Role of the prefrontal--thalamic axis in classical conditioning.

The major conclusion to be drawn from the above-described research on the role of the PFCag in classical conditioning is obviously that it plays a primary and perhaps necessary role in the establishment of visceral cues associated with exposure to classical conditioning contingencies. Specifically, these visceral changes appear to be of an inhibitory character. This is significant, since we have postulated that inhibitory cardiac changes invariably accompany initial processing of sensory stimuli for informational value. Such visceral changes are thus not epiphenomena associated with other simultaneously occurring physiological events. A variety of lesion experiments implicate the PFCm as a central structure in this process, since damage to this area greatly attenuates, and in the case of hypothalamic knife cuts, completely eliminates learned bradycardia. Neuroanatomical tract-tracing experiments revealed that the PFCm and lag have direct projections to the NTS and DVM in the dorsomedial medulla and the nucleus ambiguous in the ventral medulla, all of which provide medullary output control of visceral activities. The nucleus ambiguous and DVM have been specifically implicated in vagal control in the rabbit (Ellenberger et al., 1983). Electrical stimulation of the PFCm provides additional evidence that this area of the brain participates in parasympathetic activities, including cardiac inhibition, since stimulation of the entire MD projection cortex, including the PFCm, produces HR decelerations accompanied by depressor responses. However, since lesions of the Iag produced relatively little effect on conditioned bradycardia, this part of the PFCag does not appear to play a major role in the development of conditioned bradycardia. Electrophysiological recording studies, including both multiple unit as well as extracellular single unit studies reinforce these conclusions. A short latency (40-180 msec) CS-evoked increase in MUA was recorded from cells in both the dorsomedial as well as central PFCm. The magnitude of these CS-evoked neuronal changes (a) was correlated with the magnitude of concomitantly occurring conditioned bradycardia; (b) was trial-related; (c) was not obtained in a similar pseudoconditioning group; and (d) declined to pretraining levels during subsequent experimental extinction. Similar, but not identical, CS-evoked changes in neuronal activity were recorded from MD. Although tone-evoked increases in MUA were also obtained from the Iag, this activity did not show the characteristics of associative learning. Single unit analysis also suggests the importance of the PFCm in elicitation of conditioned bradycardia.(ABSTRACT TRUNCATED AT 400 WORDS)

Single-unit activity in the dorsomedial prefrontal cortex during the expression of discriminative bradycardia in rabbits.

Much recent evidence suggests that the medial prefrontal cortex (PFCm) participates in the development and/or expression of learned, primary bradycardiac adjustments in rabbits. Accordingly, the present experiments were undertaken to determine whether single-unit activity in the precentral agranular and anterior cingulate regions of the PFCm is systematically affected by differential aversive Pavlovian conditioning and, if so, whether such activity is correlated with concomitant heart rate (HR) variables. In these studies, extracellular recordings were made during a training procedure that involved two distinctive, tone conditioned stimuli (CSs); one of these (CS+) was often paired with eye-shock (unconditioned stimulus, US), whereas the other (CS-) was never so paired. Of the 100 spontaneously-active cells whose activity was so evaluated, 74 were found to be tone-responsive and could be classified as belonging to one of 5 subpopulations on the basis of their specific patterns of evoked changes in discharge; additional data suggested that these cells were also generally responsive to the eye-shock US. Regarding the effects of training, the vast majority of cells in these subpopulations showed greater evoked activity changes on CS+, as opposed to CS-, trials, irrespective of the sign (i.e. increase and/or decrease) of their responses. This finding was not confounded by differences in baseline activity preceding CS+ vs CS- trials, which was generally characterized as being both irregular and unrelated to concomitant HR variables; nor could it be attributed to unconditioned responses biases. Thus, the discriminative activity patterns of these cells appeared to reflect the differential Pavlovian contingencies in effect. Moreover, approximately half of these cells exhibited tone-evoked activity changes that were reliably correlated with concomitant HR changes on a trial-by-trial basis. Consequently, the present data indicate that training-induced changes in the CS-evoked activity of PFCm cells are significantly related to aversively conditioned bradycardia in rabbits.

Amygdaloid central nucleus neuronal activity accompanying pavlovian cardiac conditioning: effects of naloxone.

Rabbits were treated intravenously with either naloxone-HCl (0.5 mg/kg) or saline vehicle prior to aversive pavlovian conditioning and extinction training; heart rate conditioned responses and concomitant multiple-unit activity in the amygdaloid central nucleus were compared. Multiple-unit activity evoked by the conditioned stimulus increased during conditioning and decreased during extinction in saline-treated rabbits; naloxone treatment attenuated evoked neuronal activity but enhanced bradycardiac conditioned responses. Correlational analysis showed that, in 3 of 8 animals in the saline-treated group, larger increases in multiple-unit activity corresponded to smaller bradycardiac responses. Naloxone treatment did not alter the frequency or magnitude of this relationship, but it did augment the training-induced decrements in evoked neuronal activity at placements that were correlated with bradycardiac response magnitude. These data suggest that conditioned decreases in central nucleus neuronal activity normally may serve to disinhibit vagal mechanisms as conditioned bradycardia develops and that the neural circuits that produce these responses are sensitive to opioid modulation.

Divergent effects of deep cerebellar lesions on two different conditioned somatomotor responses in rabbits.

Rabbits with bilateral lesions involving either the anterior interpositus nucleus or the superior cerebellar peduncle were subjected to appetitive Pavlovian conditioning training involving repeated pairings of a 2-s tone with an intraoral pulse of water. Such training resulted in the rapid development of robust, anticipatory jaw-movement responses (JM CRs) to the tone, and, in fact, the performance levels exhibited by lesioned animals did not differ significantly from those observed in sham-operated control animals. Additional experiments involving unpaired tone/water presentations confirmed the associative character of the JM CRs. On the other hand, lesioned animals exhibited severe bilateral performance deficits when later subjected to aversive eyeblink conditioning procedures, consistent with previous findings. The present results thus suggest that the interpositus nucleus is not an essential neural substrate for the development of appetitively conditioned masticatory responses.

Neuronal correlates of classically conditioned bradycardia in the rabbit: studies of the medial prefrontal cortex.

Multiple-unit activity (MUA) in the agranular medial prefrontal cortex (PFC) was recorded in conscious rabbits during a classical conditioning procedure involving repeated pairings of a 4-s tone conditioned stimulus (CS) with eye shock. Prior to behavioral training, significant tone-evoked increases in prefrontal MUA were observed; the magnitude of this evoked cortical discharge declined with repeated presentations of the tone alone. However, the first few paired presentations of tone with eye shock served to rapidly reestablish the evoked activity, and subsequent pairings resulted in a significant enhancement of CS-evoked discharge, relative to pretraining response levels. These associative training-induced changes in prefrontal MUA appeared to parallel the development of bradycardiac conditioned responses (CRs), and, in fact, significant correlations between the neuronal and behavioral responses were observed. In contrast to these associative effects, non-associative training procedures involving either unpaired presentations of tone and eye shock or repeated presentations of the tone alone resulted in progressive attenuation of tone-evoked MUA, relative to pretraining levels. We had previously reported that bilateral destruction of the medial PFC seriously compromises the development of discriminative heart rate CRs in the rabbit. In light of this finding, our present results lend further support to the suggestion that associative training-induced changes in CS-evoked neuronal activity in this cortical region contribute, at least in part, to the development of learned cardiovascular adjustments in this animal.

Modification of neuronal discharge along the ascending tectofugal pathway during visual conditioning.

Visually conditioned heart-rate change in the pigeon has been developed as vertebrate model system for analysis of associative learning. The visual pathways transmitting the conditioned stimulus information were identified, and neurophysiological analyses during conditioning were then undertaken to determine if these pathways behave merely as input lines or undergo training-induced modification. After finding that the retinal output is invariant with training, we investigated the central visual pathways, beginning with the tectofugal pathway. During conditioning single neurons in the nucleus rotundus and ectostriatum, the thalamic and telencephalic relays of the tectofugal pathway, showed enhancement of their phasic light-evoked responses. In contrast, the initial phasic responses attenuated during non-associative training. The rate at which these discharge modifications developed paralleled the development of the behavioral response. Thus, the tectofugal pathway shows plasticity during conditioning and does not behave merely as an input channel for the conditioned stimulus.

Conditioning of the rabbit's nictitating membrane response to a CSA-CSB-US serial compound: manipulations of CSB's associative character.

Response acquisition to a trace conditioned stimulus (CSA) can be facilitated by insertion of a second stimulus (CSB) at the end of the trace interval just before the unconditioned stimulus (US). This effect may arise from serial mediation of trace conditioning, second-order conditioning, or both. Whereas serial mediation relies only on the presence of CSB, associative transfer relies on CSB's associative strength. In the present experiments, the presence of CSB was fixed, whereas CSB's associative strength was manipulated by (a) extinction of CSB, (b) latent inhibition of CSB, and (c) prior CSB-US pairings. In the first 2 cases, the level of responding to CSA was reduced in a fashion parallel to that of CSB. However, in the third case, partial blocking of conditioned response (CR) acquisition to CSA was observed. The results are discussed with reference to the role of associative transfer to both facilitating and blocking CR acquisition to CSA.

Associative transfer and stimulus selection in classical conditioning of the rabbit's nictitating membrane response to serial compound CSs.

Four experiments were conducted to determine whether in conditioning to a serial compound, CS1-CS2-UCS, there are (a) associative mechanisms operating to extend conditioning beyond the bounds of a CS-UCS contiguity gradient and (b) stimulus selection processes acting to attenuate the potency of CS-UCS contiguity. In Experiments 1 and 2, the CS2-UCS interval was held at .35 sec while the CS1-UCS interval was varied across groups from .75 to 2.75 sec. CS1 test trials revealed substantial CR acquisition at all CS1-UCS intervals. Moreover, Experiment 2 indicated that when the contribution of cross-modal generalization from CS2 to CS1 was factored out, there still remained a substantial level of conditioning, which Experiment 3 indicated was attributable to an associative mechanism like higher-order or sensory conditioning. The observation of CR acquisition at CS1-UCS intervals of 4.75, 8.75, and 18.75 sec in Experiment 4 suggested that serial compound training yields conditioning to CSs located well beyond the single CS contiguity gradient for the rabbit's nictitating membrane response. Experiments 1 and 2 also indicated the presence of stimulus selection processes because, at the shorter CS1-UCS intervals (.75 and 1.25 sec), the levels of test-trial responding to CS2 fell below those observed to the less contiguous CS1.

Methoxamine is an effective unconditioned stimulus for cardiovascular conditioning.

New Zealand albino rabbits received classical conditioning training in which a 35-sec tone conditioned stimulus was paired with a bolus injection of methoxamine hydrochloride (Vasoxyl), an alpha 1-adrenergic agonist. Heart rate (HR) and blood pressure (BP) responses were recorded. Methoxamine produced a precipitous rise in BP and bradycardia as an unconditioned response (UR); pairings of tone and methoxamine over a 5-day period resulted in a gradually appearing tachycardia conditioned response (CR) which occurred shortly following tone onset. On the other hand, the BP CR was a pressor response. Accordingly, the HR CR was opposite in direction and, thus, apparently compensatory to the UR, whereas the BP CR was similar in direction to the UR. Neither of these cardiovascular changes were observed in control animals receiving either unpaired presentations of tone and methoxamine or tones paired with physiological saline. Most animals receiving either paired or unpaired infusions of methoxamine also showed consistent elevations in baseline HR as training progressed, relative to their respective day 1 levels, thus suggesting the development of compensatory HR CRs to the contextual cues associated with training.

Second-order conditioning of the rabbit's nictitating membrane response. Interstimulus interval and frequency of CS-CS pairings.

Second-order conditioning of the rabbit's nictitating membrane response (NMR) was investigated when second-order trials (CS1-CS2) were intermixed with first-order trials (CS2-US) from the outset of training. Experiment 1 showed that CR acquisition to CS1 was inversely related to the CS1-CS2 interval but nevertheless extended to an interval of 8,400 ms. Experiment 2 revealed that CR acquisition of CS1 was an inverted-U function of the number of CS1-CS2 trials relative to a fixed number of CS2-US trials. Experiment 3 directly contrasted second-order conditioning with a reinforced serial compound procedure (CS1-CS2-US) and a mixed procedure in which second-order trials were intermixed with the reinforced serial compound. Second-order conditioning was about half the strength of either the reinforced serial compound or the mixed procedure, which were similar. The present results are discussed with respect to the relative strength of excitatory and inhibitory processes in second-order conditioning.

Modification of the discharge of lateral geniculate neurons during visual learning.

Visually conditioned heart rate change in the pigeon has been developed as a vertebrate model system for cellular analysis of associative learning. Previous studies have characterized the behavior, largely delineated the neural circuitry mediating the conditioning, and estimated the central processing time for the conditioned response. Most recently, this system has been used to investigate neuronal activity during conditioning along the visual pathways that transmit the conditioned stimulus (CS) information. It was first shown that neither maintained nor CS-evoked discharge of retinal ganglion cells changes during conditioning. Subsequently, we found that the thalamic and telencephalic components of the ascending tectofugal pathway show associative modification. We report here studies of the thalamofugal pathway, the avian homolog of the mammalian geniculocortical system. Single-cell activity was recorded in the thalamic relay of this pathway, the dorsal lateral geniculate equivalent (LGNe). This provided an opportunity to evaluate the generality of the training-induced modification found along the tectofugal pathway, and to determine if such modification occurs as peripherally as retinorecipient neurons. The results show that almost all LGNe neurons (97%) respond phasically to the onset of whole-field illumination. Most (94%) also respond to the unconditioned stimulus (US), footshock, some with increased and others with decreased discharge. Of cells receiving convergent input, those responding with decreased discharge to the US showed associative change (52%). Neurons that did not respond to both the CS and US, or that responded to the US with increased discharge, did not show associative modification. These findings suggest that the visual pathways transmitting CS information are not merely input lines, but undergo training-induced modification; such modification can occur as peripherally as the retinorecipient neurons of these pathways; and CS-US convergence is necessary but not sufficient for associative modification, since modifiability is apparently contingent on specific US response properties.

A comparison of multiple-unit activity in the medial prefrontal and agranular insular cortices during Pavlovian heart rate conditioning in rabbits.

Multiple-unit activity (MUA) was recorded from chronically implanted electrodes in the medial prefrontal cortex (PFCm) and the agranular insular cortex (Iag) in separate groups of rabbits during habituation training, followed by aversive Pavlovian conditioning and subsequent extinction training. Control animals received explicitly unpaired presentations of the tone conditioned stimulus (CS) and eye-shock unconditioned stimulus (US). Both the cardiac orientating reflex and the conditioned heart rate response (HR CR) consisted of bradycardia, whereas tone-evoked tachycardia was observed in animals that received unpaired stimuli. Short-latency (less than 20-60 ms), tone-evoked increases in PFCm MUA were observed during the initial trials of habituation training, with their magnitude declining predictably across repeated tone-alone presentations. Subsequent CS/US pairings, however, served systematically to reinstate and enhance this CS-evoked MUA, while both non-associative (unpaired CS/US) and extinction (CS alone) training resulted in significant attenuation of such activity. Unconditioned tone-evoked increases in MUA were also observed in the Iag during habituation; however, such unit responses appeared to be more variable than their PFCm counterparts and were of considerably lesser magnitude. Moreover, in striking contrast to the above PFCm findings, conditioning and non-associative training did not differentially affect overall mean evoked MUA in the Iag, although different post-tone patterns of activity were obtained with the two procedures. The contrasting training effects observed in animals with PFCm vs. Iag electrode placements did not appear to be attributable to differences in regional sensitivity to the US, since excitatory patterns of MUA were elicited by unsignalled presentations of eye-shock at most placements within each cortical field. Accordingly, the present findings are consistent with our previous lesion data in suggesting that, although training-induced changes in PFCm neuronal activity may contribute to the initial events in aversive Pavlovian conditioning, an involvement of the Iag in such processes, if any, remains to be demonstrated.

Treatment of affective disorder and obesity with topiramate.

OBJECTIVE: To report a case of weight loss and mood stabilization in a patient being treated with the antiepileptic drug topiramate. CASE SUMMARY: A 37-year-old obese white woman with affective instability and obesity was being treated with adjunctive topiramate therapy. The patient lost 10 kg over 10 weeks of treatment with topiramate and improved clinically, as evidenced by a reduction in the number of times that she had to be admitted to a management unit for constant observation, and a decrease in the number of times that mechanical restraints or medication interventions were required for aggressive outbursts. Furthermore, the patient successfully completed two home visits while receiving topiramate therapy and was out of the hospital on her third home visit at the time of this writing. DISCUSSION: This case further strengthens previous reports that topiramate may be useful in treating affective disorders as well as inducing weight loss in a patient population in which weight gain is common. The patient discussed in this case report had no acute illnesses or changes in health status, no changes in diet, and no changes in her medications that could have accounted for the sudden weight loss. In addition, the patient's behavior did not improve until topiramate was added as adjunctive therapy of valproic acid, citalopram, and chlorpromazine during an adequate trial period. CONCLUSIONS: Controlled studies need to be performed to evaluate the use of topiramate in the psychiatric population and, in particular, the benefits of topiramate therapy in psychiatric patients with an additional diagnosis of obesity.