Helen J. Cassaday

The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia

Latent inhibition (LI) consists in a retardation of conditioning seen when the to-be-conditioned stimulus is first presented a number of times without other consequence. Disruption of LI has been proposed as a possible model of the cognitive abnormality that underlies the positive psychotic symptoms of acute schizophrenia. We review here evidence in support of the model, including experiments tending to show that: (1) disruption of LI is characteristic of acute, positively-symptomatic schizophrenia; (2) LI depends upon dopaminergic activity; (3) LI depends specifically upon dopamine release in n. accumbens; (4) LI depends upon the integrity of the hippocampal formation and the retrohippocampal region reciprocally connected to the hippocampal formation; (5) the roles of n. accumbens and the hippocampal system in LI are interconnected.

5,7-Dihydroxytryptamine lesions in the fornix—fimbria attenuate latent inhibition

When animals are preexposed to a stimulus without consequence they are subsequently slower to associate this stimulus with an important event, such as footshock. This retarding effect of stimulus preexposure is called latent inhibition and can be demonstrated in a variety of classical and instrumental paradigms and in a wide range of species, including man. Latent inhibition is disrupted in acute schizophrenics and by amphetamine treatment in both rat and man. The present study investigated the role of hippocampal 5HT terminals in latent inhibition using a conditioned suppression procedure with male Sprague-Dawley rats. Microinjections of 5,7-dihydroxytryptamine in the fornix-fimbria significantly reduced hippocampal indoleamine levels and attenuated latent inhibition of conditioned suppression. This finding supports the hypothesis that the destruction of mesolimbic 5-hydroxytryptamine terminals reduces latent inhibition. This result is discussed in terms of the possible involvement of reduced serotonergic function in schizophrenic attentional disorder. In addition to the predicted lesion effect, biochemical analyses indicated that experimental treatments in the latent inhibition procedure altered neurotransmitter turnover: utilization ratios for 5-hydroxytryptamine and/or dopamine were increased in preexposed relative to nonpreexposed animals in four of the six brain regions sampled.

The effects of ritanserin, RU 24969 and 8-OH-DPAT on latent inhibition in the rat

When animals are exposed to a stimulus that has no consequences they are subsequently impaired in learning that this stimulus predicts an important event, such as footshock. This retarding effect of stimulus pre-exposure is called latent inhibition (LI) and is reliably disrupted by amphetamine, antipsychotics having an opposite effect. The present experiments investigated whether agents which affect serotonergic transmission also attenuate LI, using a conditioned suppression of drinking procedure. The results showed that the 5-HT2 antagonist ritanserin (2.0 mg/kg), and the 5-HT1b agonist RU 24969 (0.5 and 10.0 mg/kg) attenuated LI by increasing learning in pre-exposed animals, whilst the effects of the 5-HT1a agonist 8-OH-DPAT (0.38 mg/kg), though in a similar direction, were not significant. These experiments provide partial support for the involvement of serotonin in LI. Since amphetamine-induced attenuation of LI has been proposed as a model for the attentional deficits found in acute schizophrenia, these results are discussed in terms of the possible involvement of reduced serotonergic function in schizophrenic attentional disorder.

Fornix^fimbria section and working memory deficits in rats: Stimulus complexity and stimulus size.

Rats were trained on delayed matching-to-sample (DMS) with goalboxes containing complex objects as stimuli. On reaching the preoperative learning criterion, the rats were allocated to conventional fornix-lesioned or control groups. In a series of postoperative DMS experiments, different kinds of stimuli were used, ranging from complex object boxes to large, simple black or white goalboxes, with 3 transitional types in between. Lesions impaired choice accuracy whenever the rats were tested with large, simple goalboxes, but not with smaller boxes of otherwise identical construction. A brief, final experiment showed no amelioration of the lesion-induced impairment when complex objects were added to large, simple goalboxes. The results are discussed in terms of spatial and nonspatial accounts of hippocampal function.

Odour and Proustian memory: reduction of context-dependent forgetting and multiple forms of memory

In Experiment 1, the reintroduction of the same ambient odour (lemon or lavender) improved performance four weeks later in both free recall and recognition of a word list. This was a cross-over design that allowed direct comparison between congruent and incongruent odour conditions. A further comparison with an additional group showed that memory was not improved by the presence of a different odour. Experiment 2 investigated the effect of two odour cues (lemon and lavender) in the same cross-over design using three learning and memory tests: (1) free recall of a word list; (2) problem solving; and (3) spatial learning. While recall of the word list and spatial learning were best when the same odour was present at both learning and test, there was no such context-dependent effect for the problem-solving task. However, the presence of the lavender odour at test improved performance in the problem-solving task, irrespective of the odour present at the first exposure. Thus although lavender had some effect on problem solving, we saw context-dependent retrieval only in free recall and spatial learning. We discuss the implications of this dissociation. Copyright

Amphetamine increases aversive conditioning to diffuse contextual stimuli and to a discrete trace stimulus when conditioned at higher footshock intensity.

Amphetamine can increase conditioning to poor predictors of reinforcement in selective learning tasks (e.g. latent inhibition, LI). In the present study, a noise stimulus was contiguous with footshock or presented at a trace interval. A flashing light background stimulus was used to measure contextual conditioning. Experiment 1 used 1.5 mg/kg and 6 mg/kg dl-amphetamine. Experiments 2 and 3 used 0.5 mg/kg and 1.5 mg/kg d-amphetamine. Unconditioned stimuli parameters (intensity, number, duration) were also manipulated from one experiment to the next. Amphetamine consistently increased conditioning to the background stimulus, and increased conditioning to the trace stimulus at higher footshock intensity (Experiment 3). Thus, amphetamine increased conditioning only to relatively uninformative predictors. The effect on conditioning to trace conditioned stimuli depended on the level of reinforcer but increased conditioning to background did not. Throughout, there was no effect of amphetamine on conditioning of the contiguous stimulus. Thus, the results did not simply arise because amphetamine increased conditioning under any condition in which conditioning without amphetamine was poor. The results are discussed in terms of amphetamine effects on breadth of attention and LI to context.

Electrolytic lesions to nucleus accumbens core and shell have dissociable effects on conditioning to discrete and contextual cues in aversive and appetitive procedures respectively.

The nucleus accumbens (n. acc.) has been implicated in conditioning to both discrete and contextual cues but its precise role is as yet controversial because conflicting patterns of effect have been reported. These inconsistencies may relate to the extent to which the lesions used encroach on different subfields of n. acc. and the use of different task variants. The present study compared the effects of selective lesions of shell and core subfields of nucleus accumbens (n. acc.) across aversive and appetitive trace conditioning variants. In both experiments, an auditory stimulus was contiguous with footshock or food, or presented at a trace interval. A continuous flashing light in each case provided an experimental background stimulus. Conditioning to the cues provided by the experimental chambers was also assessed. Rats with electrolytic lesions to the n. acc. shell and core showed different patterns of effect in aversive (Experiment 1) and appetitive (Experiment 2) variants of this procedure. In Experiment 1, the core lesion reduced the difference between trace and contiguously conditioned groups, in responding to the discrete noise stimulus. However, neither lesion had any detectable effect on contextual conditioning. In Experiment 2, the shell lesion clearly increased contextual conditioning, selectively in the trace conditioned group, but neither lesion had any detectable effect on discrete cue conditioning. Thus, whilst the shell and core lesions produced dissociable effects on discrete cue and contextual conditioning, the conclusions to be drawn depend on the procedural variant in use.

From attention to memory along the dorsal-ventral axis of the medial prefrontal cortex: some methodological considerations

Distinctions along the dorsal-ventral axis of medial prefrontal cortex (mPFC), between anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) sub-regions, have been proposed on a variety of neuroanatomical and neurophysiological grounds. Conventional lesion approaches (as well as some electrophysiological studies) have shown that these distinctions relate to function in that a number behavioral dissociations have been demonstrated, particularly using rodent models of attention, learning, and memory. For example, there is evidence to suggest that AC has a relatively greater role in attention, whereas IL is more involved in executive function. However, the well-established methods of behavioral neuroscience have the limitation that neuromodulation is not addressed. The neurotoxin 6-hydroxydopamine has been used to deplete dopamine (DA) in mPFC sub-regions, but these lesions are not selective anatomically and noradrenalin is typically also depleted. Microinfusion of drugs through indwelling cannulae provides an alternative approach, to address the role of neuromodulation and moreover that of specific receptor subtypes within mPFC sub-regions, but the effects of such treatments cannot be assumed to be anatomically restricted either. New methodological approaches to the functional delineation of the role of mPFC in attention, learning and memory will also be considered. Taken in isolation, the conventional lesion methods which have been a first line of approach may suggest that a particular mPFC sub-region is not necessary for a particular aspect of function. However, this does not exclude a neuromodulatory role and more neuropsychopharmacological approaches are needed to explain some of the apparent inconsistencies in the results.

Dissociable Roles of Dopamine Within the Core and Medial Shell of the Nucleus Accumbens in Memory for Objects and Place

There is increasing focus on the role of the nucleus accumbens (NAc) in learning and memory, but there is little consensus as to how the core and medial shell subregions of the NAc contribute to these processes. In the current experiments, we used spontaneous object recognition to test rats with 6-hydroxydopamine lesions targeted at the core or medial shell of the NAc on a familiarity discrimination task and a location discrimination task. In the object recognition variant, control animals were able to discriminate the novel object at both 24-hr and 5-min delay. However, in the lesion groups, performance was systematically related to dopamine (DA) levels in the core but not the shell. In the location recognition task, sham-operated animals readily detected the object displacement at test. In the lesion groups, performance impairment was systematically related to DA levels in the shell but not the core. These results suggest that dopamine function within distinct subregions of the NAc plays dissociable roles in the modulation of memory for objects and place.

Theoretical Accounts of Gulf War Syndrome: From Environmental Toxins to Psychoneuroimmunology and Neurodegeneration

Non-specific illness includes a wide variety of symptoms: behavioural (e.g., reduced food and water intake), cognitive (e.g., memory and concentration problems) and physiological (e.g., fever). This paper reviews evidence suggesting that such symptoms can be explained more parsimoniously as a single symptom cluster than as a set of separate illnesses such as Gulf War Syndrome (GWS) and chronic fatigue syndrome (CFS). This superordinate syndrome could have its biological basis in the activity of pro-inflammatory cytokines (in particular interleukin-1: IL-1), that give rise to what has become known as the ‘sickness response’. It is further argued that the persistence of non-specific illness in chronic conditions like GWS may be (in part) attributable to a bio-associative mechanism (Ferguson and Cassaday, 1999). In the case of GWS, physiological challenges could have produced a non-specific sickness response that became associated with smells (e.g., petrol), coincidentally experienced in the Persian Gulf. On returning to the home environment, these same smells would act as associative triggers for the maintenance of (conditioned) sickness responses. Such associative mechanisms could be mediated through the hypothalamus and limbic system via vagal nerve innervation and would provide an explanation for the persistence of a set of symptoms (e.g., fever) that should normally be short lived and self-limiting. We also present evidence that the pattern of symptoms produced by the pro-inflammatory cytokines reflects a shift in immune system functioning towards a (T-helper-1) Th1 profile. This position contrasts with other immunological accounts of GWS that suggest that the immune system demonstrates a shift to a Th2 (allergy) profile. Evidence pertaining to these two contrasting positions is reviewed.