WTF - Thalamus

The thalami are bilaterally symmetrical structures in the subcortical part of the brain that are cradled by the basal ganglia.  They are major hubs of pretty much everything your brain does and all of the sensory information coming into the brain with the exception of smell.

More primitive models of the brain visualized it as a bunch of relatively isolated modules, each specialized to perform a single task when queried and able to send that information to wherever it should go.  More modern ideas propose a more integrated picture, with various regions of the brain contributing to a more diffuse process through parallel connections with other network communities and hubs.  It appears that nearly every integrated process in the brain is influenced at some level by thalamic modulation.  You could characterize the Thalamus as a brain wide gateway to the cortex, modulator and mediator of inputs, coordinator of feedback, relay between higher cognitive areas, manager of brainstem nuclei, and facilitator of attention.

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References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.

Transcript

Welcome to PsyDactic, I am Dr. O’Leary a 4th year psychiatry resident in the national capital region.  This is a podcast about psychiatry and neuroscience that I make in my free time when I am inspired to find out more about a particular topic.  I try to speak truth to you, but be aware that I am often trying to draw intricate and precise pictures with a box of jumbo crayons.  Today will illustrate this perfectly.  I am going to try to draw a picture for you of the way the thalamus affects pretty much everything to sense, do, or think about.

The thalamus or more accurately the thalami are bilaterally symmetrical structures in the subcortical part of the brain that are cradled by the basal ganglia.  They are major hubs of pretty much everything your brain does and all of the sensory information coming into the brain with the exception of smell.

More primitive models of the brain visualized it as a bunch of relatively isolated modules, each specialized to perform a single task when queried and able to send that information to wherever it should go.  More modern ideas propose a more integrated picture, with various regions of the brain contributing to a more diffuse process through parallel connections with other network communities and hubs.  It appears that nearly every integrated process in the brain is influenced at some level by thalamic modulation.  You could characterize the Thalamus as a brain wide gateway to the cortex, modulator and mediator of inputs, coordinator of feedback, relay between higher cognitive areas, manager of brainstem nuclei, and facilitator of attention.

Visual, auditory, and somatosensory information passes through the thalamus on the way to cortical regions.  Information from one cortical area to another may pass through the thalamus and even be sent simultaneously to brainstem nuclei.  Let's imagine that you are walking down the street and a siamese cat leaps off the porch in front of you.  It stops, stairs directly at you, arches its back, bristles and hisses at you.  You carefully walk a safe distance from it while keeping your eyes on it enough to know what it is doing.

In your brain there has to be a lot going on.  You are receiving retinal information, that is passing through the Thalamus and being relayed to your visual cortex, which is feeding back to the Thalamus.  You are at the same time moving in relation to the cat and the other objects on the street and you are turning your head while walking, so as not to lose sight of this frisky feline.  The fact that your head is turning needs to be understood by the neurons controlling your feet so that they don’t keep walking in the same direction your eyes are facing.  The identity of the cat is being processed (probably in your temporal lobe), its intentions are being inferred (possibly in your medial frontal lobe), its threat value may be considered in your orbital frontal cortex and amygdala, while the features of the environment like size and distance are being calculated in your parietal cortex, fed to your cingulate gyrus and premotor areas to plan you next move.  These motor areas have to constantly be aware of your sensory information in order to infer what will happen with every step, every swing of the arm, every blink of the eye.  Cortical regions may be talking directly to other cortical regions via things like the uncinate fasciculus or the superior longitudinal fasciculus or short associate fibers, but much information is being relayed through and integrated in the Thalamus before going to other cortical regions.  The cortex is also sending the exact same information to other subcortical regions like the striatum or brainstem.  Your cerebellum is also getting both direct sensory information and association tracts that run back and forth between itself and the thalamus.  All of this to avoid a cat.

The more I learn about things like the thalamus and the complex interplay of brain networks, the more I feel like it is impossible to have a purely sensory experience.  For example, when we hear a sound, it is not just a vibratory frequency, but a preparatory act, an emotion, and a history all at the same time.  For some of us, that sound might also have a color.  The thalamus is the meeting of the minds that gives depth to our experience.  They say that the expansion of our cortex, especially our frontal lobes gave us our complex reasoning abilities, but without the thalamus, the cortex would never have even had a chance.

The thalamus receives and sends out primarily excitatory signals.  It has its own population of gaba-ergic inhibitory neurons in the thalamic reticular nucleus that work only on thalamic networks.  The connections in the thalamus are also unique from the cortex, because in the cortex, there are populations of neurons within local layers that work together to ramp up activity in that network.  The thalamic networks cannot excite themselves.  They can only receive excitatory signals from other regions and send excitatory signals out.

In the past, the thalamus has been described as having different nuclei or regions that each perform a single function, but more recently it has been demonstrated that each of these nuclei have been co-opted to perform heterogeneous functions (which means that they can do more than one thing with the same machinery).  I mentioned before that nerves that innervate and leave the thalamus are glutamatergic.  Some of these neurons contain very specific information, such as retinal neurons that communicate color or merely the presence of light.  Others are modulators of activity.  The information they carry modifies the activity of other neurons in the thalamus that send signals instead of themselves sending the signals.  They might end up making other neurons more excitable, or, if they synapse with the gaba-ergic interneurons, tone down outputs from the thalamus.  [[[ACETYLCHOLINE]]]

So just because the thalamus is sending or receiving glutamate does not mean that it is always resulting in downstream excitatory activity.  If glutamate from a signal exiting the thalamus is hitting (for example) gaba-ergic parvalbumin neurons in the cortex, this will result in inhibition of that cortical region.  To make things a little more complex and beautiful at the same time, excitatory glutamatergic neurons from the thalamus also synapse with what are called vasoactive intestinal peptide-positive interneurons, and these neurons inhibit other inhibitory neurons in the cortex, which results in dis-inhibition.  By inhibiting an inhibitor, you release other neurons to fire.  I really love the complexity here.

Remember that I said that the thalamus sends excitatory signals to the cortex or other regions of the basal ganglia, or the brainstem.  Some of the neurons in the thalamus actually split and send signals to multiple regions at the same time.  Some neurons within the thalamus are receiving signals from multiple regions and may receive input from both subcortical and cortical structures simultaneously.

One cool relationship within the thalamus is called a triad.  In this system a glutamate sending neuron synapses with another glutamatergic neuron in the thalamus and also on a gaba-ergic interneuron that itself inhibits the neuron that it is exciting.  At first this might not seem to make sense.  Why inhibit the thing you are trying to excite.  A system like this can make sense in multiple ways.

For example, GABA-A receptors are ion channels that act superfast to hyperpolarize the neuron and reduce excitability.  GABA-B receptors are G-protein coupled receptors that act through second messengers to cause changes in metabolism in the cell which is a relatively slow process.  Glutamate receptors can be diverse as well, including both ion channels (like NMDA and AMPA) and metabotropic receptors, some of which are actually inhibitory.  Without getting to detailed, it is important to know that these receptors can have differential effects on target cells by their location, density, and relative affinity for their neurotransmitter.

Imagine a triad, or three neuron system where glutamate is being dumped by an incoming neuron onto both an inhibitory and excitatory neuron.  The inhibitory neuron inhibits the outgoing excitatory neuron.  If the inhibitory neuron responds faster to the glutamate and has a higher average affinity for glutamate, then it can put the brakes on a signal getting through.  It is basically decreasing the gain on the system.  You could say that it is increasing the amount of glutamate needed to send a signal, which would decrease the rate of false positive signals getting through.  It might also increase the rate of false negative signals.

Now, once the gaba-ergic interneuron is functioning at full capacity, adding more glutamate can only increase the excitability of the glutamatergic neuron sending signals out and it can start to fire, despite being inhibited.  In a system like this, the energy required to send a signal could be increased and thus regulate outputs.

One alternative is somewhat of the opposite.  Imagine that the excitatory neuron receiving the glutamate from the incoming neuron can respond faster and with a higher relative affinity for glutamate than the inhibitory interneuron.  In this system, a signal coming in would always immediately be sent through.  However, as the signal gets stronger, a ceiling is placed on the excitability of the downstream glutamatergic neuron by the inhibitory interneuron because it will start to decrease the gain of the system the louder things get.  In this way, the interneuron would just be making sure that things didn’t get too out of control.

A third way to view this is that the inhibitory interneuron might respond more to both low levels of glutamate and to very high levels of glutamate, but be relatively less able to inhibit its target neuron at moderate levels.  In this kind of system the inhibitory neuron can set both the floor and the ceiling.  It can make the system wait until enough guests have arrived before starting the party and then shut the party down once it gets out of control.

I am not saying that any of these mechanisms I just speculated are the way that any particular triad works.  I am just saying that having a triad is a potentially powerful way to modulate neural signaling, and the thalamus is heavy with triads.  One of the ways that the thalamus may need to be able to inhibit signals is through modulating our attention.  We may want to relatively suppress some sensory information, like pain for instance when we need to focus on a task or tone down distracting thoughts about the strange look someone just gave us when we are trying to figure out how to calculate change for a dollar.  Also, we can benefit from a more global suppression of activity through the thalamus when we are asleep.

Another cool aspect of how the thalamus communicates is that it often processes parallel streams of data about the same thing.  Take signals coming from the retina for example.

I remember first struggling with the idea that what I was seeing was not really what was in front of me, but some vague attempt that my brain has made to make sense of photons that hit my retina.  The better my brain is at inferring what I saw, they better decisions it can make, but fundamentally it is impossible to actually experience reality.

The retina starts our journey to approximating reality by sending out three different streams of visual information simultaneously.  Let's call these the W, X, and Y streams.  In the end, the X and Y streams both synapse in the thalamus and end up in Layer 4 of the primary visual cortex.  However, in the thalamus the X stream forms one of those triads I just talked about, while the Y stream has only a simple 1:1 synapse.  Also, even though both end up in layer 4, the X stream terminates in a deeper section of layer 4 than the Y stream.  The Y stream also splits on its way to the visual cortex after exiting the thalamus and invervates layer 4 of the secondary visual cortex with the same information.

So we have different information about the same thing coming from the retina.  One stream forms a triad in the thalamus and then heads on to layer 4 of the primary visual cortex while the other forms only a simple synapse in the thalamus before going to a different part of layer 4 in two separate parts of the visual cortex.  But what happened to the W stream?  The W stream appears more heterogeneous in its form, but the important aspect it shares is that its final target are layers 2 or 3 of the visual cortex and sometimes layer 1.

So when you look at something, it is first processed in the retinal ganglion cells and then different populations of these cells send out at least 3 parallel streams of information that are processed in the lateral geniculate nucleus of the thalamus via variable synaptic relationships, and then they send this information forward to layers 1 through 4 of the primary visual cortex and also layer 4 of the secondary visual cortex.  Before ever making it to the visual cortex, the information is processed at least twice.  Once in the retinal and again in the thalamus.  Would you be surprised if I now told you that this is a vast oversimplification?

Without the thalamus we couldn’t have higher order thoughts.  What that means is that we would be able to think things about the sensory information we were receiving and we certainly would not be able to think about the things that we are thinking.  The thalamus has been conceptualized as processing two kinds of information.  First order processing is how the thalamus routes information coming from subcortical inputs, like our senses.  Higher order processing involves information fed to it from cortical regions.

Cortical regions send different kinds of information to the thalamus.  The first kind is direct feedback.  This comes from layer 6.  Feedback means that the thalamus is getting signals about the signals it is sending.  This is distinct from what has been called “driver signaling.”  Driver signals are signals that create new streams of information in the thalamus, instead of just modulating existing streams like the feedback neurons do.  Driver signals, when they come from the cortex, come from layer 5.   Remember all the nuclei within the thalamus I mentioned earlier?  Well, some of these are specialized in first order drivers and some in higher order drivers.

When one cortical region wants to send information to another cortical region, the thalamus can act as mediator.  Layer 5 neurons send information to the thalamus which processes it (often in one of those triads) and then sends it forward to more shallow layers of a different part of the cortex, which will send feedback to the thalamus from layer 6 of the cortex. That same driver signal from layer 5 or other signals with complementary information might bypass the thalamus altogether on its way to, for example, another part of the cortex or to brainstem nuclei.

References

Shine JM, Lewis LD, Garrett DD, Hwang K. The impact of the human thalamus on brain-wide information processing. Nat Rev Neurosci. 2023 Jul;24(7):416-430. doi: 10.1038/s41583-023-00701-0. Epub 2023 May 26. PMID: 37237103; PMCID: PMC10970713.

Jones EG The thalamic matrix and thalamocortical synchrony. Trends in Neurosciences 24, 595–

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Halassa MM & Sherman SM Thalamocortical Circuit Motifs: A General Framework. Neuron 103,

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Halassa MM & Acsády L Thalamic Inhibition: Diverse Sources, Diverse Scales. Trends in Neurosciences 39, 680–693 (2016). [PubMed: 27589879]

Sherman SM. The thalamus is more than just a relay. Curr Opin Neurobiol. 2007 Aug;17(4):417-22. doi: 10.1016/j.conb.2007.07.003. Epub 2007 Aug 17. PMID: 17707635; PMCID: PMC2753250.

https://www.kenhub.com/en/library/anatomy/cortical-cytoarchitecture