Complementary medicine: a review of immunomodulatory effects of Chinese herbal medicines

Normal aging selectively impairs some forms of learning. For example, aging rabbits require more than twice as many trials to acquire 500-ms trace eyeblink conditioning than do young rabbits. N-methyl-D-aspartate (NMDA) receptor antagonists also impair trace conditioning. The effects of daily D-cycloserine (DCS; a partial agonist of the NMDA receptor-glycine site) treatment were tested on trace conditioning of young or aging rabbits using a conservative quantitative approach. DCS dose dependently improved acquisition, maximally reducing trials to criterion by approximately 50%. Dose-response curves were right-shifted by aging (twice the dose was required to achieve the same enhancement compared with controls). DCS did not affect nonassociative performance but sharpened the conditioned stimulus tone intensity discrimination. DCS thus can functionally modulate NMDA receptors in normal aging, enhance associative learning at all ages, and reduce or reverse age-dependent learning deficits.     

Age- and dose-dependent facilitation of associative eyeblink conditioning by {d}-cycloserine in rabbits.

Normal aging selectively impairs some forms of learning. For example, aging rabbits require more than twice as many trials to acquire 500-ms trace eyeblink conditioning than do young rabbits. N-methyl-{d}-aspartate (NMDA) receptor antagonists also impair trace conditioning. The effects of daily {d}-cycloserine (DCS; a partial agonist of the NMDA receptor-glycine site) treatment were tested on trace conditioning of young or aging rabbits using a conservative quantitative approach. DCS dose dependently improved acquisition, maximally reducing trials to criterion by ≈50%. Dose-response curves were right-shifted by aging (twice the dose was required to achieve the same enhancement compared with controls). DCS did not affect nonassociative performance but sharpened the conditioned stimulus tone intensity discrimination. DCS thus can functionally modulate NMDA receptors in normal aging, enhance associative learning at all ages, and reduce or reverse age-dependent learning deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Awareness in classical differential eyeblink conditioning in young and aging humans.

The role of awareness and its impact on learning the conditioned eyeblink response was investigated in both trace and delay discrimination eyeblink conditioning in young and aging participants, in 4 paradigms: delay 750, delay 1250, trace 500, and trace 1000. Participants concurrently watched a silent movie about which they were questioned afterward. Acquisition in both the trace and delay discrimination task was correlated with awareness of conditioning stimulus contingencies, regardless of age. Age-dependent deficits were observed in trace discrimination but not in delay discrimination, with more severe deficits appearing at the longer trace interval. The percentage of aware participants was also found to be greater in the young population than in the aging population. These results indicate that awareness or knowledge of stimulus contingencies may be an important contributor to successful acquisition in higher order discrimination tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice

Converging lines of evidence from rabbits, rats, and humans argue for the crucial involvement of the cerebellum in classical conditioning of the eyeblink/nictitating membrane response in mammals. For example, selective lesions (permanent or reversible) of the cerebellum block both acquisition and retention of eyeblink conditioning. Correspondingly, electrophysiological and brain-imaging studies indicate learning-related plasticity in the cerebellum. The involvement of the cerebellum in eyeblink conditioning is also supported by stimulation studies showing that direct stimulation of the two major afferents to the cerebellum (the mossy fibers emanating from the pontine nucleus and climbing fibers originating from the inferior olive) can substitute for the peripheral conditioned stimulus (CS) and unconditioned stimulus (US), respectively, to yield normal behavioral learning. In the present study, we examined the relative contribution of the cerebellar cortex versus deep nuclei (specifically the interpositus nucleus) in eyeblink learning by using mutant mice deficient of Purkinje cells, the exclusive output neurons of the cerebellar cortex. We report that Purkinje cell degeneration (pcd) mice exhibit a profound impairment in the acquisition of delay eyeblink conditioning in comparison with their wild-type littermates. Nevertheless, the pcd animals did acquire a subnormal level of conditioned eyeblink responses. In contrast, wild-type mice with lesions of the interpositus nucleus were completely unable to learn the conditioned eyeblink response. These results suggest that both cerebellar cortex and deep nuclei are important for normal eyeblink conditioning.     

Eyeblink conditioning during an interstimulus interval switch in rabbits (Oryctolagus cuniculus) using picrotoxin to disrupt cerebellar cortical input to the interpositus nucleus.

The role of the cerebellar cortex in eyeblink classical conditioning remains unclear. Experimental manipulations that disrupt the normal function impair learning to various degrees, and task parameters may be important factors in determining the severity of impairment. This study examined the role of cerebellar cortex in eyeblink conditioning under conditioned stimulus?unconditioned stimulus intervals known to be optimal or nonoptimal for learning. Using infusions of picrotoxin to the interpositus nucleus of the rabbit cerebellum, the authors pharmacologically disrupted input from the cerebellar cortex while training with an interstimulus interval (ISI)-switch procedure. One group of rabbits (Oryctolagus cuniculus) was 1st trained with a 250-ms ISI (optimal) and then switched to a 750-ms ISI (nonoptimal). A 2nd group was trained in the opposite order. The most striking effect was that picrotoxin-treated rabbits initially trained with a 250-ms ISI learned comparably to controls, but those initially trained with a 750-ms ISI were severely impaired. These results suggest that functional input from cerebellar cortex becomes increasingly important for the interpositus nucleus to learn delay eyeblink conditioning as the ISI departs from an optimal interval. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Procedural memory system supports single cue trace eyeblink conditioning in medial temporal lobe amnesia.

A number of studies investigating trace eyeblink conditioning have found impaired, but not eliminated, acquisition of conditioned responses (CRs) in both animals and humans with hippocampal removal or damage. The underlying mechanism of this residual learning is unclear. The present study investigated whether the impaired level of learning is the product of residual hippocampal function or whether it is mediated by another memory system that has been shown to function normally in delay eyeblink conditioning. Performance of bilateral medial temporal lobe amnesic patients who had a prior history of participating in eyeblink conditioning studies was compared to a control group with a similar training history and to an untrained control group in a series of single cue trace conditioning tasks with 500 ms, 250 ms, and 0 ms trace intervals. Overall, patients acquired CRs to a level similar to the untrained controls, but were significantly impaired compared to the trained controls. The pattern of acquisition suggests that amnesic patients may be relying on the expression of previously acquired, likely cerebellar based, procedural memory representations in trace conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses.

New Zealand male rabbits (Oryctolagus cuniculus) were trained on a trace eyeblink conditioning paradigm using a 250-ms tone conditioned stimulus, a 100-ms airpuff unconditioned stimulus, and a 500-ms trace interval. Rabbits received bilateral hippocampal aspirations either 1 day or 1 month after learning. Controls consisted of time-matched sham-operated and neocortical aspirated rabbits. When retested on the trace paradigm, rabbits with hippocampal aspirations 1 day after learning were significantly and substantially impaired in the retention of trace conditioned responses. In contrast, rabbits that received hippocampal aspirations 1 month after training retained trace conditioned responses at a level comparable to that of the controls. Moreover, hippocampectomy had no effect on the retention of delay eyeblink conditioning. Thus, the hippocampus appears to be necessary for the retention of recently acquired, but not remotely acquired, trace conditioned responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Age and Awareness on Eyeblink Conditional Discrimination Learning.

The present study aimed to assess the effects of aging and awareness on conditional discrimination learning within an eyeblink conditioning procedure by using a consecutive age-groups design (20-35 years, 36-50 years, 51-65 years, 66-80 years). Increasing age was associated with a decline in overall eyeblink conditioned response (CR) frequency and a deficit in conditional discrimination learning in the 2 older groups. Awareness of stimulus contingencies affected discrimination performance but not overall CR rates in younger subjects. Older subjects did not achieve eyeblink conditional discrimination learning, regardless of awareness. Discrimination performance correlated with measures of declarative memory. The pattern of results is discussed with respect to the involvement of hippocampal-cerebellar interactions and awareness in the mediation of age-related conditioning changes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of aging in delay and trace human eyeblink conditioning.

Normal aging has been shown to impact performance during human eyeblink classical conditioning, with older adults showing lower conditioning levels than younger adults. Previous findings showed younger adults can acquire both delay and trace conditioning concurrently, but it is not known whether older adults can learn under the same conditions. Present results indicated older adults did not produce a significantly greater number of conditioned responses during acquisition, but their ability to time eyeblink responses prior to the unconditioned stimulus was preserved. The decline in eyeblink conditioning that typically accompanies aging has been extended to concurrent presentations of delay and trace conditioning trials. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Motor cortex lesions do not affect learning or performance of the eyeblink response in rabbits.

The possible modulatory role of motor cortex in classical conditioning of the eyeblink response was examined by ablating anterior neocortex in rabbits and training them with an auditory conditioned stimulus (CS) and an airpuff unconditioned stimulus (US) in either a delay (Experiment 1) or a trace (Experiment 2) conditioning paradigm. Topographic measures such as amplitude and onset latency were assessed during conditioning sessions for conditioned responses (CRs) and on separate test days for unconditioned responses (URs) by using a range of US intensities. No lesion effects were observed for learning or performance measures in acquisition or retention of either delay or trace conditioning. During trace conditioning, lesioned rabbits did, however, exhibit a trend toward impairment and demonstrated significantly longer CR latencies. Damage to motor and frontal cortex does not significantly affect eyeblink response performance or learning in either a delay or a trace conditioning paradigm. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminated lateralized eyeblink conditioning in the rabbit: An experimental context for separating specific and general associative influences.

Four experiments demonstrated discriminated lateralized eyeblink conditioning in 38 male rabbits and showed how the phenomenon may be used to differentiate between the reflexive and emotive consequences of Pavlovian conditioning. Exps 1, 2, and 3 characterized how 2 conditioned stimuli (CSs), contemporaneously trained with left vs right paraorbital unconditioned stimuli (UCSs), can produce different CRs, each involving predominant closure of the eye ipsilateral to its UCS. Exp 4 showed how the associative tendencies controlled by additional stimuli could be evaluated by presentations in compound with such discriminanda: A 30-sec stimulus, presumed to acquire a conditioned emotional response but no eyeblink CR, equally potentiated the eyelid CRs elicited by both CSs. A 1,050-msec CS that evoked an eyeblink CR in isolation also increased the responding to both CSs but biased it toward its own lateralized CR. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned-reflex facilitation in young and older adults

Young (18-30 years) and elderly (63-88 years) human subjects received 70 trials of single-cue classical eyeblink conditioning (paired group), or 70 explicitly unpaired presentations of the tone conditioned stimulus (CS) and airpuff unconditioned stimulus (unpaired group). Before and after conditioning, reflex-eliciting white noise and corneal airpuff stimuli were presented alone or paired with the CS to investigate the effects of conditioning on eyeblink reflex amplitude. The results showed increased conditioned responses in the paired group compared to the unpaired group for the young but not the elderly subjects. There was, however, evidence of conditioned facilitation of noise-elicited reflexes in both young and elderly subjects. These data indicate that conditioned facilitation of the startle reflex may be a sensitive indicator of classical conditioning processes in human subjects.     

Using a 6-minute walk test to predict outcomes in patients with left ventricular dysfunction

There is increasing evidence that, in addition to its major functional role in the regulation of fine motor control, the cerebellum is involved in other important functions, such as sensory-motor learning and memory. Classical conditioning of the eyeblink or nictitating membrane response (and other discrete behavioral responses) is a form of sensory-motor learning that depends crucially upon the cerebellum. Within the cerebellum, however, the relative importance of the cerebellar cortex and the deep cerebellar nuclei in eyeblink conditioning is unclear and disputed. Recent studies employing various mutant mice provide an effective approach to resolving this controversy. Eyeblink conditioning in spontaneous mutant mice deficit in Purkinje cells, the exclusive output neurons of the cerebellar cortex, indicate that both the cerebellar cortex and the interpositus nucleus are important. Furthermore, studies involving gene knockout mice suggest that long-term depression, a process of synaptic plasticity occurring in Purkinje cells, might be involved in eyeblink conditioning.     

Hippocampal activity during classical discrimination—Reversal eyeblink conditioning in rabbits.

Multiple-unit neuronal recordings were taken from the hippocampi of 10 male, New Zealand white rabbits during classical discrimination and reversal eyeblink conditioning using 2 tones as the conditioned stimuli (CS+ and CS–) and an air-puff unconditioned stimulus. During discrimination training, characteristic learning-related activity was seen in the hippocampus on trials when a conditioned response (CR) was executed. During early phases of reversal training, however, when high numbers of CRs were evident to both the new CS+ (the former CS–) and the new CS– (the former CS+), no learning-related activity was observed. Characteristic CR-related hippocampal activity to the CS+ was observed only after the rabbits began to learn the reversal response. These results suggest that the hippocampus may encode different features of eyeblink conditioning during discrimination and reversal learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala

Fear conditioning is a paradigm that has been used as a model for emotional learning in animals. The cellular correlate of fear conditioning is thought to be associative N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity within the amygdala. Here we show that glutamatergic synaptic transmission to inhibitory interneurons in the basolateral amygdala is mediated solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast to AMPA receptors at inputs to pyramidal neurons, these receptors have an inwardly rectifying current-voltage relationship, indicative of a high permeability to calcium. Tetanic stimulation of inputs to interneurons caused an immediate and sustained increase in the efficacy of these synapses. This potentiation required a rise in postsynaptic calcium, but was independent of NMDA receptor activation. The potentiation of excitatory inputs to interneurons was reflected as an increase in the amplitude of the GABA(A)-mediated inhibitory synaptic current in pyramidal neurons. These results demonstrate that excitatory synapses onto interneurons within a fear conditioning circuit show NMDA-receptor independent long-term potentiation. This plasticity might underlie the increased synchronization of activity between neurons in the basolateral amygdala after fear conditioning.     

Nicotinic cholinergic system involvement in eyeblink classical conditioning in rabbits.

A nicotinic cholinergic antagonist, mecamylamine (MEC), was administered to rabbits tested on eyeblink classical conditioning (EBCC) in the 750-msec delay paradigm for 10 90-trial sessions. Nicotinic receptors were measured in 3 brain regions in S treatment groups: paired conditioned stimulus–unconditioned stimulus (CS–UCS) presentations with (1) vehicle, young; (2) vehicle, older; (3) 0.5 mg/kg MEC, young; unpaired CS–UCS with (4) 0.5 mg/kg MEC, young; and (5) vehicle, young. Daily MEC injections disrupted acquisition in young rabbits (769 trials to learning criterion vs 323 trials for vehicle-treated young rabbits). MEC-treated young rabbits learned similarly to older rabbits. Brain nicotinic receptors were not affected by 10 daily MEC injections. To our knowledge, this experimental protocol, using a low MEC dose to selectively inhibit nicotinic cholinergic receptors, is the first to demonstrate a role for nicotinic cholinergic receptors in EBCC. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prefrontal control of trace versus delay eyeblink conditioning: Role of the unconditioned stimulus in rabbits (Oryctolagus cuniculus).

The conditioned eyeblink (EB) response was studied with trace conditioning procedures in rabbits (Oryctolagus cuniculus) with lesions to the medial prefrontal cortex (mPFC) or sham lesions. Three experiments were performed in which either periorbital shock or a corneal airpuff served as the unconditioned stimulus (US) in separate groups of sham or mPFC-lesioned rabbits. Acquisition of the EB conditioned response (CR) was faster and reached a higher asymptote with the eyeshock US than with the airpuff US. However, mPFC lesion-induced trace conditioning deficits were obtained only in the groups that received the airpuff US. All rabbits showed normal delay conditioning and extinction. These results suggest that mPFC mediates trace EB conditioning when emotional arousal is low. However, in circumstances when emotional arousal may be high (i.e., during exposure to aversive periorbital shock), other structures (such as amygdala) may be activated to permit learning even in the absence of input from mPFC. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Central and basolateral amygdala neurons crash the aversive conditioning party: Theoretical comment on Rorick-Kehn and Steinmetz (2005).

Rorick-Kehn and Steinmetz (2005) (see record 2005-13804-012) report that neurons in the central and basolateral nuclei of the amygdala exhibit learning-related spike firing to conditional stimuli associated with shock in 3 different aversive conditioning paradigms: eyeblink conditioning, fear conditioning, and signaled avoidance conditioning. Central nucleus neurons responded in all 3 tasks, whereas basolateral nucleus neurons were more activated by fear and avoidance conditioning. These results reveal that amygdala neurons are differentially engaged by aversive conditioning, but questions remain concerning the associative basis and functional role for these unit responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ibotenic acid lesions of the medial septum retard delay eyeblink conditioning in rabbits (Oryctolagus cuniculus).

S. Berry and R. Thompson (1979) reported that electrolytic lesions of the medial septum significantly retard eyeblink conditioning. However, these electrolytic lesions were nonselective and may have also damaged the subcortical inputs to the hippocampus via the fimbria-fornix. In the present study, the medial septum was selectively lesioned with ibotenic acid in rabbits (Oryctolagus cuniculus), whose performance in a delay eyeblink conditioning paradigm was compared with that of intact controls, sham-operated controls, and intact controls given a systemic injection of scopolamine. Rabbits with selective medial septal lesions and rabbits receiving systemic scopolamine were significantly slower to condition than were intact and sham-lesioned rabbits. This finding demonstrates that the selective removal of the medial septum retards delay eyeblink conditioning in a manner similar to the disruption seen after systemic administration of scopolamine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-related deficits in retention of the classically conditioned nictitating membrane response in rabbits.

Young and aged rabbits underwent classical conditioning of the nictitating membrane response (NMR) to a tone conditioned stimulus (CS) and a corneal airpuff unconditioned stimulus (UCS) for 18 consecutive days. Rabbits were then returned to their home cages for a 90-day period in which they received no further conditioning, but they were handled daily. On Day 91 they underwent retention testing during which the CS alone was presented 20 times. This was immediately followed by reacquisition in which the CS and UCS were again paired for 100 trials. Reacquisition was repeated on the following day. As in previous studies, aged rabbits acquired the conditioned response (CR) more slowly than young rabbits; however, by the end of acquisition, both groups reached similar asymptotic levels. Retention of the CR was significantly lower for aged than young rabbits. Reacquisition was also retarded in aged vs young rabbits. Nonassociative factors, such as sensitivity to the stimuli or general health, could not account for these differences. Data are discussed in terms of using retention of the conditioned eyeblink response as a model system for studying age-related memory deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)