Many of you may notice that I have sparingly blogged about the neurobiology of drug addiction across the past year. While I am venturing into another area of research (sleep and metabolism), I still enjoy reading addiction-related papers in my spare time. Even better, we have recently reformatted our journal club to allows us to present articles not only relevant to the neurobiology of circadian and sleep processes, but also highly regarded papers in the field of neuroscience. Luckily for me, one of the top recommended articles on Faculty of 1000 since February is on the neurobiology of reward. This work was done at Harvard, and the researchers used basic electrophysiological recording techniques paired with an operant conditioning protocol and neuron-specific activation through channel rhodopsin.
In terms of the operant conditioning protocol, mice were deprived of water prior to experimentation, allowing water delivered from a sipper tube to serve as the unconditioned, biologically significant stimulus. To elicit increased licks of the sipper tube and subsequent consumption of water, the animals were presented with a fruity, olfactory [conditioned] stimulus. The extent of water delivered at each time interval was also controlled, enabling the researchers to measure behavioral and neuronal responses to bigger vs. smaller rewards. The differences in behavioral responses to the anticipation of bigger vs. smaller rewards are documented below.
During this operant conditioning protocol, the researchers also undertook electrophysiological recordings in the ventral tegmental area, which is a MAJOR structure of the central reward system. While pursuing these electrophysiological recordings, there were three, distinct types of neuronal firing patterns that emerged during the presentation of the CS, the delay phase, and the subsequent delivery of the US. This is clearly visible in the figures below. In brief, Type I neurons fired during the presentations of the CS and US, but were relatively quiescent during the delay period. Type II neurons, however, fired primarily during the delay period, while Type III neurons were largely influenced by the presentation of an aversive stimulus (air puff) instead of a reward (water).
From here, the researchers then transfected channel rhodopsin receptors in the dopaminergic and GABAergic neurons of the VTA. 60% of the VTA consists of dopaminergic neurons. The remaining are mostly GABA. While the channel rhodopsin receptor was nearly 90% specific for the dopaminergic neurons, specificity for the GABA neurons hovered around 60%. Despite this confound, three distinct patterns of neuron firing emerged again, and through the utility of channel rhodopsin, it was discovered that the Type I neurons, which fire close to the presentations of the CS and US, are dopaminergic, while Type II and III neurons are GABAergic.
There’s a reason why this study is a highly recommended read. First, the order of the experimental aims requires that one hypothesis be accepted before the next experiment can be conducted, illustrating sound experimental design. Second, the researchers use novel molecular techniques to simultaneously study the relationship between brain and behavior.
I am also attracted to this study because I wonder if the circadian timing system is involved at any level. From a neuroanatomical perspective, there are reciprocal projections from central circadian timing and reward systems (see work of Gary Aston-Jones and Larry Morin), and at a behavioral level, rodents are clearly able to entrain to daily presentations of rewards, specifically drugs of abuse, as well as show a robust, circadian pattern of drug self-administration (the basis of my dissertation and references within). Rewards are also able to shift behavioral rhythms when administered at specific time points of a 24 hr period (also from my dissertation). In relation to this study, I wonder if: 1) the unique behavioral and underlying electrophysiological responses to the presentations of the CS and subsequent US change in strength across a 24 hr period; and if they do, 2) can the presentation of the CS and US at certain time points also shift rhythms when the mice are then released to constant darkness? Lastly, it would be interesting to document if the mice show anticipatory activity near the presentation of the CS because this would indicate entrainment.
Cohen JY, Haesler S, Vong L, Lowell BB, & Uchida N (2012). Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature, 482 (7383), 85-8 PMID: 22258508