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Impact of precocious functional disruption of the ventral subiculum on the dopaminergic reactivity of the nucleus accumbens in response to diverse pharmacological agents and behavioral situations
Université de Strasbourg, Strasbourg
UMR_S 1114 - Neuropsychologie cognitive et physiopathologie de la schizophrénie
Neuroscience / Neurology Cognitive science 
Full Description:

Project: The proposed subject of thesis concerns the animal modelling of the pathophysiology of schizophrenia. It could allow the development of new therapeutic approaches. A number of data acquired during the last two decades suggests that schizophrenia would result from a functional disconnection between several cerebral integrative regions stemming in many cases from neurodevelopmental failures (Weinberger and Lipska, 1995; Bullmore et al, 1997; Friston, 1998; Lewis and Levitt, 2002; Arnold et al, 2005). The ventral subiculum (SUB), namely seems to be subjected to neurodevelopmental abnormalities in schizophrenia, as suggested by the cytoarchitectural and  morphometric aberrations, in particular in the left hemisphere (Arnold et al, 1995; Arnold, 2000; Rosoklija et al, 2000; Law et al, 2004).The existence in schizophrenia of a functional impairment of the mesencephalic dopaminergic (DA) system, of an unknown origin, is also well accepted (Harrison, 1999; Carlsson et al, 2001). This functional impairment could be related to a cortico-subcortical disconnection involving NMDA receptors (Laruelle et al, 2005). In other respects, numerous data obtained more recently suggest that there is a disturbance of a number of cognitive processes in patients with schizophrenia, reflected in particular by the disruption of latent inhibition (see Lubow and Weiner, 2010). An increase of the DA reactivity to various psychotropic substances such as amphetamine (indirect DA agonist) or ketamine (antagonist of the NMDA glutamatergic receptors), as well as deficits in social interactions are also described in patients with schizophrenia. These indexes would be markers of the positive and negative symptomatology respectively.A functional impairment of the SUB in schizophrenia has been described many years ago. The neuroanatomical and functional abnormalities observed would be the consequences of early disturbances of the brain development occurring during the perinatal period. Therefore, in a pathophysiological perspective, we studied first of all in a latent inhibition paradigm the consequences of the neonatal functional inactivation of the SUB on the behavioral and DA responses at the level of the nucleus accumbens (Meyer et al, 2009 ; Meyer and Louilot, 2011; 2014).In the continuity of the current investigations, in the thesis, to;determine the validity of our animal modelling of the pathophysiology of schizophrenia, the first
aim will be to investigate the reactivity to NMDA receptors antagonists (ketamine, MK-801), of the DA mesencephalic neurons reaching the nucleus accumbens after neonatal inactivation of the SUB by local
microinjection of tetrodotoxin (TTX) in 8-day-old newborn rats. These studies will be carried out first of all in grown-up young male rats of 11 weeks. Secondly, in these animals, the changes in the behavioural and DA responses in different kinds of social interactions will also be studied. Changes in the DA responses will be measured using in vivo voltammetry in freely moving animals. Afterward, with the PhD limit of 3 years, depending on the results obtained during the first part of the thesis the most relevant responses will be investigated in the pospubertal period i.e. at the end of the 7th week for the male rat. This part of the thesis the particular interest of which is brought to light by the clinical data in favour of the beginning of the schizophrenia in the adolescence could allow to identify a predictive marker.

Wished skills: Good training in psychopharmacology as well as in cellular and integrative neurobiology

Expertises which will be acquired during the training:
Stereotaxic surgery in neonate and adult rats

- Local microinjection

- Pharmacological analysis

-Behavioural Tasks

- In vivo voltammetry analyses of dopaminergic variations in freely moving animals

- Classical histological techniques (Nissl staining)

Posted on: 26 June 2015Deadline to apply: 30 September 2015Start Date: 15 October 2015 Duration: 36 months
The Fund category is Not Funded and the salary is Not Specified
in the Alsace Region.

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