Ogg, J. D. | bioRxiv Science

bioRxiv2022

A thalamo-parietal cortex circuit is critical for place-action coordination

The anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an animal within an environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus ALT-PC functional connectivity would be critical for moving toward remembered locations. This hypothesis was tested with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90 degrees, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as no response trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy. Only bilateral PC inactivations resulted in increased no response trials, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC network is critical for linking an action with a spatial location for successful navigation.

neuroscience↗

bioRxiv2021

High fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.

Approximately 70% of Alzheimers disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3x more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet for 3 months prior to behavior assessment. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, HF diet caused greater accumulation of amyloid beta in MxD females compared to MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. In conclusion, high fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women. HighlightsO_LICreated a mouse model of mixed dementia (MxD) with both AD + VCID pathology. C_LIO_LIHF diet caused greater metabolic impairment in AD and MxD females, compared to males. C_LIO_LIAD and MxD females showed a wider array of cognitive deficits, compared to males. C_LIO_LIAstrogliosis and A{beta} pathology were more severe in AD/MxD females, compared to males. C_LIO_LIMetabolic impairment was more consistently associated with reductions in cognitive function in females. C_LIO_LIMore severe glucose intolerance was associated with worse microgliosis in females only. C_LI

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