The touch of a fly

Our sense of touch has an innate connection with our emotions. Gentle touches are soothing for not only us but also other animals. For example, classic experiments by psychologist Harry Harlow in the 1950s found that an infant monkey raised with two robots, one providing food and the other wearing soft cloth, spends more time cuddling with the cloth robot1. When scared, the infant monkey also goes to the cloth robot for protection. Clearly, there is a special pathway that guides touch sensation to the depths of animal instincts. Working out this pathway requires knowledge about the neural circuitry processing touch sensation.

Read More

Tagging a snapshot of life with prions

“As you know, in most areas of science, there are long periods of beginning before we really make progress.” – Eric Kandel

In a typical maze experiment, a hungry rat enters a moderately complicated maze, in which it does its best to find a “reward room” with food. After some guesses, the rat finds its way, consumes the food, and is returned to the entrance of the maze. From then on, the rat makes fewer bad guesses and finds the food faster after each round. Eventually, it completely masters the maze layout and finds the perfect route every time. To explain this improvement, scientists have coined the term reward reinforcement, which essentially suggests that the reward that the rat collects at the end reinforces its correct choices, until it eventually learns a perfect route. This model may sound very simple, but is it?

The rat collects its food in the reward room, not during the navigation or decision-making. Therefore, the brain’s reward system does not turn on until the end of each run. How, then, does the reward system backtrack in time and selectively reinforce choices made in the past? If we had the ability to look into the rat’s brain and watch the activities of the synapses (the connections between neurons), we would find, as the rat navigates through the maze, millions of synapses flash on and off, while millions more remain silent. How does the brain keep track of this enormous, evolving constellation of synaptic activity, so that only the appropriate ones can be tuned up and down by the reward in the end?

One way to solve this problem is to have a logging system, in which individual synapses log their activity over time, like hourglasses that are flipped on (to let sand through) only when their corresponding synapses are active and flipped upside-down when inactive. In this way, when the reward arrives, the active synapses can be singled out by reading the hourglasses. This idea is called synaptic tagging.

What is the nature of this activity tag? One strong candidate arises from work done by Kausik Si (pronounced “See”) and Nobel Laureate Eric Kandel. It’s an RNA binding protein called CPEB (not to be confused with CREB, which is a different protein that is also important for memory). CPEB is turned on in active synapses and is necessary for maintaining long-term memory in different animal species1,2.

Fig1

How does CPEB tag synaptic activity? Si and Kandel’s answer initially flabbergasted the entire neuroscience community: it is a prion. Prions are most famous for causing spongy brains in the mad cow disease. Many proteins can be prions, as long as they spontaneously form strong aggregates (i.e. clumps) and expand the aggregates by converting single proteins into the self-aggregating form. Proteins involved in many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, have recently been thought to resemble prions. However, the CPEB aggregates are not the harbingers of disease but rather the functional essence of the protein. The aggregation of CPEB only happens in active synapses, and blocking the aggregation, either by antibody neutralization or by mutation of the gene, reduces synaptic plasticity and the animal’s ability to form long-term memory3–5.

Initial insights into the function of CPEB come from the observation that its aggregate binds RNA4. A recent paper by the Si group proposes that the aggregation of CPEB promotes memory formation by switching CPEB’s function from suppressing to promoting protein translation6. This switching phenomenon depends on CPEB’s ability to recruit other protein complexes to modify the stability of RNAs.

Is CPEB the only mechanism for synaptic tagging? Probably not. Studies of CPEB indicate that it is essential for long-term memory, on the timescale from hours to days. However, tagging synapses on a shorter time scale is also needed to explain problems such as delayed reinforcement (described above). There is strong evidence that synapses can be tagged and tuned concertedly within a much shorter timeframe, although scientists do not yet know how this happens7. When this mystery is revealed, another gasp of surprise will be heard reverberating across the neuroscience community.

 

References:

  1. Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115, 893–904 (2003).
  2. Keleman, K., Krüttner, S., Alenius, M. & Dickson, B. J. Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nat. Neurosci. 10, 1587–93 (2007).
  3. Majumdar, A. et al. Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148, 515–29 (2012).
  4. Si, K., Lindquist, S. & Kandel, E. R. A Neuronal Isoform of the Aplysia CPEB Has Prion-Like Properties. Cell 115, 879–891 (2003).
  5. Si, K., Choi, Y.-B., White-Grindley, E., Majumdar, A. & Kandel, E. R. Aplysia CPEB Can Form Prion-like Multimers in Sensory Neurons that Contribute to Long-Term Facilitation. Cell 140, 421–435 (2010).
  6. Khan, M. R. et al. Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator. Cell 163, 1468–1483 (2015).
  7. He, K. et al. Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. Neuron 88, 528–538 (2015).

 

 

Oxytocin: sculpting the maternal brain

Humans have a lot in common with prairie voles—at least when it comes to mating. Unlike the vast majority of mammalian species, we often enter into monogamous pair bonds. A crucial molecule involved in determining this mating strategy is oxytocin. Popularly known as the “cuddle hormone,” oxytocin is a neuropeptide that plays an ancient role in orchestrating social and reproductive behaviors [1], and frequently makes headlines because of its ability to influence a variety of interesting behaviors [2]. Until recently, however, it has remained unclear how and where oxytocin is exerting its effects in the brain. Using modern experimental tools, neuroscientists are beginning to develop a more mechanistic understanding of how oxytocin affects specific circuits in the brain. Chemical structure of oxytocin.

Female mice display a variety interesting behaviors that depend on their sexual experience. To an experienced female, pup vocalizations are a highly salient sensory stimulus and drive robust maternal behavior—if a mother hears a distress call from a pup that has been separated from the nest, she will quickly locate the lost pup and bring it back. This is not true for virgin females, who rarely display this behavior. However, virgin females can be made to act in a maternal fashion by systemic oxytocin administration, suggesting that oxytocin may be important for the development of this maternal behavior. In a recent study, researchers uncovered a fascinating circuit mechanism by which oxytocin sculpts the auditory system of new mothers in order for this maternal behavior to arise [3].

As a first clue to where oxytocin may be working to promote pup retrieval behavior, Marlin and colleagues used transgenic mice and immunohistochemistry to visualize where oxytocin receptors are found in the female mouse brain. One interesting location where they were detected, in both experienced mothers and naïve virgin females, was the primary auditory cortex. The receptors were found on both inhibitory interneurons within the auditory cortex and the axon terminals of hypothalamic neurons that secrete oxytocin directly into cortex. Even more intriguing was their finding that receptor expression is lateralized: oxytocin receptors are more densely expressed in the left auditory cortex than in the right, reminiscent of the lateralization of language functions in the human brain.

Next, pharmacology and optogenetics were used to manipulate neural activity in the left vs. right auditory cortex. In virgin females, they found that stimulating oxytocin signaling in the left auditory cortex promoted pup retrieval. In experienced mothers, broad-spectrum inactivation of the left auditory cortex disrupted pup retrieval behavior, but specifically blocking oxytocin signaling had no effect. Why would completely shutting down the primary auditory cortex disrupt behavior, but not disrupting oxytocin signaling specifically? One explanation could be that oxytocin is important for plasticity: in its presence, the circuits of auditory cortex are able to change with experience. These changes may then consolidate into a long-term memory—after that, oxytocin signaling no longer matters.

Female mice who have been given birth are quick to respond to distress calls from pups. Virgin females do not exhibit this maternal care behavior, but can be made to do so by either oxytocin administration, or by housing them in the same cage as a mother and her pups. Figure from Marlin et al. (2015)

To study the effects of oxytocin on activity and plasticity, they next recorded electrical activity from auditory cortex neurons. Compared to virgin females, auditory cortical neurons in maternal mice displayed larger and more reliable responses to pup distress calls. They further showed that, in the presence of oxytocin, pup calls rapidly decreased the amount of inhibition in auditory cortex. By temporarily decreasing inhibition, sensory signals can be boosted in a way that promotes synaptic plasticity, potentially resulting in the formation of new memories. Cortical disinhibition is emerging as a common circuit mechanism that the brain uses for associative learning, and has been causally linked to the acquisition of multiple behavioral functions, including conditioned fear and spatial navigation behaviors [4]. Could oxytocin-induced disinhibition lead to a persistent increase in the salience of pup distress calls in the female brain?

By pairing pup distress calls with stimulation of oxytocin signaling, researchers were able to transform how the auditory cortex of virgin females represented pup calls, making it look more like it does in maternal mice. The basic model works like this: oxytocin decreases the level of inhibition in auditory cortex. In this state of disinhibition, auditory cortical neurons are more responsive to pup calls, and the boosted responses induce plasticity. As oxytocin signaling fades, cortical inhibition returns to normal, stabilizing the oxytocin-enhanced responses to pup calls. In this way, the salience of pup calls can be stably enhanced in the maternal brain. This helps makes sense of why disrupting oxytocin signaling fails to disrupt pup retrieval behavior in experienced, maternal females: their auditory cortex had already consolidated the plastic changes needed for responding to pup distress calls

So what’s happening in natural settings? One possible model of how things work is that oxytocin levels in the maternal brain increase in response to hormonal changes during pregnancy, and by sensory cues from pups, such as pheromones. This increase in oxytocin signaling would render circuits in the maternal brain more plastic and better able to learn to respond to signals from pups. Without oxytocin, the brain’s ability to learn to relevance of these specific social cues would be impoverished. If it turns out to be generally true that oxytocin renders animals more sensitive to social cues it could have implications for our understanding of neurodevelopmental disorders such as autism, where individuals seem to lack the ability to assign importance to social cues.

Sources:

[1] Garrison JL, Macosko EZ, Bernstein S, Pokala N, Albrecht DR, Bargmann CI. Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior. Science 338, 540-3 (2012).

[2] Shen H. Neuroscience: the hard science of oxytocin. Nature | News Feature 522, 410-2 (2015).

[3] Marlin BJ, Mitre M, D'amour JA, Chao MV, Froemke RC. Oxytocin enables maternal behaviour by balancing cortical inhibition. Nature 520, 499-504 (2015).

[4] Letzkus JJ, Wolff SB, Luthi A. Disinhibition, a Circuit Mechanism for Associative Learning and Memory. Neuron 88, 264-76 (2015).