Glutamate-dopamine Interactions: how the brain decides what matters

 The brain is constantly active, yet only a fraction of that activity drives behavior. This raises the central question of how the brain determines which signals are important enough to act on. A major part of the answer lies in the interaction between glutamate and dopamine. Glutamate is the brain’s primary excitatory neurotransmitter, conveying information across neural circuits. Dopamine functions as a neuromodulator, encoding motivation and reinforcing reward-seeking behavior. Rather than acting independently, these systems operate together, as glutamate provides the signal, and dopamine assigns value.

Diagram of glutamatergic and dopaminergic afferences between brain regions. From: Gardoni  and Bellone (2015) Modulation of the glutamatergic transmission by Dopamine: a focus on Parkinson, Huntington, and Addiction diseases. Front. Cell. Neurosci. 9:25. doi: 10.3389/fncel.2015.00025

In the striatum, glutamatergic inputs from the prefrontal cortex and the thalamus converge onto neurons that also receive dopaminergic input from the substantia nigra pars compacta (SNc). Dopamine, acting through D1 and D2 receptors, does not encode detailed information itself but instead modulates how strongly glutamatergic inputs influence circuit output (Surmeier et al., 2007). This interaction transforms raw neural activity into behaviorally relevant output.

Over time, this interaction drives learning. Glutamate activates NMDA receptors, allowing calcium ion influx that initiates synaptic plasticity. Dopamine modulates this, primarily through signaling of the G-protein-coupled D1 and D2 receptors that trigger cAMP/PKA signaling, determining if synapses undergo long-term potentiation (LTP) or long-term depression (LTD). Dopaminergic neurons encode reward prediction error (RPE) signals, firing when outcomes deviate from expectations (Schultz, 2016). In this way, dopamine functions as a teaching signal, shaping which patterns of activity are retained.

Importantly, this interaction is bidirectional. Glutamatergic inputs regulate dopaminergic neuron firing, as activation of NMDA and AMPA receptors enhances dopaminergic neuron excitability and promotes phasic burst firing (Sulzer et al., 2016). Additionally, glutamate can act at dopaminergic terminals within the striatum to directly modulate dopamine release (Underhill et al., 2014). Thus, dopamine signaling is not generated independently but shaped by upstream glutamatergic activity.

Beyond synaptic events, dopamine may also be influenced by glutamate tone, which is the ambient level of extracellular glutamate. Glutamate can spill over from synapses and activate extrasynaptic receptors, including NMDA receptors, under conditions of high activity or reduced clearance, thereby influencing neuronal excitability and effectively setting the threshold for dopamine neuron activation and release. Because glutamate tone is tightly controlled by neuronal glutamate transporters, even small changes in clearance can alter dopaminergic output (Danbolt, 2001). This suggests that dopamine signaling is not only driven by discrete inputs, but is continuously tuned by the extracellular glutamate environment.

Baran Mohammadi

References

• Danbolt, N. C. (2001). Glutamate uptake. Progress in Neurobiology, 65(1), 1–105. https://doi.org/10.1016/S0301-0082(00)00067-8 
• Kreitzer, A. C., & Malenka, R. C. (2008). Striatal plasticity and basal ganglia circuit function. Neuron, 60(4), 543–554. https://doi.org/10.1016/j.neuron.2008.11.005
• Nicola, S. M., Surmeier, D. J., & Malenka, R. C. (2000). Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annual Review of Neuroscience, 23, 185–215. https://doi.org/10.1146/annurev.neuro.23.1.185 
• Papouin, T., Ladépêche, L., Ruel, J., Sacchi, S., Labasque, M., Hanini, M., Groc, L., Pollegioni, L., Mothet, J.-P., & Oliet, S. H. R. (2012). Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell, 150(3), 633–646. https://doi.org/10.1016/j.cell.2012.06.029 
• Schultz, W. (1998). Predictive reward signal of dopamine neurons. Journal of Neurophysiology, 80(1), 1–27. https://doi.org/10.1152/jn.1998.80.1.1
• Schultz, W. (2016). Dopamine reward prediction-error signalling: A two-component response. Nature Reviews Neuroscience, 17(3), 183–195. https://doi.org/10.1038/nrn.2015.26 
• Scimemi, A., & Diamond, J. S. (2013). Deriving the time course of glutamate clearance with a deconvolution analysis of astrocytic transporter currents. Journal of Visualized Experiments, 78, e50708. https://doi.org/10.3791/50708 
• Scimemi, A., Tian, H., & Diamond, J. S. (2009). Neuronal transporters regulate glutamate clearance, NMDA receptor activation, and synaptic plasticity in the hippocampus. The Journal of Neuroscience, 29(46), 14581–14595. https://doi.org/10.1523/JNEUROSCI.4845-09.2009 
• Sulzer, D., Cragg, S. J., & Rice, M. E. (2016). Striatal dopamine neurotransmission: Regulation of release and uptake. Basal Ganglia, 6(3), 123–148. https://doi.org/10.1016/j.baga.2016.02.001
• Surmeier, D. J., Ding, J., Day, M., Wang, Z., & Shen, W. (2007). D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends in Neurosciences, 30(5), 228–235. https://doi.org/10.1016/j.tins.2007.03.008
• Threlfell, S., Lalic, T., Platt, N. J., Jennings, K. A., Deisseroth, K., & Cragg, S. J. (2012). Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron, 75(1), 58–64. https://doi.org/10.1016/j.neuron.2012.04.038 
• Underhill, S. M., Wheeler, D. S., Li, M., Watts, S. D., Ingram, S. L., & Amara, S. G. (2014). Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. Neuron, 83(2), 404–416. https://doi.org/10.1016/j.neuron.2014.05.043 

Striatal dopamine release shapes responses to reward stimulation

The release of neurotransmitters in the brain allows for the transfer of information that can be associated with different functions. Dopamine is one such neurotransmitter that is used to reinforce actions through a reward stimulus. A paper by Li and Jasanhoff, published in 2020, specifically explores how dopamine release in the striatum changes responses. Here, rats were implanted with a cannula in the ventral striatum and the Lateral hypothalamus (LH), injected with dopamine-sensitive and non-dopamine-sensitive contrast agents, and scanned during LH stimulation to determine responses. The scanning methods used were multi-gradient echo MRI, functional Magnetic Resonance Imaging (fMRI), and blood-oxygen-level-dependent (BOLD) contrast responses. Additionally, some rats were injected with a mix of SCH 23390 and eticlopride, antagonists of the dopamine D1 and D2 receptors instead of a dopamine sensor, to verify non‑dopaminergic activity or postsynaptic effects of dopamine on haemodynamic signals that might account for discrepancies between BOLD and dopamine signals. 

Some key findings: 

• In two groups of rats, one was injected with a dopamine-sensitive protein-based MRI contrast agent, BM3h-9D7, and the other was injected with a control agent, BM3h-WT, which lacks dopamine sensitivity. Here we see that the haemodynamic responses, or the rate of blood flow and oxygen, as determined by BOLD, were suppressed with both agents. A map of peak stimulus-dependent dopamine release for the BM3h-9D7 rats was determined in the nucleus accumbens, medial caudate putamen, olfactory tubercle, and lateral septal area. Rats with the BM3h-WT control group had no independent dopamine signals. 
• With the rats injected with dopamine blockers, we see more correlation between BOLD and Dopamine signals. The fMRI responses here also showed an alteration in time, and no changes in the spatiotemporal properties of dopamine release. This shows us that the post-synaptic effects of dopamine contribute to the discrepancies between BOLD and dopamine signals. Further exploring striatal dopamine release in the brain using brain-wide fMRI signals, it is found that striatal dopamine can indirectly modulate reward-evoked activation in the cortex.  

Overall, these results show increased connectivity between striatal release response in various brain regions contributing to motivated action, and an increase in postsynaptic activity when dopaminergic neurons are stimulated. This allows for a better understanding of dopamine signaling in learning and memory, as well as explaining related dopamine or reward-based neuroimaging results. 

~ Alaina Jeeson

Reference: 

Li, Nan, and Alan Jasanoff. “Local and Global Consequences of Reward-Evoked Striatal Dopamine Release.” Nature, vol. 580, no. 7802, Apr. 2020, pp. 239–244, https://doi.org/10.1038/s41586-020-2158-3. Accessed 13 Apr. 2020.