Dissertations and Theses (Open Access)

Author ORCID Identifier

https://orcid.org/0000-0003-0496-0570

Date of Graduation

5-2026

Document Type

Thesis (MS)

Program Affiliation

Neuroscience

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Louise McCullough, MD, PhD, Co-Advisor

Committee Member

Venugopal Venna, PhD, Co-Advisor

Committee Member

Sean Marrelli, PhD

Committee Member

Kevin Lin, PhD

Committee Member

Andrea Stavoe, PhD

Committee Member

Marc Rhoads, MD

Abstract

Chronic cerebral hypoperfusion (CCH) is a chronic decrease in blood flow to the brain. One of the consequences of CCH is vascular cognitive impairment (VCI), which is cognitive decline due to diseases that cause limited cerebral blood flow. VCI disproportionately affects older adults due to age-related increased cerebrovascular risk. With new advances in the field of medicine and rising life expectancy, we are entering a time with an increasingly aged population, and the prevalence of VCI is expected to increase. Thus, it is important to understand the different mechanisms contributing to VCI. Recent evidence highlights the gut-brain axis as a bidirectional biochemical communication between our brain and our gastrointestinal tract. Gut microbiome produces metabolites that play a role in maintaining neurotransmission and systemic homeostasis. Dysbiosis occurs when there is an imbalance of bacterial composition, which can dysregulate host immunity and contribute to pro-inflammatory conditions. Clinical studies have identified gut dysbiosis in patients with neurological disorders, suggesting a link between microbiome changes and cognitive decline.

Given that microbiome-targeted approaches have shown to be beneficial in various diseases, and studies have shown giving unhealthy gut microbiome has unhealthy effects, it may play a role in cognitive decline seen in VCI. I hypothesized that gut dysbiosis caused by limited cerebral blood flow contributes to the worsening of cognitive impairment.

In the first aim the mice underwent either bilateral carotid artery stenosis (BCAS) surgery or SHAM surgery to model CCH. Locomotor activity was assessed using the open field test and the running wheel test. Cognition was assessed through the novel object recognition test (NORT), and the novel arm Y-maze.

In the second aim, mice were administered antibiotics for two days to deplete the existing microbiome, followed by fecal microbiota transplant (FMT) from sex-matched healthy or BCAS donors. Mice received booster FMTs to maintain the FMT microbiome one month later. Running wheel and open field were used to assess locomotor activity.  NORT and Y-maze assessed cognition. The tail suspension test and sucrose splash test were used to identify depressive-like phenotype. DigiGait was used to assess change in gait. Fecal pellets were sent for 16S sequencing to assess changes in bacterial composition.

At day 60, female SHAM mice have a higher discrimination index compared to female BCAS mice. In the novel arm Y-maze after over 100 days, the male SHAM mice spent more time in the novel are compared to the male BCAS mice. Running wheel data demonstrated that SHAM females run significantly more than BCAS females between hours 3-5 after they were initially introduced to the running wheel. The running wheel data from the FMT cohort females showed a trend with the female SHAM FMT recipients running more compared to the female BCAS FMT recipients.

Both BCAS surgery and BCAS FMT had similar results in running wheel data, suggesting that BCAS microbiome affects voluntary locomotor activity in females specifically. These findings indicate that the microbiome may play a mediator of VCI motor deficits and highlight microbiome-targeted interventions as a promising therapeutic approach.

Keywords

Vascular cognitive impairment; Chronic cerebral hypoperfusion; Bilateral carotid artery stenosis; Aging; Fecal microbiota transplant; Gut-brain axis; Gut microbiome; Gut dysbiosis

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Available for download on Tuesday, May 04, 2027

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