Cortical cholinergic abnormalities contribute to the amnesic state induced by pyrithiamine‐induced thiamine deficiency in the rat

Abstract

Although the key neuropathology associated with diencephalic amnesia are lesions to the thalamus and/or mammillary bodies, functional deactivation of the hippocampus and associated cortical regions also appear to contribute to the memory dysfunction. For example, there is loss of forebrain cholinergic neurons and alterations in stimulated acetylcholine (ACh) levels in hippocampus and cortex in animal models of diencephalic amnesia associated with thiamine deficiency. In the present study, the pyrithiamine-induced thiamine deficiency (PTD) rat model was used to assess the functional relationships between thalamic pathology, behavioral impairment, ACh efflux and cholinergic innervation of the hippocampus and cortex. In PTD-treated rats, ACh efflux during behavioral testing was blunted to differing degrees in the hippocampus, medial frontal cortex and the retrospenial cortex. In addition, significant reductions in cholinergic fiber densities were observed in each of those regions. However, only hippocampal cholinergic fiber density correlated significantly with ACh efflux in the same region suggesting that the reduction in cortical ACh efflux in cases of diencephalic amnesia cannot be fully explained by a loss of cholinergic fiber innervation. This notion supports the emerging theory that the functional consequences of the distal effects of lesions go beyond simple deafferentation. Specifically, some frontal cortical regions exhibit hypersensitivity to deafferentation that is only detected during behavioral and/or physiological demand.

Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior

“…We employed the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder KS because of its high face and construct validity in replicating neuropathology and behavioral impairment (Savage et al, 2012). Although the hallmark neuropathology in both the PTD model, and KS, is neuronal loss in the anterior and midline thalamus as well as the mammillary bodies, there is a significant loss (30–40%) loss of MS/DB cholinergic neurons with concomitant reductions in cholinergic innervation of the hippocampus that leads to blunted hippocampal behaviorally-stimulated ACh efflux (Anzalone et al, 2010; Savage et al, 2007; Schliebs and Arendt, 2011). Furthermore, the PTD model is responsive to cholinergic modulation: increasing cholinergic tone within the septohippocampal circuit reduces or eliminates the amnestic profile of the PTD model (Roland et al, 2010; Roland et al, 2008).…”

Interactions Between Chronic Ethanol Consumption and Thiamine Deficiency on Neural Plasticity, Spatial Memory, and Cognitive Flexibility

“…These cognitive deficits have been attributed to the extensive cell loss that occurs within the diencephalon, in particular the lesions that occur within the thalamus and mammillary bodies (Mair, 1994). This diencephalic damage leads to circuit level dysfunction within the hippocampus as well as the frontal cortex (Anzalone et al, 2010). These structural and functional lesions induced by PTD are coupled with a loss of cholinergic neurons in the medial septum/diagonal band (≈30%) that together produce a severe amnestic state (Roland and Savage, 2009).…”

The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat

“…This series of studies provided evidence that if cholinergic tone is increased conjointly across the PFC and HPC, by co-infusing regionally effective doses of physostigmine, the traditional spatial memory deficit observed on spontaneous alternation is eliminated in the PTD model. This was predicted given previous work demonstrating that acetylcholine levels in the HPC or FC/PFC are suppressed when PTD rats are engaging in spatial behavior (Anzalone et al, 2010, Savage et al, 2012). A second important finding was that the Rh-Re is a critical and necessary region for the effectiveness of the PFC-HPC cholinergic-based recovery in the PTD model, but it is not necessary in intact PF rats.…”

“…This task was chosen because acetylcholine efflux in the HPC and FC correlates with performance (Anzalone et al, 2010) and lesions of the HPC and PFC disruption performance on this task (Lalonde, 2002). The plus maze had wooden-floors that were painted black and clear plastic-sided arms that measured 44 cm long, 12 cm wide, and the height of the maze walls was 14.5 cm.…”