The Role of Stathmin in Emotional Regulation

Nature Reviews Neuroscience 7, 6 (January 2006)

Neurogenetics: Fear not

by Jane Qiu

Fear helps animals — including humans — to survive, as it allows them to avoid predators and dangerous situations. However, too much fear, or inability to control it, can be detrimental and result in phobias, pathological anxiety or post-traumatic stress disorder. The identification of the gene stathmin as an important mediator of both instinctive and learned fear might shed light on these disorders and help us to develop ways to erase unwanted fear.

The role of stathmin in emotional regulation was first proposed a couple of years ago. Gleb Shumyatsky and colleagues conducted a differential gene expression screen of single cell cDNA libraries derived from neurons of the hippocampus and the lateral nucleus of the amygdala (LA). They identified two genes, gastrin-related peptide (Grp) and stathmin, which are highly enriched in the LA but are almost absent from the hippocampus. As the LA lies at the crossroad where sensory information is transmitted from the auditory cortex and auditory thalamus to the amygdala — a crucial process for fear processing — the researchers set out to study whether these genes have a role in fear.

Writing in Cell, they show that mice lacking stathmin are fearless daredevils. Knockout mice do not seem to have instinctive fear, venturing bravely into potentially dangerous environments, such as open fields or elevated platforms, which normal mice would usually avoid.

Stathmin-knockout mice also have weaker memories for past aversive experiences. Shumyatsky et al. tested this using the fear conditioning paradigm. During training, mice were given a conditioned stimulus (a loud tone), which was immediately followed by an unconditioned one (a mild electric footshock). Normal mice make an association between the stimuli and freeze up when they hear the tone during testing the next day. However, the stathmin-knockout mice performed poorly in this test, which indicates that they are inept at forming fear-related memories.

To ensure that this was not due to changes in other features that might have resulted from lack of the gene, the researchers tested the mutant animals' sensitivity for pain. It was normal, as was their performance in spatial memory, which indicates that the effect of stathmin on learned fear is genuine and specific.

How does stathmin affect fear-related memory? It turns out that stathmin can inhibit the dynamics of microtubule formation. Microtubules in the amygdala of the mutant mice are more stable (less flexible) compared with those of their normal counterparts. As new memories involve the formation of new synpases, which may require asembly and disassembly of microtubules, the researchers conjecture that this might explain why mice lacking stathmin cannot effectively form fear-related memories. Consistent with this hypothesis, there was a significant decrease in long-term potentiation in the cortico-amygdala and thalamo-amygdala pathways of mutant mice.

This elegant study represents a significant step forward in our understanding of fear. Although stathmin is conserved across many species, including humans, whether this gene is also expressed in the human amygdala remains to be seen.

Pioneers of LTP: Michel Baudry and Gary Lynch Video

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) appears to be an important mediator of the early, protein synthesis-independent phase of LTP. Plus, it looks really cool.

In neuroscience, long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength. As memories are thought to be encoded by modification of synaptic strength, LTP is widely considered one of the major cellular mechanisms that underlies learning and memory.

LTP was discovered in the rabbit hippocampus by Terje Lømo in 1966 and has remained a popular subject of research since. Many modern LTP studies seek to better understand its basic biology, while others aim to draw a causal link between LTP and behavioral learning. Still others try to develop methods, pharmacologic or otherwise, of enhancing LTP to improve learning and memory. LTP is also a subject of clinical research, for example, in the areas of Alzheimer's disease and addiction medicine.


http://www.youtube.com/watch?v=BzrhxYijruE

Rebel Scientist Gary Lynch's Quest for Memory

Thanks to a two-day weekend (somewhat scarce for me), I manged to finish Joseph Ledoux's The Synaptic Self, and also start and finish Terry McDermott's 101 Theory Drive A Neuroscientist's Quest for Memory. I'm feeling pretty darn smart right now.

McDermott's book about neuroscientist's Gary Lynch's decades long research into Long-Term Poteniation. LTP is the strengthening of connections between brain cells that occures when they communicate, making subsequent communication more likely. The book gives the reader an keen appreciation on just how arduous and uncertain biological lab research is. It seems the brain's placiticity allows the growth of new "spines" on the dendrites of neurons, and these changes may be behind how memories are made and stored and even how thought is manufactured.

Lynch's quest is to find the actual structual changes in the celluar circuits that encode memory. Along the way he discovers ampakine, a class of drugs designed to enhance communication between brain cells. If they work as envisioned, the drugs, still in development, would enhance almost all cognitive activities. They may be a new drug to treat memory loss and perhaps even mood disorders.

101 Theory Drive: A Neuroscientist's Quest for Memory by Terry McDermott 

It's not fiction: Gary Lynch is the real thing, the epitome of the rebel scientist -- malnourished, contentious, inspiring, explosive, remarkably ambitious, consistently brilliant. He is one of the foremost figures of contemporary neuroscience, and his decades-long quest to understand the inner workings of the brain's memory machine has begun to pay off.Award-winning journalist Terry McDermott spent nearly two years observing Lynch at work and now gives us a fascinating and dramatic account of daily life in Lynch's lab-the highs and lows, the drudgery and eureka moments, the agonizing failures. He provides detailed, lucid explanations of the cutting-edge science that enabled Lynch to reveal the inner workings of the molecular machine that manufactures memory. And he explains where Lynch's sights are now set: on drugs that could fix that machine when it breaks, drugs that would enhance brain function during the memory process and that hold out the possibility of cures for a wide range of neurological conditions, including Alzheimer's, Parkinson's, and Attention Deficit Hyperactivity Disorder. Here is an essential story of science, scientists, and scientific achievement-galvanizing in the telling and thrilling in its far-reaching implications.

Dr. Gary Lynch is one of the most cited neuroscientists in the world and author of more than 550 scientific articles. He is Professor of Psychiatry at the University of California at Irvine. He is the co-author of Big Brain: The Origins and Future of Human Intelligence.