A considerable body of evidence has demonstrated an important role for cholinergic transmission in cognition, memory and behavioral state control. Like other amnestic or dementia-related disorders, diencephalic amnesia is accompanied by cholinergic dysfunction. Using an animal model of diencephalic amnesia we have documented cholinergic loss in the medial septum/diagonal band (MS/DB) and hypo-cholinergic output in the hippocampus that correlates with behavioral impairment, which can be alleviated by cholinomimetic drugs. These results can be attributed to 2 potentially orthogonal, mechanisms: (1) Cholinergic cell loss in the MS/DB region causes hypocholinergic output in the hippocampus during learning;(2) Lesions to thalamic and hypothalamic nuclei degrade neural activation in limbic regions and this is reflected in impaired ACh output during cognitive processing. The proposed research uses 2 rodent models of diencephalic amnesia to conduct a systems level analysis of the relationships between neuroantomical, neurochemical and behavioral dysfunctions seen in diencephalic amnesia.
Aims : Using animal models we will: (A) Apply stereological microscopy techniques, in combination with immunocytochemistry, to fully document cholinergic cell loss in several important ascending cholinergic pathways;(B) Assess functional acetylcholine disruption by a novel application of in-vivo microdialysis/HPLC to assess ACh efflux during cognitive processing on a range of tasks and brain regions (hippocampus, amygdala, and dorsal striatum) connected to nuclei damaged in diencephalic amnesia;(C) Test whether hippocampal or septal administration of drugs that increase brain ACh levels will differentially lead to recovery of learning/memory function;(D) Map the functional diversity of diencephalic nuclei using discrete neurotoxin-induced lesions to determine if such lesions cause decreased ACh output in key memory structures. Significance: The neural mechanisms of diencephalic amnesia remain undetermined. Using in-vivo microdialysis on-line during cognitive testing in animal models of diencephalic amnesia is novel and will enhance our understanding of the interdependence between diencephalic and other limbic structures. Such experiments are critical to understanding the role of acetylcholine dysfunction in amnesia and thus the development of pharmacotherapeutics.
|Bobal, M G; Savage, L M (2015) The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat. Neuroscience 285:260-8|
|Roland, Jessica J; Stewart, Amanda L; Janke, Kellie L et al. (2014) Medial septum-diagonal band of Broca (MSDB) GABAergic regulation of hippocampal acetylcholine efflux is dependent on cognitive demands. J Neurosci 34:506-14|
|Hall, J M; Vetreno, R P; Savage, L M (2014) Differential cortical neurotrophin and cytogenetic adaptation after voluntary exercise in normal and amnestic rats. Neuroscience 258:131-46|
|Savage, Lisa M (2012) Sustaining high acetylcholine levels in the frontal cortex, but not retrosplenial cortex, recovers spatial memory performance in a rodent model of diencephalic amnesia. Behav Neurosci 126:226-36|
|Vetreno, Ryan P; Ramos, Raddy L; Anzalone, Steven et al. (2012) Brain and behavioral pathology in an animal model of Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome. Brain Res 1436:178-92|
|Resende, Leticia S; Ribeiro, Angela M; Werner, David et al. (2012) Thiamine deficiency degrades the link between spatial behavior and hippocampal synapsin I and phosphorylated synapsin I protein levels. Behav Brain Res 232:421-5|
|Vetreno, Ryan P; Klintsova, Anna; Savage, Lisa M (2011) Stage-dependent alterations of progenitor cell proliferation and neurogenesis in an animal model of Wernicke-Korsakoff syndrome. Brain Res 1391:132-46|
|Dupre, Kristin B; Ostock, Corinne Y; Eskow Jaunarajs, Karen L et al. (2011) Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats. Exp Neurol 229:288-99|
|Vetreno, Ryan P; Hall, Joseph M; Savage, Lisa M (2011) Alcohol-related amnesia and dementia: animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment. Neurobiol Learn Mem 96:596-608|
|Savage, Lisa M; Guarino, Sabrina (2010) Memory for reward location is enhanced even though acetylcholine efflux within the amygdala is impaired in rats with damage to the diencephalon produced by thiamine deficiency. Neurobiol Learn Mem 94:554-60|
Showing the most recent 10 out of 22 publications