May 23, 2017

New role discovered for the thalamus

At a Glance

  • The thalamus, a brain region long assumed to be merely an information relay, also sustains the ability to distinguish types of information and hold thoughts in mind.
  • The results suggest that the region may play a pivotal role in the brain’s thinking circuity and might be a therapeutic target for certain psychiatric disorders.
Confocal microscope image of neurons Neurons in the mouse thalamus.Halassa lab, NYU Langone Medical Center

The thalamus has long been thought of as a relay station for sensory information. This belief was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain as well. One such connection is with the prefrontal cortex, an area involved in high level thinking, decision-making, and attention. Brain imaging studies in people with schizophrenia have found decreased connectivity between the mid/upper thalamus and the prefrontal cortex. People with schizophrenia often have working memory deficits, which cause problems with making decisions based on newly acquired memories.

To explore how the prefrontal cortex interacts with the thalamus, three independent research teams manipulated the activity of thalamus neurons in mice and looked at the animals’ ability to remember how to find a reward. The work was funded in part by NIH’s National Institute of Mental Health (NIMH) and National Institute of Neurological Disease and Stroke (NINDS). Results appeared online on May 3, 2017, in Nature and Nature Neuroscience.

A team led by Dr. Michael Halassa of New York University’s Langone Medical Center monitored neural activity in mice as they performed a task that required them to remember the category of cue (audio or visual) that they needed to pay attention to in order to correctly choose which door led to a milk reward. The team then altered neuron activity using a technology called optogenetics. Suppressing neuron activity in the thalamus blocked the mice’s ability to choose the correct door. Stimulating activity improved the animals’ performance. The scientists found that the thalamus didn’t relay specific information about the category of the cues the mice needed to remember. Rather, it was crucial for sustaining memory of the category in the prefrontal cortex. It accomplished this by boosting the activity, or functional connectivity, of specific sets of prefrontal cortex neurons.

A team at Columbia University led by Dr. Joshua Gordon, now NIMH Director, and Dr. Christoph Kellendonk saw similar results when they tested how the same circuit controlled a mouse’s ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward before a brief delay―and then do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of prefrontal cortex neurons and interactions with the brain’s memory hub, the hippocampus. Thalamus inputs to the prefrontal cortex sustained working memory by stabilizing activity there during the delay.

Illustration of neurons connecting the thalamus, which is near the center of the brain, to the prefrontal cortex at the front of the brain.The scientists showed that neurons connecting the thalamus to the prefrontal cortex helped mouse brains hold thoughts in mind. Halassa lab, NYU Langone Medical Center

Dr. Karel Svoboda’s team at the Howard Hughes Medical Institute Janelia Research Campus, working with Dr. Charles Gerfen of NIMH, similarly showed that the thalamus plays a crucial role in sustaining short-term memory. To gather a reward, mice needed to remember where to move after a delay of seconds. In this case, the thalamus was in conversation with a part of the motor cortex during the planning of those movements. Together, these regions sustained information held in the cortex that predicted which way the animal would subsequently move. Optogenetic probing revealed that the conversation went both ways, with cortex activity dependent on the thalamus and vice versa.

“If the brain works like an orchestra, our results suggest the thalamus may be its conductor,” Halassa says. “It helps ensembles play in-sync by boosting their functional connectivity.”

“Our findings should have translational relevance, particularly to schizophrenia,” Gordon notes. “Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.”

Related Links

References: Thalamic amplification of cortical connectivity sustains attentional control. Schmitt LI, Wimmer RD, Nakajima M, Happ M, Mofakham S, Halassa MM. Nature. 2017 May 11;545(7653):219-223. doi: 10.1038/nature22073. Epub 2017 May 3. PMID: 28467827.

Maintenance of persistent activity in a frontal thalamocortical loop. Guo ZV, Inagaki HK, Daie K, Druckmann S, Gerfen CR, Svoboda K. Nature. 2017 May 11;545(7653):181-186. doi: 10.1038/nature22324. Epub 2017 May 3. PMID: 28467817.

Thalamic projections sustain prefrontal activity during working memory maintenance. Bolkan SS, Stujenske JM, Parnaudeau S, Spellman TJ, Rauffenbart C, Abbas AI, Harris AZ, Gordon JA, Kellendonk C. Nat Neurosci. 2017 May 3. doi: 10.1038/nn.4568. [Epub ahead of print]. PMID: 28481349.

Funding: NIH’s National Institute of Mental Health (NIMH) and National Institute of Neurological Disease and Stroke (NINDS); NARSAD Young Investigator award from The Brain & Behavior Research Foundation; the Swiss National Science Foundation; Japan Society for the Promotion of Science (JSPS) fellowship, Brain and Behavior; Sloan and Klingenstein Foundations; Human Frontiers Science Program; the Howard Hughes Medical Institute; Helen Hay Whitney Foundation; Simons Collaboration on the Global Brain; the Hope for Depression Research Foundation; and the Irma Hirschl Trust.