Laboratory for Aging Neuroscience

The Laboratory for Aging Neuroscience is focused on the aging brain and the impact general anesthesia has on it. Cognitive impairment lasting days to months after surgery and general anesthesia is a very common and distressing source of postoperative morbidity in the elderly.

Our laboratory is testing the hypothesis that general anesthesia, which is controlled coma, contributes to this problem. This is of more than theoretical interest to the PIs in the lab (Drs. Crosby & Culley) because both are clinical anesthesiologists who see the benefits as well as adverse effects of the agents at the bedside. Using behavioral testing, we have demonstrated enduring spatial learning impairment in aged but not young rodents after general anesthesia with some, but not all, commonly used agents. (Culley DJ, Raghavan SV, Waly M, Baxter MG, Yukhananov RY, Deth RC, Crosby G. Nitrous oxide transiently decreases cortical methionine synthase and produces lasting memory impairment in aged rats. Anesth Analg 2007;105:83–8.) (Lee IH, Culley DJ, Baxter MG, Xie Z , Yukhananov RY, Tanzi RE, Crosby G. Propofol anesthesia does not impair spatial memory in aged rats. Anesth Analg 2008; In Press.)

These learning deficits are not easily explained by incomplete clearance of the anesthetics, since the agents in question are rapidly eliminated. This led us to postulate that general anesthesia induces persistent changes in the molecular and cellular characteristics of the hippocampus, a brain region that mediates spatial working memory. As such, the main focus of the lab currently is to examine the neurobiological basis of the persistent memory dysfunction. To that end, we are focusing on two possibilities: 1. that general anesthesia induces neuroplastic changes in the aged brain; and 2. that general anesthesia damages the aged brain. With respect to the former, we have identified long-lasting, age-dependent molecular and synaptic changes in the hippocampus of old rats. (Culley DJ, Yukhananov RY, Xie Z, Galli R, Tanzi RE, Crosby G. Hippocampal gene expression is altered 48 h after general anesthesia in aged rats. European Journal of Pharmacology. 2006 Nov 7;549(1-3):71-8.) With respect to the latter, our lab has collaborated with colleagues in anesthesia and neurology at MGH to show that in a cell culture system at least one general anesthetic agent induces apoptosis and enhances formation of β amyloid, a protein strongly implicated in the pathogenesis of Alzheimer's disease. (Xie Z, Dong Y, Maeda U, Afille P, Culley DJ, Crosby G, Tanzi RE. The common inhalation anesthetic isoflurane induces apoptosis and increases Aβ levels. Anesthesiology. 2006 May;104(5):988-94.)( Zhang B, Dong Y, Zhang G, Moir RD, Xia W, Yue Y, Tian M, Culley DJ, Crosby G, Tanzi RE, Xie Z, The inhalation anesthetic desflurane induces caspase activation and increases amyloid beta-protein levels under hypoxic conditions.J Biochem 2008;283:11866-75.)

Together, these data indicate that general anesthesia can produce ongoing neuronal dysfunction and / or toxicity in vitro and in vivo. Thus, contrary to standard teaching, it appears that general anesthesia leaves the brain different than it was before, implying the brain reacts to general anesthesia and is not just a passive bystander. Whether there is a relationship between the enduring cellular and molecular effects of general anesthesia in the aged brain and the postoperative cognitive morbidity observed commonly in elders after surgery and anesthesia remains to be determined but we have established collaborations with colleagues in geriatrics to begin to address that question. Our hope is that better understanding of the impact of perioperative events on the neurobiology of the aged brain will ultimately translate into improved cognitive outcome after surgery and anesthesia in elders.

Principal Investigators

Gregory Crosby, M.D. is an Associate Professor of Anesthesia, Harvard Medical School
Deborah J. Culley, M.D. is an Associate Professor of Anesthesia, Harvard Medical

Collaborators

  • Mark G. BaxterMark G. Baxter, Ph.D. Oxford Univ., UK, Psychology
  • Carlos Blanco-CenturionCarlos Blanco-Centurion, Ph.D. BWH, Neurology
  • Richard C. DethRichard C. Deth, Ph.D. Northeastern Univ., Biochemistry
  • Sharon InouyeSharon Inouye M.D., S.M. Beth Israel, Geriatrics
  • Vesna Jevtovic-TodorovicVesna Jevtovic-Todorovic, M.D. Ph.D. Univ Virginia, Anesthesia
  • Edward MarcantonioEdward Marcantonio, M.D., S.M. Beth Israel, Geriatrics
  • James RudolphJames Rudolph, M.D. BWH, Geriatrics
  • Priyattam ShiromaniPriyattam Shiromani, Ph.D. BWH, Neurology
  • Rudolph E. TanziRudolph E. Tanzi, Ph.D. MGH, Neurology / Genetics & Aging
  • Zhongcong XieZhongcong Xie, M.D., Ph.D. MGH, Anesthesia

Select Publications

  • Culley DJ, Yukhananov RY, Crosby G. General anesthesia does not reduce life expectancy in aged rats. Anesth Analg. 2006 Mar;102(3):956-9.
  • Xie Z, Dong Y, Maeda U, Moir R, Inouye S, Culley DJ, Crosby G, Tanzi RE. Isoflurane induced apoptosis:A potential pathologic link between delirium and dementia. J Gerontol A Biol Sci Med Sci. 2006 Dec;61(12):1300-6.
  • Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE, The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Ab Accumulation. J Neurosci, 2007;27:124754.
  • Baxter MG, Murphy KL, Crosby G, Culley DJ. Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia. Hippocampus 2008; 18:245-50.
  • Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE. Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J Neurosci. 2008;28(17):4551-60.