Defining the neural mechanisms that govern the link between PTSD, aging, and Alzheimer’s disease is consequential to the aging population and will provide a critical foundation for developing intervention strategies to remediate poor outcomes. Indeed, true functional improvement in aging will require a better understanding of these processes.

Neuroinflammation in aging and neurodegenerative states

Though it is not known what drives the hyperactive state of the BLA in PTSD and age-related disease,  it is well known that PTSD also increases peripheral inflammation. Indeed, increased peripheral inflammation is associated with increased BLA activity and decreased functional connectivity between the BLA and PFC in individuals with PTSD. Moreover, aberrant inflammation in the periphery has been associated with age-related cognitive decline, and AD. In this vein, it is now well accepted that neuroinflammation driven by activated glia increases in the aging brain, contributes to cognitive decline and neuronal hyperactivity, and is a risk factor for developing neurodegenerative disease. Specifically, the most consistent inflammatory markers associated with age-related disease measured in serum of older adults were identified as Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-alpha). In AD, amyloid and tau pathology found predominately in hippocampus and cortex is thought to initiate an inflammatory cascade of IL-6, CRP, and TNF-alpha (in addition to many others) in microglia and astrocytes. While these inflammatory markers are low in young adult individuals, they are increased in older adults irrespective of neurobiological insult.

Circuit and molecular mechanisms of cognitive and emotional affect decline in aging and Alzheimer’s Disease (AD) with a focus on amygdala and prefrontal cortex.

Dysfunction within the circuitry supporting fear memory extinction is a key neural mechanisms of PTSD. A critical anatomical structure in the circuitry underlying this dysfunctional processing is the basolateral amygdala (BLA). While many aging and AD studies focus on prefrontal cortex and hippocampus, little is known about the mechanisms of BLA dysfunction in aging and AD and the impact of co-occurring PTSD. One pathological process common to these disorders is underlying neuroinflammation.

Diet and exercise as therapeutic intervention strategies in improving cognitive aging and neurodegeneration.

Ketogenic diets and ketone diester supplementation are known to ameliorate hyperactivity, inflammation, fear-based disorders, and show promise as treatments for the contributing factors to cognitive aging and AD. It is not currently known whether a ketone diester supplement can directly influence positive outcomes despite the negative interaction between aging, AD, network hyperactivity, and neuroinflammation. To address the gap in knowledge, our program leverages rat models of aging and AD to understand the contribution of BLA inflammation, cellular dysfunction, and synaptic circuit impairment to underlying mechanisms of PTSD.

Publications (Bibliography: PubMed)

  • Hernandez, C.M., McCuiston, M.A., Davis, K., Halls, Y., Carcamo Dal Zotto, J.P., Jackson, N.L., Dobrunz, L.E., King, P.H., McMahon, L.L., (under review Brain, Behavior, and Immunity) In a circuit necessary for cognition and emotional affect, Alzheimer’s-like pathology associates with neuroinflammation, cognitive and motivational deficits in the young adult TgF344-AD rat.
  • Fletcher R., Hoppe M., McQuail, J.A., Hernandez, C.M., Hernandez, A.R., (under review) Ketogenic Diet-Induced Alterations in Neuronal Signaling-Related Proteins are Not Due to Differences in Synaptosome Protein Levels.
  • Gandy, H. M., Hollis, F., Hernandez, C. M., & McQuail, J. A. (2023). Aging or chronic stress impairs working memory and modulates GABA and glutamate gene expression in prelimbic cortex. Frontiers in Aging Neuroscience, 15.
  • Hernandez C.M., Jackson N.L., Hernandez A.R., McMahon L.L., (2022) Impairments in fear extinction memory and basolateral amygdala plasticity in the TgF344-AD rat model of Alzheimer’s disease are distinct from non-pathological aging. eNeuro 9, ENEURO.0181-22.2022. doi:10.1523/ENEURO.0181-22.2022
  • Hernandez C.M.*, McQuail J.A.*, Ten Eyck T.W., Orsini C.A., Wheeler A., Setlow B., Bizon J.L., (2022) GABABreceptors in prelimbic cortex and basolateral amygdala differentially influence intertemporal decision making and decline with age. Neuropharmacology, 109001.
  • Hernandez C.M., Hernandez A.R., Hoffmam J.M., King P.H., McMahon L.L., Buford T.W., Carter C.S., Bizon J.L., Burke S.N., (2022) A Neuroscience Primer for Integrating Geroscience with the Neurobiology of Aging. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 77(1), e19–e33.
  • Hoffmam J.M., Hernandez C.M., Hernandez A.R., Austad S.N., Buford T.W., Carter C.S., (2022) Bridging the gap: A geroscience primer for neuroscientists with potential collaborative applications. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 77(1), e10–e18.
  • McQuail, J.A., Beas, B.S., Kelly, K.B., Hernandez, C.M., Bizon, J.L., & Frazier, C.J. (2021). Attenuated NMDAR signaling on fast-spiking interneurons in prefrontal cortex contributes to age-related decline of cognitive flexibility. Neuropharmacology, 197, 108720.
  • Hernandez A.R., Hoffmam J.M., Hernandez C.M., Cortes C.J., Jumbo-Lucioni P., Baxter M.G., Esser K.A., Liu A.C., McMahon L.L., Bizon J.L., Burke S.N., Buford T.W., Carter C.S. (2021). Reuniting the Body “Neck Up and Neck Down” to Understand Cognitive Aging: The Nexus of Geroscience and Neuroscience. The Journals of Gerontology: Series A.
  • Hernandez C.M., Orsini C.A., Blaes S.L., Bizon J.L., Febo M., Bruijnzeel A.W., Setlow B., (2020). Effects of repeated adolescent exposure to cannabis smoke on cognitive outcomes in adulthood. Journal of Psychopharmacology, 0269881120965931.
  • Hernandez C.M., Orsini C.A., Wheeler A., Ten Eyck T.W., Betzhold S.M., Labiste C.C., Setlow B., Bizon J.L., (2020) Testicular hormones mediate robust sex differences in impulsive choice. eLife 9.
  • Orsini C.A., Blaes S.L., Hernandez C.M., Betzhold S.M., Perera H., Wheeler A-R., Ten Eyck T.W., Garman T.S., Bizon J.L., Setlow B., (2020) Regulation of risky decision making by gonadal hormones in males and females. Neuropsychopharmacology, 46(3), 603-613.
  • Hernandez A.R.*, Hernandez C.M.*, Truckenbrod L.M., Campos K.T., McQuail J.A., Bizon J.L., Burke S.N., (2019)Age and ketogenic diet have dissociable effects on synapse-related gene expression between hippocampal subregions. Frontiers in Aging Neuroscience, 11.
  • Hernandez C.M., Orsini C.A., Labiste C.C., Wheeler A-R., Ten Eyck T.W., Bruner M.M., Sahagian T.J., Harden S.W., Frazier C.J., Setlow B., Bizon J.L., (2019) Optogenetic dissection of basolateral amygdala contributions to intertemporal choice in young and aged rats. eLife 8. 
  • Hernandez C.M., McQuail J.A., Schwabe M.R., Burke S.N., Setlow B, Bizon J.L., (2018) Age-Related Declines in Prefrontal Cortical Expression of Metabotropic Glutamate Receptors That Support Working Memory. eNeuro5(3) e0164-18.2018, 1-17. 
  • Hernandez A.R., Hernandez C.M., Campos K., Truckenbrod L., Federico Q., Moon B., McQuail J.A., Maurer A.P., Bizon J.L., Burke S.N., (2018) A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus. Front Aging Neurosci 10. 
  • Orsini C.A., Hernandez C.M., Bizon J.L., Setlow B., (2018) Deconstructing value-based decision making: lessons from animal models. Cognitive, Affective, & Behavioral Neuroscience, 1-18. 
  • Hernandez C.M.*, Vetere L.M.*, Orsini C.A., McQuail J.M., Maurer A.P., Burke S.N., Setlow B., Bizon J.L., (2017) Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats. Neurobiology of Aging 60, 141–152. 
  • Orsini C.A., Hernandez C.M., Singhal S., Kelly K.B., Frazier C.J., Bizon J.L., Setlow B., (2017) Optogenetic Inhibition Reveals Distinct Roles for Basolateral Amygdala activity at discrete timepoints during risky decision making. The Journal of Neuroscience 37, 11537–11548.Hernandez A.R., Hernandez C.M., Campos K.T., Truckenbrod L.M., Sakarya Y., McQuail J.A., Carter C.S., Bizon J.L., Maurer A.P., Burke S.N., (2017) The Anti-Epileptic Ketogenic Diet Alters Hippocampal Transporter Levels and Reduces Adiposity in Aged Rats. The Journals of Gerontology Series A 73, 450-458.