Impaired Discrimination Learning Research Articles

Alzheimer's disease risk gene CD2AP is a dose-sensitive determinant of synaptic structure and plasticity.

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease.

Dopamine D2 receptors in discrimination learning and spine enlargement.

Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3-5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.

Genetic inactivation of synaptosomal-associated protein 25 (SNAP-25) in adult hippocampal neural progenitors impairs pattern discrimination learning but not survival or structural maturation of newborn dentate granule cells.

Adult neurogenesis is necessary for proper cognition and behavior, however, the mechanisms that underlie the integration and maturation of newborn neurons into the pre-existing hippocampal circuit are not entirely known. In this study, we sought to determine the role of action potential (AP)-dependent synaptic transmission by adult-generated dentate granule cells (DGCs) in their survival and function within the existing circuitry. We used a triple transgenic mouse (NestinCreERT2 :Snap25fl/fl : tdTomato) to inducibly inactivate AP-dependent synaptic transmission within adult hippocampal progenitors and their progeny. Behavioral testing in a hippocampal-dependent A/B contextual fear-discrimination task revealed impaired discrimination learning in mice harboring SNAP-25-deficient adult-generated dentate granule cells (DGCs). Despite poor performance on this neurogenesis-dependent task, the production and survival of newborn DGCs was quantitatively unaltered in tamoxifen-treated NestinCreERT2 :Snap25fl/fl : tdTomato SNAP compared to tamoxifen-treated NestinCreERT2 :Snap25wt/wt : tdTomato control mice. Although SNAP-25-deficient adult DGCs displayed a small but statistically significant enhancement in proximal dendritic branching, their overall dendritic length and distal branching complexity was unchanged. SNAP-25-deficient newborn DGCs also displayed robust efferent mossy fiber output to CA3, with normal linear density of large mossy fiber terminals (LMTs). These studies suggest that AP-dependent neurotransmitter release by newborn DGCs is not essential for their survival or rudimentary structural maturation within the adult hippocampus.

Interaction between age and perceptual similarity in olfactory discrimination learning in F344 rats: relationships with spatial learning

Emerging evidence suggests that aging is associated with a reduced ability to distinguish perceptually similar stimuli in one's environment. As the ability to accurately perceive and encode sensory information is foundational for explicit memory, understanding the neurobiological underpinnings of discrimination impairments that emerge with advancing age could help elucidate the mechanisms of mnemonic decline. To this end, there is a need for preclinical approaches that robustly and reliably model age-associated perceptual discrimination deficits. Taking advantage of rodents' exceptional olfactory abilities, the present study applied rigorous psychophysical techniques to the evaluation of discrimination learning in young and aged F344 rats. Aging did not influence odor detection thresholds or the ability to discriminate between perceptually distinct odorants. In contrast, aged rats were disproportionately impaired relative to young on problems that required discriminations between perceptually similar olfactory stimuli. Importantly, these disproportionate impairments in discrimination learning did not simply reflect a global learning impairment in aged rats, as they performed other types of difficult discriminations on par with young rats. Among aged rats, discrimination deficits were strongly associated with spatial learning deficits. These findings reveal a new, sensitive behavioral approach for elucidating the neural mechanisms of cognitive decline associated with normal aging.

Probabilistic Reversal Learning in Schizophrenia: Stability of Deficits and Potential Causal Mechanisms.

Although individuals with schizophrenia show impaired feedback-driven learning on probabilistic reversal learning (PRL) tasks, the specific factors that contribute to these deficits remain unknown. Recent work has suggested several potential causes including neurocognitive impairments, clinical symptoms, and specific types of feedback-related errors. To examine this issue, we administered a PRL task to 126 stable schizophrenia outpatients and 72 matched controls, and patients were retested 4 weeks later. The task involved an initial probabilistic discrimination learning phase and subsequent reversal phases in which subjects had to adjust their responses to sudden shifts in the reinforcement contingencies. Patients showed poorer performance than controls for both the initial discrimination and reversal learning phases of the task, and performance overall showed good test-retest reliability among patients. A subgroup analysis of patients (n = 64) and controls (n = 49) with good initial discrimination learning revealed no between-group differences in reversal learning, indicating that the patients who were able to achieve all of the initial probabilistic discriminations were not impaired in reversal learning. Regarding potential contributors to impaired discrimination learning, several factors were associated with poor PRL, including higher levels of neurocognitive impairment, poor learning from both positive and negative feedback, and higher levels of indiscriminate response shifting. The results suggest that poor PRL performance in schizophrenia can be the product of multiple mechanisms.

Reduced autobiographical memory specificity is associated with impaired discrimination learning in anxiety disorder patients.

Associative learning plays an important role in the development of anxiety disorders, but a thorough understanding of the variables that impact such learning is still lacking. We investigated whether individual differences in autobiographical memory specificity are related to discrimination learning and generalization. In an associative learning task, participants learned the association between two pictures of female faces and a non-aversive outcome. Subsequently, six morphed pictures functioning as generalization stimuli (GSs) were introduced. In a sample of healthy participants (Study 1), we did not find evidence for differences in discrimination learning as a function of memory specificity. In a sample of anxiety disorder patients (Study 2), individuals who were characterized by low memory specificity showed deficient discrimination learning relative to high specific individuals. In contrast to previous findings, results revealed no effect of memory specificity on generalization. These results indicate that impaired discrimination learning, previously shown in patients suffering from an anxiety disorder, may be—in part—due to limited memory specificity. Together, these studies emphasize the importance of incorporating cognitive variables in associative learning theories and their implications for the development of anxiety disorders. In addition, re-analyses of the data (Study 3) showed that patients suffering from panic disorder showed higher outcome expectancies in the presence of the stimulus that was never followed by an outcome during discrimination training, relative to patients suffering from other anxiety disorders and healthy participants. Because we used a neutral, non-aversive outcome (i.e., drawing of a lightning bolt), these data suggest that learning abnormalities in panic disorder may not be restricted to fear learning, but rather reflect a more general associative learning deficit that also manifests in fear irrelevant contexts.

Acute Ethanol Reduces Reversal Cost in Discrimination Learning by Reducing Perseverance in Adolescent Rhesus Macaques

Acute alcohol exposure produces cognitive deficits in adults but less is known about the acute cognitive effects of alcohol in adolescents. The cognitive impact of acute alcohol exposure includes deficits in discrimination and reversal learning, but traditional experimental approaches make it difficult to distinguish the effect of alcohol on discrimination learning from the effect of alcohol on reversal learning. Young rhesus macaques can be used to model some aspects of human adolescence because of their anatomical, neurophysiological, and cognitive similarities with humans. Adolescent male rhesus monkeys (n=10) were trained to respond to visual stimuli on touch-sensitive LCD panels controlled by the nonhuman primate version of CANTAB software. Discrimination and reversal learning tasks were subsequently assessed after monkeys were allowed to consume varying amounts of ethanol (EtOH) in a flavored vehicle (vehicle only, up to 0.5g/kg EtOH, up to 1.0g/kg EtOH, and up to 1.5g/kg EtOH). Acute exposure to EtOH reduced perseverance, increased response accuracy, and reduced errors during reversal learning when the task was completed within 90minutes of EtOH consumption. No reduction in reversal errors was observed when EtOH was consumed 3 or 24hours prior to reversal learning. EtOH only impaired discrimination learning when monkeys had very little previous EtOH exposure. The temporal relationship between EtOH consumption and reversal learning was consistent with selective EtOH-induced impairment of retrieval, but not storage, processes. This was evidenced by diminished perseverance on the previously correct stimulus leading to decreased errors to criterion.

Effects of embryonic light stimulation on the ability to discriminate left from right in the domestic chick

Following an early suggestion by Mach [Mach E. The analysis of sensations. Chicago: Open Court Publishing House; 1897 [reprinted by Dover Publications, 1959]] it has been claimed that brain asymmetry would be crucial for biological organisms in order to discriminate left from right. However, direct evidence in support of this hypothesis is scanty. In the animal system model provided by the newly hatched domestic chick ( Gallus gallus) it has been proved feasible to manipulate lateralization on visual tasks by exposing the eggs to light for a brief period before hatching. The light exposure leads to the development of lateralization of some visual functions and generates asymmetry in the thalamofugal visual projections to the forebrain, because the late-stage embryo is turned in the egg so that it occludes its left but not its right eye. Thus, it is possible to obtain organisms with strong (light-incubated chicks, Li-chicks) or weak (dark-incubated chicks, Di-chicks) lateralization. Li- and Di-chicks were trained to discriminate between two small beads for food reward on the basis of their relative left–right position. Li-chicks performed better than Di-chicks. In order to check whether Di-chicks showed a general impairment in discrimination learning, not confined to left–right discrimination only, chicks were tested in a spatial re-orientation task in a square-shaped arena, in which a target located in a corner could be identified using the left–right location of a conspicuous cue (the colour of a wall) which could be used as a landmark. Results showed that Di-chicks were impaired with respect to Li-chicks in use of left–right information for re-orientation, but not in use of the cue as a landmark. These results provide direct evidence that modulation of the strength of visual lateralization may affect left–right discrimination abilities.

Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder

Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discriminative learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger cues. Importantly, this discrimination deficit was driven by enhanced startle-potentiation to the learned safety cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety cues.

Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit

N-Methyl-D-aspartate receptors (NMDARs) mediate certain forms of synaptic plasticity and learning. We used a touchscreen system to assess NR2A subunit knockout mice (KO) for (1) pairwise visual discrimination and reversal learning and (2) acquisition and extinction of an instrumental response requiring no pairwise discrimination. NR2A KO mice exhibited significantly retarded discrimination learning. Performance on reversal was impaired in NR2A KO mice during the learning phase of the task; with no evidence of heightened perseverative responses. Acquisition and extinction of an instrumental behavior requiring no pairwise discrimination was normal in NR2A KO mice. The present findings demonstrate a significant and selective deficit in discrimination learning following loss of NR2A.

Monkey Perirhinal Cortex is Critical for Visual Memory, but not for Visual Perception: Reexamination of the Behavioural Evidence from Monkeys

Overdependence on discrimination learning paradigms to assess the function of perirhinal cortex has complicated understanding of the cognitive role of this structure. Impairments in discrimination learning can result from at least two distinct causes: (a) failure to accurately apprehend and represent the relevant stimuli, or (b) failure to form and remember associations between stimulus representations and reward. Thus, the results of discrimination learning experiments do not readily differentiate deficits in perception from deficits in learning and memory. Here I describe studies that do dissociate learning and memory from perception and show that perirhinal cortex damage impairs learning and/or memory, but not perception. Reanalysis and reconsideration of other published data call into further question the hypothesis that the monkey perirhinal cortex plays a critical role in visual perception.

Impairments in visual discrimination learning and recognition memory produced by neurotoxic lesions of rhinal cortex in rhesus monkeys.

Much work on the cognitive functions of the primate rhinal (i.e. entorhinal plus perirhinal) cortex has been based on aspiration lesions of this structure, which might disrupt fibres passing nearby and through the rhinal cortex in addition to removing the cell bodies of the rhinal cortex itself. To determine whether damage limited to the cell bodies of the rhinal cortex is sufficient to impair visual learning and memory, four rhesus monkeys (Macaca mulatta) were preoperatively trained on a battery of visual learning and memory tasks, including single-pair discrimination learning for primary reinforcement, single-pair discrimination reversals, concurrent discrimination learning and reversal, and delayed matching-to-sample. Following acquisition of these tasks and a preoperative performance test, ibotenic acid was injected bilaterally into the rhinal cortex, and the monkeys were retested. Consistent with the results of studies using aspiration lesions, the monkeys were impaired on single-pair discrimination learning as well as recognition memory performance postoperatively, although reliable reversal learning impairments were not observed. The magnitude of postoperative impairment in discrimination learning was not correlated with the magnitude of postoperative impairment in recognition memory, suggesting a possible dissociation between these functions within the rhinal cortex. The correspondence of behavioural deficits following aspiration and neurotoxic lesions of the rhinal cortex validates the attribution of various cognitive functions to this structure, based on the results of studies with aspiration lesions.

Effects of prenatal exposure to cocaine on the developing brain: anatomical, chemical, physiological and behavioral consequences.

Earlier studies of human infants and studies employing animal models had indicated that prenatal exposure to cocaine produced developmental changes in the behavior of the offspring. The present paper reports on the results obtained in a rabbit model of in utero exposure to cocaine using intravenous injections (4 mg/kg, twice daily) that mimic the pharmacokinetics of crack cocaine in humans. At this dose, cocaine had no effect on the body weight gain of dams, time to delivery, litter size and body weight or other physical characteristics of the offspring. In spite of an otherwise normal appearance, cocaine-exposed neonates displayed a permanent impairment in signal transduction via the D1 dopamine receptor in caudate nucleus, frontal cortex and cingulate cortex due to an uncoupling of the receptor from its associated Gs protein. This uncoupling in the caudate nucleus was shown to have behavioral consequences in that young or adult rabbits, exposed to cocaine in utero, failed to demonstrate amphetamine-elicited motor responses normally seen after activation of D1 receptors in the caudate. The cocaine progeny also demonstrated permanent morphological abnormalities in the anterior cingulate cortex due to uncoupling of the D1 receptor and the consequent inability of dopamine to regulate neurite outgrowth during neuronal development. Consistent with the known functions of the anterior cingulate cortex, adult cocaine progeny demonstrated deficits in attentional processes. This was reflected by impairment in discrimination learning during classical conditioning that was due to an inability to ignore salient stimuli even when these were not relevant to the task. The impairment in discrimination learning also occurred in an instrumental avoidance task and could be shown to be due to an impairment of cingulothalamic learning-related neuronal coding. It was proposed that the selective loss of D1-related neurotransmission in the anterior cingulate cortex prevented an appropriate activation of GABA neurons and thus a loss of inhibitory regulation that is necessary for processes involved in associative attention. Taken together, these findings suggest that the uncoupling of the D1 receptor from its G protein may be the fundamental source of the anatomic, cognitive and motor disturbances seen in rabbits exposed to cocaine in utero. Moreover, the long-term cognitive and motor deficits observed in the rabbit model are in agreement with the recent reports indicating that persistent attentional and other behavioral deficits may be evident in cocaine-exposed children as they grow older and are challenged to master more complex cognitive tasks.

P03.442 Impaired conditional discrimination learning in patients with social phobia

P03.442 Impaired conditional discrimination learning in patients with social phobia

Structural and functional neuropathology in transgenic mice with CNS expression of IFN-α

Cytokines belonging to the type I interferon (e.g. interferon-α) family are important in the host response to infection and may have complex and broad ranging actions in the central nervous system (CNS) that may be beneficial or harmful. To better understand the impact of the CNS expression of the type I interferons (IFN), transgenic mice were developed that produce IFN-α 1 chronically from astrocytes. In two independent transgenic lines with moderate and low levels of astrocyte IFN-α mRNA expression respectively, a spectrum of transgene dose- and age-dependent structural and functional neurological alterations are induced. Structural changes include neurodegeneration with loss of cholinergic neurons, gliosis, angiopathy with mononuclear cell cuffing, progressive calcification affecting basal ganglia and cerebellum and the up-regulation of a number of IFN-α-regulated genes. At a functional level, in vivo and in vitro electrophysiological studies revealed impaired neuronal function and disturbed synaptic plasticity with pronounced hippocampal hyperexcitability. Severe behavioral alterations were also evident in higher expressor GFAP-IFNα mice which developed fatal seizures around 13 weeks of age precluding their further behavioral assessment. Modest impairments in discrimination learning were measured in lower expressor GFAP-IFNα mice at various ages (7–42 weeks). The behavioral and electrophysiological findings suggest regional changes in hippocampal excitability which may be linked to abnormal calcium metabolism and loss of cholinergic neurons in the GIFN mice. Thus, these transgenic mice provide a novel animal model in which to further evaluate the mechanisms that underlie the diverse actions of type I interferons in the intact CNS and to link specific structural changes with functional impairments.

Chronic cerebral hypoperfusion disrupts discriminative behavior in acquired-learning rats

We describe an `acquired-learning' rat model that was used to investigate the effects of chronic cerebral hypoperfusion on the maintenance of previously acquired discriminative behavior using the discriminating learning task. Male Wistar rats, aged 11 weeks, were trained to discriminate between lamp-on and lamp-off states under an operant-type learning procedure. After 30 sessions, we selected `acquired-learning' rats with an average discrimination ratio higher than 75% recorded during the last three sessions. Chronic hypoperfusion was then induced by permanent ligation of both common carotid arteries under pentobarbital anesthesia. The rats were tested after surgery over a period of 12 weeks and brain tissue was analyzed for muscarinic acetylcholine receptor (mACh-R) binding. Cerebral hypoperfusion resulted in a significant reduction in the discrimination ratio throughout the observation period, compared with sham-operated rats. However, chronic hypoperfusion would not affect on motor function. The maximum number of mACh-R examined 12 weeks after the operation was significantly reduced in the frontal cortex and hippocampus in the hypoperfusion group. Impaired discrimination learning was associated with a reduction in mACh-R. Our findings suggest that chronic cerebral hypoperfusion in acquired-learning rats is a useful model for investigating the pathophysiology of dementia and that cortical and/or hippocampal cholinergic systems contributes to learning impairment, at least, in our learning task.

Prenatal Cocaine Exposure: Long-Term Deficits in Learning and Motor Performancea.

We have developed a rabbit model of in utero exposure to intravenous injections of cocaine given twice daily to dams from gestational days 8-29. At the doses employed (4 mg/kg, injected twice daily), no differences were found in the body weight gain of dams, time to delivery, litter size, and body weight or other physical characteristics of the offspring. However, cocaine-exposed pups displayed an abnormal structural and neurochemical development of the anterior cingulate cortex which persisted into adulthood. In agreement with the known functions of the anterior cingulate cortex, we found that adult, sexually mature rabbits, exposed to cocaine prenatally, demonstrate impairments in motor function, alterations in associative learning and severe impairments in discrimination learning. Moreover, the alterations in discrimination learning were interpreted to be due to deficits in attentional processes. Specifically, cocaine progeny preferentially attend to more salient stimuli even when these are not relevant to the task. Consequently they have difficulty in attending to less salient but relevant stimuli when more salient but irrelevant stimuli occur in the same context. We concluded that the learning deficits are a reflection of the morphologic and neurochemical abnormalities of the anterior cingulate cortex. Alterations in dopamine function of the caudate nucleus may also contribute to the deficits in motor performance.

Acetylcholine in the hippocampus during the discrimination learning performance in a rat model of chronic cerebral ischaemia.

Acetylcholine (ACh) release in the hippocampus of Wistar strain rats with permanent bilateral occlusion of the common carotid arteries was examined during a discrimination learning task using a microdialysis method. Such occlusion resulted in obvious impairment of the discrimination performance. The state, the basal value and released patterns, of ACh in the hippocampus differed in the sham-operated control and the experimental group, while ACh release was elevated during the dialysis experiment in both groups. These findings suggested that the bilateral occlusion produced persistent learning deficits from an early stage after the operation and that the impaired discrimination learning performance might be related to the diffusion of ACh in the hippocampus.

Prenatal exposure to cocaine disrupts discrimination learning in adult rabbits

Previous studies had shown that intrauterine exposure to cocaine produces an increase in the number of immunoreactive GABA neurons and abnormal dendritic structure of pyramidal cells in the anterior cingulate cortex, a brain region known to be involved in attentional processes and discrimination learning. Because structural abnormalities might be expected to produce related functional deficits, we examined whether intrauterine exposure to cocaine would affect discrimination learning in adult rabbits. We previously reported that cocaine progeny undergoing concurrent acquisition to visual and auditory CSs show a normal rate of learning to a light CS and an accelerated rate of learning to a tone. Here, we report that adult, Dutch-belted rabbits exposed to cocaine in utero showed impaired discrimination learning when responding to a positive visual cue but not when responding to a positive auditory cue. The nature of the deficit consisted of an impaired ability to acquire learned responses to the visual CS + rather than in an impaired ability to withhold responses to the auditory CS−. Given that auditory stimuli tend to be more salient than visual stimuli in the normal rabbit, the preceding pattern of results suggests that intrauterine cocaine exposure affected the ability to preferentially attend to less salient but relevant stimuli and to ignore more salient, irrelevant stimuli. More importantly, these results indicate that prenatal exposure to cocaine produces neurobehavioral abnormalities which persist into adult life.

Neonatal exposure to triethyltin disrupts olfactory discrimination learning in preweanling rats

Triethyltin is an organotin compound that is known to produce neurotoxicity in both adult and developing organisms. Although this neurotoxicity has been documented with a variety of behavioral and biological measures, the effects of this compound on learning during early development have been less extensively studied. The present study reports four experiments that examined this question with an odor aversion learning paradigm in which pups received presentations of one odor paired with footshock and an alternate odor without shock. In Experiment 1, Long-Evans rat pups were injected IP on postnatal day 5 (PND 5) with either 0, 3 or 5 mg/kg TET and then tested for olfactory discrimination learning on PND 18. Only the 5-mg/kg dose impaired discrimination learning. In Experiment 2, PND 5 exposure to TET (5 mg/kg) disrupted olfactory learning on PND 18 but not on PND 12, whereas exposure on PND 10 disrupted learning at both ages of testing. In Experiment 3, PND 16 exposure to TET (5 mg/kg) also disrupted acquisition of olfactory learning on PND 18 but had no effect on retention of an olfactory discrimination that was acquired prior to TET exposure (i.e., on PND 14 and PND 15). Unconditioned responses to footshock were also unaffected by TET (Experiment 4). These findings indicate that neonatal exposure to TET impairs associative learning in developing rats and are discussed in relation to other studies of the developmental neurotoxicity of this compound.