Does a high fat diet lead to a less 'rewarding' life?

Some interesting research out of the University of Pennsylvania suggests that a high fat diet can disrupt dopamine signalling.

This high-fat fed rat sure looks happy to me (source)

As I briefly discussed during my SfN Neuroblogging binge, a high fat diet can alter dopamine levels in the brain. To expand on this, we'll look at new research on how exactly this might happen and which specific areas of the brain are affected.  

Vucetic et. al. (2012) tested the levels of dopamine-related gene expression (via mRNA) in the hypothalamus and the ventral tegmental area (VTA). The hypothalamus is important because it controls your levels of hunger as well as many other things. The VTA is important because it is the main source of dopamine to the ventral striatum (AKA the Nucleus Accumbens). The VTA-nucleus accumbens pathway is generally thought to signify 'reward' when it is activated. Sex, Drugs, Music, and lots of other 'pleasurable' activities all activate this pathway. So alterations in the dopamine levels here might change how 'rewarded' a person (or mouse in this case) feels in response to pleasurable stimuli.

So Vucetic et al., (2012) found that in the VTA, the levels of tyrosine hydroxylase ("TH", an enzyme indicative of how much dopamine can be made) and dopamine active transporter ("DAT", which gets rid of excess dopamine at the synapse) are both reduced in the mice eating the high fat diet.

Vucetic et al. (2012) Figure 1

By contrast, in the hypothalamus, TH and DAT are both increased due to the high fat diet.

So what does this mean? The authors point out that increased dopamine in the hypothalamus actually promotes eating. Consistent with this idea, the authors show that mice eating the high fat diet actually ate more frequently and ate more total food. Secondly, when there is less dopamine in the VTA, it is likely that a rewarding stimuli will seem less rewarding. 

In the author's words:

"Collectively, these behaviors have the potential to promote obesity in two distinct ways: (i) through an increase in food intake and (ii) by increasing the drive for palatable food, as the animal with a blunted response to palatable foods may seek and/or consume these food relatively more than a normal animal in order to reach the same rewarding response. "

So basically the mice aren't obese because the food they are eating is high fat, they are obese because they are eating MORE food. But of course, they are eating more food because the high fat diet makes them 'want' to eat more food, so the high fat diet is indirectly causing the weight gain.

It is truly a vicious cycle.

 *Note: They also look at epigenetic effects on the TH and DAT promoter DNA. If you are interested in that aspect of the study, comment and I can do a follow-up post explaining it, or you can just read the study for yourself, following the link below. 

© TheCellularScale


Vucetic Z, Carlin JL, Totoki K, & Reyes TM (2012). Epigenetic dysregulation of the dopamine system in diet-induced obesity. Journal of neurochemistry, 120 (6), 891-8 PMID: 22220805

A new look at light

You might know that your retina senses light primarily through its rods and cones which are sensory cells specialized in converting photons into electrical signals.


Pisa at Sunset (I took this picture)


What you might not know is that there is a third light-sensitive cell in the mammalian eye. These cells are retinal ganglion cells (RGCs), but not all RGCs are directly sensitive to light.

But what you really probably don't know is that these RGCs sense light using the same protein that allows a toad's (Xenopus Laevis) skin to sense light (melanopsin). 


"It's true, I tell ya!"

These cells (the non-rod, non-cone light sensors) react to light directly, but they aren't exactly good at it. Their sensitivity is lower than the rods and cones, and they don't seem to transmit shape or color information.  So what is their purpose? Why have a secondary set of cells that sense light in a poor and unfocused way when you already have highly specialized rods and cones? 

To make it even more confusing, the rods and cones actually connect to these cells, adding their light-sensing information to theirs. 

weird, right? In a recent review paper, Pickard and Sollars (2012) explain that these cells likely play a role in controlling the sleep-wake cycle (circadian rhythm). Rats and mice with strongly degenerated rods and cones still set their circadian clock by the light cycle they are exposed to.  These cells send strong projections to the hypothalamus which controls everything sleep-wake cycle.


In addition, these cells or at least the melanopsin gene, may play a role in Seasonal Affective Disorder (SAD) by modulating the light-dependent cycles of the suprachiasmatic nucleus (a part of the hypothalamus).



SAD (source)

Their vague ability to sense 'brightness' makes these cells nicely suited to regulating the body's response to daily and seasonal changes in light. But whether these cells need to be light-sensitive to perform these functions or whether their sensitivity to light is just an evolutionary remnant is unclear. 



© TheCellularScale



 Pickard GE, & Sollars PJ (2012). Intrinsically photosensitive retinal ganglion cells. Reviews of physiology, biochemistry and pharmacology, 162, 59-90 PMID: 22160822



The cells that make us eat: Part 2

In the last post, we discussed the finding that stimulating the AgRP neurons in the hypothalamus directly causes mice to eat.  You can see the video of the mouse eating with the light stimulation here.

Today we will look at a follow up paper by the same group.  This paper looks at the mechanisms that might naturally stimulate these neurons.  As the authors mention in the discussion, the origin of the pathways that naturally cause these neurons to fire is not known. (as in, the part of the brain that sends the main signals to these neurons is still a mystery)  However, they can investigate what is happening at the junction between these pathways and the AgRP neurons, that is, at the synapse.

Using brains from mice that are either hungry or full, the researchers found that in hungry mice, the AgRP neurons recieve more synaptic input. 

But why?

There are a few ways this could happen.  One possibility is that the upstream neurons are firing more frequently because they are receiving more input from other pathways. But since it is not known where these neurons are, that is difficult to test.  Another possibility is that the output ends of these neurons, the part which arrives at the synapse, releases neurotransmitter more easily in hungry mice than in full mice. 

The research in this paper supports option number 2, that the hunger signal modulation occurs right at the synapse.

The researchers find that through a complex molecular pathway, involving ghrelin, leptin, and opioid signalling, the neurotransmitter release at the synapse is regulated by the animal's hunger state. Although too detailed to fully summarize here, the paper presents a satisfying and thorough explanation for how the AgRP neurons (the ones that cause eating when stimulated) could be modulated by hunger signals from the body. 

One of the nice parts about this explanation is that it avoids the 'never ending chain of neurons' problem, where activity in one neuron is caused by a neuron stimulating it, which in turn is caused by a neuron stimulate that one, which is caused by... you get the point. 
This paper strongly suggests that dynamic modulation of eating behavior can happen right at the synapse.

Yang Y, Atasoy D, Su HH, & Sternson SM (2011). Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell, 146 (6), 992-1003 PMID: 21925320

The cells that make us eat: Part 1

It is always exciting when a specific behavior can be directly linked to particular neurons. 

In this case, eating.  In March 2011, a paper came out from the Sternson lab at Janelia Farm explaining that when certain neurons (AgRP) in the mouse hypothalamus were stimulated with light, the mouse would spontaneously start eating.  The mouse would pretty much keep eating (except for water breaks) until the stimulation stopped.  What's even more interesting is that the neurons right next to these (POMC) had pretty much the opposite effect.  When they were stimulated, the mouse didn't eat much and over time lost weight.

This may seem like the basis for the next miracle diet,  find a way to stimulate POMC neurons and suppress AgRP neurons, right?

Unfortunately it's not that easy.  There is a lot more work to be done.  In fact this is just the beginning of understanding the hunger circuit.  Sure stimulating the neurons directly with light causes eating, but what naturally stimulates those neurons? 

Neurons fire when they recieve signals from other neurons which in turn fire when they receive signals from other neurons.... and so forth in a never ending chain.

So, where does the 'must eat' signal ultimately come from?
where is the beginning of that neural chain?

We will investigate this a little more in Part 2, when we look at a follow up paper.

Aponte Y, Atasoy D, & Sternson SM (2011). AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature neuroscience, 14 (3), 351-5 PMID: 21209617