Summary: The interaction between the limbic system and the subcortical dopaminergic system, is important in the experience of reward by the individual. The hypothesis in the present study is that, increased excitability of the medial prefrontal cortex, exerts a suppressive effect on the interaction between subcortical dopaminergic system and the limbic striatum structures (Ferenczi et al.). Lack of a reward seeking behavior is seen in patients with depression and MRI studies in these subjects have identified increased excitability of the medial prefrontal cortex. This finding was suggested as a rationale for the study. The experiments were designed to demonstrate the cause and effect relation, between the excitability of the median prefrontal cortex and the subcortical to striatum circuit. The findings of the study support the hypothesis. There is less scope of bias in this study and it helps improve the understanding about the physiology of reward seeking behavior. (Ferenczi et al.)
Background: Modulating once behavior, according to rewarding or aversive experience is a part of the adaptation process. Exhibiting behavioral flexibility based on previous learning experience is important for survival. It will be interesting to know how the brain modulates behavior and helps in the adaptation process. A dysfunction of the neural circuit that enables a person to respond appropriately to reward and adverse circumstances, will result in maladaptive syndrome and psychiatric problems. The median prefrontal cortex controls motor activities and is also a regulator of emotional, neuronal and endocrine response. The present study is highly specific as it helps identify the specific cell types in the neural circuit that are controlled by the cue or signals received from the median prefrontal cortex. The study provides a blueprint of the precise cell types and neural circuit mechanism that are involved in responding to rewarding or aversive cues. Understanding this physiology is critical to understanding complex behavioral states. (Ferenczi et al.)
The scientists use photo stimulation to inhibit the signals in the parvalbumin-positive fast spiking interneurons (PV+FSIs), present in the mPFC (median prefrontal cortex. These cells secrete GABA neurotransmitters and are efficient in converting excitatory input signals into inhibitory output signals (Hu, Gan and Jonas). By its feedback and feed forward inhibitory function, these cells can modulate even the complex neuronal network (Hu, Gan and Jonas). These cells are essential for spatial working memory. Lack of spatial memory in diseases like Schizophrenia is associated with deficit in the functioning of PV+FSIs cells in the prefrontal cortex (Murray et al.). Increased activity of PV+FSIs, inhibits the excitatory function of mPFC and promotes reward seeking behavior. The researchers of this study, have made a reasonable hypothesis is the light of current evidences. In the literature review that was presented in the introduction, the authors have discussed published paper that help understand the importance of the study. The authors claim that, understanding the physiology behind reward seeking behavior, can help the individual predict and signal the availability of rewards. fMRI experiments were used in the study. The authors have explained the salient feature of this technique and its usefulness in psychiatric research, such as this one. The technique enables brain wide mapping of the activation and inhibitory signals. fMRI can prove a causal relationship between neural signaling and will also help map brain wide blood oxygen level dependent (BOLD) patterns. Though existing literature provided evidences for the inhibitory effect of PV+FSIs in the vicinity of prefrontal cortex, studies were required to understand the influence of these cells on distant areas in the brain.
Method and Results: The study was done with transgenic tyrosine hydroxylase driver (TH-Cre) rats. Optogenic stimuli were used to excite the dopaminergic neurons via the excitatory channel rhodopsin. It is a stimulatory opsin. In a similar way the optogenic stimuli were used to target an inhibitory opsin as well. Following these stimulation, the BOLD mapping of the brain was done. Unlike other studies, this particular study required the animals to be active and alert during MRI imaging and thus the animals were not anesthetized. They were nevertheless accustomed, by being trained in a mock MRI environment. A well-defined (bursts of 13 s, 10 Hz, 20-ms pulse width, ~0.5 mW) green light was used as a stimulus. Activation of dopaminergic neurons promotes reward seeking behavior in rodents. The paper has used imaging techniques, which needs a prior understanding of the subject to be understood. Nevertheless, certain key sentence summarizes the result of each step and thus on thorough reading, it may be possible to understand the idea. It would be better for the experts in the field to suggest if the technique is well described. The researchers observed an increase in BOLD activity during stimulation and a decrease in activity when dopaminergic neurons were inhibited. (Ferenczi et al.)
A Ca2+/calmodulin kinase II a (CaMKIIa) promoter linked to a optogenic neural sensitizer was used for synchronizing neuronal excitability in the mPFC. This helps easy imaging. A blue light was used to activate neurons in the mPFC and a yellow light was used to inhibit excitation of neurons. I personally found the technical details difficult to understand. However, each technique is elaborately explained and the results are provided below each step. So the reader can associate each experiment to the corresponding result. The result section is too long and I thought it could be presented as two papers, for easy understanding. (Ferenczi et al.)
The graphical representation of the result and the elaborate explanation provided in the legend, compensates for the complex technicalities discussed in the main paper. A bachelor student can understand the results from the pictorial and graphical files and refer the main text for explanation. The associated details and the experiences gained during the study is shared. The bias that may arise are taken care of. It is a good reference for those who want to repeat the study or conduct similar study. (Ferenczi et al.)
The results of the study, suggest that dopamine neurons in the mid brain, drives striatal fMRI BOLD activity. This is associated with reward seeking behavior. The silencing of dopamine neurons was associated with the opposite effect. After conducting experiments to show this. The authors then studied the effect of elevated mPFC excitability on this particular circuit (BOLD activity). The results suggest that mPFC excitability, causes a suppression of striatal activity and reward seeking behavior. Stably elevated mPFC was associated with anhedonia behavior. The initially claim that PV+FSIs disturbance was the reason for elevated mPFC excitability, is supported through the study. The authors have used glutamate receptor to study these cells. However, there is a lack of clarity in the way this is linked to the result and the study. Though mPFC excitability disrupts reward seeking behavior, the effect is down stream of the BOLD response. Employing MRI, the researchers have also shown that suppression of mPFC excitability, affects BOLD activity in distant regions of the brain. (Ferenczi et al.)
My opinion: The way reward seeking behavior is assessed is not very clear. On issues like drug addition, there is a neuroplasticity in the circuit between the cortex and striatum neurons. In depression, some people seek drug and thus the reward seeking behavior is not completely inhibited (Everitt and Robbins; Grosser et al.). Thus the significance of this neural circuit and reward seeking needs to be further substantiated.
Work cited
Everitt, Barry J, and Trevor W Robbins. "Neural Systems of Reinforcement for Drug Addiction: From Actions to Habits to Compulsion". Nature Neuroscience 8.11 (2005): 1481-1489. Web. 30 Mar. 2016.
Ferenczi, E. A. et al. "Prefrontal Cortical Regulation of Brainwide Circuit Dynamics and Reward-Related Behavior". Science 351.6268 (2015): aac9698-aac9698. Web.
Grosser, Sabine M. et al. "Cue-Induced Activation of the Striatum and Medial Prefrontal Cortex Is Associated With Subsequent Relapse In Abstinent Alcoholics". Psychopharmacology 175.3 (2004): 296-302. Web. 30 Mar. 2016.
Hu, H., J. Gan, and P. Jonas. "Fast-Spiking, Parvalbumin+ Gabaergic Interneurons: From Cellular Design To Microcircuit Function". Science 345.6196 (2014): 1255263-1255263. Web. 29 Mar. 2016.
Murray, Andrew J et al. "Parvalbumin-Positive CA1 Interneurons Are Required for Spatial Working But Not For Reference Memory". Nature Neuroscience 14.3 (2011): 297-299. Web. 29 Mar. 2016.
