Basal Ganglia Output Has a Permissive Non-Driving Role in a Signaled Locomotor Action Mediated by the Midbrain

Abstract

The basal ganglia are important for movement and reinforcement learning. Using mice of either sex, we found that the main basal ganglia GABAergic output in the midbrain, the substantia nigra pars reticulata (SNr), shows movement-related neural activity during the expression of a negatively reinforced signaled locomotor action known as signaled active avoidance; this action involves mice moving away during a warning signal to avoid a threat. In particular, many SNr neurons deactivate during active avoidance responses. However, whether SNr deactivation has an essential role driving or regulating active avoidance responses is unknown. We found that optogenetic excitation of SNr or striatal GABAergic fibers that project to an area in the pedunculopontine tegmentum (PPT) within the midbrain locomotor region abolishes signaled active avoidance responses, while optogenetic inhibition of SNr cells (mimicking the SNr deactivation observed during an active avoidance behavior) serves as an effective conditioned stimulus signal to drive avoidance responses by disinhibiting PPT neurons. However, preclusion of SNr deactivation, or direct inhibition of SNr fibers in the PPT, does not impair the expression of signaled active avoidance, indicating that SNr output does not drive the expression of a signaled locomotor action mediated by the midbrain. Consistent with a permissive regulatory role, SNr output provides information about the state of the ongoing action to downstream structures that mediate the action.

Bidirectional Control of Orienting Behavior by the Substantia Nigra Pars Reticulata: Distinct Significance of Head and Whisker Movements

“…However, when the continuous blue light is applied to ChR2-expressing presynaptic terminals, the initial presynaptic depolarization is very effective at triggering neurotransmitter release and postsynaptic actions but the ensuing sustained presynaptic depolarization does not correspond with sustained postsynaptic effects (Hormigo et al, 2019), possibly because sustained presynaptic depolarization is generally associated with presynaptic inhibition of neurotransmitter release (MacDermott et al, 1999). The distinct ability of blue light patterns to drive electrophysiological effects in networks of GABAergic neurons expressing ChR2 has been previously noted (Hormigo et al, 2016;Hormigo et al, 2019;Hormigo et al, 2021). For instance, activation of ChR2 expressed in somatodendritic regions of the recorded SNr neurons (Vgat-SNr-ChR2 mice) with continuous blue light is much more effective than trains (1 ms pulses) of blue light at evoking sustained neuronal firing in SNr neurons (Fig.…”

“…1B). Therefore, when ChR2 is expressed in presynaptic terminals, continuous blue light produces an IPSP at light onset that adapts strongly and fades over time, while trains of blue light produce an IPSP on each pulse of the train which results in a robust sustained IPSP over the course of the light train (Hormigo et al, 2019;Hormigo et al, 2021).…”

“…In these mice, SNr cells are inhibited without exciting afferent fibers reaching SNr, which could inhibit other nuclei via fiber collaterals and complicate interpretation of the effects mediated by SNr. These opsins are effective at inhibiting SNr cells both in slices and in vivo (Hormigo et al, 2016;Hormigo et al, 2021). Here we employed three groups of mice.…”

“…In particular, unilateral inhibition of SNr neurons causes contraversive orienting movement that may have a moving away significance. Previous studies have shown that signaled active avoidance, a goal-directed behavior during which mice must move away to avoid an aversive US, depends on the firing of GABAergic SNr neurons (Hormigo et al, 2016;Hormigo et al, 2019;Hormigo et al, 2021); excitation of SNr neurons in Vgat-SNr-ChR2 mice blocks signaled active avoidance, while inhibition of these neurons in Vgat-SNr-Arch drives active avoidance in the absence of an external signal (CS). The bidirectional control of SNr firing in Vgat-ChR2 mice provides a unique opportunity to test the effect of exciting and inhibiting SNr neurons on signaled active avoidance within the same animal.…”

“…However, stimulation of GABAergic afferents from the nucleus accumbens were not effective at driving orienting head movements. This is despite the fact that both of these fibers show abundant ChR2 expression in SNr and fibers from the nucleus accumbens are effective at inhibiting SNr neurons (Hormigo et al, 2021). Perhaps, striatal and accumbens afferents target different populations of SNr neurons, which have different functional roles; segregation of direct pathways to SNr from different regions of striatum has been reported (Lee et al, 2020).…”