Abstract
Despite substantial effort and immense need, the treatment options for major neuropsychiatric illnesses like schizophrenia are limited and largely ineffective at improving the most debilitating cognitive symptoms that are central to mental illness. These symptoms include cognitive control deficits, the inability to selectively use information that is currently relevant and ignore what is currently irrelevant. Contemporary attempts to accelerate progress are in part founded on an effort to reconceptualize neuropsychiatric illness as a disorder of neural development. This neuro-developmental framework emphasizes abnormal neural circuits on the one hand, and on the other, it suggests there are therapeutic opportunities to exploit the developmental processes of excitatory neuron pruning, inhibitory neuron proliferation, elaboration of myelination, and other circuit refinements that extend through adolescence and into early adulthood. We have crafted a preclinical research program aimed at cognition failures that may be relevant to mental illness. By working with a variety of neurodevelopmental rodent models, we strive to identify a common pathophysiology that underlies cognitive control failure as well as a common strategy for improving cognition in the face of neural circuit abnormalities. Here we review our work to characterize cognitive control deficits in rats with a neonatal ventral hippocampus lesion and rats that were exposed to Methylazoxymethanol acetate (MAM) in utero. We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain's cognitive circuitry.
Highlights
Schizophrenia is a complex mental disorder with varying degrees of severity
We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain’s cognitive circuitry
We have chosen to utilize three neurodevelopmental rodent models to examine the hypothesis that poor cognitive control is a result of failed neural coordination, manifest as inappropriate temporal organization of neural electrical activity within and between neural circuits
Summary
Schizophrenia is a complex mental disorder with varying degrees of severity. One of the most debilitating deficits in schizophrenia patients is impoverished cognitive control, the inability to ignore irrelevant information while using relevant information to complete a task (Nuechterlein et al, 2008). We have chosen to utilize three neurodevelopmental rodent models to examine the hypothesis that poor cognitive control is a result of failed neural coordination, manifest as inappropriate temporal organization of neural electrical activity within and between neural circuits. This neural discoordination hypothesis is agnostic to the etiology of the discoordination. The hypothesis predicts that if neural coordination can be restored, cognitive function will be restored We are investigating this hypothesis using different neurodevelopmental models because the disease is increasingly thought to have diverse neurodevelopmental origins. Because altering neurodevelopment likely alters a host of nonspecific, or even unidentified factors within the brain, the ability to overcome the functional consequences of abnormal development is quite compelling, especially if compensation for neural discoordination may be achieved without having to target, study, or reverse the original neurodevelopmental insult
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