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A new paper from the Molnár Group has shed light on substantial rewiring of corticothalamic connections that is triggered by early sensory loss during development. The study has identified a new mechanism that significantly rearranges the cortico-thalamo-cortical circuits but has not been considered before in patients with sensory loss for potential therapies.

The corticofugal projections from layers 5, 6a, and 6b have distinct relationships to first order (also called relay) nuclei and higher-order (also called association) nuclei of the thalamus. Only the first-order thalamic nuclei receive direct input from the sensory periphery. The higher order thalamic nuclei receive their input from the cortex and relay this back to other cortical areas, providing a route for trans thalamic cortico-cortical communication. Projections from cortical layer 6a provide abundant inputs to all thalamic nuclei and modulate how sensory information is relayed to the cortex. Layer 5 usually provides input to higher-order thalamic nuclei, via axon collaterals of subcortical projections targeting the superior colliculus and spinal cord, among others. These are powerful and large, feed-forward “driver” inputs for relay to other cortical areas. My laboratory discovered that a subgroup of layer 6b neurons (Drd1a-Cre line) preferentially target posterior thalamic nucleus, lateral posterior nucleus of thalamus, and other higher-order and midline thalamic nuclei in the ipsi- and contralateral thalamus, as well as frontal and lateral association cortices. Their axons do not form side branches in (pre)thalamic reticular nucleus. Our work suggests that there is a third type of cortico-thalamic projection in addition to layers 5 and 6a, from layer 6b.
Projections from layer 5 (red) from visual cortex (green) form direct synapses projections in the visual thalamus at the end of the first postnatal week that is maintained to adulthood if the innervation from the eye is lost at birth in mice.

Our brain starts receiving information from our sensory organs even before we are born. Our sensory organs together with our brain produce spontaneous activity patters during development. This begins before our brain and sensory organs are fully functional or able to detect signals. The thalamus, a large structure in our interbrain (diencephalon) comprised of dozens of nuclei, plays a key role in relaying these signals to the cerebral cortex, where they will be interpreted and relayed back to the thalamus to select the stimuli that we should pay more attention to. In fact, the cortex sends ten times more projections to the thalamus than it receives from the thalamus.

There are two types of thalamic nuclei according to the input they receive. Only the first order thalamic nuclei receive direct input from sensory organs. The higher order thalamic nuclei receive most of their input from the cortex, particularly from cortical layer 5 projections. In the case of sight, our eye connects to the primary (first order) visual thalamus that relays information to our primary visual cortex. The primary visual cortex then projects back to the thalamus. Layer 6 projections target both the first (dorsal lateral geniculate nucleus, dLGN) and higher order visual thalamic nuclei (LP pulvinar), whereas layer 5 cortical projections exclusively target the higher order thalamic nucleus (LP). Separate thalamic nuclei will then receive input from sensory organs (first order) and from the layer 5 neurons (higher order) of the visual cortex that ultimately enables us to interpret what we see and where to focus our attention to. While thalamocortical and corticothalamic connectivity in normal circumstances is well understood, what happens to these connections upon early sensory loss has so far been much less clear. In particular, the changes in selective targeting of corticothalamic projections from layer 5 has not been explored in the event of early sensory loss, such as being born without one or both eyes (anophthalmia).

A new study from the Molnár Group has highlighted the importance of peripheral input in the development and plasticity of the corticothalamic connections to the first and higher order thalamic nuclei and the regulation of their transcriptional profile. In mice, anophthalmia from birth elicited drastic changes in the formation of thalamo-cortico-thalamic circuits that may contribute to altered corticothalamic behaviour following early sensory loss. While layer 5 neurons of the cortex do not normally innervate the primary thalamic nuclei that receive input from the sensory organs, researchers have been able to show that early removal of sensory input from the eye causes layer 5 projections to input to the first order, rather than the higher order, thalamic visual nucleus.  Moreover, the gene expression of the first order thalamic nuclei became like younger stages and more like higher order thalamic nuclei. Professor Zoltán Molnár said: “The previous views suggested that the various sensory inputs just “plug” into thalamocortical circuits that are more or less pre-prepared. The switch in connectivity and gene expression patterns in the thalamus has huge implications how the thalami-cortico-thalamic circuits are re-configured, which impacts how the brain is processing information after early sensory lesion.”

“Understanding how the brain is rewired upon sensory loss is essential for unravelling the mechanisms underlying plasticity in the sensory deprived brain, thus gaining better insights into the translational investigation and possible therapeutic targets for individuals with a form of sensory deprivation. Our results allow us to hypothesise that early peripheral input to the thalamus contributes to the transcriptional and circuit hierarchy identity of thalamic nuclei.”

The team’s results also provide novel cues to further understanding the compensatory mechanisms that the brain uses to adapt to altered peripheral inputs. These may go some way to explaining why some patients experiencing early sensory loss can develop enhanced skills across their remaining senses. Professor Molnár said: “The brain compensates for sensory loss on many different levels, especially early sensory loss. During development, the sensory signals shape our brain and determine how large an area we dedicate to certain functions. Our study shows a new mechanism that was not considered before.  The proportions of the first and higher order thalamic circuits can change, further shaping the representations in our cortex. The neuronal connections and the gene expression patterns both change. We showed that the first order thalamic nuclei now receive cortical inputs that normally they do not receive, and they also express genes that normally only the higher order thalamic nuclei express. Our brain adjusts where to pay more attention to.”

The study started during the doctoral thesis of Dr Eleanor Grant, then continued as the MSc thesis of Chrysoula Giasafaki co-supervised by Departmental Lecturer Dr Anna Hoerder-Suabedissen and Prof Zoltán Molnár.  The full paper, joint first authored by Chrysoula Giasafaki, Dr Eleanor Grant, and Dr Anna Hoerder-Suabedissen, entitled “Cross-hierarchical plasticity of corticofugal projections to dLGN after neonatal monocular enucleation” is available to read in The Journal of Comparative Neurology in a special issue dedicated to Thalamus

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