Dopamine triggers rise in intracellular calcium concentration in astrocytes and depresses excitatory synaptic transmission in the nucleus accumbens

Dopaminergic inputs to the nucleus accumbens (NAc), originating in the ventral tegmental area, are key for motor control and reward. Previous reports suggested that dopamine reduces excitatory synaptic transmission by acting on presynaptic D1 receptors, and by altering adenosine signaling. What remains unknown is how dopamine changes the functional properties of NAc astrocytes. Given that various neurotransmitters increase the intracellular calcium concentration in astrocytes, Corkrum et al.  hypothesize that dopamine may be able to evoke similar effects.

To test this hypothesis, Corkrum et al. used a combination of transgenic mice, optogenetics and pharmacogenetics to show that dopamine evokes a rise in the intracellular calcium concentration in NAc astrocytes by activating D1 dopamine receptors. The work is based on the use of elegant controls, like those relying on the use of astrocyte-specific deletion of D1 dopamine receptors. Dopamine also impairs excitatory synaptic transmission through signaling pathways that rely on activation of presynaptic A1 receptors in NAc neurons. The hypothesized chain of events include a rise in intracellular calcium concentration evoked by activation of D1 receptors in astrocytes that promotes ATP/adenosine release from these cells. Adenosine binds to presynaptic A1 receptors in neurons, thereby reducing excitatory synaptic transmission.

Since dopamine is also implicated with drug addiction, the authors analyzed the effects of the amphetamine, a psycho-stimulant known to disrupt dopamine release, re-uptake and degradation. Just like dopamine, amphetamine increased the intracellular calcium concentration in astrocytes evoked by dopamine release, and inhibited excitatory transmission.

These findings are important because they show that astrocytes modulate excitatory glutamatergic transmission in the NAc by responding to changes in dopamine release. Therefore, future strategies to understand the molecular basis of addiction, should take into account the contribution of these cells to the regulation of synaptic strength.

Saad Ahmad and Nikhita Kumar

Reference

Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A (2020). Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron 105(6):1036-1047.e5.

Perforated patch clamp recordings reveal new facets of dopaminergic modulation of striatal neurons

Dopaminergic neurons in the substantia nigra projecting to the basal ganglia nucleus of the striatum control movement initiation and acceleration. This effect is thought to be mediated by altering the cell excitability of the two main types of long-projection neurons in the striatum, which differ for their expression of either D1 or D2 dopamine receptors. In previous studies, the effect of dopamine has been investigated using reduced preparations (i.e. brain slices) and by analyzing the biophysical properties of striatal medium spiny neurons using whole-cell patch clamp recordings and by mimicking dopamine release through exogenous applications. Whole-cell patch clamp recordings disrupt the physiological composition of the intracellular milieu, as the solution of the patch pipette dialyzes the intracellular cytoplasm. In addition, the exogenous application of dopamine may not recapitulate the physiological time course of dopamine release in vivo. As a result, there are conflicting results on how D1 dopamine receptor activation alters cell excitability in striatal medium spiny neurons. Here, Lahiri and Bevan combine perforated-patch recordings from D1 medium spiny neurons (MSNs) with optogenetic stimulation of dopamine release from nigro-striatal afferents to the dorsolateral striatum. They show that dopamine release increases the firing rate of D1-MSNs elicited by long domatic current injections, which mimic up-states. This effect persists for more than 10 min and is mediated by PKA activation. To mimic both up and down states, the authors apply 250 ms current steps once a second for 41 seconds, a protocol that they applied every 5 minutes for 3-4 trials. Based on the fact that the latency to action potential firing decreases and the firing frequency increases during optogenetic stimulation, they conclude that dopamine promotes the transitions from down to up states. Through the use of a wide range of pharmacological assays, they show that dopamine reduces the fast and medium after-hyperpolarization, consistent with an effect on slowly inactivating A-type potassium channels and calcium activated potassium channels. Together, this extensive array of heroic experiments shed light on previously unknown molecular mechanisms  through which the firing output of MSNs responds to changing levels of extracellular dopamine. Although the optogenetic stimulation of nigro-striatal afferents used by the authors may not capture aspects of asynchrony in dopamine release from nigro-striatal afferents, this is the closest we have got to understand the molecular machinery regulating the complex functional properties of striatal neurons.

Ian Tschang and Sam Barron

Reference
Lahiri AK, Bevan MD (2020). Dopaminergic transmission rapidly and persistently enhances excitability of D1 receptor-expressing striatal projection neurons. Neuron (xx), xxx–xx.

Example of three patch clamp configurations

Dopaminergic neurons from the VTA and SNc control movement reinforcement

The work presented in this manuscript aims to determine how dopaminergic midbrain neurons contribute to movement reinforcement and movement generation. To address this, the authors used in vivo optogenetics to activate halorhodopsin (eNpHR3.0) expressed in the ventral tegmental area (VTA), the region containing the cell body of mesolimbic dopaminergic neurons. They subjected mice to a Pavovian paradigm, in which they paired a conditioning olfactory cue with an unconditioned sweetened milk reward. After training, the olfactory cue triggered an anticipatory licking that began before reward delivery. Light inhibition of VTA neurons reduced this anticipatory licking (which occurs in the time window between cue presentation and reward delivery) more than consummatory licking (which occurs after reward delivery) and this effect scaled with reward size. Together, these results suggest that dopaminergic neurons control movement reinforcement more than generation. In subsequent experiments, they show that post-reward inhibition of dopaminergic neurons in the substantia nigra pars compacta (SNc) also inhibits anticipatory licking, suggesting that dopaminergic neurons in these two brain regions might have overlapping functions. Through a series of fiber photometry measures of GCaMP6f fluorescence, they showed that dopaminergic neurons are active both before and after reward delivery, with post-reward dopamine neuron activity regulating learning. These findings are important because they support the hypothesis that VTA and SNc neurons both contribute preferentially to movement reinforcement rather than generation, although they do not rule out the possibility that specific subsets of dopaminergic neurons may have specialized roles in controlling specific features of the movement execution process. 

Nikki Dolphin and Anna Tuttman

Reference
Lee K, Claar LD, Hachisuka A, Bakhurin KI, Nguyen J, Trott JM, Gill JL and Masmanidis SC (2020). Temporally restricted dopaminergic control of reward-conditioned movements. Nat Neurosci (23), 209–16.

The striatal way of encoding information about locomotor speed

Movement execution relies on the activity of the striatum, but there are current unknowns on how the striatum selects actions and controls their speed. The “discrete encoding model” posits that striatal neurons generate a burst of activity at the beginning and the end of a movement. By contrast, the “continuous encoding model” posits that striatal neurons fire continuously during movement execution, to encode information about the sensory and/or motor state of an animal. In this work, the authors tested the validity of these two models. They performed experiments in which they obtained single and multi-unit recordings from the dorsomedial striatum of mice in an open field. By analyzing neuronal firing rates during bouts of locomotor activity, they showed that 18% of all recorded units increased their firing near the start of locomotion, and 15% of them increased firing near the end of it. The changing in firing rates in these cohorts of neurons reflected changes in locomotor speed. A close comparison of the firing activity of striatal neurons during head-fixed and free-moving locomotion suggest that the speed representation features of most striatal neurons may show continuous changes in firing rates and might be context-dependent. One of the main caveats of in vivo experiments on head-restrained mice is that the vestibular inputs are not comparable to those of freely moving mice. In addition, we wondered whether the results might change depending on the selection criteria used to identify neurons that encode locomotor information (as opposed to other types of movements like grooming, rearing or digging). Therefore, this interpretation holds for locomotor activity at speeds greater than 5 cm/s, it may or may not hold true for at slower speeds. Future works may shed light on the behavior of striatal neurons over all ranges of speed.

Nurat Affinnih and Haley Chesbro

Reference
Fobbs WC, Bariselli S, Licholai JA, Miyazaki NL, Matikainen-Ankney BA, Creed MC, Kravitz AV (2020). Continuous representations of speed by striatal medium spiny neurons. J Neurosci 40(8):1679-1688.