On the Role of Thalamic Pathology in Diencephalic Amnesia

Abstract

Although it is now accepted that medial diencephalic lesions can produce severe amnesia in humans, the specific nuclei and neural pathways that must be damaged to impair memory have not yet been identified. Recent studies have shown that pyrithiamine-induced thiamine deficiency (PTD) in the rat can produce a consistent pattern of pathology in the thalamus and mammillary bodies and result in permanent impairments on behavioral measures of working memory. Behavioral deficits comparable to the PTD model have been observed in rats with thalamic lesions involving lateral portions of the internal medullary lamina (the L-IML site). Such impairments are not observed following lesions of limbic-related pathways associated with the fornix, mammillary bodies, or midline thalamus. The L-IML lesion affects the mediodorsal nucleus (MDn) and both the intralaminar and paralaminar non-specific thalamic nuclei. The relationship between the non-specific thalamic nuclei and working memory is underscored by the limited behavioral effects of MDn lesions, as compared to either L-IML or PTD-induced lesions, and by anatomical analyses of PTD-related pathology, which seems to destroy the non-specific nuclei while sparing large portions of the MDn. Recent physiological studies of thalamocortical processes suggest that there are several possible mechanisms by which the non-specific nuclei might participate in memory and by which lesions in these pathways might interfere with the consolidation of memories within the cortex.

Blunted hippocampal, but not striatal, acetylcholine efflux parallels learning impairment in diencephalic-lesioned rats

“…In both the human disease of Wernicke-Korsakoff's syndrome (WKS) and the animal model of this disorder [pyrithiamine-induced thiamine deficiency (PTD)] the long-term cognitive impairment is associated with damage to the midline thalamus and mammillary bodies caused by thiamine deficiency (Kopelman, 1995;Mair, 1994;Victor, Adams, & Collins, 1971). However, the cognitive impairment and sparing of function observed in WKS is related to the hippocampal-dependent nature of the assessment task.…”

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

“…Damage to certain nuclei and fiber systems within the diencephalon interrupts the flow of information between key memory structures and thus causes severe and long-lasting amnesia [25,29,45]. Although there is evidence that lesions to particular diencephalic nuclei result in memory impairment in their own right, there is also evidence that damage to diencephalic nuclei can disrupt memory circuits leading to dysfunction in other regions of the brain [4,29,45,49,53].Corresponding author: Lisa M. Savage, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, 13902, e-mail: lsavage@binghamton.edu, fax: 607-777-4890. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

“…Furthermore, these authors found that acetylcholinesterase (AChE) activity was decreased in both the hippocampus and cortex after PTD treatment [42]. In addition, compounds that enhance ACh levels decrease mortality and sickness behaviors (attacking, antinociception, altered startle response) as well as improve learning in thiaminedeficient mice [36] and spontaneous alternation in PTD-treated rats [unpublished data].Reviews of the pathology produced by the PTD treatment have consistently demonstrated that although mild to moderate cell loss occurs outside the diencephalon, the anterior and midline thalamic damage are critical and responsible for the majority of the loss of learning and memory function that occurs after thiamine deficiency [26,29]. These changes, along with the white matter loss that occurs in key fiber tracts from the diencephalon after PTD treatment [27], suggest that thiamine deficiency likely causes system level dysfunction.…”

“…In cases of diencephalic amnesia associated with thiamine deficiency (i.e., WernickeKorsakoff Syndrome [WKS]) there is neuronal loss and lesions in multiple limbic thalamic nuclei, mammillary bodies [25,26,28,29], as well as degeneration in key fiber tracts connecting limbic structures [fornix and mammillothalamic tract; 24,27]. The damage to both key diencephalic nuclei and fiber tracts likely results in a "disconnection syndrome" within the limbic system [see 2,30,59].…”

“…Reviews of the pathology produced by the PTD treatment have consistently demonstrated that although mild to moderate cell loss occurs outside the diencephalon, the anterior and midline thalamic damage are critical and responsible for the majority of the loss of learning and memory function that occurs after thiamine deficiency [26,29]. These changes, along with the white matter loss that occurs in key fiber tracts from the diencephalon after PTD treatment [27], suggest that thiamine deficiency likely causes system level dysfunction.…”