The Impact of Normative Aging and Alzheimers Disease on Fear based Disorders and Amygdala Dysfunction - Not only do fear-based disorders such as posttraumatic stress disorder (PTSD) quintuple the rate of suicide
relative to those without these disorders, but they also increase the magnitude of age-related cognitive decline
and double the risk for developing Alzheimer’s disease and other dementias in older adults. Fear-based
disorders like PTSD are linked to fear memories. Due to the seemingly indelible and hyperactive properties of
such fear memories, fear-based disorders can worsen with age. Although normative aging and Alzheimer’s
disease have dissociable trajectories, one factor that negatively impacts cognitive aging and Alzheimer’s disease
is the comorbidity of PTSD. Perturbations in the functional circuitry supporting fear memory extinction are also
key neural mechanisms of PTSD. A critical anatomical structure within the neural circuitry underlying this
dysfunctional processing is the basolateral amygdala (BLA), which is considered an integrative hub as it receives
sensory and contextual information from the prefrontal cortex and hippocampus. While much of the current
scientific focus on cognitive aging and Alzheimer’s disease centers on the prefrontal cortex and hippocampus,
little is known about the underlying mechanisms of BLA dysfunction in aging, Alzheimer’s disease (AD), and the
impact of co-occurring PTSD. One pathological process common to these disorders is underlying
neuroinflammation. Importantly, ketogenic and ketone ester diets are known to ameliorate hyperactivity,
inflammation, fear-based disorders, and show promise as treatments for the contributing factors to cognitive
aging and AD. To date, no study has investigated how aging and AD act in concert to further impair the BLA’s
role in extinguishing hyperactive fear memories (a central component of PTSD). To address the current gap in
knowledge, this proposal will leverage the TgF344AD rat model of AD to understand the contribution of BLA
inflammation, cellular dysfunction, and synaptic circuit impairment to underlying mechanisms of PTSD. Recent
data from the lab suggests, relative to young wild type rats, aging and AD impairs fear extinction and recall, and
furthermore, the BLA in aged and AD rats is hyperactive. As such, the overarching hypothesis of this
proposal is that hyperactive fear memory, the core element of PTSD, increases with aging and is
accelerated in AD due to progressive inflammatory-driven neurophysiological deficits in the BLA. In
Specific Aim 1, this proposal will leverage a rodent fear conditioning protocol that models a critical component of
PTSD (i.e., the inability to extinguish hyperactive fear memory) and assess how aging and Alzheimer’s disease
contribute to BLA cellular dysfunction (both ex vivo and in vivo during fear extinction) and inflammation.
Additionally, in Specific Aim 2, this proposal will determine if a ketone ester dietary intervention (known to have
anti-epileptic and anti-inflammatory properties) or BLA inactivation can facilitate fear memory extinction and
improve BLA hyperactivity and pathology in age and AD. The outcomes of this proposal will be critical to
developing translational strategies to combat poor quality of life outcomes in older adults.
