Modulation of cortical slow oscillatory rhythm by GABA_Breceptors: an experimental and computational study

Abstract

<jats:title>Abstract</jats:title><jats:p>Slow wave oscillations (SWO) dominate cortical activity during deep sleep, anesthesia and in some brain lesions. SWO consist of Up states or periods of activity interspersed with Down states or periods of silence. The rhythmicity expressed during SWO integrates neuronal and connectivity properties of the network and it is often altered in neurological pathological conditions. Different mechanisms have been proposed to drive the transitions between Up and Down states, in particular, adaptation mechanisms have been proposed to contribute to the Up-to-Down transition. Synaptic inhibition, and specially GABA<jats:sub>B</jats:sub> receptors, have also been proposed to have a role in the termination of Up states. The interplay between these two potential mechanisms, adaptation and inhibition, is not well understood and the role of slow inhibition is not yet clear regarding the full cycle of the slow oscillatory rhythm. Here we contribute to its understanding by combining experimental and computational techniques. GABA<jats:sub>B</jats:sub> receptors-blockade not only elongated Up states, but also affected the subsequent Down states, and thus the whole cycle of the oscillations. Furthermore, while adaptation tends to yield a rather regular behavior, GABA<jats:sub>B</jats:sub> receptors-blockade decreased the variability of the sequence of Up and Down states. Interestingly, variability changes could be accomplished in two different ways: either accompanied by a shortening or by a lengthening of the duration of the Down state. Even when the most common observation is the lengthening of the Down states, both changes are expressed experimentally and also in numerical simulations. Our simulations suggest that the sluggishness of GABA<jats:sub>B</jats:sub> receptors to follow the excitatory fluctuations of the cortical network can explain these different network dynamics modulated by GABA<jats:sub>B</jats:sub> receptors.</jats:p>

Medium spiny neurons activity reveals the discrete segregation of mouse dorsal striatum

“…Our results show more positive and negative ratio to the DMS-MSNs during the upward and downward Up states transitions slopes respectively, suggesting a different inhibitory recruitment in the DLS compared to DMS. In active cortical slices with SWO, both upward and downward transition slopes are controlled by GABAA and GABAB receptor activation (Perez-Zabalza et al, 2020;Sanchez-Vives et al, 2010). Based on these evidences, and beyond the glutamatergic inputs, we hypothesize that PV interneurons may greatly influence the SWO of DLS-MSNs making them different from DMS ones.…”

Thalamus mediates neocortical Down state transition via GABAB-receptor-targeting interneurons

“…Many factors contribute to terminating Up states in cortical slice preparations, including mechanisms intrinsic to L5 neurons, synaptic depression, and GABAergic inhibition (Sanchez-Vives and McCormick, 2000;Mann et al, 2009;Perez-Zabalza et al, 2020). Our findings that midline thalamic neurons take part in controlling Down transition and that blocking GABABRs prolongs Up states in naturally sleeping mice (Figure S1) indicate an active mechanism governing Up state termination, which may help explain the remarkable synchrony of Down transition across cortical areas (Volgushev et al, 2006;Sheroziya & Timofeev, 2014).…”

Cortical Activity and Rhythmic Patterns in Mouse Models of Aging and Alzheimer’s Disease

“…Evidence in support of the theory that slow oscillations can be generated by isolated cortex comes from the finding that they emerge from cortical slabs [6] and cortical slices [7] ( Figure 1D). The slow oscillation is a rhythm generated and maintained by the cortex [6,8,9] through the interaction between the synaptic reverberation of the network and activity-dependent adaptation mechanisms [7,10] and/or slow inhibition [11][12][13]. Furthermore, it is a rhythm of local origin, in which the long-range connectivity that characterizes the wakeful state of the brain is significantly reduced [14][15][16], slow oscillations being rather similar across different cortical areas [17].…”