Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

The temporal structure of goal-directed and habitual operant behavior.

Operant behavior can reflect the influence of goal-directed and habitual processes. These can be distinguished by changes to response rate following devaluation of the reinforcing outcome. Whether a response is goal directed or habitual depends on whether devaluation affects response rate. Response rate can be decomposed into frequencies of bouts and pauses by analyzing the distribution of interresponse times. This study sought to characterize goal-directed and habitual behaviors in terms of bout-initiation rate, within-bout response rate, bout length, and bout duration. Data were taken from three published studies that compared sensitivity to devaluation following brief and extended training with variable-interval schedules. Analyses focused on goal-directed and habitual responding, a comparison of a habitual response to a similarly trained response that had been converted back to goal-directed status after a surprising event, and a demonstration of contextual control of habit and goal direction in the same subjects. Across experiments and despite responses being clearly distinguished as goal directed and habitual by total response rate, analyses of bout-initiation rate, within-bout rate, bout length, and bout duration did not reveal a pattern that distinguished goal-directed from habitual responding.

Prior experience modifies acquisition trajectories via response-strategy sampling.

Few studies have considered how signal detection parameters evolve during acquisition periods. We addressed this gap by training mice with differential prior experience in a conditional discrimination, auditory signal detection task. Naïve mice, mice given separate experience with each of the later correct choice options (Correct Choice Response Transfer, CCRT), and mice experienced in conditional discriminations (Conditional Discrimination Transfer, CDT) were trained to detect the presence or absence of a tone in white noise. We analyzed data assuming a two-period model of acquisition: a pre-solution and solution period (Heinemann EG (1983) in The Presolution period and the detection of statistical associations. In: Quantitative analyses of behavior: discrimination processes, vol. 4, pp. 21-36). Ballinger. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.536.1978andrep=rep1andtype=pdf ). The pre-solution period was characterized by a selective sampling of biased response strategies until adoption of a conditional responding strategy in the solution period. Correspondingly, discriminability remained low until the solution period; criterion took excursions reflecting response-strategy sampling. Prior experience affected the length and composition of the pre-solution period. Whereas CCRT and CDT mice had shorter pre-solution periods than naïve mice, CDT and Naïve mice developed substantial criterion biases and acquired asymptotic discriminability faster than CCRT mice. To explain these data, we propose a learning model in which mice selectively sample and test different response-strategies and corresponding task structures until they exit the pre-solution period. Upon exit, mice adopt the conditional responding strategy and task structure, with action values updated via inference and generalization from the other task structures. Simulations of representative mouse data illustrate the viability of this model.

Assessing complex odor discrimination in mice using a novel instrumental patterning task.

Negative patterning tasks are a key tool to unveil the mechanisms by which stimulus representations are acquired-a central concern in Robert Rescorla's research. In these tasks, target stimuli are reinforced when presented individually (A+/B+) but not when presented in compound (AB-). The discrimination of single stimuli from their compound presentation is a challenge for theories of associative learning, because it cannot be explained by the simple accrual of associative strength. The present study examined the conditions under which mice learn this part-whole discrimination in olfactory stimuli using a novel instrumental methodology. In two experiments, reinforcement was contingent on distinct responses depending on whether a set of odor mixtures were presented in isolation or as a compound. Using C57BL/6 mice, Experiment 1 showed a mutual interference between learning a response to individual odors and learning a different response to those odors presented in compound. Using wild-type APP/PS1 mice (a control strain for a murine model of Alzheimer's disease), Experiment 2 replicated this interference and showed that it is stimulus-specific. These experiments show that the instrumental patterning task may not only complement Pavlovian negative patterning tasks but may also motivate its own questions on the representation of complex stimuli. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition.

Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.

A computational formulation of the behavior systems account of the temporal organization of motivated behavior.

The behavior systems framework suggests that motivated behavior-e.g., seeking food and mates, avoiding predators-consists of sequences of actions organized within nested behavioral states. This framework has bridged behavioral ecology and experimental psychology, providing key insights into critical behavioral processes. In particular, the behavior systems framework entails a particular organization of behavior over time. The present paper examines whether such organization emerges from a generic Markov process, where the current behavioral state determines the probability distribution of subsequent behavioral states. This proposition is developed as a systematic examination of increasingly complex Markov models, seeking a computational formulation that balances adherence to the behavior systems approach, parsimony, and conformity to data. As a result of this exercise, a nonstationary partially hidden Markov model is selected as a computational formulation of the predatory subsystem. It is noted that the temporal distribution of discrete responses may further unveil the structure and parameters of the model but, without proper mathematical modeling, these discrete responses may be misleading. Opportunities for further elaboration of the proposed computational formulation are identified, including developments in its architecture, extensions to defensive and reproductive subsystems, and methodological refinements.

The differential role of the dorsal hippocampus in initiating and terminating timed responses: A lesion study using the switch-timing task.

This study investigated the role of the dorsal hippocampus (dHPC) in the temporal entrainment of behavior, while addressing limitations of previous evidence from peak procedure experiments. Rats were first trained on a switch-timing task in which food was obtained from one of two concurrently available levers; one lever was effective after 8 s and the other after 16  s. After performance stabilized, rats underwent either bilateral NMDA lesions of the dHPC or sham lesions. After recovery, switch-timing training resumed. In a subsequent condition, the switch-timing task was modified such that food was available after either 8 or 32 s. Although dHPC lesions had subtle and complex effects on when rats stopped seeking for food at the 8-s lever (departures), it more systematically reduced the time when rats started seeking for food at the 16-s and 32-s lever (switches). No systematic effect of dHPC lesions were observed on the coefficient of quartile variation (normalized dispersion) of latencies to switch. Within the context of the pacemaker-accumulator framework of interval timing, these findings suggest that partially or wholly independent mechanisms control the initiation and termination of timed responses, and that the dHPC is primarily involved in encoding the time to start responding.

An associability decay model of paradoxical choice.

Paradoxical choices in human and nonhuman animals represent substantial deviations from rational models of behavior; such deviations often demand models that incorporate multiple perspectives, including psychology, biology, and economics. The past couple of decades have seen an increased interest in the paradoxical choice of pigeons in 2-armed bandit tasks (2ABT) developed by Zentall and colleagues. In these 2ABTs, pigeons, but not rats, systematically choose an alternative that yields less reward over multiple trials but provides more information on events within a trial, over an alternative that yields more reward over trials but provides less information on events within a trial. Although current computational models account for much of the extant data generated in studies on 2ABT choice, they do not explain, in a trial-by-trial basis, how pigeons learn to ignore some stimuli and not others in 2ABTs. To address the provenance of this differential allocation of attention, a simple model composed of Bush-Mosteller linear operators and a Pearce-Hall-like associability mechanism is proposed. This model, referred to as the Associability Decay Model (ADM) of paradoxical choice, adequately accounts for the performance of pigeons and rats in 2ABTs. The ADM yields an untested prediction that is inconsistent with other computational models of 2ABT performance, and offers potential explanations for why differences in motivation, social enrichment, and impulsivity alter the degree to which pigeons systematically choose information despite earning fewer rewards. The success of the ADM shows that a relatively simple dynamic trial-by-trial model can account for much of the extant paradoxical-choice data while identifying opportunities for further study and refinement of models of 2ABT performance. (PsycINFO Database Record

Between-session memory degradation accounts for within-session changes in fixed-interval performance.

A common assumption in the study of fixed-interval (FI) timing is that FI performance is largely stable within sessions, once it is stable between sessions. Within-session changes in FI performance were examined in published data (Daniels and Sanabria, 2017), wherein some rats were trained on a FI 30-s schedule of food reinforcement (FI30) and others on a FI 90-s schedule (FI90). Following stability, FI90 rats were pre-fed for five sessions. Response rates declined as a function of trial, due more to latency lengthening than to run-rate reduction. Latencies were best described by a dynamic gamma-exponential mixture distribution, in which latency lengthening was driven by the growth of the criterion pulse count for a response and not by a reduction in the speed of an endogenous clock. The speed of the clock was selectively sensitive to the length of the FI; the prevalence and length of exponentially-distributed latencies were selectively sensitive to pre-feeding. These findings reveal (a) that parameters governing FI latencies are selectively sensitive to a range of manipulations, (b) a potential degradation of the criterion pulse count between consecutive sessions, and (c) a subsequent recovery of the criterion pulse count within sessions.

Effects of nicotine self-administration on incentive salience in male Sprague Dawley rats.

RATIONALE: Prolonged use of nicotine appears to enhance incentive salience, a motivational-cognitive process that transforms an otherwise neutral stimulus into a "wanted" stimulus. It has been suggested that nicotinic enhancement of incentive salience contributes to the potential of relapse in individuals with tobacco addiction. However, there are two main limitations of prior research that caution this claim: (a) the use of passive experimentally delivered nicotine and (b) the use of sign-tracking as an index of incentive salience, without acknowledging the competing nature of goal- and sign-tracking responses. OBJECTIVES: To determine whether nicotinic enhancement of incentive salience attributed to non-nicotinic stimuli occurs when rats self-administer nicotine, and whether it is facilitated by a prior history of nicotine self-administration. METHODS: Twenty-three male rats were trained daily, for 24 days, on a nicotine self-administration (SA) paradigm in the morning, and on a four-conditioned-stimuli Pavlovian conditioned approach (4-CS PCA) task in the afternoon. Self-administration was followed by extinction and cue reinstatement. A subcutaneous nicotine challenge was performed during the last 7 days of the study. RESULTS: Nicotine self-administration selectively enhanced sign-tracking in the 4-CS PCA. Upon extinction, sign-tracking quickly declined to control levels. Experimenter-administered nicotine enhanced sign-tracking similarly regardless of nicotine history. CONCLUSIONS: The results suggest that nicotinic enhancement of incentive salience is transient, and a previous history of nicotine use does not cause further sensitization. Taken together, these results suggest that nicotine enhances incentive salience, particularly-and perhaps exclusively-while onboard.

Suppressive and enhancing effects of nicotine on food-seeking behavior.

The present study examined how systemic low doses of nicotine affect the microstructure of reinforced food-seeking behavior in rats. Rats were first given an acute saline or nicotine treatment (0.1-0.6mg/kg, with an inter-injection interval of at least 48h), and then a chronic saline or nicotine treatment (0.3mg/kg/day for 10 consecutive days). Immediately after each injection, rats were required to press a lever five times to obtain food that was available at unpredictable times (on average every 80s) with constant probability. Acute nicotine dose-dependently suppressed behavior prior to the delivery of the first reinforcer, but enhanced food-reinforced behavior afterwards. These effects were primarily observed in the time it took rats to initiate food-seeking behavior. Enhancing effects were also observed in the microstructure of food-seeking behavior, with lower nicotine doses (0.1-0.3mg/kg) increasing the rate at which response bouts were initiated, and higher doses (0.3-0.6mg/kg) increasing within-bout response rates. A pre-feeding control suggests that changes in appetite alone cannot explain these effects. Over the course of chronic nicotine exposure, tolerance developed to the suppressive, but not to the enhancing effects of nicotine on food-seeking behavior. These results suggest that (a) lower doses of nicotine enhance the reward value of food and/or food-associated stimuli, (b) higher doses of nicotine enhance motoric activity, and (c) ostensive sensitization effects of nicotine on behavior partially reflect a tolerance to its transient suppressive motoric effects.

About bouts: A heterogeneous tandem schedule of reinforcement reveals dissociable components of operant behavior in Fischer rats.

According to the biexponential refractory model (BERM) of variable-interval (VI) performance, operant behavior is organized in bouts, described by 3 dissociable components: between-bout interresponse times (IRTs), within-bout IRTs, and bout lengths. Research has shown that between-bout IRTs are sensitive to changes in rate of reinforcement and reinforcer efficacy, the length of some bouts is selectively sensitive to changes in response-reinforcer contingencies, and within-bout IRTs are relatively insensitive to both manipulations. BERM assumes that within- and between-bout IRTs are exponentially distributed, and bout lengths are described by a mixture of negative binomial and geometric distributions. To assess BERM assumptions and the interpretation of associated findings, Fischer 344/DuCrl rats were trained on a heterogeneous tandem VI fixed-ratio (FR) schedule of reinforcement intended to dissociate the components of operant behavior. Initial (VI) and terminal (FR) links were programmed on separate levers; no stimulus signaled the completion of the initial link. FR requirement, VI requirement, and deprivation level were varied. Typical performance consisted of single responses on the VI lever separated by response runs on the FR lever. It was hypothesized that (a) the interval between the end of each FR run and the first subsequent VI response (FR-VI IRTs) would constitute between-bout IRTs, and would be sensitive to changes in VI requirement and deprivation level, (b) FR runs would constitute response bouts, so the length of a fraction of them would be selectively sensitive to changes in FR requirement, and (c) intervals between consecutive FR responses (FR-FR IRTs) would constitute within-bout IRTs, and would be relatively robust to all manipulations. Findings were consistent with these expectations. The underlying distributions of FR-FR IRTs, FR-VI IRTs, and FR run lengths, however, were inconsistent with BERM assumptions. These data support the distinct components of operant performance, but challenge the simple processes assumed to underlie their generation. (PsycINFO Database Record

The Effect of Methylphenidate on the Microstructure of Schedule-Induced Polydipsia in an animal model of ADHD.

Schedule-induced polydipsia (SIP) was established in spontaneously hypertensive rats (SHR), Wistar Kyoto rats (WKY), and Wistar rats, using a multiple fixed-time (FT) schedule of food delivery, with 30- and 90-s components. Thereafter, animals were exposed to methylphenidate (MPH; 2.5mg/kg/d) for six consecutive SIP sessions. A test to assess possible sensitization effects was also conducted four days after termination of the drug treatment. At baseline, FT 90-s produced longer and more frequent drinking episodes in SHR than in WKY. An analysis of the distribution of inter-lick intervals revealed that drinking was organized in bouts, which were shorter in SHR than in WKY. Across strains and schedules, MPH shifted drinking episodes towards the beginning of inter-food intervals, which may reflect a stimulant effect on SIP. MPH transiently reduced the frequency of drinking episodes in WKY in FT 30-s, and more permanently reduced the frequency of licking bouts in Wistar rats. MPH also increased the length of licking bouts in Wistar rats. Overall, SHR displayed a hyperactive-like pattern of drinking (frequent but short bouts), which 2.5mg/kg MPH appears to reduce in WKY and Wistar but not in SHR rats. It appears that therapeutic effects of MPH on hyperactive-like SIP require higher doses in SHR relative to control strains.

Interval timing under a behavioral microscope: Dissociating motivational and timing processes in fixed-interval performance.

The distribution of latencies and interresponse times (IRTs) of rats was compared between two fixed-interval (FI) schedules of food reinforcement (FI 30 s and FI 90 s), and between two levels of food deprivation. Computational modeling revealed that latencies and IRTs were well described by mixture probability distributions embodying two-state Markov chains. Analysis of these models revealed that only a subset of latencies is sensitive to the periodicity of reinforcement, and prefeeding only reduces the size of this subset. The distribution of IRTs suggests that behavior in FI schedules is organized in bouts that lengthen and ramp up in frequency with proximity to reinforcement. Prefeeding slowed down the lengthening of bouts and increased the time between bouts. When concatenated, latency and IRT models adequately reproduced sigmoidal FI response functions. These findings suggest that behavior in FI schedules fluctuates in and out of schedule control; an account of such fluctuation suggests that timing and motivation are dissociable components of FI performance. These mixture-distribution models also provide novel insights on the motivational, associative, and timing processes expressed in FI performance. These processes may be obscured, however, when performance in timing tasks is analyzed in terms of mean response rates.

I can time with a little help from my friends: effect of social enrichment on timing processes in Pigeons (Columba livia).

There is evidence that impulsive decision-making is associated with errors in timing. However, there has been little attempt to identify the putative mechanism responsible for impulsive animals' timing errors. One means of manipulating impulsivity in non-human animals is providing different levels of access to conspecifics. These preclinical models have revealed that social isolation increases impulsive responding across a wide range of tasks. The goal of the present study was to determine whether social isolation modulates time perception in pigeons by inducing more variability or a bias to underestimate the passage of time in temporal judgments. A temporal bisection task was used to characterize time perception. One group of pigeons performed the bisection following social enrichment, and the remaining half of the pigeons were tested following social isolation. Results revealed pigeons in the social isolation condition categorized a temporal stimulus sample as "long" at shorter durations than pigeons in the social enrichment condition. These data highlight the mechanism(s) thought to underlie timing-based interventions aimed at reducing impulsivity in humans. Future work should consider whether impulsivity is produced by misperceptions of time or a reduced threshold for a response.

Nicotine-induced place conditioning and locomotor activity in an adolescent animal model of attention deficit/hyperactivity disorder (ADHD).

Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.0, 0.1, 0.3 and 0.6 mg/kg). Prior to conditioning, SHRs were more active and less biased toward one side of the CPP chamber than WKY rats. Following conditioning, SHRs developed CPP to the highest dose of nicotine (0.6 mg/kg), whereas WKYs did not develop CPP to any nicotine dose tested. During conditioning, SHRs displayed greater locomotor activity in the nicotine-paired compartment than in the saline-paired compartment across conditioning trials. SHRs that received nicotine (0.1, 0.3, 0.6 mg/kg) in the nicotine-paired compartment showed an increase in locomotor activity between conditioning trials. Nicotine did not significantly affect WKY locomotor activity. These findings suggest that the SHR strain is a suitable model for studying ADHD-related nicotine use and dependence, but highlights potential limitations of the WKY control strain and the CPP procedure for modeling ADHD-related nicotine reward.

Revisiting the effect of nicotine on interval timing.

This paper reviews the evidence for nicotine-induced acceleration of the internal clock when timing in the seconds-to-minutes timescale, and proposes an alternative explanation to this evidence: that nicotine reduces the threshold for responses that result in more reinforcement. These two hypotheses were tested in male Wistar rats using a novel timing task. In this task, rats were trained to seek food at one location after 8s since trial onset and at a different location after 16s. Some rats received the same reward at both times (group SAME); some received a larger reward at 16s (group DIFF). Steady baseline performance was followed by 3 days of subcutaneous nicotine administration (0.3mg/kg), baseline recovery, and an antagonist challenge (mecamylamine, 1.0mg/kg). Nicotine induced a larger, immediate reduction in latencies to switch (LTS) in group DIFF than in group SAME. This effect was sustained throughout nicotine administration. Mecamylamine pretreatment and nicotine discontinuation rapidly recovered baseline performance. These results support a response-threshold account of nicotinic disruption of timing performance, possibly mediated by nicotinic acetylcholine receptors. A detailed analysis of the distribution of LTSs suggests that anomalous effects of nicotine on LTS dispersion may be due to loss of temporal control of behavior.

Less means more for pigeons but not always.

When humans are asked to judge the value of a set of objects of excellent quality, they often give this set higher value than those same objects with the addition of some of lesser quality. This is an example of the affect heuristic, often referred to as the less-is-more effect. Monkeys and dogs, too, have shown this suboptimal effect. But in the present experiments, normally hungry pigeons chose optimally: a preferred food plus a less-preferred food over a more-preferred food alone. In Experiment 2, however, pigeons on a less-restricted diet showed the suboptimal less-is-more effect. Choice on control trials indicated that the effect did not result from the novelty of two food items versus one. The effect in the less-food-restricted pigeons appears to result from the devaluation of the combination of the food items by the presence of the less-preferred food item. The reversal of the effect under greater food restriction may occur because, as motivation increases, the value of the less-preferred food increases faster than the value of the more-preferred food, thus decreasing the difference in value between the two foods.

Transitive inference by pigeons: does the geometric presentation of the stimuli make a difference?

In studies of transitive inference (TI), nonhuman animals are typically trained with the following 5-term task: A+B-, B+C-, C+D-, D+E- where the letters stand for arbitrary stimuli and [+] indicates that choice is reinforced and [-] indicates that choice is not reinforced. A TI effect is found when, given the untrained test pair BD, subjects choose B. TI effects have been found in many nonhuman species. Although reinforcement history has been posited as an account of the TI effect, it has failed to account for a variety of conditions under which TI effects have been found. A more cognitive account of TI is that organisms are able to form a representation of the series (A>B>C>D>E). In support of this hypothesis, Roberts and Phelps (Psychol Sci 5:368-374, 1994) found that presentation of the pairs of stimuli in a linear arrangement facilitated TI performance by rats, whereas presentation of the pairs of stimuli in a circular arrangement did not. Using methods adapted from Roberts and Phelps, we trained pigeons on either a linear or a circular arrangement of stimuli with the 5-term task. Results indicated that on the BD test pair, pigeons trained with a circular arrangement did not differ from those trained with a linear arrangement. Furthermore, we found that memory for training pairs was variable and was highly correlated with degree of TI. The results suggest that regardless of how pigeons are able to represent the stimuli, choice was not affected by the spatial arrangement of the stimuli during training.

Six-term transitive inference with pigeons: successive-pair training followed by mixed-pair training.

In nonhuman animals, the transitive inference (TI) task typically involves training a series of four simultaneous discriminations involving, for example, arbitrary colors in which choice of one stimulus in each pair is reinforced [+] and choice of the other color is nonreinforced [-]. This can be represented as A+B-, B+C-, C+D-, D+E- and can be conceptualized as a series of linear relationships: A > B > C > D > E. After training, animals are tested on the untrained non-endpoint pair, BD. Preference for B over D is taken as evidence of TI and occurs because B is greater than D in the implied series. In the present study we trained pigeons using a novel training procedure-a hybrid of successive pair training (training one pair at a time) and mixed-pair training (training all pairs at once)-designed to overcome some of the limitations of earlier procedures. Using this hybrid procedure, we trained five premise pairs (A+B-, B+C-, C+D-, D+E-, and E+F-) which allowed us to test three untrained non-endpoint pairs (BD, CE, and BE). A significant TI effect was found for most subjects on at least two out of three test pairs. Different theories of TI are discussed. The results suggest that this hybrid training is an efficient procedure for establishing mixed-pair acquisition and a TI effect.