Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction

Abstract

18The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate 19 hippocampal theta oscillations and arousal. However, recent studies reported that the 20 stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is 21reinforcing. We conducted experiments to illuminate how SuM neurons mediate such effects. 22The excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was 23 relayed by the projections to septal GLU neurons. SuM neurons were active during exploration 24and approach behavior and diminished activity during sucrose consumption. Consistently, 25inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such 26functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-27to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated 28 mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway is 29 important in reinforcement and approach motivation and may play an important role in mood 30and substance-use disorders. 31 32 102The SuM is comprised of a heterogeneous population of neurons including GLU, DA and 103GABAergic neurons 3 , 9 , 28 , 29. To determine which type of neurons are responsible for the 104 reinforcing effect, we selectively expressed ChR2 in these three respective neuron subtypes 105 ( Fig. 1f-g; Fig. S2). To address site specificity, we prepared a second cohort of vGlut2-Cre 106 mice injected with a small volume (50nL, instead of 200nl) of the vector (n=6). Regardless of 107 injection volumes, both vGlut2-Cre groups quickly learned to press on the active lever with no 108 group difference ( Fig. 1h; a 2group x 2lever x 7session ANOVA, Fgroup(1,16)=0.29, p=0.59); thus, these 109 data were combined. By contrast, TH-Cre and vGat-Cre mice failed to significantly acquire 110 active-lever pressing (a 3group x 5session ANOVA; Fgroup(2,33)=5.79; Tukey HSD posthoc tests for 111 main group effects PvGlut2 vs Th=0.037, PvGlut2 vs vGat=0.016, PvGat vs Th=0.99). These results suggest 112 that the excitation of SuM GLU, but not DA or GABA, neurons is reinforcing. 113

The Role of the Medial Septum—Associated Networks in Controlling Locomotion and Motivation to Move

“…This network seems to be also related to reinforcement and motivation through MSDB inputs to the VTA. When self-stimulating these projections, the animals will increase lever pressing and this action in turn increases nucleus accumbens (NAc) DA release (Kesner et al, 2020), classically associated to rewarding mechanisms.…”

ezTrack—A Step‐by‐Step Guide to Behavior Tracking

“…Since its original publication, ezTrack has grown in popularity, owing to many of its key features (Bitzenhofer, Pöpplau, Chini, Marquardt, & Hanganu‐Opatz, 2021; Bourdenx et al., 2021; Kesner et al., 2021; McCauley et al., 2020; Montanari et al., 2021; Rajbhandari et al., 2021; Shuman et al., 2020; Zeidler, Hoffmann, & Krook‐Magnuson, 2020). It is free, easy to use, produces highly reliable and accurate results, contains a range of interactive data exploration/visualization tools, has a suite of functions to refine videos, and has no operating system or hardware requirements.…”

GPCR-Based Dopamine Sensors—A Detailed Guide to Inform Sensor Choice for In Vivo Imaging

“…Next, among the sensors selected, it is best to favor a sensor with maximal dynamic range (if possible, >250–300%). We found that dLight1.1, dLight1.2 and RdLight1 displayed an optimal combination of medium ligand affinity (330 nM, 765 nM and 860 nM, respectively) and good dynamic range (230%, 340% and 250%, respectively), making them ideally suited for in vivo bulk (photometry) imaging of large DA transients in response to rewards or cues in the heavily innervated striatum or NAc [ 58 , 59 ], see also: [ 107 , 110 , 111 , 112 , 113 , 115 , 224 , 225 ]. On the other hand, sensors with high and extremely high affinity such as GRAB-DA2m (K d = 90 nM; dFFmax = 340%; validated in vivo), GRAB-DA2h (K d = 7 nM; dFFmax = 280%; validated in vivo) [ 61 ] and dLight1.4 (K d = 4.1 nM; dFFmax = 170%; not validated in vivo yet) [ 58 ]; as well as other sensors in development (not shown) are ideally suited to detect DA release in brain regions with sparser and extremely sparse innervation or may potentially be used to track tonic DA changes in the nanomolar range [ 11 ] (this remains to be determined).…”