Mouse dressage

Neuroscientists often use mouse models to understand learning and neural disease. Much of our understanding of mammalian biology comes from these amazing animals. It is commonly said that highly inbred lab mice are unintelligent. But is it true for wild mice too? In a talk last week at Harvard, Karl Svoboda referred to this fascinating YouTube video showing a mouse trained to complete an obstacle course:

Other training videos from the same trainer are available along with an official website with interesting tips about mouse training. Perhaps highly inbred lab mice are unable to replicate such feats but it is amazing to see in what detail this trainer understands mouse behavior and development:

An absolute necessity for any pet training is to understand the animal’s needs and to know about its generic behaviour, since appropriate animal training is only based on certain natural habits. For mouse agility, this means e.g. their great spatial orientation abilities and spatial memory which is worth bringing to light by relevant trick training. In nature, mice always prefer the familiar (= safe) route to their feeding site, no matter if it’s a long way round. This is also the reason why mice are unbeatable in maze tests – and a mouse agility course is nothing else than a maze without walls!
But many owners forget that if you expect your pet to show some natural habits and abilities, first and foremost the husbandry has to be species-appropriate. If your mice have to live in a small ground level cage, their three-dimensional consciousness and orientation abilities will surely be stunted or never fully develop.

Neuroengineering memory: Something old, something new

Over the last week, it seems like everyone has sent me this NYT piece on PKM-zeta (about work in Todd Sacktor’s lab). I’m not sure why this work is being featured in the Times right now, since it’s a few years old. But it was news to me and I think it is of interest to anyone trying to understand structure-function relationships in the brain. In the original Science paper (from 2007), a pseudosubstrate inhibitor of PKM-zeta caused irreversible loss of a conditioned taste aversion memory (news and views here). I was unfamiliar with PKM-zeta, which appears to be a constitutively active form of PKC-zeta (a kinase that some might be more familiar with) and that lacks the autoinhibitory regulatory domain of PKC. The amazing phenomena is that, after treatment with ZIP (the pseudosubstrate that ties up PKM-zeta), the memory is permanently erased and doesn’t seem to return.

What’s going on? One tantalizing possibility is that the enzyme itself is directly related to the memory trace. This contradicts the (unproven) assumption of modern neuroscience that memories are stored solely in the synaptic strengths (ie. membrane-bound receptors) of a neuron. The other suggestion is that PKM-zeta is actively maintaining synapses and that enzymatic inhibition disrupts the precise maintenance of receptors or synaptic machinery. The effects happen quite fast (within 2 hours after drug injection), which seems short for receptor recycling but perhaps long enough for structural change to occur. I’m no expert on receptor movement: Is 2 hours long enough to add/remove a significant number of receptors?

Fascinating work but the method is blunt, wiping all experimentally-induced memories (and probably others too). Last month, another group reported (also in Science) selective erasure of a fear-conditioned memory using an interesting new genetic tool. Here, neurons in the amgydala that overexpressed CREB were found to be preferentially recruited into a fear memory trace (as shown in a previous Science paper). Incorporation into the memory trace was assayed by expression of the immediate-early gene (ie. activity-dependent) Arc. In the present study, they combine overexpression of CREB in a subset of neurons with cell death (via Diphtheria toxin in a transgenic mouse vulnerable to diphtheria). Apparently, normal mice lack the receptor (here a simian version is used) that confers pathogenicity for diphtheria. Thus, the viral construct both overexpresses CREB in a subset of neurons and selectively makes the same subset vulnerable to diphtheria. Ablation of just these neurons causes a permanent loss of the memory. Subsequent similar learning proceeds just fine (using the remaining neurons).

Can we say that the race is officially on to ablate just the synapses involved in the memory? I think so. Extra points if the ablation is reversible too!