Circuits That Mediate Expression of Signaled Active Avoidance Converge in the Pedunculopontine Tegmentum

Abstract

An innocuous sensory stimulus that reliably signals an upcoming aversive event can be conditioned to elicit locomotion to a safe location before the aversive outcome ensues. The neural circuits that mediate the expression of this signaled locomotor action, known as signaled active avoidance, have not been identified. While exploring sensorimotor midbrain circuits in mice of either sex, we found that excitation of GABAergic cells in the substantia nigra pars reticulata blocks signaled active avoidance by inhibiting cells in the pedunculopontine tegmental nucleus (PPT), not by inhibiting cells in the superior colliculus or thalamus. Direct inhibition of putative-glutamatergic PPT cells, excitation of GABAergic PPT cells, or excitation of GABAergic afferents in PPT, abolish signaled active avoidance. Conversely, excitation of putative-glutamatergic PPT cells, or inhibition of GABAergic PPT cells, can be tuned to drive avoidance responses. The PPT is an essential junction for the expression of signaled active avoidance gated by nigral and other synaptic afferents.

Zona Incerta GABAergic Output Controls a Signaled Locomotor Action in the Midbrain Tegmentum

“…The electrophysiological effects of these optogenetic light patterns (Cont and 2-to 100-Hz trains of 1-ms pulses) were previously characterized using both wholecell recordings in slices and single-unit recordings in anesthetized mice (Hormigo et al, 2016(Hormigo et al, , 2019. Similar validation experiments in some of the animals from this study verified the conclusions obtained previously.…”

“…Regarding blue light applied to fibers or synaptic terminals of ChR2-expressing GABAergic cells at their targets, trains of 1-ms pulses at 40-to 66-Hz drive the most sustained IPSPs in postsynaptic neurons. In contrast, continuous pulses drive strong IPSPs at light onset but the IPSPs rapidly adapt (Hormigo et al, 2019). Thus, 40-to 66-Hz blue light trains drive the strongest sustained inhibition, while continuous pulses of blue light drive strong inhibition only at light onset.…”

“…All procedures were reviewed and approved by the Animal Care Committee of Drexel University and conducted in adult (more than eight weeks) male and female mice. The results from both sexes were combined since there is no sex difference in the behavior measured for the strains used (Hormigo et al, 2019).…”

“…The substantia nigra pars reticulata (SNr), a main output of the basal ganglia, appears to have such a gating role because it fully controls signaled active avoidance (Hormigo et al, 2016); excitation of SNr GABAergic cells blocks signaled active avoidance while inhibition drives active avoidance. The control exerted by SNr occurs in the midbrain pedunculopontine tegmental nucleus (PPT), which is part of the midbrain locomotor region (MLR; Shik et al, 1966;Skinner and Garcia-Rill, 1984;Ryczko and Dubuc, 2013;Mena-Segovia and Bolam, 2017) and an essential junction for the expression of signaled active avoidance (Hormigo et al, 2019). However, it is unlikely that the control exerted by SNr in PPT is unique.…”

“…The zona incerta is a good candidate because it has been generally proposed to have a gating role between sensory stimuli and motor responses (Mitrofanis, 2005), and because of the already mentioned putative roles in thalamocortical transmission, defensive behaviors and fear. Moreover, zona incerta cells project to PPT (Kolmac et al, 1998;Mitrofanis, 2005), which has an essential role in active avoidance (Hormigo et al, 2019), and to other sites also innervated by SNr cells, such as superior colliculus in the midbrain, and separate portions of the thalamus (Di Chiara et al, 1979;Barthó et al, 2002). Like SNr GABAergic cells, zona incerta GABAergic cells may be able to control signaled active avoidance.…”