Post by Shireen Parimoo
What's the science?
In sensory regions of the brain, like the primary somatosensory cortex (S1), sensory inputs from adjacent regions on the body are represented in adjacent populations of neurons (barrels). In mice, for example, whiskers are somatotopically represented in the cortex in barrels, which means that stimulating neighboring whiskers activates neighboring barrels in the mouse S1. Sensory input from the body travels through the thalamus (part of the forebrain) before reaching the cortex, and these connections are formed early in development. Interestingly, there is evidence of co-occurring spontaneous activity in the thalamus and S1 before the cortical barrels have fully developed. It is currently unclear whether this spontaneous co-activation of the thalamus and S1 facilitates the development of somatotopically organized cortical barrels or whether cortical barrel organization is dependent on external sensory input after birth. This week in Science, Antón-Bolaños and colleagues investigated the functional characteristics of thalamocortical connections in developing and newborn mice.
How did they do it?
First, the authors electrically stimulated the ventral posteromedial nucleus (VPM) of the thalamus in mouse embryos and used calcium imaging to measure the change in the response of S1 neurons. To determine how specific the projections were from the thalamus to S1, they also stimulated three other regions adjacent to the VPM and measured the cortical response. They then used a transgenic mouse line “Kir” to examine the effect of altered spontaneous thalamic activity on barrel development. Control mice have high-amplitude and synchronized neural activity in the VPM, whereas Kir mice have asynchronous and low-amplitude activity in 10-day old embryos (E10). They stimulated the VPM and adjacent thalamic regions and compared the cortical response in the Kir and control mice at 17.5 and 18.5 days.
To determine the longer term effect of altered thalamic activity on barrel development, the authors stimulated the VPM in Kir and control mice four days after birth (P4) and recorded cortical activity. They also stimulated the whiskers to determine if providing external sensory input could facilitate the development of cortical barrels. They used multichannel electrodes to measure extracellular activity in S1 of Kir and control mice at postnatal days 2 amd 3. To further examine the mechanism underlying cortical activity in Kir mice, a glutamate receptor antagonist was applied to S1 and change in cortical response was measured. Finally, axon tracing and immunostaining were used to detect cortical barrels and axons projecting between the thalamus and S1.
What did they find?
Stimulating the VPM resulted in a large cortical calcium response at day 17.5, but a smaller and more localized response at 18.5 days. Stimulation of VPM-adjacent regions at 18.5 days activated a population of neurons altogether. In transgenic Kir mice, on the other hand, VPM stimulation resulted in widespread cortical activation, and stimulating VPM-adjacent neurons activated overlapping neuronal populations in S1. In newborn control mice, VPM stimulation led to an even more localized cortical response, but this localization did not occur to the same extent in the Kir mice. This means that specific and functionally organized thalamocortical projections developed in 18.5-day old embryos, but altering thalamic activity disrupted the formation of cortical somatotopic maps. These effects persisted even after birth; control mice but not the Kir mice showed evidence of cortical barrels at postnatal day 4. Similarly, although stimulating the whiskers activated different S1 barrels in control mice, cortical activity was less distinct in the transgenic Kir mice and could not be rescued by sensory input after birth.
Axon tracing and staining revealed that in control mice, thalamic neurons projected to the corresponding cortical neurons in a barrel, but these axonal projections were less spatially specific in Kir mice. This means that neurons originating from a larger region of the thalamic VPM project to the S1 in Kir mice compared to the control mice. Finally, the transgenic mice had more glutamate receptors than control mice. Blocking glutamate receptors with an antagonist reduced the spatial extent of cortical activity in Kir mice, making it more similar to that of control mice. These results suggest that glutamate receptors underlie the widespread cortical response to thalamic activation in Kir mice, which subsequently affects the development of somatotopic maps in S1.
What's the impact?
This study is the first to demonstrate that spontaneous activity in the thalamus during embryonic development is critical for the formation of somatotopic maps in the mouse primary sensory cortex. Moreover, the finding that the concentration of glutamate receptors might underlie this relationship has important implications for understanding the role of genetic factors in cortical development. Overall, this study provides further insight into the importance of prenatal factors in the development of functionally organized cortical maps.
Antón-Bolaños et al. Prenatal activity from thalamic neurons governs the emergence of functional cortical maps in mice. Science (2019). Access the original scientific publication here.