August 11, 2020
Written by: Yarden Wiesenfeld
This is the third and final post from summer guest author Yarden Wiesenfeld. Yarden is a Penn undergraduate student in Dr. Michael Granato’s lab who studies the molecular mechanisms that drive learning in zebrafish. She is a dancer in Penn’s swing dancing troupe and also loves art and cooking.
Imagine you are standing in the middle of Times Square during Christmas time. You are engulfed in a sea of people (think: pre-COVID). You look up to see bright billboards, dynamic screens, and skyscrapers towering above you while tourists, vendors, and jaded New Yorkers bustle past. Strangers are yelling on their cell phones, struggling to be heard over blaring cars. You smell a mixture of city, car exhaust, and some old woman’s perfume. You are hyperstimulated, to say the least. And hungry.
Among all this, you catch a wondrous waft of…. honey-roasted peanuts? You hear someone call, “Nuts! Getcha nuts!” as though they are beckoning just to you, and you escape in pursuit of the Nuts4Nuts cart from heaven.
Something amazing just happened here. In the flurry of sights, smells and sounds, you managed to pick out the most important stimuli, ignoring the rest in the process.
Though this may be an extreme case, filtering out distractions is something we do all the time. We block out chatter when writing in a cafe or grow accustomed to the pungent smell of garlic only to catch a whiff of peppers just added to the pot. How do our brains focus on what is most relevant?
For a long time, neuroscientists have tried to piece together how our mind magnifies important sensory input. Francis Crick, famous for his discovery of the helical structure of DNA, described the brain as a searchlight that does not blindly shine on random stimuli, but instead “intensifies part of a scene that is already visible to some extent” (1984)1. Research probing the circuits that drive this attentional spotlight have focused on the cortex, the region of the brain that is associated with sensory abilities, consciousness, and other higher-order cognitive processes. Studies have confirmed that a subregion of the cortex, called the prefrontal cortex (PFC), is critical for attention, amplifying stimuli of interest2, 3.
Though perhaps even more important than the ability to brighten certain features is the capacity to dim others. This is achieved by a mechanism called sensory gating. Sensory gating allows us to inhibit or suppress a response to unnecessary input so that we can focus on only the most important stimuli around us3.
Here’s how it works. Imagine two identical stimuli – say, sound pulses – in succession. The first ding creates a memory trace. When the second sound is heard, it is compared to the memory trace. The second input is weakened if it does not contain any new information3. How does this interference occur? Fundamentally, the first chime excites a set of sensory neurons while simultaneously stimulating another set of neurons that are on guard to inhibit further response4.
The neural circuits that govern sensory gating seem to involve older brain regions, in addition to the cortex. Crick postulated decades ago that the thalamus may play a significant role1. The thalamus is an egg-shaped structure that transmits sensory and motor signals from the brainstem to the cortex (Figure 1). Crick believed that while the region had so far been thought of as a “mere relay” center, a transit station for shuttling sensory information, it may actually have a modulatory function and act as a “gatekeeper”, allowing certain information to pass through to the cortex while blocking others. Specifically, inhibitory neurons in the thalamic reticular nucleus (TRN), a thin sheet of neurons that surrounds the rest of the thalamus, are thought to play a key role in this process.
Yet Crick’s hypothesis of thalamic control was not validated until recently, due to limitations in technology for studying brain activation and animal models of attention.
However, a group of researchers at MIT have finally resolved the pathway that allows us to focus on one sensory stimulus over others. To measure selective attention, mice were exposed to flashing lights and sweeping sounds at the same time5. For each trial, only one type of stimulus indicated the location of a reward, while the other gave conflicting information. Background noise at two different frequencies signaled to the mice whether they should pay attention to either the visual or auditory stimulus – and ignore the other – in order to find the reward (Figure 2).
The researchers then disrupted certain brain regions during the task to determine their function in selecting between sensory inputs. As expected, they found that the prefrontal cortex was essential to divided-attention. Mice with disrupted PFC activity could accurately follow either cue when it was presented alone, yet when they had to choose between cues, they could not decide when to heed to the sounds or lights.
But interruption of the thalamus led to surprising effects. When neurons in the visual portion of the TRN were silenced, the mice performed better in visual trials and had a harder time following the sounds. When the visual TRN was stimulated, performance on visual trials dropped while attention to auditory stimuli was enhanced. This suggested that the job of these neurons is not to augment meaningful input. Instead, it is to suppress distractors.
How does the TRN know which stimuli to inhibit? Does the PFC speak directly to the thalamus to dampen irrelevant sensory information, or is there a middleman? This was the next question that the group ventured to answer.
The researchers found that the PFC does not directly talk to the TRN. Rather, it works through the basal ganglia (Figure 3), another ancient brain structure that is involved in motor control6. The pathway creates a series of “on” and “off” switches that change their configurations depending on what should be filtered out. For example, when a cue to ignore visual stimuli is perceived, the PFC calls on the basal ganglia to activate visual TRN neurons and rapidly obstruct less useful information. This pathway also kicks in to block stimuli of the same type, like if you are engaging in a conversation in a noisy environment.
This circuit is not only important to understand because it’s engaged frequently to get the most out of our busy world; it is also a pathway that is impaired in neurological disorders. Deficits in sensory gating are associated with several psychiatric disorders, such as Alzheimer’s disease, schizophrenia and epilepsy3. Understanding how this pathway works could help us discover how to treat or prevent these symptoms, improving quality of life for patients with these diseases.
- Crick, F. Function of the thalamic reticular complex: the searchlight hypothesis. PNAS 81, 4586-4590 (1984).
- Humphreys, G. W. et al. Sensory gain control (amplification) as a mechanism of selective attention: electrophysiological and neuroimaging evidence. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 353, 1257-1270 (1998).
- Cromwell, H. C., Mears, R. P., Wan, L. & Boutros, N. N. Sensory gating: a translational effort from basic to clinical science. Clin EEG Neurosci 39, 69-72 (2008).
- Jones, L. A., Hills, P. J., Dick, K. M., Jones, S. P. & Bright, P. Cognitive mechanisms associated with auditory sensory gating. Brain Cogn 102, 33-45 (2016).
- Wimmer, R. D. et al. Thalamic control of sensory selection in divided attention. Nature 526, 705-709 (2015).
- Nakajima, M., Schmitt, L. I. & Halassa, M. M. Prefrontal Cortex Regulates Sensory Filtering through a Basal Ganglia-to-Thalamus Pathway. Neuron 103, 445-458.e10 (2019).
Cover photo by Terabass from Wikimedia Commons, public domain: https://www.publicdomainpictures.net/en/view-image.php?image=284042&picture=times-square-in-new-york
Figure 1 from The Database Center for Life Science, Wikimedia Commons (licensed under CC Attribution-Share Alike 2.1 Japan). https://commons.wikimedia.org/wiki/File:Thalamus_image.png
Figure 2 created using PowerPoint.
Figure 3 created using BodyParts3D/Anatomography (The Database Center for Life Science, licensed under CC Attribution-Share Alike 2.1 Japan). http://lifesciencedb.jp/bp3d/
Strong work !