Sense of Smell

The intra–cerebro-ventricular injected mice were analyzed by a variety of established, well-validated neurological tests. To our surprise, in contrast to the control injected mice (who received irrelevant immunoglobulins), the anti-P-R antibody–treated mice developed defects in cognition and a severe depressive behavior. In a standard method to assess depression, mice are placed into a bucket of water. While normal mice will swim endlessly in the bucket to rescue themselves, depressed mice will give up and just float (see Figure 1, p. 17). In this model, mice injected with anti-P-R antibodies floated, indicating that they were depressed.¹⁰

As shown subsequently in immunohistochemistry experiments, the anti-P-R antibodies bound specifically to the limbic areas of the mice brains and amygdala.10 Moreover, the anti-P-R antibodies were able to bind to the hippocampal cells as well as to penetrate their cytoplasm. A similar pattern of binding and behavior was also shown by us later on, also for the anti-DNA monoclonal antibodies carrying the pathogenic 16/6 idiotype.¹¹

Because the limbic areas of the brain are involved in smelling capabilities, we analyzed the mice subjected to the anti-P-R and anti-DNA autoantibodies (16/6+) and found a lower capability to smell (determined by studying the mice exposed to obnoxious odors) (see Figure 2, p. 17). After resection of the olfactory bulb, mice develop a depressive pattern of behavior that can be overcome by fluoxetine (Prozac). Similarly, fluoxetine can shorten the time of floating of mice injected with anti-P-R antibodies, indicating that depressive behavior was reduced.

Figure 2: In the smell threshold detection test, exposure to menthol essential oil irritates a normal control mouse (top) while the mice injected with anti-P-R antibodies (bottom) stay indifferent, indicating a defect in smell.

An important breakthrough came when we investigated the influence of fragrance on mouse behavior. We found that exposing the mice to an orange fragrance increased their mobility time while swimming in the bucket, an idea we had after reading several papers on experimental models showing that lemon and citrus exposure of rats normalized neuroendocrine levels and immune function and were rather more effective than anti-depressants.¹² Similar results were achieved by lavender fragrance, which also had a beneficial effect on insomnia and depression in female college students.¹³

The interbrain connections between specific smells have yet to be analyzed for their mechanisms, and the results of such study may lead to novel anti-depressant agents.

On to Human Trials

Given the observations in mice, my colleagues and I wanted to see whether patients with SLE also had an olfactory abnormality. We performed the test of smell, a simple evaluation that uses 48 smell sticks. The person examined is first trained to recognize the smells, and is then exposed to sticks that also contain “control” smells. The ability to recognize smell is absolute as well as “dose” dependent.