Lisa M. Savage

Thiamine deficiency in rats produces cognitive and memory deficits on spatial tasks that correlate with tissue loss in diencephalon, cortex and white matter

Exploratory activity, spontaneous alternation, learning and memory abilities were examined in the pyrithiamine-induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoffs syndrome and pair-fed controls (CT). PTD and CT animals showed normal retention of a single trial of a passive avoidance task acquired prior to the acute stages of thiamine deficiency. While there were no significant group differences in spontaneous activity, PTD animals with extensive damage to internal medullary lamina (IML-lesioned) of thalamus and mammillary body nuclei demonstrated a significant decrease in spontaneous alternation and were significantly impaired in learning both the initial spatial non-matching-to-position (NMTP) task and the reverse MTP task. PTD animals without IML damage (IML-spared) were only impaired on the acquisition of NMTP. Examination of response patterns suggest that the learning impairment was related to an inability to adopt or shift to the appropriate response rule. Performance of PTD IML-lesioned animals on NMTP mixed-delay sessions (4, 30, 60, 90 s) was similar to controls and PTD IML-spared, but was significantly lower on MTP delay trials. These IML-lesioned rats also had significant reductions in thickness of frontal and parietal cortex, corpus callosum and severe neuronal loss in anterior and reticular thalamic nucleic. Four PTD IML-lesioned animals that were unable to learn the NMTP task had more extensive cortical, white matter and thalamic damage than the PTD IML-lesioned animals that did learn the task. These results demonstrate that thiamine deficiency in the rat produces behavioral changes ranging from mild cognitive deficits to severe learning and memory impairments. Pathologic damage following a bout of thiamine deficiency also varies from neuronal loss in select thalamic nuclei to tissue loss in large regions of thalamus, mammillary bodies and cortex. Learning and memory deficits are closely related to the degree of cortical and diencephalic damage.

Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats

Serotonin 1A receptor (5-HT(1A)R) agonists reduce both L-DOPA- and D1 receptor (D1R) agonist-mediated dyskinesia, but their anti-dyskinetic mechanism of action is not fully understood. Given that 5-HT(1A)R stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT(1A)R agonists may diminish dyskinesia in part through modulation of pro-dyskinetic striatal glutamate levels. To test this, rats with unilateral medial forebrain bundle dopamine or sham lesions were primed with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, sc) or the D1R agonist SKF81297 (0.8 mg/kg, sc) until abnormal involuntary movements (AIMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT(1A)R agonist ±8-OH-DPAT (1.0 mg/kg, sc), followed by L-DOPA or SKF81297, or intrastriatal ±8-OH-DPAT (7.5 or 15 mM), followed by L-DOPA. In some cases, the 5-HT(1A)R antagonist WAY100635 was employed to determine receptor-specific effects. In vivo microdialysis was used to collect striatal samples for analysis of extracellular glutamate levels during AIMs assessment. Systemic and striatal ±8-OH-DPAT attenuated L-DOPA-induced dyskinesia and striatal glutamate efflux while WAY100635 reversed ±8-OH-DPATs effects. Interestingly, systemic ±8-OH-DPAT diminished D1R-mediated AIMs without affecting glutamate. These findings indicate a novel anti-dyskinetic mechanism of action for 5-HT(1A)R agonists with implications for the improved treatment of Parkinsons disease.

Alcohol-related amnesia and dementia: Animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment

Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol-related neurological disorders, alcohol-associated dementia and Wernicke-Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models--from repeated and chronic ethanol exposure to thiamine deficiency--is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone.

The effects of lesions to thalamic lateral internal medullary lamina and posterior nuclei on learning, memory and habituation in the rat

The behavioral effects of radiofrequency lesions to the lateral internal medullary lamina region (IML) or the posterior region (Po: containing the parafascicular and posterior nuclei) of the thalamus were compared to sham operated controls. Subjects were pre-operatively trained and then tested for post-operative retention of a NMTP task. Whereas the Po-lesion group was impaired only on long delays (60, 90 s), the IML-lesion group was impaired on retention and re-acquisition and demonstrated lower performance at all delays (5-90 s) of the NMTP task. Post-operative training and testing was conducted on three additional tasks: Morris water maze, acoustic startle, and passive avoidance. The IML-lesion group was impaired in finding a hidden and visual platform in the Morris water maze, demonstrated a blunted response but normal habituation to an acoustic startle stimulus, and showed normal retention of a passive avoidance task. On those three tasks, the performance of the Po-lesion group was similar to controls. In the IML-lesion group, neuronal loss resulting from axotomy and/or transneuronal degeneration was observed within nuclei of the midline and anterior thalamus and the mammillary body. These results suggest that lesions to the IML region disrupt a range of cognitive functions and produce pathological destruction in distant brain regions; whereas damage to the posterior thalamus causes spatial delay-sensitive deficits.

Microdialysis measures of functional increases in ACh release in the hippocampus with and without inclusion of acetylcholinesterase inhibitors in the perfusate

Because brain extracellular acetylcholine (ACh) levels are near detection limits in microdialysis samples, an acetylcholinesterase (AChE) inhibitor such as neostigmine is often added to microdialysis perfusates to increase ACh levels in the dialysate, a practice that raises concerns that the inhibitor might alter the results. Two experiments compared functional differences in ACh release with and without neostigmine. In the first experiment, 30–60% increases in extracellular ACh concentrations in the hippocampus were evident during food‐rewarded T‐maze training with 20–500 nm neostigmine in the perfusate but no increases were seen without neostigmine. In the second experiment, 78% increases in ACh release in the hippocampus were seen after injections of the GABAA receptor antagonist, bicuculline, into medial septum only if neostigmine (50 nm) was included in the perfusate. These findings suggest that, in the hippocampus, endogenous brain AChEs are very efficient at removing extracellular ACh, obscuring differences in ACh release in these experiments. Therefore, inclusion of AChE inhibitors in the microdialysis perfusate may be necessary under some conditions for observations of functional changes in release of ACh in the hippocampus.

Differential outcomes attenuate memory impairments on matching-to-position following pyrithiamine-induced thiamine deficiency in rats

Numerous studies have demonstrated that rats with pyrithiamine-induced thiamine deficiency (PTD) have extensive diencephalic damage and are severely impaired at acquiring new tasks that require the use of “working memory.” The differential outcomes (DO) procedure, which correlates specific reinforcers with specific discriminative stimuli, improves performance of normal subjects on various conditional discrimination tasks. The present study revealed that, relative to PTD rats’ receiving uncorrelated reinforcers, implementing the DO procedure in the T-maze version of matching-to-position completely eliminated the PTD learning deficit. These results suggest that utilizing different information processing systems in brain-damaged subjects may reduce their memory impairments.

Reward expectation alters learning and memory : The impact of the amygdala on appetitive-driven behaviors

The capacity to seek and obtain rewards is essential for survival. Pavlovian conditioning is one mechanism by which organisms develop predictions about rewards and such anticipatory or expectancy states enable successful behavioral adaptations to environmental demands. Reward expectancies have both affective/motivational and discriminative properties that allow for the modulation of instrumental goal-directed behavior. Recent data provide evidence that different cognitive strategies (cue-outcome associations) and neural systems (amygdala) are used when subjects are trained under conditions that allow Pavlovian-induced reward expectancies to guide instrumental behavioral choices. Furthermore, it has been demonstrated that impairments typically observed in a number of brain-damaged models are alleviated or eliminated by embedding unique reward expectancies into learning/memory tasks. These results suggest that Pavlovian-induced reward expectancies can change both behavioral and brain processes.

In search of the neurobiological underpinnings of the differential outcomes effect

Correlating unique rewards with to-be-remembered events (the Differential Outcomes Procedure [DOP]) enhances learning and memory performance in a range of species. Recently, we have demonstrated that the DOP can be used to reduce or eliminate the learning and memory impairments associated with animal models of amnesia and dementia. This powerful phenomenon, the Differential Outcomes Effect (DOE), has led to the question: How does such a simple manipulation exert such dramatic influence on learning and memory performance? A revised two-process account of the DOE states that using the DOP results in the activation of reward expectancies through Pavlovian mechanisms. The use of unique reward expectancies alters the nature of cognitive processing used to solve discrimination tasks. The change in cognitive processing is represented by utilization of a different memory system than that commonly used to acquire and remenber information when a Nondifferential Outcomes Procedure (NOP) is used. Using neurochemical manipulations, it has been demonstrated that different, potentially independent, brain systems modulate memory performance when subjects are trained with a NOP versus a DOP. This memory-based DOP/NOP distinction resembles other dissociative memory theories in which two psychological processes are purportedly served by distinct neurobiological mechanisms. In addition, such results have important ramifications for the treatment of memory disorders because they demonstrate that stimulus and behavioral manipulations, like drugs, can influence neurotransmitter functioning.

Aging potentiates the acute and chronic neurological symptoms of pyrithiamine-induced thiamine deficiency in the rodent.

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.

MEMORY ENHANCEMENT IN AGED RATS : THE DIFFERENTIAL OUTCOMES EFFECT

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.