diminution was also observed independent of differential UCS expectancies. Our findings demonstrate conditioned diminution of the unconditioned SCR. Further, these findings suggest that although UCR amplitude is modified by conscious expectations of the UCS, conditioned diminution of the UCR can be expressed independent of learning-related changes in these expectations.     

Potentiation of conditioned freezing following dorsomedial prefrontal cortex lesions does not interfere with fear reduction in mice

In Experiment 1, an auditory conditioned stimulus (CS) was paired with footshock, except when it was preceded by another stimulus (a visual conditioned inhibitor [CI]). After conditioning, all mice displayed less CS-evoked freezing when the CI-CS compound was presented than when the CS was presented alone. However, lesions of the dorsomedial prefrontal cortex (dmPFC) potentiated CS-evoked freezing on each of the 2 sessions (i.e., CI CS and CS alone). In Experiment 2, mice were submitted to fear extinction (CS-alone presentation for 3 days). Lesioned mice exhibited a higher level of freezing behavior than controls on each of the 3 sessions. However, lesioned mice and controls displayed the same rate of reduction of freezing over the 3 days of extinction. These data in mice support previous studies in rats, which suggests that the dmPFC is not critical for either conditioned inhibition or extinction of acquired freezing behavior.     

Eyeblink conditioning in the rabbit (Oryctolagus cuniculus) with stimulation of the mystacial vibrissae as a conditioned stimulus.

Eyeblink conditioning is a well-understood paradigm for the study of learning and memory and has been successfully employed with the use of auditory and visual conditioned stimuli (CSs). In this study, vibrotactile stimulation of the mystacial vibrissae was examined as an alternative CS in the rabbit (Oryctolagus cuniculus). The technique is described and acquisition of eyeblink conditioning (EBC) with stimulation of a single row of vibrissae in a delay paradigm is reported. Extinction of EBC with presentation of the CS alone is demonstrated, as well as reacquisition with stimulation of a single whisker. Finally, control experiments ensure that the CS has no auditory components. Ipsilateral presentation of the CS and airpuff is a more effective combination for training than contralateral presentations. Vibrotactile stimulation of the vibrissae as a CS will enable further examination of the neural correlates of learning in a well-characterized sensory system.     

Conditional discrimination learning in patients with bilateral medial temporal lobe amnesia

The ability of bilateral medial temporal lobe amnesic patients (MT; n=8) and normal participants (NC; n=8) to acquire a conditional discrimination in trace and delay eyeblink conditioning paradigms was investigated. Experiment 1 assessed trace conditional discrimination learning by using a light conditional stimulus (S+/S-) and tone conditioned stimulus (CS) separated by a 1-s trace. NCs responded differentially on S+ trials (mean percent conditioned responses=66) versus S- trials (30). Whereas MTs were impaired in their acquisition of the conditional discrimination (S+ =51, S- =43). In Experiment 2, the temporal separation was eliminated. NCs acquired the conditional discrimination (S+ =70, S- =29). MTs were unable to respond differentially (S+ =42, S- =37). The findings indicate that the hippocampal system is essential in acquiring a conditional discrimination, even in a delay paradigm.     

Immunohistochemical assessment of mesotelencephalic dopamine activity during the acquisition and expression of Pavlovian versus instrumental behaviours

Dopaminergic activity during Pavlovian or instrumental learning in key target regions of the mesotelencephalic dopamine system was investigated immunohistochemically using antibodies raised against glutaraldehyde-conjugated dopamine. Experiment 1 examined dopamine immunoreactivity during acquisition of a Pavlovian conditioned-approach response. Observations were taken at three stages of learning: initial, intermediate and asymptotic; each with a conditioned stimulus+ (CS+) group for whom visual or auditory stimuli immediately preceded an unconditioned stimulus (sucrose), and a conditioned stimulus- (CS-) group for whom stimuli and the unconditioned stimulus were unpaired. Animals learned to approach the alcove during CS+ presentations, whilst approach behaviour of the CS- group remained low. In general, target regions exhibiting a dopaminergic reaction responded maximally during the intermediate stage of acquisition, and were less responsive initially, and not responsive at all at asymptote. Specifically, the pattern of dopaminergic response was: shell more than core of the nucleus accumbens; prefrontal cortex, central and basolateral nuclei of the amygdala also significantly responsive. Mediodorsal and laterodorsal striatal regions were reactive only very early in training. Experiment 2 examined dopaminergic reaction following acquisition of a novel conditioned instrumental response. The conditioned response+ (CR+) group responded at a much higher rate on the lever for which unconditioned stimulus-associated stimuli were presented, than on the control lever. The conditioned response- (CR-) group responded at a low rate on both levers. In contrast with experiment 1, the most responsive regions were the core of the nucleus accumbens, medial prefrontal cortex and basolateral area of the amygdala. Thus, the acquisition, but not expression of Pavlovian associations activated dopamine within several key target regions of the mesotelencephalic dopamine system, and preferentially within the shell rather than core of the nucleus accumbens. By contrast, acquisition of a novel instrumental response preferentially activated the core of the nucleus accumbens, and basolateral area of the amygdala. These data carry significant implications for the potential role of these regions in learning and memory.