Control of locomotor speed, arousal, and hippocampal theta rhythms by the nucleus incertus

Abstract

Navigation requires not only the execution of locomotor programs but also high arousal and real-time retrieval of spatial memory that is often associated with hippocampal theta oscillations. However, the neural circuits for coordinately controlling these important processes remain to be fully dissected. Here we show that the activity of the neuromedin B (NMB) neurons in the nucleus incertus (NI) is tightly correlated with mouse locomotor speed, arousal level, and hippocampal theta power. These processes are reversibly suppressed by optogenetic inhibition and rapidly promoted by optogenetic stimulation of NI NMB neurons. These neurons form reciprocal connections with several subcortical areas associated with arousal, theta oscillation, and premotor processing. Their projections to multiple downstream stations regulate locomotion and hippocampal theta, with the projection to the medial septum being particularly important for promoting arousal. Therefore, NI NMB neurons functionally impact the neural circuit for navigation control according to particular brains states.

Mapping Cell Types and Efferent Pathways in the Ascending Relaxin-3 System of the Nucleus Incertus

“…The present results help to clarify the neurotransmitter identity of neurons in this region of the pontine tegmentum as a basis for future functional studies. Lu et al reported that about 50% of NMB expressing neurons in the NI also express Rln3, although only a single anatomical level was described (Lu et al, 2020). Here, in the region usually defined as the NI, we observe a higher degree of co-expression of NMB and Rln3 mRNA, with a minor population of neurons expressing NMB alone.…”

“…Expression of Rln3 has been used as a defining marker of the NI in rodents and primates (Burazin et al, 2002;Ma et al, 2007;Ma et al, 2009a), although the area encompassing the anatomical NI contains a mixture of Rln3 expressing and non-expressing neurons (Ma et al, 2007). Recently, expression of Cre-recombinase targeted to the Nmb gene has also been used for functional studies of the NI (Lu et al, 2020). The present results help to clarify the neurotransmitter identity of neurons in this region of the pontine tegmentum as a basis for future functional studies.…”

“…Examination of the entire CNS rarely revealed ZsGreen-labeled neurons outside of the brain regions previously described as containing Rln3 neurons (Smith et al, 2010). The only exception noted was very sporadic expression in the dentate gyrus ( Figure 2B A subset of neurons in the pontine tegmentum express the neuropeptide neuromedin B (NMB), and NMB Cre mice have been used to target the NI in tract-tracing and optogenetic experiments (Lu et al, 2020). In order to understand the relationship between the Rln3 and NMB expressing neuron populations in this area, we used duallabel FISH for Rln3 and NMB mRNA in serial sections throughout their entire extent of expression in the pons (Figure 3).…”

“…In the neocortex, fibers were prominent in the infralimbic (IL) and dorsal peduncular (DP) areas ( Figure 8A,B), and in the retrosplenial cortex (RS, Figure 8C,D,F,G). Functional studies of the NI have focused on its input to the septohippocampal system (Martinez-Bellver et al, 2015;Martinez-Bellver et al, 2017;Szőnyi et al, 2019;Lu et al, 2020). In the hippocampus, labelled fibers were prominent in CA3, and sparse in CA1, and lacking in the dentate gyrus (DG, Figure 8C,D,F,G).…”

“…The presence of dense NI-Rln3 fiber endings in the septum suggest a pathway for the modulation of theta, in that MS GABAergic neurons project to CA1, where they synapse on other GABAergic neurons, which in turn modulate hippocampal pyramidal cell activity (Unal et al, 2015). Both enhancement and inhibition of theta activity by the manipulation of the NI have been reported (Szőnyi et al, 2019;Lu et al, 2020), but the relevant synaptic pathway from NI-Rln3 neurons to the septohippocampal system has not been determined.…”