Falling Short: The Contribution of Central Insulin Receptors to Gait Dysregulation in Brain Aging

Abstract

Insulin resistance, which manifests as a reduction of insulin receptor signaling, is known to correlate with pathological changes in peripheral tissues as well as in the brain. Central insulin resistance has been associated with impaired cognitive performance, decreased neuronal health, and reduced brain metabolism; however, the mechanisms underlying central insulin resistance and its impact on brain regions outside of those associated with cognition remain unclear. Falls are a leading cause of both fatal and non-fatal injuries in the older population. Despite this, there is a paucity of work focused on age-dependent alterations in brain regions associated with ambulatory control or potential therapeutic approaches to target these processes. Here, we discuss age-dependent alterations in central modalities that may contribute to gait dysregulation, summarize current data supporting the role of insulin signaling in the brain, and highlight key findings that suggest insulin receptor sensitivity may be preserved in the aged brain. Finally, we present novel results showing that administration of insulin to the somatosensory cortex of aged animals can alter neuronal communication, cerebral blood flow, and the motivation to ambulate, emphasizing the need for further investigations of intranasal insulin as a clinical management strategy in the older population.

Keywords: ambulatory function; gerontology; insulin resistance; signaling.

Figure 1

Aging-related structural and functional changes in key brain regions that control gait.

Figure 2

Impact of acute INI administration and motivation on measures of ambulatory performance in aged animals. Measures of time spent ambulating across 4 surfaces obtained in aged animals receiving INS (n = 5) or INI (n = 5). Compared to ad libitum-fed animals, a significant reduction in average time ambulating was noted in animals that were food deprived and were therefore motivated to complete the task (2-way ANOVA; F_(1,16) = 7.34, p = 0.02). Additionally, a significant interaction term was also detected (F_(1,16) = 6.19, p = 0.02), with INI-treated animals ambulating more quickly than INS-treated under ad libitum conditions, while this effect was reversed when animals were fasted. Data represent means ± SEM. Asterisk (*) indicates significance at p < 0.05. Figure reproduced from Lin et al., 2022 [137].

Figure 3

Analysis of the S1 neuronal Ca²⁺ network in response to intranasal saline (INS) or INI in aged F344 animals. Measures of synchronicity were derived from a correlation matrix across ~1000 neurons in each group. Main effects of both time following intranasal delivery (2-way ANOVA; F_(1.36,12.25) = 9.90, p = 0.01) and INI (F_(1,9) = 7.43, p = 0.02) were detected. Data represent means ± SEM. Asterisks indicate main effects of time (t*) or drug (d*) at p < 0.05. Cent symbols (¢) denote Bonferroni post hoc significance (p < 0.05) between INS and INI at the timepoints indicated. Figure reproduced from Lin et al., 2022 [137].

Figure 4

Measures of S1 CBF at rest and in response to tactile stimulation following INI delivery. (Left) Compared to young (n = 3) F344 animals, aged (n = 3) animals showed a trend (#) for reduced absolute red blood cell velocity in S1 (Student’s t-Test; p = 0.09). (Middle) No change in vessel diameter was detected (Student’s t-Test; p > 0.05). (Right) Measures of Δvelocity during tactile activation was measured across age and in response to INI administration. A significant interaction (i*) was noted, with young animals responding to INI with reduced Δvelocity while aged animals responded with an increase (2-way RM ANOVA; F_(2,17) = 4.43; p = 0.05) [173].