Thalamic Proteome Changes and Behavioral Impairments in Thiamine-deficient Rats.

Thiamine deficiency (TD) has been used as an experimental model in rodents to study the molecular mechanisms of neurodegeneration and its association with behavioral changes. The aims of the present study were to investigate the spatial cognitive performance of pyrithiamine-induced thiamine deficiency (PTD) in adult male rats and disclose the thalamic proteome alterations caused by a severe TD episode. After the onset of the neurological signs, such as seizure and/or loss of righting reflex, the TD treatment was interrupted. Following 15 days of recovery, all rats were submitted to the spatial cognitive tasks in the Morris Water Maze (MWM). The results show that the PTD rats exhibited deficits during the learning process, which was reverted by repeated training. However, despite the spatial cognitive recovery, some protein changes were not reversible. The proteomic analysis, using label-free quantification, revealed deregulation of 183 thalamic proteins. Using bioinformatic tools, these proteins were categorized according to Gene Ontology functional annotation and metabolic pathways. We show that a severe TD affects proteins involved in different biological processes, such as, oxidative stress, neurotransmitter synthesis and synaptic vesicle cycle. These could explain the outcome in neurotransmitter release changes caused by TD, previously observed by our group and by other authors. These findings disclose the role of key proteins and metabolic pathways probably involved in the neurodegeneration process induced by TD. These proteins represent relevant molecular targets for future studies focusing also on the molecular basis of selective vulnerability of some brain areas to TD insult.

Perinatal thiamine restriction affects central GABA and glutamate concentrations and motor behavior of adult rat offspring.

The purposes of the present study were to investigate the effects of perinatal thiamine deficiency, from the 11th day of gestation until the 5th day of lactation, on motor behavior and neurochemical parameters in adult rat offspring, using 3-month-old, adult, male Wistar rats. All rats were submitted to motor tests, using the rotarod and paw print tasks. After behavioral tests, their thalamus, cerebellum and spinal cord were dissected for glutamate and GABA quantifications by high performance liquid chromatography. The thiamine-restricted mothers (RM) group showed a significant reduction of time spent on the rotarod at 25 rpm and an increase in hind-base width. A significant decrease of glutamate concentration in the cerebellum and an increase of GABA concentrations in the thalamus were also observed. For the offspring from control mothers (CM) group there were significant correlations between thalamic GABA concentrations and both rotarod performance and average hind-base width. In addition, for rats from the RM group a significant correlation between stride length and cerebellar GABA concentration was found. These results show that the deficiency of thiamine during an early developmental period affects certain motor behavior parameters and GABA and glutamate levels in specific brain areas. Hence, a thiamine deficiency episode during an early developmental period can induce motor impairments and excitatory and inhibitory neurotransmitter changes that are persistent and detectable in later periods of life.

Maternal thiamine restriction during lactation induces cognitive impairments and changes in glutamate and GABA concentrations in brain of rat offspring.

Maternal thiamine deficiency causes changes in cellular energy metabolism that can interfere with offspring brain development. The purpose of the present study was to investigate the effects of thiamine restriction, during lactation, on offspring neurochemistry and cognitive parameters. Male young (31 days old) and adult (75 days old) rats, from control and restricted mothers, were submitted to spatial learning and memory assessment. GABAergic and glutamatergic parameters were measured in thalamus, prefrontal cortex and hippocampus by high performance liquid chromatography (HPLC). The young animals were assessed immediately after thiamine restricted period; the adults, however, underwent a recovery period of 45 days. In young rats, thiamine restriction significantly hindered body weight gain and learning speed; however, it did not affect the brain weight, GABA and glutamate parameters in any of the brain assessed areas. In adult rats the body weight gain was significantly hampered by thiamine restriction, while brain weight and spatial task were not affected. Also, in adult offspring, maternal thiamine restriction significantly decreased the glutamate and GABA contents in the three assessed brain areas and thalamus, respectively. One possible explanation for these findings is that an adjustment of the inhibitory (GABAergic) and stimulatory (glutamatergic) neuromodulation systems occurs, in order to reverse the behavioral deficits detected in young rats but not in adult ones. The present data show, for the first time, that maternal thiamine restriction during lactation induces cognitive impairments and neurochemical changes in offspring, corroborating the important role of thiamine in brain development.

Spatial memory deficits and thalamic serotonergic metabolite change in thiamine deficient rats.

The purposes of the present study were to verify the effects of a severe thiamine deficiency episode on spatial cognitive aspects and thalamic serotonergic parameters. The animals were submitted to a severe thiamine deficiency treatment that was interrupted after the onset of the last neurological signs. The results obtained confirm previous findings about TD deficiency effects on cognitive function and, further show that this vitamin increases the thalamic serotonine metabolite, 5-hidroxyindolacetic acid (5-HIAA), level. In addition, the present data shed light on the importance of this metabolite in spatial cognitive function.