Cognition and neural circuits involved in schizophrenia

Schizophrenia patients suffer from a broad spectrum of deficits in cognition, which have a conspicuous depressing influence on the social and occupational functions of the patient (Green, 1996). Before discussing further with respect to the neural circuit deficits speculated to be responsible for cognitive and the other symptoms of schizophrenia, it will first briefly be discussed what is mean by learning and memory.

2.1.2.1. Learning, memory and LTP

Memory can be categorised in two types; it can be either procedural memory (also referred to as non-declarative or implicit memory) or declarative memory (also referred to as explicit memory). These phrases have been described in the preparatory project, see part ‘2.1.5. Cognition, Memory and Hippocampus’, but briefly procedural memory is the unconscious memory learned through repetition of a certain performance and includes classical conditioning (the association of a reward e.g. a biscuit with a tone,

where the tone provokes the reflex responses associated with the biscuit after a number of tone and biscuit ‘pairings’), whereas declarative memory is the conscious memory of facts (sematic memory) or events (episodic memory) (Delcomyn, 1998). Declarative memory also includes working memory, which is categorised as a higher level cognitive function (Baddely, 1982) that for example includes the ability to create and explain strategies and solve problems. Additionally, memory can be classified as either short-tem or long-term. (Delcomyn, 1998). Procedural memory is primarily associated with structures in the cerebellum and basal ganglia (reviewed in Thompson et al., 1994; Saint-Cyr et al., 1998), while the hippocampus has an important role in declarative memory (Squire et al., 1991) and especially in working memory (Olton et al., 1979) together with the prefrontal cortex (Milner et al., 1985).

Learning and memory processes alter the structure and function of nerve cells and their connections (Wenzel et al., 1980), a phenomenon referred to as plasticity. The nerve cells involved are not specialised ‘memory cells’, but often the sensory neurons, which following a stimulus via synaptic connection affects motor neurons or interneurons (Bear et al., 2001). The simplest learning-processes are named habituation, sensitisation and conditioning (Bear et al., 2001). Habituation and conditioning are terms closely connected to the fear conditioning experiment, which has been executed in this project and in which the freezing of the rats is measured. Fear conditioning is observed when an animal over one or a few trials learns to associate a conditioned stimulus (a neutral stimulus) with an unconditioned stimulus (an electric foot shock) and subsequently starts to respond (i.e.

freeze) when it is presented with the previously neutral but now conditioned stimuli, see part ‘2.1.5. Cognition, Memory and Hippocampus’ and part ‘2.3.3. Fear Conditioning’

in the preparatory project. The unconditioned stimulus activates interneurons that via axo-axonic connections influence sensory neurons of the conditioned stimuli. If the unconditioned stimulus activates these sensory neurons immediately after they are stimulated by the conditioned stimulus it causes an elevated presynaptic facilitation and an increased presynaptic firing(Ibid.).

Declarative learning is an even more complex form of learning than procedural learning and is dependent on the hippocampus, which is important for the storage of declarative memory. In the storage process, different afferent pathways are involved, which starts in the entorhinal cortex, running through the CA1 region and ending in the pyramidal cells of the CA3 region of the hippocampus. If a brief high frequency

stimulus enters these pathways an elevated excitatory postsynaptic potential in the hippocampus will be established, which could last for hours or weeks and provoke sustained presynaptic action potentials (Bliss et al., 1973; Bear et al., 2001). This is named Long-Term Potentiation (LTP) and is thought to be the basic mechanism underlying formation and the storage of declarative memory. LTP occurs in many parts of the brain including the hippocampus as mentioned above and the prefrontal cortex (Laroche et al., 1990). In addition, the hippocampus is important in spatial memory and the recognition of a familiar environment (Morris et al., 1982; Morris et al., 1996).

2.1.2.2. Corticolimbothalamic circuit deficits

The most consistent finding in association to schizophrenia is the impairment of higher cognitive functions (reviewed byGreen, 1996) that require active information processing, and which include sustained selective attention, executive functions, working memory, language skills, and motor processing (reviewed by Antonova et al., 2004). Imaging studies of cerebral blood flow and metabolic activity of schizophrenia patients has shown decreases in activity in the prefrontal cortex, hippocampus, striatum, nucleus accumbens, and thalamus (reviewed by Morris et al., 2005). The deficit in processing of memory and working memory is related to the prefrontal cortex and important in the pathology of schizophrenia. The prefrontal cortex does not function individually, but is part of corticolimbothalamic circuits which runs from different parts of the prefrontal cortex to different parts of striatum, pallidum, thalamus and thereafter returning to the prefrontal cortex; the latter are also influenced by the hippocampus (Ibid.) (see figure 2.3).

These forebrain circuits are thought to participate in the regulation of pre-pulse inhibition, which is a useful tool in the study of information processing and gating mechanisms (sensorimotor gating) (reviewed by Braff et al., 2001). Pre-pulse inhibition of the acoustic startle response is seen as an attenuation of the startle response, when prior to the startle eliciting stimulus a weaker, non-startle-provoking stimulus occurs (reviewed by Geyer et al., 2001). The acoustic startle response is depressed for about one second by the pre-pulse and mediated by active neuronal inhibitory processes (Davis, 1979). Back in 1978 it was reported that schizophrenia patients showed impairment in the normal inhibition of the acoustic startle response after presentation of a pre-pulse (reviewed by Hamm et al., 2001), and today the evidence for impairment of pre-pulse inhibition in schizophrenic patients is accumulating (

2001). See section ‘2.3.1.2. Pre-pulse inhibition’, where pre-pulse inhibition is described further, since the model is used in the experimental part of this project.

Even more interesting than the decreased activity in forebrain structures of schizophrenic patients is the robust and consistent finding of reduced metabolic activity observed in schizophrenic patients when they are executing cognitive tasks, and the correlation of these reductions with the severity of the cognitive and negative symptoms in the individual patients (reviewed by Morris et al., 2005).

Chronic exposure to PCP has been reported to produce dopamine hypofunction in the dorsolateral prefrontal cortex of monkeys and long-lasting cognitive deficits. These were ameliorated by the atypical antipsychotic clozapine, which does not have strong D2 receptor antagonist properties (Jentsch et al., 1997). Dysfunction of the amygdala is also considered to contribute to cognitive abnormalities. In post mortem studies of schizophrenic patients substantial histopathological alterations in the CA2 and CA3 areas of hippocampus have been observed (Falkai et al., 1986; Jeste et al., 1989; Benes et al., 1998), which is suggested to be induced by amygdala dysfunction (Benes et al., 2000). Grace and Rosenkranz made in 1999 a study with rats which suggested that the prefrontal cortex inhibits projecting neurons in the amygdala and that this inhibition was induced by activation of dopamine receptors in amygdala (Rosenkranz et al., 1999); but more research is needed concerning the role of amygdala in cognition and schizophrenia (Antonova et al., 2004).

Overall, it is suggested that schizophrenia and cognitive impairments are associated to dysfunction in the corticolimbothalamic circuit and hypofunction of glutamatergic activity, and that the cognitive deficits include dopaminergic hypoactivity in the dorsolateral prefrontal cortex. The activity of this circuit is strongly regulated by GABAergic interneurons (reviewed by Morris et al., 2005), which will be presented in section

‘2.1.3.1. GABAergic interneurons’.