In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

Abstract

Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.

Subthreshold repertoire and threshold dynamics of midbrain dopamine neuron firingin vivo

“…In vivo patch-clamping enabled the systematic investigation of subthreshold signatures underlying tonic and phasic firing patterns in the intact brain. We found that a majority of neurons fired in a single spiking pattern, similar to our previous in vivo extracellular studies of identified dopamine neurons (Farassat et al, 2019;Schiemann et al, 2012). A representative recording and the immunohistochemistry of an in vivo pacemaking dopamine neuron located in the VTA is shown in Figures 2AB.…”

“…Upon further investigation of the subthreshold signatures underlying tonic and phasic firing patterns in vivo, we found that a majority of neurons fired in a single spiking pattern, similar to our previous in vivo extracellular studies of identified dopamine neurons (Farassat et al, 2019;Schiemann et al, 2012). While there is some variability in the subthreshold membrane minima as compared to the maxima, the respective ISIs of both plots show the high degree of steady spiking in pacemaking dopamine neurons.…”

“…We and others have previously demonstrated considerable functional diversity among SNc/VTA dopamine neurons (de Jong et al, 2019;Evans et al, 2017;Heymann et al, 2020;Lammel et al, 2008;Tarfa et al, 2017). This diversity was in part associated with distinct axonal projections both in vitro (Lammel et al, 2008) and in vivo (Farassat et al, 2019). In vivo patch-clamping of dopamine neurons allowed for the first time to study differences in subthreshold integration in the intact brain.…”

“…For many years, transient cue-or reward-associated increases in firing rate -from a low tonic background frequency (about 1-8 Hz) into the beta and gamma range (15-30 Hz and 40-100 Hz, respectively) -were thought to encode positive reward prediction errors (RPEs), while short rate reductions or pauses in baseline firing were believed to encode negative RPEs, induced for instance by the omission of an expected reward. However, increasing experimental evidence points to a multitude of other dopamine functions such as salience and novelty, action control (Coddington and Dudman, 2018;Jin and Costa, 2010) as well as aversion (Menegas et al, 2018) which are in line with the emerging molecular (Heymann et al, 2020;Poulin et al, 2020), cellular, and anatomical diversity of the midbrain dopamine system (Beier et al, 2019;Beier et al, 2015;Farassat et al, 2019;Lammel et al, 2008;Lammel et al, 2012;Morales and Margolis, 2017;Watabe-Uchida et al, 2012). Even within canonical RPE signaling, the interpretation of the transient burst has become more complex.…”

Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons

“…Past studies have classified substantia nigra dopamine neurons subpopulations according to their projection targets (Farassat et al, 2019;Lerner et al, 2015;Schiemann et al, 2012), expression of neurochemical markers (La Manno et al, 2016;Poulin et al, 2018;Wu et al, 2019), and intrinsic membrane properties Neuhoff et al, 2002). Based on the anatomical results, Crittenden et al (2016) proposed that dopamine neuron clusters (in bouquets) may form specialized nigral compartments.…”