It’s midnight on a chilly February evening, and you’re waiting at the station. A train pulls in on another platform, and through the window, you think you see your long lost love from elementary school. Just as the doors are closing, you make eye contact, and an electric spark of recognition passes between you. As the train slowly pulls away, he/she breaths heavily against the window and writes a phone number in the condensation. You have no time to get out your phone. You sprint across the platform, all the while repeating those digits in your head. Now, the train is out of sight, and all you have is your memory. Can you recall them?

If you answered “yes” to the above question, then congratulations, you have confidence in your working memory! Besides getting you a date, the circuits in the dorsolateral prefrontal cortex involved in working memory also underlie abstract thought, and are disrupted in schizophrenia and Alzheimer’s disease. This is the subject of Amy Arnsten’s research.

Consistent with its transient nature, working memory relies on temporary changes in synaptic strength within a network, in contrast to LTP. This process, termed dynamic network connectivity, is accomplished through neuromodulators without altering synaptic architecture.

For a closer look, this post will discuss Wang et al 2013, which assesses the role of NMDA receptor signaling in working memory. The neural basis for working memory is represented by a network of Cue, Delay, and Response cells. During spatial working memory tasks in primates, populations of Delay cells exhibit sustained firing in the absence of sensory input, doing so through recurrent connections. Delay cells receive input from Cue cells, which fire during the onset of visual stimulus, and relay information to Response cells, which project to the motor system. This network contrasts with those of rodents, which have combined Delay and Response cells.

Resus monkeys performed a task in which they were required to recall the location of a visual cue after a 2.5 second delay. In the presence of systemic ketamine, an NMDAR antagonist, single cell recordings of Delay cells and Response cells during this task revealed decreased Delay cell firing (Figure D), but increased Response cell firing (Figure F), concurrent with reduced performance on the task (Figure A). Ketamine has been used as a model for schizophrenia, and weakened NMDA signaling is linked to schizophrenia.

(From Wang et al, 2013, Figure 7)

By using primates instead of rodents, this study refines previous models for schizophrenia. Even though systemic ketamine in humans overall reduces activity in the prefrontal cortex, as measured through MRI BOLD response, systemic ketamine administration in rodents increases firing in the prefrontal cortex. This difference is likely accounted for by the absence of separate Delay and Response cells in rodents. Rodent models of ketamine administration have led to the development of the hyperglutamate theory for schizophrenia, which points to increased glutamate signaling as a mechanism of disease.

These results are directly applicable for developing mechanisms to treat disease (as is representative of Amy Arnsten’s lab, see her work developing guanfacine as a treatment for ADHD http://medicine.yale.edu/lab/arnsten/research/guanfacine.aspx). The hyperglutamate theory resulted in clinical trials using NMDA antagonists as a potential form of treatment for schizophrenia. Consistent with the results of Wang et al, these drugs were either ineffective or worsened symptoms. In light of this research, NMDA agonists may be a more effective treatment.

Amy Arnsten received her PhD from UCSD. Her work represents an exceptionally talented form of advocacy for mental health, as she was originally inspired by the inadequacy of mental health care during her high school volunteer work (see http://www.medicineatyale.org/janfeb2010/people/peoplearticles/55147/ for more information).

Please join Amy Arnsten herself in the CNCB Marilyn Farquhar Seminar Room at 4 PM on February 23 to hear more about her research.

Wang, M., Yang, Y., Wang, C.-J., Gamo, N. J., Jin, L. E., Mazer, J. A., … Arnsten, A. F. T. (2013). NMDA Receptors Subserve Persistent Neuronal Firing During Working Memory In Dorsolateral Prefrontal Cortex. Neuron77(4), 736–749. http://doi.org/10.1016/j.neuron.2012.12.032

Stephanie Bohaczuk is a first year graduate student in the Neurosciences program. She is currently rotating in Jerold Chun’s lab, focusing her research on genomic mosaicism. She also enjoys long walks on the beach (or in the desert, or in the mountains, or just about anywhere).

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