Cognition and Neuronal Injury Research

Deficits in intellectual function are comorbid with many mental illnesses and neurological disorders. Cognitive decline and memory impairments accompany age-related changes in the brain and can indicate the onset of dementia. Furthermore, cognitive impairments characterize neuronal insults including those resulting from stroke, traumatic brain injury (TBI) and neurotoxic exposures such as those that can result from chemotherapy. Cognitive enhancement strategies may help to slow the effects of aging on brain function while neuroprotective interventions may limit the effects of trauma events or neurotoxin exposure. We are characterizing signaling mechanisms that underlie memory formation. We are also examining the cellular and molecular causes of loss of neuronal function that underlies neuronal injury and insult. The use of multiomic analysis at the protein, phosphoprotein, gene, and gene expression level is revealing new mechanism that we can study using advanced transgenics, viral-mediated gene editing, neurophysiology, photometrics, and behavioral studies, and the development of small molecules that selectively interfere with specific signaling mechanisms is providing insight into the processes underlying learning and revealing new therapeutic approaches to prevent cognitive impairments.

Short list of publications to learn more about our Cognition and Neuronal Injury Research:

  • Thomas, R. Hernandez, A., Benavides, D.R., Tan, C., Plattner, F., Taylor, S. S., Bibb, J.A. (2021) Integration of fast and slow neurotransmission via PKA regulation in nucleus accumbens. bioRxiv doi:https://doi.org/10.1101/2021.09.29.462408,  In review, Nat. Comm.
  • Umfress, A., Speed, H.E., Tan, C., Ramezani, S., Birnbaum, S., Brekken, R., Sun, X., Plattner, F., Powell, C.P., Bibb, J.A.(2021) Neurological effects of common chemotherapeutics Gemcitabine and Cisplatin in mice, ACS Chel Neurosci. 12:3038-3048.
  • Hernandez, A., Tan, C., Plattner, F., Logsdon, A.F., Yousuf, M.A., Singh, T., Ryan C. Turner, R.C., Luke-Wold, B.P. D, Alkon, D.L., Huber, J.D., Rosen, C.L., Bibb, J.A.(2018) Exposure to mild blast forces induces neuropathological effects, neurophysiological deficits and biochemical changes, Mol. Brain 11:64.
  • Hernandez A, Tan C, Mettlach G, Pozo K, Plattner F, Bibb JA. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum. Sci Rep. 2016 Jul 22; 6:29812.
  • Plattner F, Hernández A, Kistler TM, Pozo K, Zhong P, Yuen EY, Tan C, Hawasli AH, Cooke SF, Nishi A, Guo A, Wiederhold T, Yan Z, Bibb JA. Memory enhancement by targeting Cdk5 regulation of NR2BNeuron. 2014 Mar 5; 81(5): 1070-83.
  • Meyer, D., Altoro, M.I., Tan, Z., Tan, Tozzi, Al, Di Filippo, M., DiNapoli, V., Plattner, F., Kansy, J.W., Benkovic, S.A., Huber, J., C.F., Miller, D.B., Greengard, P., Calibressi, P., Rosen, C.L., Bibb, J.A. (2014) Ischemic stroke is mediated by aberrant Cdk5, J. Neurosci 34:8259-67.
  • Bibb, J.A., Mayford, M.R., Tsien, J.Z., Alberini, C.M. (2010) Cognition Enhancement Strategies, J. Neurosci. 30:14987-92.
  • Hawasli, A.H., Benavides, D.R., Nguyen, C., Kansy, J.W., Chambon, P, Greengard, P., Powell, C.M., Cooper, D.C., and Bibb, J.A. (2007) Cdk5 governs learning, memory and synaptic plasticity via control of NMDA receptor degradation. Nature Neuroscience10:880-886.

Mental Illness, Gut-Brain Comorbidity, and Addiction Research

he causes of mood-based mental disorders such as depression remain poorly understood. There is great need for more effective therapies. How we feel, our mood, is dictated by the circuitry of the limbic system. In general This circuitry allows us to interpret sensory input as good (reward) or bad (aversive). While ligand gated excitatory neurotransmission mediates sensory input, salience requires metabotropic neurotransmission such as that which mediates dopamine sensing. Dysregulation of dopaminergic neurotransmission may impart a negative mood which characterizes depression. Interestingly, this negative mood may also be caused by overactivation of dopamine signaling by drugs of abuse such as cocaine. More recently, it has become apparent that some of the most important factors affecting mood and contributin to mental illness may come from outsid ethe brain. For example, peripheral inflammation from inflamed bowel disease or eating disorders that cause metabolic syndrome appear to target features of dopamine neurotransmission through mechanisms that overlap with depression and addiction. We are combining animal behavior, neurophysiology, in vivo photometric sensing, and multiomic analysis to indentify novel mechanisms that may serve as therapeutic targets for drug development and treatment of these disorders.

Short list of publications to learn more about our Mental Illness, Gut-Brain Comorbidity, and Addiction Research:

  • Thomas, R. Hernandez, A., Benavides, D.R., Tan, C., Plattner, F., Taylor, S. S., Bibb, J.A. (2021) Integration of fast and slow neurotransmission via PKA regulation in nucleus accumbens. bioRxiv doi:https://doi.org/10.1101/2021.09.29.462408,  In review, Nat. Comm.
  • Chakraborti, A. Graham C., Bru, S., Vashi, B., Umfress, A., Kurup, P., Vickers, B., Chen, A., Telange, R., Johnson, M.S.,Berrihill, T.F., Powell, M.L., Barnes,S., Morrow, C Smith,D., Mukhtar, S., Watts, S., Kennedy, G., Bibb, J.A. (2021) High Fructose Corn Syrup-Enriched Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling. Frontiers in Neuroscience 15:669410.
  • Plattner F, Hayashi K, Hernández A, Benavides DR, Tassin TC, Tan C, Day J, Fina MW, Yuen EY, Yan Z, Goldberg MS, Nairn AC, Greengard P, Nestler EJ, Taussig R, Nishi A, Houslay MD, Bibb JA. The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci. 2015 Aug; 18(8):1094-100
  •  Drerup, J.M., Hayashi, K, Cui, H., Mettlach, G.L., Long, M.A., Marvin, M., Sun, X., Goldberg, M.S., Lutter, M. Bibb, J.A. (2010) Attention-Deficit/Hyperactivity-like phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35, Jour. of Biol. Psych. 68:1163-71 Dec. 15, 2010 issue cover photo.

Neuroendocrine Cancer Research

Neuroendocrine tumors (NETs) are rare cancers that are often metastatic by the time they are detected. These lethal tumors  frequently produce debilitating side effects and can arise from various types of neuroendocrine cells sparsely dispersed throughout the body including enterochromaffin cells in the intestine (e.g., carcinoid), chromaffin cells of the adrenal medulla (pheochromocytoma), beta islet cells of the pancreas (pancreatic neuroendocrine tumors), and C cells of thyroid (medullary thyroid carcinoma). While mutation have been causally linked to these cancers, this information has not successfully progressed to the development of personalized medicine approaches and surgical resection for these remains the principle treatment approach. We discovered that the aberrant signaling mediated by the protein kinase Cdk5 was a major driver of NETs. We have developed new inducible-arrestable animal models, identified new signaling mechanisms, are conducting multiomic analysis of mouse models and human patients, and are testing new therapeutic approaches coupled to novel diagnostic biomarkers we have discovered. Our goal is to understand the causes and bring new treatments cancers to the clinic for these and related.

Short list of publications to learn more about our Cancer Research:

  • Carter AM,Kumar N, Herring B, Tan C, Guenter R, Telange R, Howse W, Viol F, McCaw TR, Bickerton HH, Gupta P, Gillardon F, Woltering EA, Dhall D, Totenhagen J, Banerjee R, Kurian EM, Reddy S, Chen H, Schrader J, Rose JB, Mukhtar MS, Bibb JA. “Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.” bioRxiv 2021.05.25.445594; doi:https://doi.org/10.1101/2021.05.25.445594, (in press at Oncogenesis).
  • Carter, A.M., Tan, C., Pozo, K., Telange, K., Molinaro, R., Guo, A.,  De Rosa, E., Martinez, J.O.,  Zhang, S., Takahashi, M.,  Wiederhold, T., Oltmann, S.C.,  Pacak, K., Woltering, E.A.,  Hatanpaa, K.J.,  Nwariaku, F.E.,  Grubbs, E.G.  Robinson, B., Reddy, S., Jaskula-Sztul, R., Chen, H., Mobley, J.A., Mukhtar, M.S.  Tasciotti, E.  BibbJ.A. (2020) Phosphoprotein-based Biomarkers as a Prognostic for Cancer Therapy, PNAS 117:18401-18411.
  • Pozo, K., Zahler, S., Ithimatsu, K., Carter, A.M., Telange, R., Wang, S., Pfragner, R., Fujimoto, J., Grubbs, E.G., Takahashi, M., Oltman, S.C., Bibb, J.A. (2018) Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer, Oncotarget, 9: 37662-37675.

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