Abstract Body: Background: The hippocampus and cortex are susceptible to changes in blood supply, metabolites,
and oxygenation. However, how disrupted cardiac function affects these critical areas of the brain,
leading to the cognitive and neurological consequences of heart failure, remains unclear. Hypothesis:
We hypothesize that disrupted cardiac function cross-talks with the brain by inducing region-specific
mitochondrial stress responses, leading to adaptive changes. Methods: We utilized cardiac-specific
LonP1 knockout (LonP1cKO) mice to induce heart failure within 21 days of birth. Alongside cre-
control mice, we assessed cerebral blood flow using Laser speckle contrast imaging, locomotor
activity through a comprehensive laboratory animal monitoring system (CLAMS), and gene
expression profiles in the hippocampus and cortex by RT-PCR. Student’s ‘t’ test determined statistical
significance with a p-value<0.05. Results: At 21 days, LonP1cKO mice demonstrated a significant
(p<0.0001) reduction in cerebral blood flow (587.1±33.68, n=7) compared to the control
(1034±31.26, n=5). Additionally, there were notable decreases in both X and Y-axis ambulatory and
total locomotor activities in LonP1cKO mice [XAMB (100.3±6.6 vs 224±13.6 n=16), YAMB)
(67.9±4.7 vs 150±8.5 n=16), XTOT (351.8±18.1 vs 534.4±26.3 n=16) and YTOT (190.7±9.6 vs
354.9±17.07 n=16). RT-PCR analysis revealed significant upregulation of genes related to hypoxia
and cellular stress (Hif1a, FGf2, Atf6), mitochondrial biogenesis (mtDNA, Tfam, mt-COI, mt-COII),
mitochondrial stress response proteases (LonP1, Afg3l2, Spg7, Yme1l1), and downregulation in
neurotrophic factors (Bdnf, Ngf, Gfap) in the hippocampus and cortex. Conclusion: The study
highlights that cardiac dysfunction in LonP1cKO mice leads to mitochondrial and cellular stress
response in the brain to adapt neuronal changes, suggesting a critical link between cardiac health and
brain function regulated through mitochondrial stress response pathways.