Delayed Spatial Alternation Research Articles

Lack of selective developmental neurotoxicity in rat pups from dams treated by gavage with chlorpyrifos.

Pregnant Sprague-Dawley rats were given chlorpyrifos (O:, O-diethyl-O:-[3,5,6-trichloro-2-pyridinyl] phosphorothioate; CPF) in corn oil by gavage from gestation day 6 (GD 6) through lactation day 10 (LD 10) at dosages of 0, 0.3, 1, or 5 mg/kg/day in a developmental neurotoxicity study that conformed to U.S. Environmental Protection Agency 1991 guidelines. GD 0 was the day when evidence of mating was observed and postnatal day 0 (PND 0) was the day of birth. Toxicity was limited to the highest dosage level (5 mg/kg/day) and, in the dams, consisted of muscle fasciculation, hyperpnea, and hyperreactivity. A nonsignificant overall trend toward weight gain and feed consumption was also observed in the high-dosage dams, with a statistically significant Group x Time interaction for reduced weight gain in the 5-mg/kg/day group near the end of gestation. Although many developmental indices were normal, pups from high-dosage dams had increased mortality soon after birth, gained weight more slowly than controls, and had several indications of slightly delayed maturation. The early deaths and delayed maturation were attributed to maternal toxicity, though a possible contributing role of direct pup toxicity in delayed development cannot be eliminated. In spite of the apparent delay in physical development, high-dosage pups tested just after weaning had normal learning and memory as tested on a T-maze spatial delayed-alternation task. Habituation, a primitive form of learning, was tested in 2 tasks (motor activity and auditory startle) and was not affected. No overt effects were noted in either dams or pups at 1 or 0.3 mg/kg/day. Based on these data, chlorpyrifos produced maternal and developmental toxicity in the 5-mg/kg/day-dosage group. There was no evidence of selective developmental neurotoxicity following exposure to chlorpyrifos.

Effects of age and gender but not prenatal cocaine on random ratio and delayed spatial alternation responding in rats

This investigation employed a longitudinal analysis of rat operant behavior under two different schedules of reinforcement following prenatal exposure to cocaine. Offspring were derived from four maternal exposure groups: 50 mg/kg cocaine, their pair-fed controls, 25 mg/kg cocaine, and freely fed controls. Cocaine was administered via gavage from gestation day 6–20. A maternal fostering procedure was used. Pairs of male and female littermates were assigned to a 7-, 14-, or 21-month cohort and at the appropriate age were trained to respond on one lever in a two-lever operant chamber. Reinforcement was delivered with a series of random ratio (RR) schedules where the RR value was increased across sessions. After RR training, animals were examined with a delayed spatial alternation (DSA) procedure in the same chambers. Male offspring responded at higher rates than females during high-probability RR schedules, whereas advancing age was associated with lower response rates during low-probability RR schedules in both males and females. Prenatal cocaine exposure exerted only limited effects on RR responding during transition and did not affect DSA behavior. The results of this longitudinal analysis suggest that prenatal cocaine does not exert global or far-reaching learning deficits in prenatally exposed rats.

The cerebellum and cognition: cerebellar lesions do not impair spatial working memory or visual associative learning in monkeys.

Anatomical studies in non-human primates have shown that the cerebellum has prominent connections with the dorsal, but not the ventral, visual pathways of the cerebral cortex. Recently, it has been shown that the dorsolateral prefrontal cortex (DPFC) and cerebellum are interconnected in monkeys. This has been cited in support of the view that the cerebellum may be involved in cognitive functions, e.g. working memory. Six monkeys (Macaca fascicularis) were therefore trained on a classic test of working memory, the spatial delayed alternation (SDA) task, and also on a visual concurrent discrimination (VCD) task. Excitotoxic lesions were made in the lateral cerebellar nuclei, bilaterally, in three of the animals. When retested after surgery the lesioned animals were as quick to relearn both tasks as the remaining unoperated animals. However, when the response times (RT) for each task were directly compared, on the SDA task the monkeys with cerebellar lesions were relatively slow to decide where to respond. We argue that on the SDA task animals can prepare their responses between trials whereas this is not possible on the VCD task, and that the cerebellar lesions may disrupt this response preparation. We subsequently made bilateral lesions in the DPFC of the control animals and retested them on the SDA task. These monkeys failed to relearn the task. The results show that, unlike the dorsal prefrontal cortex, the cerebellum is not essential for working memory or the executive processes that are necessary for correct performance, though it may contribute to the preparation of responses.

Effects of Predator-Induced Stress and Age on Working Memory in Rats

The effects of age and predator-induced stress, by exposing rats to a cat, were examined during subsequent testing of spatial working memory. Male rats (3 months and 20 months of age) were trained on a spatial delayed-alternation task using an elevated T maze. After subgroups were given intermittent protected-exposure sessions over a 3-day period to cats or to a control condition, they were tested on the working memory task. The old rats took more trials to reach training criterion. Overall, both stress-exposed groups exhibited a decline in accuracy 24 hr later and recovered completely during the subsequent test sessions. Surprisingly, young stressed rats showed significantly greater decrements in accuracy than old stressed rats. However, exposure to the stressor resulted in decreases in response speed that were comparable for both age groups. These findings are discussed in terms of possible changes in glucocorticoids, plasma corticosterone, and endogenous opioids that are known to be affected by age and stress and have been shown to influence spatial working memory.

Prenatal cocaine exposure alters performance in reversal learning and delayed spatial alternation (DSA) tasks: Assessment of inhibitory control, proactive interference, and memory

Prenatal cocaine exposure alters performance in reversal learning and delayed spatial alternation (DSA) tasks: Assessment of inhibitory control, proactive interference, and memory

Spatial delayed alternation of rats in a T-maze: effects of neurotoxic lesions of the medial prefrontal cortex and of T-maze rotations

The medial prefrontal cortex (mPFC) is usually considered to be a brain area important for working memory processes. In rats this statement is evidenced by their diminished performance in delay-type tasks following mPFC damage, notably in spatial delayed alternation (SDA) in a T-maze. This study has addressed two questions. First, to examine whether the functional deficiency in SDA, observed in rats with (usually large) mPFC damage, can be ascribed to an anatomically defined subarea of mPFC, the dorsal anterior cingulate area (AU). Small, bilateral, NMDA-induced lesions were made, restricted to the dorsal part of mPFC. The performance of such animals in a T-maze paradigm, using delays of 0 and 15 s, was compared with sham-operated animals. Although these small lesions resulted in an increased number of perseverative errors, this effect was not delay-dependent, and, moreover, by the end of the training group differences had disappeared. The second aim was to study whether or not spatial (extra-maze) cues are important for the performance of this task. This was achieved by subjecting the well-trained sham-operated animals to a series of systematic trial-to-trial variations in the position of the maze in the experimental room. These spatial manipulations severely impaired the performance of the SDA task, indicating that extra-maze information is required to solve this task. In animals with AU lesions, subjected to the same manipulations, the deficiency was comparable to that of the shamoperated animals.

Dissociation of mnemonic coding and other functional neuronal processing in the monkey prefrontal cortex.

Single-neuron activity was recorded in the prefrontal cortex of three monkeys during the performance of a spatial delayed alternation (DA) task and during the presentation of a variety of visual, auditory, and somatosensory stimuli. The aim was to study the relationship between mnemonic neuronal processing and other functional neuronal responsiveness at the single-neuron level in the prefrontal cortex. Recordings were performed in both experimental situations from 152 neurons. The majority of the neurons (92%) was recorded in the prefrontal cortex. Nine of the neurons were recorded in the dorsal bank of the anterior cingulate sulcus and two in the premotor cortex. Of the total number of neurons recorded in the prefrontal area, 32% fired in relation to the DA task performance and 39% were responsive to sensory stimulation or to the movements of the monkey outside of the memory task context. Altogether 42% of the recorded neurons were neither activated by the various stimuli nor by the DA task performance. Three types of task-related neuronal activity were recorded: delay related, delay and movement related, and movement related. The majority of the task-related neurons (n = 33, 73%) fired in relation to the delay period. Of the delay-related neurons, 26 (79%) were spatially selective. The number of spatially selective delay-related neurons of the whole population of recorded neurons was 18%. Twelve task-related neurons (27%) fired in relation to the response period of the DA task. Five of these neurons changed their firing rate during the delay period and were classified as delay/movement-related neurons. Contrary to the delay-related neurons, less than half (42%) of the response-related neurons were spatially selective. The majority (70%) of the delay-related neurons could not be activated by any of the sensory stimuli used and did not fire in relation to the movements of the monkey. The remaining portion of the delay-related neurons was activated by stationary and moving visual stimuli or by visual fixation of an object. In contrast to the delay-related neurons, the majority (66%) of the task-related neurons firing in relation to the movement period were also responsive to sensory stimulation outside of the task context. The majority of these neurons responded to visual stimulation, visual fixation of an object, or tracking eye movements. One neuron gave a somatomotor and another a polysensory response. The majority (n = 37, 67%) of all neurons responding to stimulation outside of the task context did not fire in relation to the DA task performance. The majority of their responses was elicited by visual stimuli or was related to visual fixation of an object or to eye movements. Only six neurons fired in relation to auditory, somatosensory, or somatomotor stimulation. This study provides further evidence about the significance of the dorsolateral prefrontal cortex in spatial working memory processing. Although a considerable number of all DA task-related neurons responded to visual, somatosensory, and auditory stimulation or to the movements of the monkey, most delay-related neurons engaged in the spatial DA task did not respond to extrinsic sensory stimulation. These results indicate that most prefrontal neurons firing selectively during the delay phase of the DA task are highly specialized and process only task-related information.

Effects of Gestational and Lactational Exposure to TCDD or Coplanar PCBs on Spatial Learning

Recently we reported that in utero and lactational exposure to specific ortho-substituted polychlorinated biphenyl (PCB) congeners resulted in a learning deficit on a delayed spatial alternation (DSA) task in female rats. In this study, spatial learning and memory was assessed following in utero and lactational exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). Time-mated Sprague-Dawley rats were dosed with PCB 77 (3,3′,4,4′-tetrachlorobiphenyl), 2 or 8 mg/kg/day; PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), 0.25 or 1.0 μg/kg/day; TCDD, 0.025 or 0.1 μg/kg/day; or corn oil vehicle via gavage on gestation days 10–16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on an eight-arm radial maze working memory task. The TCDD-exposed rats displayed pronounced decreases in errors relative to controls. PCB 77- and PCB 126-exposed rats showed similar, but less pronounced, decreases in errors. The same animals were later tested on a T-maze DSA task, but no differences among groups were observed. In conclusion, perinatal exposure to low doses of TCDD or structurally related coplanar PCBs appeared to facilitate acquisition of a working memory task on the radial arm maze. This effect was very different from that previously observed in rats exposed to ortho-substituted PCB congeners. The rats exposed to ortho-substituted PCBs did not differ from controls on the radial arm maze and were impaired on the T-maze DSA task. Together these findings suggest that coplanar and ortho-substituted PCBs may have different mechanisms of action on the CNS.

Effects of gestational and lactational exposure to TCDD or coplanar PCBs on spatial learning

Recently we reported that in utero and lactational exposure to specific ortho-substituted polychlorinated biphenyl (PCB) congeners resulted in a learning deficit on a delayed spatial alternation (DSA) task in female rats. In this study, spatial learning and memory was assessed following in utero and lactational exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Time-mated Sprague-Dawley rats were dosed with PCB 77 (3,3′,4,4′-tetrachlorobiphenyl), 2 or 8 mg/kg/day; PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), 0.25 or 1.0 μg/kg/day; TCDD, 0.025 or 0.1 μg/kg/day; or corn oil vehicle via gavage on gestation days 10–16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on an eight-arm radial maze working memory task. The TCDD-exposed rats displayed pronounced decreases in errors relative to controls. PCB 77- and PCB 126-exposed rats showed similar, but less pronounced, decreases in errors. The same animals were later tested on a T-maze DSA task, but no differences among groups were observed. In conclusion, perinatal exposure to low doses of TCDD or structurally related coplanar PCBs appeared to facilitate acquisition of a working memory task on the radial arm maze. This effect was very different from that previously observed in rats exposed to ortho-substituted PCB congeners. The rats exposed to ortho-substituted PCBs did not differ from controls on the radial arm maze and were impaired on the T-maze DSA task. Together these findings suggest that coplanar and ortho-substituted PCBs may have different mechanisms of action on the CNS.

Prelimbic cortex specific lesions disrupt delayed-variable response tasks in the rat.

The role of the prelimbic cortex (PL) in rats was investigated with excitotoxic lesions. PL lesions altered the alternation scores in spontaneous and reinforced spatial delayed-alternation tasks. PL lesions induced a delay in conditioning under a temporal go/no-go alternation schedule but not under a continuous food-reinforcement schedule in a runway. PL lesions had no effect on the acquisition of a standard radial-arm-maze task nor on a fixed-goal location task but disrupted the acquisition of a variable-goal location task in a radial-arm maze. The present results indicate that PL lesions replicated most of the behavioral deficits obtained with larger prefrontal lesions. PL lesions disrupted the acquisition of delayed-variable response tasks while leaving unaffected fixed-response tasks. These results are discussed in relation with a working-memory, a response-selection, and an attentional hypothesis.

Activation of mesocortical dopaminergic system in the rat in response to neonatal medial prefrontal cortex lesions. Concurrence with functional sparing

Neonatal lesions of the medial part of the rat prefrontal cortex (mPFC) (performed at the age of 6 days) resulted in a sparing in the performance of spatial delayed alternation (SDA) and an increase in dopaminergic (DA) innervation. The increased DA innervation was primarily observed in the remaining part of the mPFC. The DA fibre density was considerably higher in the non-ablated part of the mPFC, and the fibres were thicker with more large varicosities compared with sham-operated controls. Biochemical measurements showed a 3.5-fold increase in DA concentration in the remaining part of the mPFC of the animals with neonatal lesions when compared with the mPFC of sham-operated animals. In addition the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased. The metabolite/transmitter ratios, indicating DA utilisation, did not significantly differ from controls. The increased DA innervation and the increased concentration of DA and its metabolites in the animals with neonatal lesions further support our hypothesis that the mesocortical DA system is involved in the neural mechanism of sparing of function observed after neonatal mPFC lesions. However, sparing of function in animals with no discernable mPFC forces us to conclude that this DA response cannot be the only factor involved in the mechanism of sparing of function.

Neocortical Memory Circuits

P.S. GOLDMAN-RAKIC, S. FUNAHASHI, AND C.J. BRUCE Section of Neuroanatomy, Yale University School of Medicine, New Haven, Connecticut 06510 For many decades, the hippocampus and associated limbic areas of the mammalian central nervous system have been the structures most closely associated with (Scoville and Miner 1957; Mishkin 1982; Amaral et al. 1987). Indeed, the hippocampus is essen- tial for acquiring and consolidating new knowledge about events, people, and places. In the unusual cir- cumstance that both medial temporal lobes are dam- aged, as in the famous case of H.M., is re- duced to that acquired before the injury (Scoville and Milner 1957); after suffering this type of injury, an individual is unable to remember most events for even a few minutes. Other areas of the central nervous system are also important for processes. Among these, the prefrontal cortex has been consistently implicated in mnemonic functions (see, e.g., Warrington and Weis- krantz 1982; Fuster 1985; Kesner 1985; Milner et al. 1985), although the precise nature of these functions has been difficult to define. The question naturally arises as to the character of the prefrontal contribution compared to that of other areas and whether and how it differs from these other areas. In this paper, we review our recent studies on the physiological properties of prefrontal neurons engaged in oculomotor tasks (Funahashi et al. 1989, 1990, 1991). An under- standing of the prefrontal contribution to should allow more precise comparisons with that of the hippocampus and other brain regions. Delayed Response: Basic Probe of Short-term Memory Evidence that the prefrontal cortex is involved in processes comes from the well-established, and often repeated, finding that monkeys with bilateral prefrontal lesions, primarily of the dorsolateral princi- pal sulcus (PS) region of the frontal lobe, are severely impaired on delayed-response tasks (for review, see Goldman-Rakic 1987a; Fuster 1989). As their name implies, these tasks employ a temporal delay to sepa- rate the process of encoding a stimulus from the execu- tion of a response to that stimulus. The simple expedi- ent of introducing a time delay forces the monkey to guide its response on the basis of an internal representa- tion, or memory, of the reward location. In the classic version of the task, after the monkey watches a reward being hidden under the cover of one of two food wells, an opaque screen is lowered to prevent the animal from reaching the hidden reward immediately. Following a 1-5-second delay, the screen is raised and selection of one of the locations is then allowed. Since the place- ment of the concealed item is randomly varied from trial to trial, the animal has to continually update his memory; accordingly, what is relevant on trial n be- comes irrelevant on trial n + 1. Distinct from associa- tive memory, this transient process is analo- gous to the process that cognitive psychologists refer to as memory (Just and Carpenter 1985; Bad- deley 1986). Neuronal Elements of Short-term Memory In a remarkable set of studies, in which monkeys performed the delayed-response task while activity was recorded from individual prefrontal neurons, neuro- physiologists have observed neuronal activity in precise registration with the cue, the delay, or response periods of this task, suggesting that separate and distinct neuro- nal populations encode the input, hold, and output functions required in delayed-response tasks (Kubota and Niki 1971; Fuster 1973; Niki 1974c). These results confirm, at a neuronal level, what could be analytically derived; namely, that performance on a delayed- response task involves several levels of information processing: sensory encoding, temporary storage of in- formation, and response execution. It has been hypoth- esized that the prefrontal cortex contains multiple working each dedicated to a differ- ent information-processing domain, and that within these centers, specific classes of neurons are specialized for carrying out the subfunctions necessary to accom- plish an integrated memory-driven act (Goldman- Rakic 1987a, 1988). Issues in the Study of Short-term Memory Although the basic neuronal elements for construc- tion of a cortical circuit have been identified, some of them are complex, and their role in behavior is not well understood. Fuster (1973) identified at least five types of prefrontal activity in monkeys performing a manual delayed-response task. Subsequently, addi- tional neuronal profiles have been described as inves- tigators have employed a variety of behavioral paradigms and/or variations of delayed-response tasks, including spatial delayed-alternation tasks (Kubota and Niki 1971; Niki 1974a,b), nonspatial delay tasks (Kubota et al. 1980; Rosenkilde et al. 1981; Fuster et al. 1982; Quintana et al. 1988; Yajeya et al. 1988), and

Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

TCDD is an extremely toxic chemical pollutant which bioaccumulates in maternal adipose tissue, and is transferred to the developing organism during gestation and lactation. Long-term cognitive deficits have been reported following perinatal exposure to polychlorinated biphenyls, which are structurally and toxicologically similar to TCDD. In the current study, monkeys exposed to TCDD perinatally were later tested in two cognitive paradigms, discrimination-reversal learning (RL) and delayed spatial alternation (DSA). RL detected effects; whereas DSA, as analyzed, did not. RL consisted of a series of simple spatial reversals, followed by spatial reversals with color and shape as irrelevant cues, then by color reversals and finally by shape reversals. TCDD-exposed monkeys exhibited retarded learning of the shape reversals. The deficit was most pronounced on the first reversal following overtraining. There were no group differences on the spatial or color reversals. However, the number of trials the TCDD-exposed monkeys individually took to learn the spatial reversals was positively correlated with TCDD concentration in body fat. Conversely, the number of trials they took to learn the color reversals was negatively correlated wtih TCDD in body fat.

Long-term effects of chronic postnatal lead exposure on delayed spatial alternation in monkeys

Two cohorts of monkeys chronically exposed to lead during the first year after birth and their controls were tested during adulthood for choice accuracy on a learning and memory task, delayed spatial alternation (DSA). Neither cohort showed significant lead-related deficits, as had been seen in a previous experiment with monkeys exposed to similar chronic levels of lead during the first year with an additional high pulse given five-six weeks after birth (18,19). On the contrary, the lead-exposed monkeys in the present experiment actually performed slightly better than controls. In the previous (pulse-chronic) study, the deficit occurred at short intertrial delays, suggesting an attentional rather than mnenomic deficit. A lead-induced decrease in attentiveness could also explain the present results. The lower level lead intoxication may have decreased attentiveness to a lesser degree, so that the monkeys were less susceptible to irrelevant stimuli and performed better.

Delayed spatial alternation deficits resulting from perinatal PCB exposure in monkeys.

Monkeys exposed to low, chronic levels of polychlorinated biphenyls (PCBs) in utero and during nursing until 4 months after birth were tested at 4-6 years of age on delayed spatial alternation (DSA), a spatial learning and memory task. Deficits in performance accuracy were detected in two cohorts of monkeys whose mothers had been fed 2.5 ppm of the PCB mixture, Aroclor 1248, in their diet for an 18-month period ending at least 12 months prior to pregnancy. The deficit was most apparent at the shorter delays, suggesting that it was not due to memory impairment, but may have been due to impairments in associational or attentional processes. There may also have been a deficit in a group of monkeys whose mothers were fed 1.0 ppm of the PCB mixture, Aroclor 1016. However, the deficit in this group was less pronounced than in the other groups. The appearance of a PCB-induced cognitive deficit more than 3 years after the end of exposure indicated the existence of very long-term adverse consequences of low-level perinatal PCB exposure.

Psychopharmacological investigations of a lead-induced long-term cognitive deficit in monkeys.

This study investigated pharmacological manipulations of the cholinergic (ACh) and dopaminergic (DA) transmitter systems in monkeys with a long-term lead-induced cognitive deficit on delayed spatial alternation (DSA). Both ACh and DA have been found to be affected by developmental lead exposure and to be involved with performance on spatial learning and memory tasks. The lead-induced deficit in performance accuracy on DSA persisted throughout the 2 years of this experiment, which ended more than 8 years after the end of the postnatal lead exposure. Acute administration of agonists and antagonists of the ACh and DA systems did not elicit differential effects from the lead-exposed and control groups in terms of DSA per cent correct performance. The ACh antagonist, scopolamine, caused a dose-related decline in performance in both groups. Significant amelioration of the lead-induced DSA deficit was achieved by chronic treatment with the DA agonist, L-dopa. After withdrawal from L-dopa, the lead-related deficit reappeared. Improvement in performance of the lead-treated group was also seen after chronic amphetamine administration, but this effect was not significant. These data implicate DA mechanisms in the long-lasting cognitive effects of developmental lead exposure. The alleviation of the deficit with chronic administration of a DA precursor points to a possible line of treatment for the cognitive effects of developmental lead exposure.

Behavioural responses to diazepam of drug-naive and experienced monkeys (Macaca mulatta).

Effects of 5 mg/kg diazepam given once a week for several weeks to drug-naive and drug-experienced monkeys were studied on a spatial delayed-alternation task. In both groups response latency was increased and the number of correct responses was reduced. The effects were consistent over weeks in the experienced monkeys, but in the naive monkeys there were greater initial effects on response latency and on repeat errors, and these lessened over 2-3 weeks. Thereafter, effects resembled those observed in the experienced group. Results are discussed in terms of the possible factors involved in the development and persistence of tolerance to benzodiazepines.

Activity of the chloro- and triazolo-benzodiazepines: Behavioural studies in the monkey ( Macaca mulatta)

The effects of 1,4-benzodiazepines with various heterocyclic ring structures (triazolo, triazino and imidazo), and of 1,4-benzodiazepines with chlorine substitution in the phenyl ring (4'-chlorodiazepam, 2'-chlorodiazepam and 2'-chloronordiazepam) were studied on spatial-delayed alternation and delayed matching-to-sample tasks in the monkey. Within the dose range 0.25–0.75 mg kg −1, the triazolo compounds had marked activity, decreasing the number of correct responses and increasing total response time. The triazino was less potent and the imidazo compounds were the least likely to disrupt performance. Smaller doses (0.005, 0.01 and 0.05 mg kg −1) of triazolam did not impair performance on the tasks, and larger doses of imidazo (1.0, 3.0 and 7.5 mg kg −1) were without effect on delayed alternation. Within the dose range 1.0–10.0 mg kg −1, 4'-chlorodiazepam was without effect and only the largest dose of diazepam and 2'-chlorodiazepam impaired performance. 2'-chloronordiazepam decreased the number of correct responses at all doses (1.0, 3.0 and 10.0 mg kg −1) and with the largest dose, the total response time was increased. The studies suggest that the effects of a drug on higher nervous function in the monkey cannot easily be predicted from standard pharmacological tests in other animals or other species of monkey.

Retention performance of a learned delayed-alternation task after chemical lesions of the cat's mediodorsal nucleus

The mediodorsal nucleus of the thalamus was lesioned in cats, which had learned a spatial delayed-alternation task. Lesions were carried out with kainic acid or ibotenic acid. From altogether 29 cats, 9 cats with bilateral and 6 cats with unilateral lesions of the mediodorsal nucleus together with a control group of 4 cats, were included in the final data analysis. Lesions in the operated cats destroyed variable portions of the mediodorsal nucleus. Consistently, however, neither the midline nuclei, situated next to the damaged mediodorsal nucleus, nor fiber tracts traversing or by-passing the mediodorsal nucleus, were damaged. Furthermore, remote lesion effects were not detected either in the diazepam-pretreated cats with kainic acid-induced lesions or in the ibotenic acid-lesioned animals. Cats injected with ibotenic acid at a concentration 8-fold higher than the kainic acid solution, showed smaller thalamic lesions than kainic acid-injected cats. A direct correlation was found between the extent of neuronal damage within the mediodorsal nucleus and the degree of the behavioral impairment. Cats with complete or almost complete bilateral lesions of the mediodorsal nucleus manifested severe deficits in retention of the delayed-alternation task, while cats with small, bilateral lesions of the mediodorsal nucleus or with unilateral lesions were impaired less severely or even not at all.

Delayed-alternation performance after kainic acid lesions of the thalamic mediodorsal nucleus and the ventral tegmental area in the rat

The relative importance of two subcortical structures, projecting to the rat's prefrontal cortex, in mediation of delayed-alternation performance, was tested. These structures, the thalamic mediodorsal nucleus and the ventral tegmental area, were lesioned with kainic acid after the rats had learned a spatial delayed-alternation task. It was found that both structures are apparently involved to a similar degree in the performance of this task and that the behavior of both experimental groups differed from that of a sham-operated control group of rats.