ABSTRACT
The present study aimed to assess the role of advanced age in the development and manifestation of thiamine deficiency using an animal model of Wernicke-Korsakoff syndrome (WKS). Interactions between pyrithiamine-induced thiamine deficiency (PTD) and age were examined relative to working memory impairment and neuropathology in Fischer 344 rats. Young (2-3 months) and aged (22-23 months) F344 rats were assigned to one of two treatment conditions: PTD or pair-fed control (PF). Rats in the former group were further divided into three groups according to duration of PTD treatment. Working memory was assessed with an operant matching-to-position (MTP) task; after testing, animals were sacrificed and both gross and immunocytochemical measures of brain pathology were obtained. Aged rats exhibited acute neurological disturbances during the PTD treatment regime earlier than did young rats, and also developed more extensive neuropathology with a shorter duration of PTD. Aged rats displayed increased brain shrinkage (smaller frontal cortical and callosal thickness) as well as enhanced astrocytic activity in the thalamus and a decrease in ChAT-positive cell numbers in the medial septum; the latter two measures of neuropathology were potentiated by PTD. In both young and aged rats, and to a greater degree in the latter group, PTD reduced thalamic volume. Behaviorally, aged rats displayed impaired choice accuracy on the delayed MTP task. Regardless of age, rats with lesions centered on the internal medullary lamina of the thalamus also displayed impaired choice accuracy. Moreover, increased PTD treatment duration led to increased response times on the delayed MTP task. These results suggest that aging does indeed potentiate the neuropathology associated with experimental thiamine deficiency, supporting an age coupling hypothesis of alcohol-related neurological disorders.
Subject(s)
Korsakoff Syndrome/physiopathology , Mental Recall/physiology , Thiamine Deficiency/physiopathology , Wernicke Encephalopathy/physiopathology , Age Factors , Animals , Brain/pathology , Brain/physiopathology , Korsakoff Syndrome/chemically induced , Korsakoff Syndrome/pathology , Male , Mental Recall/drug effects , Pyrithiamine , Rats , Rats, Inbred F344 , Thiamine Deficiency/chemically induced , Thiamine Deficiency/pathology , Wernicke Encephalopathy/chemically induced , Wernicke Encephalopathy/pathologyABSTRACT
Aged (23 months) and young (3 months) rats were trained on an operant Matching-To-Position (MTP) task that had either (a) specific outcomes (reinforcers) correlated (differential groups), or (b) outcomes uncorrelated (nondifferential groups) for each correct sample-choice sequence. The traditional version of MTP uses a common outcome and is thought to assess spatial working memory. Aged rats are impaired on the traditional version of MTP. However, aged animals trained with the Differential Outcomes Procedure (DOP) did not display the typical age-related decline in spatial working memory. Differences in choice accuracy between old and young rats reached significance only if the subjects were trained with a nondifferential outcomes procedure (NOP)-similar to when a common outcome is used. These data demonstrate that employing behavioral procedures to tap intact cognitive functions is an effective means of enhancing spatial working memory in normal as well as aged subjects.
Subject(s)
Aging/physiology , Behavior, Animal/physiology , Conditioning, Operant , Memory/physiology , Animals , Discrimination Learning/physiology , Male , RatsABSTRACT
Pyrithiamine-induced thiamine deficiency (PTD), which has been used as a model of Wernicke-Korsakoff syndrome (WKS), produces a range of neuropathological and behavioral abnormalities in rodents. The extent of the diencephalic damage produced by this treatment varies from moderate to extreme cell loss. The magnitude of working memory impairment tends to correlate with the degree of neuropathology. In this study a PTD protocol that produces moderate thalamic pathology was used to gain further insight into the neurobehavioral consequences of thiamine deficiency. Towards this end, two distinct manipulations were conducted. First, the differential outcomes procedure (DOP), which correlates specific reinforcers with specific to-be-remembered events, was applied to an operant version of matching-to-position (MTP). This behavioral manipulation was conducted to determine if the DOP would improve memory performance in PTD-treated rats, demonstrating some intact cognitive functions. Additionally, to assess the functional integrity of the cholinergic and glutamatergic systems, normal and PTD-treated rats were administered i.p. injections of scopolamine and MK-801. It was found that the DOP enhanced memory, but not acquisition performance, in both normal and PTD-treated rats. Furthermore, when administered scopolamine, but not MK-801, rats trained with the DOP continued to outperform rats trained with a non-differential outcomes procedure (NOP). However, PTD-treated rats, regardless of training procedure (DOP, NOP), were more disrupted by the 'amnestic' effects of both scopolamine and MK-801. The differential sensitivity of treatment groups to the amnestic effects of scopolamine and MK-801 reveals insights into the neurochemical correlates of memory processes and WKS.
