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Translational Rodent Models of Korsakoff Syndrome Reveal the Critical Neuroanatomical Substrates of Memory Dysfunction and Recovery

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Abstract

Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

AChE-I:

Acetylcholinesterase inhibitor

AT:

Anterior thalamus

ATN:

Anterior thalamic nuclei

BDNF:

Brain-derived neurotrophic factor

ChAT:

Choline acetyltransferase

DNMTS:

Delayed non-matching-to-sample

DMTS:

Delayed matching-to-sample

EAS:

Early acute stage

IML:

Intralaminar

KS:

Korsakoff syndrome

LAS:

Late acute stage

MAS:

Middle acute stage

MB:

Mammillary bodies

MTP:

Matching-To-Position

MTS:

Matching-To-Sample

NeuN:

Neuronal-Specific nuclear protein

NMTP:

Non-Matching-To-Position

NMTS:

Non-Matching-To-Sample

PTD:

Pyrithiamine-induced thiamine deficiency

TD:

Thiamine deficiency

TPP:

Thiamine pyrophosphate

WE:

Wernicke’s encephalopathy

WKS:

Wernicke-Korsakoff syndrome

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Acknowledgements

We would like to thank Ryan Vetreno for assistance with photographs of the brain. This research was funded by grants NINDS 054272 and ARRA NINDS 054272-S1 to LMS.

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Authors and Affiliations

  1. Behavioral Neuroscience Program, Department of Psychology, State University of New York at Binghamton, Binghamton, NY, 13902, USA

    Lisa M. Savage & Joseph M. Hall

  2. Laboratorio de Neurociencia e Comportamento, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-010, Brazil

    Leticia S. Resende

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  1. Lisa M. Savage
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  2. Joseph M. Hall
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  3. Leticia S. Resende
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Correspondence to Lisa M. Savage.

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Savage, L.M., Hall, J.M. & Resende, L.S. Translational Rodent Models of Korsakoff Syndrome Reveal the Critical Neuroanatomical Substrates of Memory Dysfunction and Recovery. Neuropsychol Rev 22, 195–209 (2012). https://doi.org/10.1007/s11065-012-9194-1

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