Limbic networks and associative learning: I. Entorhinal contributions to instrumental conditioning

The hippocampal formation is a highly delineated brain structure that is believed to play a prominent role in learning and memory. The present experiment evaluated the contributions of medial and lateral perforant path input to bar press-conditioning under (a) continuous and (b) differential reinforcement of low rates of responding (DRL) schedules, and (c) shuttlebox avoidance conditioning. Bilateral deafferentation of either pathway had no effect on the acquisition of bar press responses or on performance under the DRL schedule. Deafferentation of the medial pathway facilitated acquisition of avoidance responses in a manner much like the effects seen in hippocampectomized animals. It is suggested that the medial perforant path participates in the expression of correlated patterns of neuronal discharge known to develop within the hippocampus and that this “model” serves to modulate the temporal characteristics of simple conditioned reflexes. Loss of the modulatory influence of the model may affect acquisition and extinction rates. Contributions of other hippocampal circuits are discussed in relation to established deficits. Preliminary results of this experiment were presented at the second annual convention of the American Psychological Society, Dallas, Texas, June 1990.     

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation,passive avoidance,and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.     

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation, passive avoidance, and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.     

Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region

The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.     

Selective lesions in the temporal-hippocampal region of the rat: effects on acquisition and retention of a visual discrimination task.

The first purpose of this study was to investigate whether lesions in the temporal region may affect acquisition or retention of a discrimination task. In Experiment 1, rats with lesions of the temporal cortex (TC), the lateral entorhinal cortex (LEC), or their interconnections were tested postoperatively in simultaneous brightness discrimination. The results show that neither TC lesions nor LEC lesions affected acquisition of the task, and only LEC lesions impaired retention. TC/LEC transections impaired both acquisition and retention. The second purpose was to investigate effects of hippocampal lesions and perforant path transections on the discrimination task (Experiment 2). Both hippocampal and perforant path lesions impaired acquisition of the task, whereas retention was unaffected. It is suggested that TC and LEC are primarily involved in information storing and that hippocampal function is primarily involved in information processing.     

Effects of dl-amphetamine under concurrent VI DRL reinforcement

Three adult, food-deprived rats were given IP injections of dl-amphetamine sulfate under DRL and concurrent VI DRL reinforcement schedules. The drug results were as follows.(1) The IRT distributions of DRL responses shifted to the left, but some temporal discrimination remained. (2) The IRT distributions of VI responses shifted slightly to the left. (3) The distinguishing characteristics of VI and DRL IRT distributions were preserved. (4) The frequency distribution of number of VI responses between two consecutive DRL responses was relatively unaffected. (5) Over-all response rates on the two components of the concurrent schedules increased more or less proportionately.These findings imply that the primary behavioral effect of dl-amphetamine was a motor excitatory one. The drug's disruption of timing behavior was not due to a derangement of internal timing mechanisms, nor to interference with the topography or pattern of behavior. Rather, it might be a secondary result of the accelerated emission of overt behavior patterns mediating the temporal spacing of DRL bar presses.     

A developmental study of timing behavior in 4 1/2- and 7-year-old children

The present study investigated effects of age and instructions on temporal regulations of behavior in children. In the first experiment 4 1/2-year-old and 7-year-old subjects were trained with a DRL (differential reinforcement of low rates) 5-s and a DRL 10-s schedule. Results demonstrate that age and timing performance are related. Seven-year-olds are more efficient than the 4 1/2-year-olds. A striking decline in the 4 1/2-year-old children's capacity to space responses was observed in the DRL 10-s schedule as compared to the DRL 5-s schedule. Analysis of individual performances suggests that the evolution of DRL performance between 4 and 7 years of age depends not only on the development of the capacity to delay responding but also on the acquisition of the ability to represent the reinforcement contingencies, that is, the temporal parameters of the task to oneself. In order to test this hypothesis a second experiment was conducted where instructions to wait between operant responses were given to a group of 4 1/2-year-old subjects at the beginning of a DRL 5-s and a DRL 10-s schedule. The results show that these instructions enhance DRL performance. By directing the 4 1/2-year-old subjects' attention to the temporal requirements of the task, instructions led to efficient performance and accurate timing of responses to the DRL schedule.     

Induction and activity-dependent reversal of persistent LTP and LTD in lateral perforant path synapses in vivo

The reversibility of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) lasting weeks was examined in the lateral perforant path of freely moving adult Sprague-Dawley rats. LTP lasting weeks was rapidly reversed within minutes by high-frequency heterosynaptic stimulation of the medial perforant path, in an N-methyl-D-aspartate receptor-dependent manner. LTP reversal also occurred, albeit more slowly and to a lesser extent, when animals were given 1-3 weeks of overnight exposure to an enriched environment (EE). LTD likewise was reversed upon repeated EE exposure. A covert similarity between the degrees of LTP and LTD reversal was revealed when the small potentiation effect of EE treatment by itself on lateral path responses was taken into account. Despite its ability to reverse previously acquired synaptic plasticity, two weeks of EE treatment had no effect on animals' retention of the platform location in a spatial watermaze task, although it did facilitate new learning. These data are in agreement with the hypothesis that hippocampal synapses retain the capacity for rapid synaptic change even when otherwise relatively stable plasticity has previously been induced. Slow reversal of such plasticity did not correlate with a loss of memory retention, possibly because either slow changes permit reorganization of representations such that both old and new information can be accommodated, or else the new information is synaptically represented in orthogonal fashion to the old information.     

Effects of a DRL contingency added to a fixed-interval reinforcement schedule

Following 30 days of reinforcement for the bar press response of two white rats on 30-sec fixed-interval (FI), a DRL component was added so that a minimal interresponse time (IRT) for the reinforced response, in addition to the FI variable, was necessary for reinforcement. Marked control over response rate by the superimposed DRL requirement was demonstrated by an inverse hyperbolic function as the DRL component was increased from 1 to 24 sec within the constant 30-sec FI interval. Interresponse time and post-reinforcement (post-S^R) “break” distributions taken at one experimental point (DRL = 24 sec) suggested that a more precise temporal discrimination was initiated by an S^R than by a response, since the relative frequency of a sequence of two reinforced responses appeared greater than that of a sequence of a non-reinforced response followed by a reinforced one. This latter finding was confirmed with new animals in a follow-up experiment employing a conventional 24-sec DRL schedule.     

Effects of reversible inactivation of locus coeruleus on long-term potentiation in perforant path-DG synapses in rats

The locus coeruleus (LC) is the main source of noradrenergic innervations to the forebrain and the hippocampal formation but does not receive noradrenergic projections itself. Previous studies have suggested that hippocampal neural response is modulated by the noradrenergic pathway and that the experimental activation of the LC can potentiate hippocampal responses. Most studies have suggested that the noradrenergic system has controversial effects on long-term potentiation (LTP) in hippocampal neurons, because its influence on synaptic plasticity in perforant path-DG synapses is ambiguous. The aim of this article was to study the LC's role in baseline activity and LTP in perforant path-DG cells of hippocampus by in vivo LC inactivation. Rats were anesthetized with urethane, and LC was temporarily suppressed by intra-LC injection of lidocaine. Population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in DG were recorded 10 min before and 5, 10, 20, 40, 60, and 120 min after tetanization (400 Hz). Saline or lidocaine was injected during the baseline recording (experiment 1), 5 min before tetanus (experiment 2), and 5 min after tetanus (experiment 3). The results from this study indicated that the LC inactivation has no effect on baseline activity of granular cells or maintenance of LTP after tetanization. Moreover, LC inactivation before tetanus had no effect on LTP induction but decreased PS-LTP amplitude 60 and 120 min after tetanization. Taken together, the LC noradrenergic system likely influences LTP induction in later time periods while it has no effect on LTP in earlier time periods.     

同一学习中海马不同区的习得性长时程突触增强的形成

本研究探查大鼠分辨学习中海马齿状回(DG)和CA_3区突触效应的变化及其相互关系,以探讨同一学习中海马不同区突触可塑性变化的特点及其相互关系,进一步论证习得性长时程增强(LTP)是学习和记忆的神经基础。发现:(1)穿通纤维的单个刺激可在DG和CA_3同时记录到潜伏期、峰值和波形各异的群体峰电位(PS);在一定范围内PS随刺激强度的增加而增大,但DG的PS增大程度比CA_3的小;据此,检测刺激的强度应选在该范围内。(2)随着行为训练,DG和CA_3区的突触传递同时产生LTP,两者LTP的发展是显著正相关关系(P<0.01),PS峰值同时达到最高水平,且先于分辨反应达学会标准,首次表明在同一学习中大鼠海马的DG和CA_3的习得性LTP是同时产生的。本研究还表明,在慢性实验下同时记录和分析行为学习中海马两个区突触效应的变化及其相互关系是可能的,这给从神经环路角度研究学习和记忆的突触机制提供了有用的模型。     

Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus

The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.     

Visual evoked potential augmenting/reducing slopes in cats—2. Correlations with behavior

Relationships were studied in cats between the augmenting/reducing slopes of visual evoked potentials (VEP) and three types of behavioral responses: learning and performance measures in (1) fixed interval (FI), and (2) differential reinforcement of low rate of response (DRL) bar pressing tasks for food reward, and (3) the effect of noise stress or increasing task difficulty on performance of an FI, DRL or 2 bar discrimination task. The most reliable slope measure (N1 at a medium intensity range) was found to correlate most highly with inhibitory behaviors such that reducers were most successful in controlling bar pressing behavior during an inhibitory DRL task or when stress was introduced. At a higher range of flash intensity slopes tended to be more negative, and the P1 - N1 slopes although more variable correlated most consistently with general temperament. Augmenters at a high intensity range were more active and explaratory, and learmed to bar press more quickly and efficiently.     

Hippocampal synaptic plasticity during instrumental learning

present research examined the role of hippocampal NMDA-dependent synaptic potentiation on appetitive instrumental conditioning under a continuous reinforcement schedule. In the first experiment, low (.025 mg.kg) or moderate (.05 mg/kg) dosages of the NMDA receptor antagonist, MK801, failed to increase the number of training days required to reach acquisition criterion; number of training days required to reach criterion for extinction were also unaffected. In the second experiment, a higher dosage (.10 mg/kg) of MK801 or induction of long-term potentiation failed to alter the number of responses occurring during acquisition. These data suggest that hippocampal synaptic potentiation does not play a prominent role in instrumental learning with simple contingency conditions. It is suggested that hippocampal LTP reflects a perceptual process that contributes differentially to spatial cognition, classical and instrumental conditioning.     

Hippocampal synaptic plasticity during instrumental learning

present research examined the role of hippocampal NMDA-dependent synaptic potentiation on appetitive instrumental conditioning under a continuous reinforcement schedule. In the first experiment, low (.025 mg.kg) or moderate (.05 mg/kg) dosages of the NMDA receptor antagonist, MK801, failed to increase the number of training days required to reach acquisition criterion; number of training days required to reach criterion for extinction were also unaffected. In the second experiment, a higher dosage (.10 mg/kg) of MK801 or induction of long-term potentiation failed to alter the number of responses occurring during acquisition. These data suggest that hippocampal synaptic potentiation does not play a prominent role in instrumental learning with simple contingency conditions. It is suggested that hippocampal LTP reflects a perceptual process that contributes differentially to spatial cognition, classical and instrumental conditioning.     

The neural cell adhesion molecule-derived peptide FGL facilitates long-term plasticity in the dentate gyrus in vivo

The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as well as to rescue some pathological cognitive impairments. Whether its facilitating impact may be mediated through promoting neuronal plasticity is not known. The present study was therefore designed to test whether FGL modulates the induction and maintenance of synaptic plasticity in the dentate gyrus (DG) in vivo. For this, we first assessed the effect of the FGL peptide on synaptic functions at perforant path-dentate gyrus synapses in the anesthetized rat. FGL, or its control inactive peptide, was injected locally 60 min before applying high-frequency stimulation (HFS) to the medial perforant path. The results suggest that although FGL did not alter basal synaptic transmission, it facilitated both the induction and maintenance of LTP. Interestingly, FGL also modified the heterosynaptic plasticity observed at the neighboring lateral perforant path synapses. The second series of experiments, using FGL intracerebroventricular infusion in the awake animal, confirmed its facilitating effect on LTP for up to 24 h. Our data also suggest that FGL could alter neurogenesis associated with LTP. In sum, these results show for the first time that enhancing NCAM functions by mimicking its heterophilic interaction with FGFR facilitates hippocampal synaptic plasticity in the awake, freely moving animal.     

Punishment and the potential for negative reinforcement with histamine injection

The present study examined punishment of responding with histamine injection, and its potential to generate avoidance of punishment. Sprague–Dawley rats were trained under concurrent schedules in which responses on one lever (the punishment lever) produced food under a variable‐interval schedule, and under some conditions intermittent injections of histamine, which suppressed behavior. Responses on a second (avoidance) lever prevented histamine injections scheduled on the punishment lever. After stabilization of punished responding, a variable‐interval 15‐s schedule of cancellation of histamine (avoidance) was added for responding on the second/avoidance lever, without subsequent acquisition of responding on that lever. Progressive decreases in the length of the punishment variable‐interval schedule increased suppression on the punishment lever without increases in response rates on the avoidance lever. Exchanging contingencies on the levers ensured that response rates on the avoidance lever were sufficiently high to decrease the histamine injection frequency; nonetheless response rates on the avoidance lever decreased over subsequent sessions. Under no condition was responding maintained on the avoidance lever despite continued punishing effectiveness of histamine throughout. The present results suggest that avoidance conditioning is not a necessary condition for effective punishment, and confirm the importance of empirical rather than presumed categorization of behavioral effects of stimulus events.     

Perforant path activation modulates the induction of long-term potentiation of the schaffer collateral--hippocampal CA1 response: theoretical and experimental analyses

In one computational model of hippocampal function, the entorhinal cortical input to CA1 is hypothesized to play a key role in the ability of CA1 to decode CA3 recodings. Here, we develop a modification of this CA1 decoder hypothesis that is applicable to several computational theories of hippocampal function, and then we electrophysiologically investigate one assumption of this new hypothesis. First, using biologically realistic estimates, we calculate that CA3-induced CA1 excitation is too high and that inhibition plausibly plays a role in this CA1 decoder model. Thus motivated, we turn to a physiological demonstration to substantiate the plausibility of the proposed mechanism. Using the rat hippocampal slice, we examine an interlaminar interaction between the distal perforant path input to hippocampal CA1 stratum moleculare and the more proximal Schaffer collateral input to stratum radiatum. Perforant path activation provides sufficient inhibition to block homosynaptic long-term potentiation elicited by a suitably strong stratum radiatum input. For this interlaminar interaction to be most effective, perforant path activation must both precede and follow Schaffer collateral activation. Perforant path-evoked inhibition in CA1 can thus serve as a viable mechanism in the learned decoder theory of hippocampal CA1.     

Acquisition and extinction of signaled avoidance as a function of intermittent reinforcement

Signaled, shuttle-box avoidance responding in female rats of the Fischer₃₄₄ strain was examined as a function of four separate contingencies of intermittent reinforcement. In Experiment 1, when avoidance responses during acquisition were reinforced 25% of the time with prompt CS termination, animals responded equally often during acquisition and significantly more often during extinction than animals who received such reinforcement on a 100% schedule. Similar results were found under a trace procedure in Experiment 2 when avoidance responses were reinforced 25% of the time with informational feedback stimuli. In contrast, during Experiment 3, when animals were shocked on only 25% of the trials on which they failed to respond, the level of avoidance responding during both acquisition and extinction was significantly less than it was when animals were shocked on a 100% schedule. Comparable results were found in Experiment 4 when avoidance responses during acquisition averted shock on only 25% of the trials. Thus, intermittent reinforcement contingencies involving response-contingent feedback stimuli and shock have differential effects on avoidance responding during both acquisition and extinction trials under the signaled avoidance procedure.     

The role of signals in two variations of differential‐reinforcement‐of‐low‐rate procedures

Differential‐reinforcement‐of‐low‐rate (DRL) schedules are used to decrease the overall rate of, but not eliminate, a target response. Two variations of DRL, spaced‐responding and full‐session, exist. Preliminary comparative analyses suggest that the two schedules function differently when unsignaled. We compared response rates under these two DRL variations with and without signals. In Experiment 1, five preschool students played a game in which points were earned under DRL schedules. In some sessions, a stimulus signaled when responses would be reinforced (S+) or not reinforced (S‐). In others, only an S‐ was present. Signals (S+/S‐) facilitated and maintained responding in both types of DRL schedules. In Experiment 2, we modified the signals with five different preschoolers. Instead of an S‐ only, we did not present any signals. Elimination and high variability of the target response were observed with the S‐ only and absence of S+/S‐, respectively. Signaled DRL schedules are recommended for application.