Dataset Information

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

ABSTRACT: Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.

SUBMITTER: Johnson AW

PROVIDER: S-EPMC3725079 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

Johnson Alexander W AW Jaaro-Peled Hanna H Shahani Neelam N Sedlak Thomas W TW Zoubovsky Sandra S Burruss Daniel D Emiliani Francesco F Sawa Akira A Gallagher Michela M

Proceedings of the National Academy of Sciences of the United States of America 20130709 30

Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxida ...[more]

PMID: 23840059

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Project description:Neuropsychiatric illnesses are associated with dysfunction in distributed prefrontal neural systems that underlie perception, cognition, social interactions, emotion regulation, and motivation. The high degree of learning-dependent plasticity in these networks-combined with the availability of advanced computerized technology-suggests that we should be able to engineer very specific training programs that drive meaningful and enduring improvements in impaired neural systems relevant to neuropsychiatric illness. However, cognitive training approaches for mental and addictive disorders must take into account possible inherent limitations in the underlying brain 'learning machinery' due to pathophysiology, must grapple with the presence of complex overlearned maladaptive patterns of neural functioning, and must find a way to ally with developmental and psychosocial factors that influence response to illness and to treatment. In this review, we briefly examine the current state of knowledge from studies of cognitive remediation in psychiatry and we highlight open questions. We then present a systems neuroscience rationale for successful cognitive training for neuropsychiatric illnesses, one that emphasizes the distributed nature of neural assemblies that support cognitive and affective processing, as well as their plasticity. It is based on the notion that, during successful learning, the brain represents the relevant perceptual and cognitive/affective inputs and action outputs with disproportionately larger and more coordinated populations of neurons that are distributed (and that are interacting) across multiple levels of processing and throughout multiple brain regions. This approach allows us to address limitations found in earlier research and to introduce important principles for the design and evaluation of the next generation of cognitive training for impaired neural systems. We summarize work to date using such neuroscience-informed methods and indicate some of the exciting future directions of this field.

Project description:Background: The interaction between neuropsychiatric symptoms, mild cognitive impairment (MCI), and dementia is complex and remains to be elucidated. An additive or multiplicative effect of neuropsychiatric symptoms such as apathy or depression on cognitive decline has been suggested. Unraveling these interactions may allow the development of better prevention and treatment strategies. In the absence of available treatments for neurodegeneration, a timely and adequate identification of neuropsychiatric symptom changes in cognitive decline is highly relevant and can help identify treatment targets. Methods: An existing memory clinic-based research database of 476 individuals with MCI and 978 individuals with dementia due to Alzheimer's disease (AD) was reanalyzed. Neuropsychiatric symptoms were assessed in a prospective fashion using a battery of neuropsychiatric assessment scales: Middelheim Frontality Score, Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD), Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale (30 items). We subtyped subjects suffering from dementia as mild, moderate, or severe according to their Mini-Mental State Examination (MMSE) score and compared neuropsychiatric scores across these groups. A group of 126 subjects suffering from AD with a significant cerebrovascular component was examined separately as well. We compared the prevalence, nature, and severity of neuropsychiatric symptoms between subgroups of patients with MCI and dementia due to AD in a cross-sectional analysis. Results: Affective and sleep-related symptoms are common in MCI and remain constant in prevalence and severity across dementia groups. Depressive symptoms as assessed by the CSDD further increase in severe dementia. Most other neuropsychiatric symptoms (such as agitation and activity disturbances) progress in parallel with severity of cognitive decline. There are no significant differences in neuropsychiatric symptoms when comparing "pure" AD to AD with a significant vascular component. Conclusion: Neuropsychiatric symptoms such as frontal lobe symptoms, psychosis, agitation, aggression, and activity disturbances increase as dementia progresses. Affective symptoms such as anxiety and depressive symptoms, however, are more frequent in MCI than mild dementia but otherwise remain stable throughout the cognitive spectrum, except for an increase in CSDD score in severe dementia. There is no difference in neuropsychiatric symptoms when comparing mixed dementia (defined here as AD + significant cerebrovascular disease) to pure AD.

Dataset Information

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

Publications

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.

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