Conditioned inhibition in a rodent model of attention-deficit/hyperactivity disorder.

A deficit in inhibition may underlie some of the symptoms of attention-deficit/hyperactivity disorder (ADHD), particularly impulsivity. However, the data on inhibitory deficits in children with ADHD are mixed. Moreover, there has been little characterization of inhibitory processes in animal models of ADHD. Pavlov's conditioned inhibition procedure allows a direct assessment of the inhibitory status of a stimulus via summation and retardation tests. Therefore, in the current study, we examined conditioned inhibition in spontaneously hypertensive rats (SHRs), the most well-validated animal model of ADHD. SHRs and Wistar rats were trained in a simultaneous feature-negative discrimination in eyeblink conditioning. Each session consisted of a mixture of 2 trial types: a tone paired with a periocular stimulation (A+) or a tone and light presented simultaneously without a periocular stimulation (XA-). Both SHRs and Wistars were able to discriminate A+ from XA- trials. In subsequent summation (X presented simultaneously with a different conditioned excitor, B) and retardation (X paired with the periocular stimulation) tests, the presence of inhibition to X was confirmed in both SHRs and Wistars: X reduced responding to B, and X was slow to develop excitation when paired with periocular stimulation. These results are the first to demonstrate Pavlovian conditioned inhibition in SHRs and to use summation and retardation tests to confirm X as a conditioned inhibitor. The data indicate that conditioned inhibition is intact in SHRs; thus, inhibitory processes that do not require prefrontal cortex or cerebellum may be normal in this strain.

Set shifting in a rodent model of attention-deficit/hyperactivity disorder.

Two experiments compared spontaneously hypertensive rats (SHRs; a rodent model of attention-deficit/hyperactivity disorder) and Wistar rats (a normoactive control strain), on the acquisition of a set-shifting strategy. In Experiment 1, SHRs and Wistar rats were equivalent in trials to criterion to learn a brightness or a texture discrimination but SHRs were faster than Wistar rats in shifting to the opposite discrimination when there was 1 or 2 days between the initial discrimination and the shift. In Experiment 2, SHRs and Wistar rats were equivalent in shifting when the shift between discriminations occurred immediately after a criterion had been met in the first discrimination. The results are discussed in terms of a failure of SHRs to store or retrieve an initial discrimination and/or latent inhibition over a delay, leading to faster acquisition of a set-shift. This failure in storage or retrieval may be the result of a hypoactive dopamine system in the prefrontal cortex and nucleus accumbens shell as well as abnormalities in entorhinal cortex in SHRs.

The effects of two forms of physical activity on eyeblink classical conditioning.

Voluntary exercise, in the form of free access to a running wheel in the home cage, has been shown to improve several forms of learning and memory. Acrobatic training, in the form of learning to traverse an elevated obstacle course, has been shown to induce markers of neural plasticity in the cerebellar cortex in rodents. In three experiments, we examined the effects of these two forms of physical activity on delay eyeblink conditioning in rats. In Experiment 1, exercising rats were given 17 days of free access to a running wheel in their home cage prior to 10 days of delay eyeblink conditioning. Rats that exercised conditioned significantly better and showed a larger reflexive eyeblink unconditioned response to the periocular stimulation unconditioned stimulus than rats that did not exercise. In Experiment 2, exercising rats were given 17 days of free access to a running wheel in their home cage prior to 10 days of explicitly unpaired stimulus presentations. Rats that exercised responded the same to tone, light, and periocular stimulation as rats that did not exercise. In Experiment 3, acrobatic training rats were given 15 days of daily training on an elevated obstacle course prior to 10 days of eyeblink conditioning. Activity control rats underwent 15 days of yoked daily running in an open field. Rats that underwent acrobatic training did not differ in eyeblink conditioning from activity control rats. The ability to measure the learned response precisely, and the well-mapped neural circuitry of eyeblink conditioning offer some advantages for the study of exercise effects on learning and memory.

L-kynurenine treatment alters contextual fear conditioning and context discrimination but not cue-specific fear conditioning.

The glia-derived molecule kynurenic acid (KYNA) is an antagonist of alpha7 nicotinic acetylcholine receptors and the glycine(B) binding site on NMDA receptors. KYNA levels are elevated in the brain and cerebrospinal fluid of persons with schizophrenia and Alzheimer's disease, both of which are characterized by deficits in contextual learning and memory. The present study tested the hypothesis that increases in KYNA concentration would impair contextual fear conditioning but spare cue-specific fear conditioning. Rats in each experiment received injections of vehicle solution or l-kynurenine (L-KYN, 100mg/kg), the precursor for KYNA. Administration of L-KYN has been shown to produce clinically relevant increases in KYNA concentration. In Experiment 1, L-KYN-treated rats exhibited impaired contextual fear memory compared to control rats, while fear conditioning to a discrete auditory cue was unaffected. In Experiment 2, rats were trained to discriminate between two different training environments, one in which foot shock was delivered and one that was not paired with foot shock. Although both groups of rats eventually learned the discrimination, learning was slower in L-KYN-treated rats. The results of Experiment 3 demonstrated that the deficits in context discrimination could not be explained by the preferential use of an elemental learning strategy by L-KYN-treated rats. Together, these findings indicate that elevated concentration of endogenous KYNA interferes with contextual learning and memory and support the notion that increased concentration of KYNA may contribute to cognitive dysfunction. In addition, these data provide new insight into how novel 'gliotransmitters' may modulate neuronal function and behavior.

Abnormal topography and altered acquisition of conditioned eyeblink responses in a rodent model of attention-deficit/hyperactivity disorder.

The spontaneously hypertensive rat (SHR) has been suggested as a possible animal model of attention-deficit/hyperactivity disorder (ADHD). Reductions in the volume of the cerebellum and impairments in cerebellar-dependent eyeblink conditioning have been observed in ADHD, prompting investigation into whether SHRs also exhibit eyeblink conditioning impairments. In Experiment 1, SHRs and a control strain, Wistar, were trained on a long-delay eyeblink conditioning task in which a tone conditioned stimulus was paired with a periorbital stimulation unconditioned stimulus (750-ms delay paradigm). SHRs exhibited faster acquisition of eyeblink conditioned responses (CRs) and displayed mistimed (early onset and peak latency) and larger CRs in comparison with Wistar rats. In subsequent extinction training, SHRs were slower to extinguish CRs. The authors conducted Experiment 2 using separate rats to rule out the possibility that the results of Experiment 1 were due to nonassociative responding. SHRs and Wistar rats were presented with explicitly unpaired tone and periorbital stimulation stimuli. There was no evidence of conditioning in either group, nor were there differences between the groups in terms of the number of eyeblink responses elicited by the tone. The current results support the hypothesis of cerebellar abnormalities in this rodent model of ADHD.

Elevations of endogenous kynurenic acid produce spatial working memory deficits.

Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the alpha7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.

Increased concentration of cerebral kynurenic acid alters stimulus processing and conditioned responding.

Kynurenic acid (KYNA) is a tryptophan metabolite synthesized and released by glia and recently shown to be a non-competitive antagonist of alpha7 nicotinic acetylcholine receptors at physiologically relevant concentrations, and NMDA receptors at higher concentrations. KYNA concentration is elevated in individuals with schizophrenia and those with Alzheimer's disease, two populations exhibiting cholinergic-related cognitive impairments. The present study investigated the effects of elevated KYNA concentration on conditioned stimulus processing in rats. For the first 2 days of the experiment, a subset of rats received intracerebroventricular infusions of either KYNA (0.1 microM) or vehicle and were either returned to the home cage or received non-reinforced presentations of a visual stimulus. All rats subsequently received presentations of the same visual stimulus followed by food reward during a 6-day training phase. In vehicle-treated rats, pre-exposure to the visual stimulus reduced orienting behaviour to the light (standing on the hind legs and orienting towards the visual stimulus) when it was later reinforced (i.e., conditioned orienting). In contrast, pre-exposure to the visual cue or 2 days of KYNA pretreatment reduced conditioned orienting behaviour. Finally, the reduction of orienting in KYNA-treated rats following pre-exposure was not as robust as in vehicle-treated rats. These results suggest that elevated KYNA levels can alter specific aspects of attentional processing of environmental stimuli and are discussed in terms of the potential contribution of KYNA to cognitive function and dysfunction.

Stimulus processing and associative learning in Wistar and WKHA rats.

This study assessed basic learning and attention abilities in Wistar-Kyoto hyperactive (WKHA) rats using appetitive conditioning preparations. Two measures of conditioned responding to a visual stimulus, orienting behavior (rearing on the hind legs), and food cup behavior (placing the head inside the recessed food cup) were measured. In Experiment 1, simple conditioning, but not extinction, was impaired in WKHA rats compared with Wistar rats. In Experiment 2, nonreinforced presentations of the visual cue preceded the conditioning sessions. WKHA rats displayed less orienting behavior than Wistar rats but comparable levels of food cup behavior. These data suggest that WKHA rats exhibit specific abnormalities in attentional processing as well as in learning stimulus-reward relationships.

Specific changes in conditioned responding following neurotoxic damage to the posterior parietal cortex.

The central nucleus (CN) of the amygdala and basal forebrain cholinergic projections to the posterior parietal cortex (PPC) are involved in regulating changes in attentional processing of conditioned stimuli. In a previous study, lesions of the CN produced a deficit in conditioned orienting behavior (rearing on the hind legs) when a visual stimulus was paired with food. Unconditioned orienting (rearing to nonreinforced presentations of the stimulus) and conditioned food cup behavior were unaffected. The present study examined the contribution of the PPC to attentional orienting behavior. Damage to the PPC did not affect orienting behavior but produced deficits in food cup behavior. These findings help define the specific contributions of the PPC to attentional processing and associative learning.