Summary
Over the past few years, there has been a growing interest among neurosurgeons on the potential for therapies that impact on diseases, over and above the movement disorders and pain. One of the biggest targets of this increasing interest has been the nucleus accumbens. It has been studied for long, as an area of the brain that mediates a variety of behaviors, including reward and satisfaction (Salgado & Kaplitt, 2015). With this in mind, the modulation of the biology of the Nucleus Accumbens through either deep brain stimulation or through biological therapies like gene therapy or the transplantation of cells could have important impacts on such disorders and conditions like depression and addiction (Salgado & Kaplitt, 2015). It is important, therefore, for the development of these therapies and their efficient deliveries, that the biology, anatomy and physiology of the Nucleus Accumbens be fully understood (Salgado & Kaplitt, 2015).
Background and Perspective
According to research, the nucleus accumbens regulates the natural reward system of the brain mostly through changes in the accumbal dopamine (DA) (Salgado & Kaplitt, 2015). When there is a naturally rewarding stimuli, like food for instance, the levels of DA in the accumbens increase. However, and perhaps more importantly, the levels seem to reduce with increased access. However, when one uses drugs of abuse, the functioning of this reward system can be distorted or overwhelmed, such that the waning with repeated access is no longer exhibited. According to studies, there are a number of substances that can influence the accumbens, and chief among them are opiates (Salgado & Kaplitt, 2015). The role of DA in drug abuse and dependence has been hypothesized for a long time, with its relationship with the reward being reviewed. As opposed to non-abused drugs, drugs of abuse tend to increase the level of DA in the accumbens and change synaptic plasticity (Ungless, et al., 2001).
The study by Zhu et al (2016) investigates how thalamic input into the nucleus accumbens mediates the dependence on opiates. Chronic use of opiates results in dependence, which then results in extremely unpleasant emotional and physical reactions after the termination of the use of the drug (Zhu, et al., 2016). When an individual is addicted to drugs, both the need to enjoy the pleasant effects of the drug and the desire to avoid the symptoms of withdrawal keep them hooked. The nucleus accumbens is important for the orchestration of both the reward and the withdrawal symptoms. A lot is known about how the nucleus accumbens modulates reward, but not much is known about the circuitry underlying the process of withdrawal (Pascoli, Turiault, & Lüscher, 2012). This paper investigates the paraventricular nucleus of the thalamus as an important input to the nucleus accumbens with regards to the mediation of the expression of both the physical symptoms of withdrawal and aversive memory (Zhu, et al., 2016).
Methods and results
In order to systematically map the areas of the brain that affect the nucleus accumbens, Zhu et al (2016) stereotaxically injected a rabies virus into the nucleus accumbens medial shell. In the rabies virus, the red florescent protein mCherry replaced the viral glycoprotein. Besides the normal inputs into the nucleus accumbens like the prefrontal cortex and the ventral hippocampus, the researchers also detected mCherry expressing neurons in the paraventricular nucleus (PVT) of the thalamus. This was interesting because despite the fact that studies have revealed the role of the PVT in drug seeking behavior, not much is known about the underlying circuitry mechanism (Zhu, et al., 2016).
Opiate withdrawal in human comes not from the blockage of opioid receptors as done in the study but from reduction or cessation of opiate use. This process can be modelled in mice. To measure the motivational states during withdrawal, the mice were confined for up to 45 minutes in one side of a CPA training chamber, 16 hours after each morphine injection. After about 4 training sessions, the mice developed aversion to the training chamber.
Chronic use of opiates causes changes in the chemistry of the nucleus accumbens. Since the pathway between the PVT and the nucleus accumbens transmits negative valence and mediates symptoms of withdrawal from opiates, the researchers anticipated that extreme exposure to opiates might cause plasticity of the PVT input selectively onto the medium spiny neurons of the nucleus accumbens. To examine this plasticity, the researchers prepared brain slices from transgenic animals with florescent proteins under the control of the D1R or D2R promoter. To reduce the experimental variability, the researchers used a measure of light evoked in the neurons. The results showed that chronic morphine treatment resulted in a change in the synaptic brain function.
Since the morphine potentiation of the PVT neuron synapses was proven important to the expression of symptoms of withdrawal from opiates, it makes sense, then, that the depotentation of these synapses would result in relief from these symptoms. To test this, the researchers used light stimulation of the PVT D2 MSN synapses for up to 1 hours 15 minutes. The results together revealed a causal relationship between the plasticity in the nucleus accumbens and the negative somatic and motivational states that come with opiate withdrawal.
The experimental group used in this study was mice, with several of the processes modelled in experimental mice. The number of mice used in was different with every different model, but the number varied between 6 and 10. For instance, in the optical activation of the PVT-nucleus accumbens pathway, there were 10 ChR2 expressing mice and 8 eGFP expressing mice in the control group.
Analysis
Previous studies have revealed the contribution of the ventral hippocampus and the prefrontal cortex inputs into the nucleus accumbens in mediating drug reward and plasticity after chronic exposure. This paper, on the other hand, shows that the PVT input transmits negative valence into the synapses that are associated with the withdrawal from opiates. This study is largely complementary, but it tackles an area of study that has not had much as much focus, at least relatively. Most of the studies have looked at the PVT-D1 synapses, while this one investigates the effects of chronic drug use on the PVT-D2 MSN synapses in the nucleus accumbens. It is particularly important as it starts with the mapping of the relatively unknown circuitry of the nucleus accumbens underlying withdrawal. It is from such pioneering studies that complementary studies can be conducted to understand the processes underlying not only the reward but also the withdrawal symptoms during chronic opiate use.
References
Hyman, S. E., Malenka, R. C., & Nestler, E.J. "Neural mechanisms of addiction: the role of reward-related learning and memory."Annu. Rev. Neurosci. 29 (2006): 565-598.
Pascoli, V., Turiault, M., & Lüscher, C. "Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour."Nature 481.7379 (2012): 71-75.
Salgado, S., & Kaplitt, M. G. "The nucleus accumbens: a comprehensive review." Stereotactic and functional neurosurgery 93.2 (2015): 75-93.
Ungless, M. A., et al. "Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons." Nature 411.6837 (2001): 583-587.
Zhu, Y., et al. "A thalamic input to the nucleus accumbens mediates opiate dependence." Nature (2016).
