Obsessive compulsive disorder (OCD) is one of a spectrum of disorders characterized by obsessions (intrusive, unwanted thoughts) and compulsions (ritualized behaviours intended to overcome the anxiety and tension resulting from the obsessions). Other similar conditions include Tourette’s syndrome; sufferers with this disorder show several motor, and occasionally vocal, tics, often accompanied by obsessions and compulsions. Although the evidence is less convincing, another disorder that might fit into this spectrum is trichotillomania, the hallmark of which is compulsive pulling out of scalp hair1. On page 894 of this issue, Welch et al.2 describe a genetically engineered mouse that shows some behavioural features similar to those of the obsessive compulsive spectrum of disorders in humans3.

Often beginning early in life and running a chronic and relapsing course, OCD causes significant distress and disability. The avail-able treatments for this condition are only moderately effective. They include cognitive behavioural psychotherapies and antidepres-sant drugs that increase levels of the neuro-transmitter serotonin at synapses (junctions between neurons). As is often the case in psy-chiatric disorders, the existing drugs for OCD stem from exploitation of serendipitous clinical observations. Neither the pathophysiology of the disorder nor the mechanism of action of these drugs is understood.

Given the toll of OCD and other psychiatric disorders, safer and more effective medica-tions are much needed; but four main obstacles remain. First, understanding the neurobiol-ogy of higher cognition, emotion and con-trol of complex behaviour is still a daunting frontier. Second, those with psychiatric disor-ders lack obvious and visible signs of damage to the nervous tissue, the presence of which could point the way to identifying molecular culprits. Third, the genetic and non-genetic factors contributing to psychiatric disorders are highly complex4. And fourth, good animal models have been lacking.

The mice studied by Welch et al.2 showed excessive grooming, which resulted in hair loss and skin injuries, as well as anxiety-like traits. These mice lack the gene encoding SAPAP3

NEUROSCIENCE

Obsessed with groomingSteven E. Hyman

Roughly 2% of humans suffer from obsessive compulsive disorder, but a lack of animal models has impeded research into this condition. Could a genetically engineered mouse model provide an exciting lead?

— a scaffolding protein that is found in exci-tatory, glutamate-responsive synapses and is highly expressed only in the striatum region of the brain. The behavioural abnormalities in these mice were reversed by local expression of Sapap3 in the striatal region, which indicates that loss of this gene is responsible for the observed behavioural abnormalities.

The authors also found that a drug from the SSRI class — which selectively enhance serotonin-mediated neurotransmission throughout the brain — that is used to treat OCD in humans decreases both grooming and anxiety in these mice. This is interesting because a condition responsive to an enhancer of serotonin neurotransmission does not sig-nify a primary defect in serotonin-mediated signalling; instead, the defect is in glutamate-responsive synapses. So alterations in serotonin seem to modulate glutamate action. These findings are also noteworthy because Welsh and colleagues have generated a possible mouse model of OCD. Moreover, these observations add to the accumulating, if circumstantial, evi-dence that OCD and its associated disorders result from abnormalities in neural circuits

spanning the frontal, striatal and thalamic regions of the brain.

Studies involving structural neuroimag-ing of the striatum in the brains of patients with OCD5,6 have often indicated abnormali-ties in the volume of striatum components, although they do not agree on the nature of these changes. However, a long-term study7 of patients with Tourette’s syndrome suggests that the relationship between the volume of the caudate nucleus (a component of the striatum) and the symptoms of this disorder is complex; at the time of the scan (childhood), smaller caudate volumes did not correlate with symp-toms, but they did predict persistence of severe symptoms into early adulthood.

Functional neuroimaging studies8 on patients with OCD, based on cognitive and emotional tasks, also point to abnormalities in frontal–striatal–thalamic circuits, although we cannot yet claim to be on firm ground. That said, a striatal origin for OCD-like symptoms would make a lot of sense. The medium spiny neurons of the striatum receive convergent glutamate-mediated inputs from the cerebral cortex, which provide detailed information

Compulsive hand-washing is a common symptom of obsessive compulsive disorder.

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about the context in which behaviours occur. These neurons also receive dopamine-medi-ated inputs from the midbrain that report on the significance of the behaviour — for exam-ple, whether it yields an unexpected reward.

When something important happens, the striatum stimulates circuits that project via the thalamus to the prefrontal cortex; this leads to the formation of memories that can later guide the planning and control of behav-iour. Abnormalities in synaptic function within frontal–striatal–thalamic loops could lead to unintended behaviours or even unintended thoughts. The main significance of the Sapap3-deficient mouse is that it represents a model of how such a pathological process might work. In this case, abnormal synaptic function causes grooming behaviours that are repetitive enough to produce skin injuries and unrespon-sive enough to control by the prefrontal cor-tex that they continue even after the injuries have occurred.

The mouse model described by Welsh and colleagues will excite those interested in the pathophysiology of OCD or in developing treatments for it. But we must retain a healthy caution. Genetic animal models of psychiatric disorders have been produced by inbreeding for desired traits9, by introducing human disease genes10, by mutating existing animal genes11 or, as in this case, by observing an unexpected behavioural response in a genetically engi-neered animal. It is highly unlikely that such animal models will ever recapitulate human psychiatric disorders in their entirety. However, as in this case, it is possible to model significant aspects of these diseases.

The core symptom of OCD — unwanted intrusive thoughts — cannot be mimicked in mice, at least not in any obvious way. Instead, Sapap3-deficient mice show excessive groom-ing that continues past the point of self-harm. This is reminiscent, perhaps, of compulsive hand-washing, which in patients with OCD represents a never fully successful attempt to neutralize fears of contamination.

In OCD patients, the main cause of anxiety is the unwanted intrusive thoughts. The suffer-ers are anxious because they cannot be certain that the door is locked, the gas has been turned off, or that they are free of dreaded microbes. The anxiety-like behaviours observed in these mice may also resemble OCD, but this requires a stretch of the imagination.

Even if we can gain assurance with addi-tional research that the behaviours observed in Sapap3-deficient mice reflect abnormalities in circuits that produce human symptoms, we cannot assume that OCD-related conditions in humans involve variations in this gene. These disorders, like other major psychiatric dis-eases, seem to be heterogeneous with complex underpinnings — probably involving several genes — that, in interaction with developmental and environmental factors, could lead to abnor-malities in frontal–striatal–thalamic circuits.

Despite these reservations, the work of Welsh

et al.2 sharpens our focus on frontal–striatal–thalamic circuits both in human patients and in animal models of OCD. It also gives us a compelling clue that the compulsive behaviour associated with this condition is due to a syn-aptic abnormality in these neural loops. Such cellular insight should aid an understanding of OCD at a molecular level. ■

Steven E. Hyman is in the Department of Neurobiology, Harvard Medical School, Massachusetts Hall, Cambridge, Massachusetts 02138, USA.e-mail: seh@harvard.edu

QUANTUM PHYSICS

Wave goodbyeLuis A. Orozco

When measuring photons, it’s a case of ‘wanted, dead’ — catching them alive is not an option. But we can observe how a superposition of many photon waves progressively collapses as it interacts with a beam of atoms.

Earlier this year, a team from the Ecole Nor-male Supérieure in Paris recorded jumps of light heralding the birth and death of a pho-ton trapped in a cavity1. As they describe in this issue (Guerlin et al., page 889)2, the same researchers have now performed a similar, more complex trick — recording exactly how a coherent state of many photons collapses as it is measured.

A measurement process differs fundamentally between the classical and quantum worlds. In the classical realm, there is no explicit limitation on a measurement’s accuracy. In the quantum domain, by contrast, accuracy is constrained by the Heisenberg uncertainty principle: a measurement will produce a definite result, but one whose value is distributed according to the laws of probability. What is more, the meas-ured object will itself be fundamentally altered by the measurement. Thus, the clicking sound produced when a photon is caught by a detector says two things: yes, a particle was detected; but sorry, the way you detected it killed it, and its energy was converted into an electric pulse.

But the quantum world has more subtle states to investigate than a single photon. Pho-tons, or the probabilistic wavefunctions associ-ated with them, can add together, or superpose. If they superpose coherently (in phase), their combined wavefunction begins to look like a classical wave. This coherent electromagnetic field is the complex beast whose collapse was monitored by Guerlin et al.2.

But how did they achieve this feat, given the difficulties of measuring a quantum object without instantly destroying it? The authors’ ‘quantum non-demolition measurements’ in a cavity quantum-electrodynamical (QED) system required profound understanding of quantum mechanics, continuous theoretical

elucidation of subtle details of cavity QED, and unprecedented dedication in realizing a simple theoretical model in the laboratory. This model3 first required the development of a pair of superconducting mirrors for the walls of the cavity whose losses are low enough that light remains captured between them for the length of time it would take the light to circle Earth at the Equator.

The second pivotal ingredient is individual rubidium atoms in a ‘Rydberg’ state in which one electron is highly excited. These atoms are like little planetary systems, with the excited electrons on a distant orbit around a remote atomic nucleus. They can oscillate between two different excited states, and the regularity of this oscillation makes them excellent time-keepers. The frequency of that oscillation is easily disturbed in the presence of light — to the extent that it can be used to detect the pres-ence of a single photon non-destructively1.

And so Guerlin et al.2 prepared a coherent state of a microwave electromagnetic field in their cavity that contained up to seven photons, and then sent in the Rydberg atoms. They made sure that these atomic clocks had their ‘hands’ — their initial phase — set to one of eight pos-sible values. Each of these settings is a possible answer to the question “How many photons are there in the cavity?” The interaction with the electromagnetic field modifies the setting of the hands according to the answer, from none to seven. The atoms leave the cavity, and the new direction of the hands is recorded.

Guerlin and colleagues’ measurement method had to fulfil certain conditions for success4. First, the interaction of the quantum probe (the atom) with the remaining, classi-cal part of the measuring device (the ‘click’ of the detector) must not begin until the

1. Chamberlain, S. R., Menzies, L., Sahakian, B. J. & Fineberg, N. A. Am. J. Psychiatry 164, 568–574 (2007).

2. Welch, J. M. et al. Nature 448, 894–900 (2007).3. Hollander, E., Kim, S., Khanna, S. & Pallanti, S. CNS Spectr.

12 (suppl. 3), 5–13 (2007). 4. Merikangas, K. R. & Risch, N. Am. J. Psychiatry 160,

625–635 (2003). 5. Robinson, D. et al. Arch. Gen. Psychiatry 52, 393–398

(1995).6. Pujol, J. et al. Arch. Gen. Psychiatry 61, 720–730 (2004).7. Bloch, M. H., Leckman, J. F., Zhu, H. & Peterson, B. S.

Neurology 65, 1253–1258 (2005). 8. Remijnse, P. L. et al. Arch. Gen. Psychiatry 63, 1225–1236

(2006). 9. Bice, P. J. et al. Behav. Genet. 36, 248–260 (2006).10. Shahbazian, M. et al. Neuron 35, 243–254 (2002).11. Clapcote, S. J. et al. Neuron 54, 387–402 (2007).

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