Coactivating Large Neuronal Populations Enhances Cortical Excitability

Post by Elisa Guma

What's the science?

Our brain’s ability to structurally and functionally remodel in response to sensory inputs is critical to our survival. Repetitive exposure to the same sensory stimulus can induce long-term changes in underlying neural circuits, which in turn can alter future responses to the same stimulus. Importantly, exposure to sensory stimuli typically coactivates large groups of cortical neurons, leading to correlated neuronal activity and increased efficacy of synaptic transmission and neuronal excitability. This week in PNAS, Zhang and colleagues used optogenetic methods to directly activate populations of cortical neurons in the mouse cortex to determine the mechanisms underlying enhanced neuronal excitability in response to repetitive stimulus exposure. 

How did they do it?

The authors injected the adult mouse primary visual cortex with adeno-associated virus vector that would transfect pyramidal neurons with channelrhodopsin 2 (ChR2), a blue light sensitive channel, and implanted them with multi-unit electrodes in layers 2 and 3 of the visual cortex. With this set up, the authors were able to stimulate the visual cortex (using a laser to activate ChR 2) and measure neuronal activity in discrete response areas (RAs) at each electrode in anesthetized mice.

In their first experiment, the authors examined whether repetitive synchronous coactivation (compared to random stimulation) of multiple neuronal populations in 4 identified RAs of the visual cortex could alter the spiking rate of the neurons in these areas in response to a test (light) stimulus. The authors characterized the duration of the enhancement of evoked spiking following neuronal coactivation, as well as the dependence of the enhancement of the number of coactivation stimuli, and the size of the neuronal population coactivated. The experiments were repeated in the motor cortex (to understand whether they were generalizable or specific to the visual cortex. To better understand how synaptic transmission might affect neuronal response to synchronous coactivation, the authors infused the visual cortex with an antagonist for the AMPA or NMDA subtype of glutamate receptors and measures stimulus-evoked synaptic activity using in vivo whole cell recording.

Next, the authors wanted to know if the enhancement of neuronal excitability could be achieved at a longer range. First, they examined cross-cortical enhancement between the visual cortex and somatosensory cortex, and then examined whether the cross-hemispheric spread of spiking enhancement could occur between the right and left visual cortices. The size of coactivated populations and distance between regions were considered to be modulating factors. Finally, for contralateral communication to occur between hemispheres, neuronal activity passes through subcortical regions. To understand the underlying mechanisms of this pathway, the authors also chemogenetically inhibited neuronal activity in the midline/intralaminar thalamus, as there is evidence for it being connected to the visual cortex and measured whether spiking enhancement between hemispheres could still be achieved.

What did they find?

First, the authors confirmed that repetitive activation of neuronal populations caused enhancement of neuronal spiking rates in all RAs recorded, which was not observed if the sequence was random, suggesting that the synchronous coactivation of cortical neurons is required for the observed enhancement of neuronal firing. The enhancement induced by synchronous coactivation was long-lasting (persisted up to 100 minutes following the coactivation), saturable (plateaued after 3 episodes of coactivation), and dependent on the size of the coactivation area (smaller area only show enhancement of closer RAs). Similar coactivation was observed in the motor cortex suggesting that enhancement is a general property of the cerebral cortex. AMPA receptor blockade led to a reduction or elimination of spiking of neurons, whereas NMDA receptor blockade abolished enhanced test stimulus-evoked spiking highlighting the critical role these glutamate receptor subunits play in inducing neuronal excitability. Many of the features observed thus far are reminiscent of long-term potentiation.

To achieve cross-cortical neuronal enhancement, the size of coactivated neuronal populations needed to be increased; no enhancement was observed if only one region within the visual and somatosensory cortices were stimulated, however, there was a significant elevation of test-stimulus-evoked spiking if two visual RAs and one somatosensory RA (or vice versa) were coactivated. Finally, the authors found that repeatedly coactivating four RAs in the left visual cortex led to enhanced neuronal spiking in both hemispheres. This was markedly reduced by silencing the midline/intralaminar thalamus, suggesting that it plays a critical role in mediating contralateral coactivation.

What's the impact?

This study shows that repetitive coactivation of large populations of cortical neurons results in persistent enhancement of neuronal spiking evoked by optogenetic stimulation. This effect was dependent on NMDA receptor activity and could be observed in local cortical areas, distance cortical areas, and even in different hemispheres. Finally, neuronal activity in the thalamus may be involved in the enhancement of cortical excitability. This work elucidates some of the mechanisms underlying cortical excitability and may help in understanding disorders in which cortical excitability is aberrant, such as epilepsy.

Zhang et al. Global enhancement of cortical excitability following coactivation of large neuronal populations. PNAS (2020). Access the original scientific publication here