Diss. (sammanfattning) Stockholm : Karol. inst. : 2001. / Härtill 5 uppsatser.

Thesis (M.Sc.)--University of Hong Kong, 1970. / Also available in print.

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We hypothesize that brain glycogen, a stored form of glucose, may provide fuel for the brain conferring both negative and positive effects throughout the brain. The over accumulation of brain glycogen, or supercompensation, is hypothesized to exacerbate hypoglycemia associated autonomic failure (HAAF), promote memory and learning, and reduce neuron cell death during severe episodes of hypoglycemia. It was determined that brain glycogen supercompensation does occur in the mouse 6 hours following single and recurrent hypoglycemic episodes, but it is not likely a significant mechanism behind HAAF due to the supercompensation subsiding at 27 hours following the hypoglycemic episodes. In regard to memory and learning, brain glycogen is not required for motor skill learning while euglycemic, however, it does enhance motor memory while hypoglycemic as determined using a rotarod treadmill in mouse. In regard to associative learning, brain glycogen is important for contextual, but not cued, memories while both euglycemic and hypoglycemic, as assessed by contextual and cued fear conditioning. Two different genetically engineered models of mice lacking brain glycogen yielded opposing results when assessing whether brain glycogen is neuroprotective during severe and prolonged hypoglycemia. In conclusion, brain glycogen does not appear to play a role in HAAF, is important for learning and memory, and its role in neuronal cell survival during hypoglycemia requires further study. / Department of Biology

Astrocytes are the most abundant type of glial cell in the brain, required to ensure optimal neuronal functioning, neurogenesis, and brain vascular tone. Moreover, they play a crucial role in support of neuronal metabolism. The human brain utilizes around 20% of the energy consumed to ensure its proper function. Glucose, an important energy source for the brain, access the neuropil across the blood-brain barrier (BBB), and then is transported into astrocytes through their perivascular end-feet, where it can be stored as glycogen. Furthermore, lactate can be synthesized through glycogenolysis and then shuttled via monocarboxylate transporters (MCTs) to neurons to fuel their tricarboxylic acid (TCA) cycle. This mechanism is known as astrocyte-neuron lactate shuttle (ANLS) and is involved in learning and memory formation. Aging is associated with a decline of faculties such as memory, motor skills, and sensory perception. These deficits are not thought to be due to a substantial loss of neurons but rather changes at the level of connectivity, morphological changes, and white matter structure. In the present study, we aim to compare the glycogen distribution in layer I of the somatosensory cortex between adult (4 months old) and geriatric mice (24 months old). We carried out the visual analysis using Connectome Explorer, which allows us to explore, in real-time, brain reconstructions at the nanometric-level. Using the computational tool GLAM (Glycogen-derived Lactate Absorption Map), we can infer a probability map of the locations where astrocytic glycogen-derived lactate is most likely accessing the surrounding neurites. We analyzed and compared the probability maps on axons, dendrites, boutons, and spines to make a functional hypothesis about single compartments’ energy consumption. Our results indicate that aging brains have a more glycolytic metabolism, with fewer peaks facing mitochondria, and smaller glycogen granules.

Mother-infant separation (MS) is an early-life stressor which affects stress-related processes in brain and behaviors in rats. Changes associated with MS were investigated in the brain and behavior of two rat strains, Holtzman and Sprague-Dawley, at three points in development. The hypothesis was that MS would affect the prefrontal cortex (PFC), both in metabolic capacity and PFC-related behaviors across the lifespan. First, cytochrome oxidase (CO), an enzyme that directly reflects metabolic capacity in the brain, was quantified in two-week old Holtzman rats after MS, early handling (EH), or nohhandled controls. MS reduced CO activity in the PFC of female rats but not males. Path analysis of the CO data revealed a stronger descending influence of the medial PFC, a region associated with behavioral inhibition, in females; contrasted with a stronger descending influence of the lateral PFC, a region associated with motor output, in males. Second, adolescent rats were tested in the open field to assess MS effects on ambulatory activity and impulsivity. MS increased ambulatory activity and impulsivity in Sprague-Dawley males. In a separate study, MS reduced ambulation and impulsivity in Holtzman rats in the open field. Brains of Sprague- Dawley adolescents showed reduced PFC thickness in MS males relative to EH males. Across groups, male adolescents had reduced metabolic capacity relative to females in the PFC. Finally, extinction of Pavlovian fear, a PFC-related behavior, was not affected by sex or separation group in adult Holtzman rats. Across groups, males showed greater fear renewal than females, despite the extinction process. An unexpected finding was that EH attenuated fear renewal. Findings from these MS studies in Sprague-Dawley rats are similar to human psychopathology of ADHD, which is reported more frequently in young males and is related to PFC dysfunction. The opposite behavioral findings between Holtzman and Sprague-Dawley rats suggest that genetic predisposition can affect long-term responses to the same early-life stressor. Knowledge about baseline sex differences in brain and behavior gained from the studies on Holtzman rats may help future research to consider sex-dependent effects of disruptions during development, as it appears that some basic neural substrates are sexually dimorphic. / text