Encoding taste and place in the hippocampus

The ambience of a good meal can sometimes be as memorable as the taste of the food itself. A new study from Shantanu Jadhav and Donald Katz’s labs, published in the February 18 edition of The Journal of Neuroscience, may help explain why. This research identified a subset of neurons in the hippocampus of rats that respond to both places and tastes.

The hippocampus is a brain region that has long been implicated in learning and memory, especially in the spatial domain. Neurons in this area called “place cells” respond to specific locations as animals explore their environments. The hippocampus is also connected to the taste system and active during taste learning. However, little is known about taste processing in the hippocampus. Can place cells help demarcate the locations of food?

To test this hypothesis, Neuroscience PhD student Linnea Herzog, together with staff member Leila May Pascual and Brandeis undergraduates Seneca Scott and Elon Mathieson, recorded from neurons in the hippocampus of rats as the rats explored a chamber. At the same time, different tastes were delivered directly onto the rats’ tongues.

Analyzing how place cells responded to tastes delivered inside or outside of their place field

The researchers found that about 20% of hippocampal neurons responded to tastes, and could discriminate between tastes based on palatability. Of these taste-responsive neurons, place cells only responded to tastes that were consumed within that cell’s preferred location. These results suggest that taste responses are overlaid onto existing mental maps. These place- and taste-responsive cells form a cognitive “taste map” that may help animals remember the locations of food.

Read more:  So close, rats can almost taste it

Sleep suppresses brain rebalancing

Why humans and other animals sleep is one of the remaining deep mysteries of physiology. One prominent theory in neuroscience is that sleep is when the brain replays memories “offline” to better encode them (“memory consolidation”). A prominent and competing theory is that sleep is important for re-balancing activity in brain networks that have been perturbed during learning while awake. Such “rebalancing” of brain activity involves homeostatic plasticity mechanisms that were first discovered at Brandeis University, and have been thoroughly studied by a number of Brandeis labs including the Turrigiano lab. Now, a study from the Turrigiano lab just published in the journal Cell shows that these homeostatic mechanisms are indeed gated by sleep and wake, but in the opposite direction from that theorized previously: homeostatic brain rebalancing occurs exclusively when animals are awake, and is suppressed by sleep. These findings raise the intriguing possibility that different forms of brain plasticity – for example those involved in memory consolidation and those involved in homeostatic rebalancing – must be temporally segregated from each other to prevent interference.


The requirement that neurons carefully maintain an average firing rate, much like the thermostat in a house senses and maintains temperature, has long been suggested by computational work. Without homeostatic (“thermostat-like”) control of firing rates, models of neural networks cannot learn and drift into states of epilepsy-like saturation or complete quiescence. Much of the work in discovering and describing candidate mechanisms continues to be conducted at Brandeis. In 2013, the Turrigiano Lab provided the first ­in vivo evidence for firing rate homeostasis in the mammalian brain: lab members recorded the activity of individual neurons in the visual cortex of freely behaving rat pups for 8h per day across a nine-day period during which vision through one eye was occluded. The activity of neurons initially dropped, but over the next 4 days, firing rates came back to basal levels despite the visual occlusion. In essence, these experiments confirmed what had long been suspected – the activity of neurons in intact brains is indeed homeostatically governed.

Due to the unique opportunity to study a fundamental mechanism of brain plasticity in an unrestrained animal, the lab has been probing the possibility of an intersection between an animal’s behavior and homeostatic plasticity. In order to truly evaluate possible circadian and behavioral influences on neuronal homeostasis, it was necessary to capture the entire 9-day experiment, rather than evaluate snapshots of each day. For this work, the Turrigiano Lab had to find creative computational solutions to recording many terabytes of data necessary to follow the activity of single neurons without interruption for more than 200 hours. Ultimately, these data revealed that the homeostatic regulation of neuronal activity in the cortex is gated by sleep and wake states. In a surprising and unpredicted twist, the homeostatic recovery of activity occurred almost exclusively during periods of activity and was inhibited during sleep. Prior predictions either assumed no role for behavioral state, or that sleeping would account for homeostasis. Finally, the lab established evidence for a causal role for active waking by artificially enhancing natural waking periods during the homeostatic rebound. When animals were kept awake, homeostatic plasticity was further enhanced.

This finding opens doors onto a new field of understanding the behavioral, environmental, and circadian influences on homeostatic plasticity mechanisms in the brain. Some of the key questions that immediately beg to be answered include:

  • What it is about sleep that precludes the expression of homeostatic plasticity?
  • How is it possible that mechanisms requiring complex patterns of transcription, translation, trafficking, and modification can be modulated on the short timescales of behavioral state-transitions in rodents?
  • And finally, how generalizable is this finding? As homeostasis is bidirectional, does a shift in the opposite direction similarly require wake or does the change in sign allow for new rules in expression?

Authors on the paper include postdoctoral fellow Keith Hengen, Neuroscience grad student Alejandro Torrado Pachedo, and Neuroscience undergraduate James McGregor ’14 (now in grad school at Emory).

Hengen KB, Torrado Pacheco A, McGregor JN, Van Hooser SD, Turrigiano GG. Neuronal Firing Rate Homeostasis is Inhibited by Sleep and Promoted by Wake. Cell. 2016.

Methylgloxal and anxiety disorder

methylglyoxal, aka pryuvaldehyde

A recent paper in The Journal of Clinical Investigation by researchers from the University of Chicago, working together with Assistant Research Professor of Biochemistry Leigh Plant from Brandeis, reveals a new mechanism for anxiety disorders involving the metabolite methylglyoxal (MG) (right).  The researchers investigated the effect of Glyoxalase 1 (Glo1) expression in mice. Increasing Glo1 copy number, and hence expression, in mice increased anxiety-like behavior. Since Glo1 metabolizes MG, they looked for a direct effect by administering MG, and found it had an anxiolytic effect in the mouse model (n.b.. MG is toxic, so don’t take it to treat anxiety). Inhibitors of Glo1 might therefore have anxiolytic effects, which they showed for the inhibitor S-bromobenzylglutathione cyclopentyl diester

Electrophysiology experiments were conducted to elucidate the mechanism of action of MG, suggesting that it had a GABAergic effect in vivo, and specifically that it is an agonist of the GABAA receptor in multiple neuron types.

So why is a relatively reactive small molecule, normally considered a by-product of glycolysis in animals, acting at neuronal receptors? Can this be exploited with pharmacological methods? What other functions does methylglyoxal have in the nervous system?  It may have many — another very recent paper in Nature Medicine suggests a role for MG in pain sensitivity and diabetic neuropathy, so there may be many interesting parts to this story.

Pre-med undergraduates should take note — keeping track of all those metabolites in glycolysis that you learn about in introductory biochemistry is far from irrelevant to modern medicine!



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