Unexpected global impact of VTA dopamine neuron activation as measured by opto-fMRI
Lohani, S., Poplawsky, A. J., Kim, S. G., & Moghaddam, B. (2017). Unexpected global impact of VTA dopamine neuron activation as measured by opto-fMRI. Molecular psychiatry, 22(4), 585–594. https://doi.org/10.1038/mp.2016.102
Journal club, teaching others about science and new innovations are some of the things I love. However, most of the peer-reviewed articles are very dense and many times even a small bit of help understanding them can go a long way. This week we will be taking a look at an important paper on fMRI. Often, I re-read these papers with others and try to formulate a method to help everyone understand them. I am not the original author of this paper, and I hope I have given proper credit to the authors. Research takes time, and every time you read a paper like this one please understand, it may represent years of research. Hopefully, the link to the original paper works, if not, copy-paste the title.
fMRI Measure how active a brain region is over time, signaling with nearby blood vessels. More oxygenated blood flows into that region of the brain as blood has a high iron content so it changes the magnetic field of neural tissue ever so slightly. Modern MRI is able to measure those fluctuations ever so slightly.
Protons in the nuclei of hydrogen atoms respond to this procedure by emitting an electromagnetic signal that is detected by the fMRI scanner. The fMRI can detect differences in oxygenated vs. deoxygenated blood.
fMRI has lower spatial information but higher temporal resolution, here they can relate changes in information. Changes in oxygenation in areas of the brain over time.
Voxel= a spatial location, voxel value is intensity.
BOLD blood oxygen level-dependent. It does not measure neuronal activity directly; it measures the metabolic demands (oxygen consumption) of active neurons.
Hemoglobin exists in 2 different states. Linus Pauling 1936
Oxyhemoglobin is diamagnetic
Deoxygenation is paramagnetic= suppresses the MR signal, so as the concentration of deoxyhemoglobin decreases the fMRI signal increases. I wondered if the anesthesia has a depressive effect on respiration…they used isoflurane, which has less respiratory effects than other anesthesia but do you think it affected the BOLD signal?
The change in MR signal triggered by instantaneous neuronal activity is known as the hemodynamic response function. As neuronal activity increases, so does the metabolic demand for oxygen and nutrients. As the oxygen is extracted from the blood the hemoglobin becomes paramagnetic which creates distortions in the magnetic field that creates a T2* decrease (a fasted decay of the signal).
SNR signal to noise ratio is the strength of a signal divided by its variability, a basic measure of effect size.
CNR contrast to ratio is the difference in 2 tissue types divided by the variability in their measurements. CNR measures the ability to differentiate between 2 tissue in an anatomical image, or image and background noise.
Temporal SNR or functional SNR is the mean signal intensity across time divided by the variability in the data across time points calculated at each voxel in an image so a map can be created.
Rats: transgenic Th::Cre that express the Cre recombinase under the control of the tyrosine hydroxylase (TH) promoter29. Injected with channelrhodopsin-2 (yellow fluorescent protein).
Behavior 2–20 days before fMRI ICSS intracranial self-stimulation task is a crude measure of dopamine activation- just to provide a pre-histological assessment. Male rats, nose poke only resulted in VTA stimulation. Optical stimulation of VTA. 2 types of fMRI contrasts: endogenous BOLD, followed by contrast-enhanced CBVw fMRI. WT mouse as control. SPM8 calculated maps. The functional maps were co-registered to the anatomical images. Paxinos and Watson brain atlas. Subdivision (dorsal medial, dorsolateral, ventromedial, and ventrolateral). Forepaw data, similar to VTA stimulation activation maps. Highly unlikely that SN dopamine neurons were affected, not sufficient to elicit action potentials. However, optical stimulation robustly increased CBVw activity in the DS.
Dopamine-innervated limbic regions that include the VS, VP, OFC, and amygdala. fMRI activation also observed in regions that do not receive substantial VTA dopamine projections, such as thalamus, hippocampus, and basal ganglia regions (DS and GP), DS exhibited the most robust BOLD and CBVw signal increase, compared to other regions upon activation of VTA dopamine neuron. Glucose in the rat cortex is estimated to be due to glutamate release and uptake.
Ventral tegmental area (VTA) found in the midbrain, next to the substantia nigrae. VTA has a large population of dopamine neurons, one of the 2 dopaminergic areas in the brain the other being the substantia nigrae. 2 major pathways mesocortical (projects from the VTA, prefrontal, orbital frontal and cingulate the mesocortical are very diverse with a wide range of function) and mesolimbic (projects to several limbic structures the largest of these pathways is to the nucleolus accumbens associated with the reward system, possible encoding memories about drug use experiences.
Ventral tegmental area (VTA) projections
VTA → Amygdala= Almond-shaped clusters of nuclei deep and medial within the role of the temporal lobes in processing emotions, part of the limbic system.
VTA → Entorhinal cortex= memory and time perception, the main interface between the hippocampus and neocortex.
VTA → Cingulate gyrus= emotions and behavior regulation. Helps to regulate autonomic motor function.
VTA → Hippocampus Small curved formation, part of the limbic system, involved in the formation of new memories also associated with learning and emotions.
VTA → Nucleus accumbens located in the basal forebrain, plays a central role in the reward circuit, the 2 neurotransmitters dopamine(desire) and serotonin (satiety and inhibition)
VTA → Olfactory bulb sends olfactory information to be further processed by the amygdala and the hippocampus, where it plays a role in emotion, memory, and learning.
VTA → Prefrontal cortex in the frontal lobe, implicated in planning complex cognitive behavior, personality expression, decision making, and moderating social behavior.
Substantia nigra (SN) is a midbrain dopaminergic nucleus which has a critical role in modulating motor movement and reward functions, contains a high level of a pigment called neuromelanin.
Dorsal striatum (DS) consists of the caudate nucleus and putamen (CP) that controls the motor and cognitive function, fluid movement, receives afferent fibers from the substantia nigra and thalamus.
Methodological considerations
Several potential methodological concerns should be addressed. First, a recent study reported significant ectopic Cre expression in the VTA of Th::Cre mice, suggesting that optogenetic stimulation in Th::Cre transgenic lines may activate non-dopamine cells. The Th::Cre rat strain we used here, however, is a different genetic line, and we and others have observed very little ectopic expression of ChR2 in the VTA of these rats. Thus, it is unlikely that our results are due to significant activation of non-dopamine VTA neurons. I am not a rat/mouse expert, so when I read this, I wondered where is the demonstration that the researchers were in the VTA?
Second, optogenetic stimulation of VTA dopamine neurons is, obviously, an artificial method of activation and may result in synchronous firing of a large group of dopamine neurons. This may not represent the spatial and temporal dynamics of VTA neuron firing that we typically observe during task performance.
I questioned if they did have the correct placement for optogenetic stimulation, and as well as wondering about the artificial nature of the experiment?
Regardless, the results of the current study are important because they highlight the existence of VTA dopamine-dependent dynamic circuits that may come online during certain behaviors or pathological conditions.
Finally, the choice and level of anesthesia could have impacted our observed fMRI activation maps. For example, isoflurane anesthesia suppresses BOLD fMRI activation, which could explain the paucity of significant BOLD activations outside the striatum in the present study. We accounted for some of this anesthesia-induced reduction in sensitivity by the use of a CBV contrast that increased fMRI activations in many areas.
This was a very interesting paper (I am glad I did not have to present it-but my colleague did a great job) I was supposed to be the devil's advocate, but I found the experiments were very robust and had a hard time pulling it apart. Ah, science..
