Selective effects of isoflurane on cortico-cortical feedback afferent responses in murine non-primary neocortex

Abstract

Background: General anaesthetics affect loss of consciousness by disrupting information-passing and integration within thalamo-cortical (TC) networks. Feedback cortical connections that carry internally generated signals such as expectation and attention appear more sensitive to anaesthesia than feedforward signals. However, direct evidence for this effect in non-primary cortex is lacking. In addition, direct comparisons between TC core and matrix, and between cortico-cortical (CC) feedforward and feedback responses have not been reported. Methods: We investigated the disruption of synaptic responses by isoflurane of four distinct afferent pathways to nonprimary neocortex. We independently activated TC core and matrix and reciprocal CC (feedforward and feedback) pathways using optogenetic techniques, and compared the relative sensitivity of synaptic responses to isoflurane. Results: Under control conditions, activation of axon terminals of all pathways evoked postsynaptic currents (recorded extracellularly) and postsynaptic potentials in pyramidal neurones. CC feedback responses were substantially more sensitive to isoflurane (0 to 0.53 mM) compared with TC core, TC matrix, or CC feedforward pathways. Conclusion: Differential sensitivity of CC feedback synaptic responses to isoflurane in a clinically relevant range suggests a role for disruption of these afferents in the hypnotic effects of anaesthetic agents.

Cell type-specific effects of isoflurane on two distinct afferent inputs to cortical layer 1

“…Despite their overlapping terminal fields and similar synaptic dynamics under control conditions, TC and CC inputs to layer 1 were differentially affected by isoflurane ( Figure 1; Table 2), consistent with previous results from our lab 11 . Amplitudes of layer 1 current sinks were suppressed by isoflurane by 21.8% for CC inputs, while current sinks evoked by TC inputs were relatively resistant to isoflurane (Figure 1; Table 2).…”

“…on corticothalamic circuits, disrupting integration of information throughout the cortical hierarchy [1][2][3] . Activity in higher order cortical areas is particularly sensitive to anaesthetics 4,5 , as is corticocortical (CC) feedback connectivity [6][7][8][9][10][11] . In addition to cortical effects, higher order thalamocortical (TC) connectivity is suppressed during both sleep 12 and anaesthesia [13][14][15] .…”

“…Recent studies from our lab have shown that in ex vivo slices, isoflurane diminishes synaptic responses in a pathway-specific manner 10,11 . In the latter study, despite overlapping terminal fields in layer 1, CC feedback afferents to a non-primary cortical area were preferentially suppressed by isoflurane compared to non-primary TC inputs.…”

Optogenetic activation of afferent pathways in brain slices and modulation of responses by volatile anesthetics

“…Cortical inputs arriving from higher order cortical areas or from non-primary thalamic nuclei have partially overlapping terminal fields in layer 1 of non-primary visual cortex 24 . To isolate independent thalamocortical or corticocortical afferent pathways, we injected a viral vector containing ChR2 and an eYFP fluorescent reporter (Figure 1A) into either Po or Cg.…”

“…The elusiveness of the mechanisms underlying loss and return of consciousness during anesthesia may be attributed partially to non-linear, synergistic actions of anesthetics at the cellular, network, and systems levels 15 . Isoflurane, for example, suppresses activity within select brain regions 16-18 , impairs connectivity between distant brain regions 19-23 , and diminishes synaptic responses in a pathway-specific manner 24,25 . Which effects of anesthetics, from the molecular to the systems level, are necessary or sufficient to effect loss of consciousness remains unclear.…”